Ascend-7: A Phase II Study to Evaluate the Efficacy and Safety of Oral Ceritinib in Patients With ALK-positive NSCLC Metastatic to the Brain and/or to Leptomeninges

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02336451
• Collaborator: (none)
• Enrollment: 156
• Locations: 57
• Arms: 5
• Actual Duration (Months): 46.2
• Patients Per Site: 2.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This was a phase II, multi-center, open-label, five-arm study in which the efficacy and safety of oral ceritinib treatment was assessed in patients with NSCLC metastatic to the brain and/or to leptomeninges harboring a confirmed ALK rearrangement, using the FDA approved Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular Inc.) test and scoring algorithm (including positivity criteria). If documentation of ALK rearrangement as described above was not locally available, a test to confirm ALK rearrangement was performed by a Novartis designated central laboratory. Patients waited for the central laboratory result of the ALK rearrangement status before initiating treatment with ceritinib.

Condition or Disease	Intervention/Treatment	Phase
ALK-positive Non-small Cell Lung Cancer	Drug: Ceritinib	Phase 2

Detailed Description

Approximately 160 patients diagnosed with ALK-positive metastatic NSCLC (according to the 7th edition of the AJCC [American Joint Committee on Cancer] Cancer Staging Manual) and active lesions in the brain and/or diagnosed with leptomeningeal carcinomatosis were included in the study, approximately 40 patients in Arm 1 and Arm 2, approximately 30 patients in Arms 3 and Arm 4, and approximately 20 patients in Arm 5. Additional patients were enrolled in Arm 4 to achieve approximately 60 patients in Arms 3 and 4 together (i.e. ALKi naïve patients), if enrollment rate in Arm 3 was slow.

• Arm 1 included patients with metastases in the brain without evidence of leptomeningeal carcinomatosis, previously treated with radiation to the brain and with prior exposure to an ALKi.

• Arm 2 included patients with metastases in the brain without evidence of leptomeningeal carcinomatosis, previously untreated with radiation to the brain but with prior exposure to an ALKi.

• Arm 3 included patients with metastases in the brain without evidence of leptomeningeal carcinomatosis, previously treated with radiation to the brain but with no prior exposure to an ALKi.

• Arm 4 included patients with metastases in the brain without evidence of leptomeningeal carcinomatosis, previously untreated with radiation to the brain and with no prior exposure to an ALKi

• Arm 5 included any patients with leptomeningeal carcinomatosis with or without evidence of active lesion at the baseline Gadolinium-enhanced brain MRI.

Note: Previous treatment with ALK inhibitors other than crizotinib was not allowed in Arms 1, 2, and 5.

Ceritinib was administered orally once daily at a dose of 750 mg (five 150 mg capsules) on a continuous dosing schedule. The treatment period started on Cycle 1 Day 1.

Complete tumor assessments including gadolinium enhanced brain MRI was repeated at Week 8 (on Cycle 3 Day 1) and every 8 weeks (i.e. every 2 cycles) thereafter or earlier if clinically indicated. Safety evaluations included (S)AEs, physical examination, vital signs, ECGs, laboratory parameters and WHO performance status. Blood and CSF samples for PK were also collected.

Study Design

• Study Type: Interventional
• Actual Enrollment: 156 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II, Multi-center, Open-label, Five-arm Study to Evaluate the Efficacy and Safety of Oral Ceritinib Treatment for Patients With ALK-positive Non-small Cell Lung Cancer (NSCLC) Metastatic to the Brain and/or to Leptomeninges
• Actual Study Start Date: Apr 1, 2015
• Actual Primary Completion Date: Feb 6, 2019
• Actual Study Completion Date: Feb 6, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm 1 (PrALKi=Y, PrBRad=Y) Participants with metastases in the brain without evidence of leptomeningeal carcinomatosis (LC), previously treated with radiation to the brain and with prior exposure to an Anaplastic lymphoma kinase inhibitor (ALK-I). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Drug: Ceritinib; LDK378 is a gelatin capsule, administered orally once daily at a dose of 750 mg (five 150 mg capsules) on a continuous dosing schedule on an empty stomach.; Other Names: LDK378
Experimental: Arm 2 (PrALKi=Y, PrBRad=N) Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain but with prior exposure to an ALK-I. Previous treatment with ALK-I other than crizotinib was not allowed in this arm 2 as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Drug: Ceritinib; LDK378 is a gelatin capsule, administered orally once daily at a dose of 750 mg (five 150 mg capsules) on a continuous dosing schedule on an empty stomach.; Other Names: LDK378
Experimental: Arm 3 (PrALKi=N, PrBRad=Y) Participants with metastases in the brain without evidence of LC, previously treated with radiation to the brain but with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Drug: Ceritinib; LDK378 is a gelatin capsule, administered orally once daily at a dose of 750 mg (five 150 mg capsules) on a continuous dosing schedule on an empty stomach.; Other Names: LDK378
Experimental: Arm 4 (PrALKi=N, PrBRad=N) Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain and with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Drug: Ceritinib; LDK378 is a gelatin capsule, administered orally once daily at a dose of 750 mg (five 150 mg capsules) on a continuous dosing schedule on an empty stomach.; Other Names: LDK378
Experimental: Arm 5 (LepDis) Participants had LC with or without evidence of active lesion at the baseline Gadolinium-enhanced brain magnetic resonance imaging (MRI). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3.	Drug: Ceritinib; LDK378 is a gelatin capsule, administered orally once daily at a dose of 750 mg (five 150 mg capsules) on a continuous dosing schedule on an empty stomach.; Other Names: LDK378

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate (ORR) Per Investigator Assessment [43 months]

   Overall response rate (ORR) is defined as the percentage of participants with a best overall confirmed response of complete response (CR) or partial response (PR) in the whole body as assessed per RECIST 1.1 by the investigator. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.

Secondary Outcome Measures

1. Disease Control Rate (DCR) Per Investigator Assessment [43 months]

   DCR: percentage of parts. with best overall response of CR, PR or stable disease (SD) in the whole body, as assessed per RECIST 1.1 by investigator. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed and non-target lesions are not in progression or in complete response. SD: Neither sufficient shrinkage in the target lesion to qualify for PR or CR nor an increase in lesions which would qualify for PD & non-target lesions are not in unequivocal progression.

2. Overall Intracranial Response Rate (OIRR) Per Modified RECIST 1.1 Per Investigator Assessment [43 months]

   OIRR was calculated based on response assessments in the brain for patients having measurable brain metastases at baseline. OIRR was defined as the percentage of participants with a best overall confirmed response of CR or PR in the brain as assessed per modified RECIST 1.1. This was applied to the brain only. CR: Disappearance of all non-nodal target & non-target lesions. All lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or decreased by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) & non-target lesions are not in progression or in complete response.

3. Overall Intracranial Response Rate (OIRR) Per Modified RECIST 1.1 Per Blinded Independent Review Committee (BIRC) Assessment [43 months]

   OIRR was calculated based on response assessments in the brain for patients having measurable brain metastases at baseline. OIRR was defined as the percentage of participants with a best overall confirmed response of CR or PR in the brain as assessed per modified RECIST 1.1. This was applied to the brain only. CR: Disappearance of all non-nodal target & non-target lesions. All lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or decreased by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) & non-target lesions are not in progression or in complete response.

4. Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per Investigator Assessment at Weeks 8 & 16 [Week 8 and Week 16]

   IDCR overall: percentage of participants with a best overall response of CR, PR, SD or non-CR/non-PD in the brain, as assessed per modified RECIST 1.1 by the Investigator. This was applied to the brain only. CR: Disappearance of all non-nodal target & non-target lesions. All lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response. SD: Neither sufficient shrinkage in the target lesion to qualify for PR or CR nor an increase in lesions which would qualify for PD & non-target lesions are not in unequivocal progression.

5. Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per Investigator Assessment - Overall [43 months]

   IDCR overall: percentage of participants with a best overall response of CR, PR, SD or non-CR/non-PD in the brain, as assessed per modified RECIST 1.1 by the Investigator. This was applied to the brain only. CR: Disappearance of all non-nodal target & non-target lesions. All lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response. SD: Neither sufficient shrinkage in the target lesion to qualify for PR or CR nor an increase in lesions which would qualify for PD & non-target lesions are not in unequivocal progression.

6. Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per BIRC Assessment at Weeks 8 & 16 [Week 8 and Week 16]

   IDCR overall: percentage of participants with a best overall response of CR, PR, SD or non-CR/non-PD in the brain, as assessed per modified RECIST 1.1 by Investigator. This was applied to the brain only. CR: Disappearance of all non-nodal target & non-target lesions. All lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response. SD: Neither sufficient shrinkage in the target lesion to qualify for PR or CR nor an increase in lesions which would qualify for PD & non-target lesions are not in unequivocal progression.

7. Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per BIRC Assessment - Overall [43 months]

   IDCR overall: percentage of participants with a best overall response of CR, PR, SD or non-CR/non-PD in the brain, as assessed per modified RECIST 1.1 by Investigator. This was applied to the brain only. CR: Disappearance of all non-nodal target & non-target lesions. All lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response. SD: Neither sufficient shrinkage in the target lesion to qualify for PR or CR nor an increase in lesions which would qualify for PD & non-target lesions are not in unequivocal progression.

8. Time to Intracranial Tumor Response (TTIR) Per Modified RECIST 1.1 Per Investigator Assessment [43 months]

   TTIR was defined as the time from the date of the first dose of ceritinib to the date of the first documented response (CR or PR) in the brain as assessed per modified RECIST 1.1 criteria for patients with measurable brain metastases at baseline. This was applied to the brain only. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.

9. Time to Intracranial Tumor Response (TTIR) Per Modified RECIST 1.1 Per BIRC Assessment [43 months]

   TTIR was defined as the time from the date of the first dose of ceritinib to the date of the first documented response (CR or PR) in the brain as assessed per modified RECIST 1.1 criteria for patients with measurable brain metastases at baseline. This was applied to the brain only. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.

10. Duration of Intracranial Response (DOIR) by Modified RECIST 1.1 Per Investigator Assessment [43 months]

    Defined as the time from the first documented response (PR or CR) in the brain to the date of the first documented disease progression in the brain or death due to any cause, amongst participants with measurable brain metastases at baseline and a confirmed response (PR or CR) in the brain as per modified RECIST 1.1. This was applied to the brain only. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.

11. Duration of Intracranial Response (DOIR) by Modified RECIST 1.1 Per BIRC Assessment [43 months]

    Defined as the time from the first documented response (PR or CR) in the brain to the date of the first documented disease progression in the brain or death due to any cause, amongst participants with measurable brain metastases at baseline and a confirmed response (PR or CR) in the brain as per modified RECIST 1.1. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.

12. Overall Extracranial Response Rate (OERR) Per RECIST 1.1 Per Investigator & BIRC Assessment [43 months]

    OERR was defined as the percentage of participants with a best overall confirmed response of CR or PR outside of the brain, as assessed per RECIST 1.1. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.

13. Extracranial Disease Control Rate (EDCR) Per RECIST 1.1 Per Investigator & BIRC Assessment - Overall [43 months]

    EDCR overall was defined as the percentage of participants with a best overall response of CR, PR or SD outside of the brain as assessed per RECIST 1.1. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed and non-target lesions are not in progression or in complete response. SD: Neither sufficient shrinkage in the target lesion to qualify for PR or CR nor an increase in lesions which would qualify for PD & non-target lesions are not in unequivocal progression.

14. Extracranial Disease Control Rate (EDCR) Per RECIST 1.1 Per Investigator & BIRC Assessment at Weeks 8 & 16 [Week 8 and Week 16]

    EDCR at weeks 8 & 16: defined as percentage of parts. with CR, PR or SD outside of the brain at Wk 8 & 16 extracranial tumor evaluations respectively, per RECIST 1.1. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed and non-target lesions are not in progression or in complete response. SD: Neither sufficient shrinkage in the target lesion to qualify for PR or CR nor an increase in lesions which would qualify for PD & non-target lesions are not in unequivocal progression.

15. Time to Extracranial Tumor Response (TTER) Per RECIST 1.1 Per Investigator Assessment [43 months]

    TTER was defined as the time from the date of the first dose of ceritinib to the date of the first documented response (CR or PR) outside of the brain as assessed per RECIST 1.1 criteria. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.

16. Time to Extracranial Tumor Response (TTER) Per RECIST 1.1 Per BIRC Assessment [43 months]

    TTER was defined as the time from the date of the first dose of ceritinib to the date of the first documented response (CR or PR) outside of the brain as assessed per RECIST 1.1 criteria. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.

17. Duration of Extracranial Response (DOER) Per RECIST 1.1 Per Investigator Assessment [43 months]

    DOER was defined as the time from the first documented response (PR or CR) outside of the brain to the date of the first documented disease progression outside of the brain or death due to any cause, amongst patients with a confirmed response (PR or CR) outside of the brain per RECIST 1.1. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.

18. Duration of Extracranial Response (DOER) Per RECIST 1.1 Per BIRC Assessment [43 months]

    DOER was defined as the time from the first documented response (PR or CR) outside of the brain to the date of the first documented disease progression outside of the brain or death due to any cause, amongst patients with a confirmed response (PR or CR) outside of the brain per RECIST 1.1. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.

19. Overall Response Rate (ORR) (Whole Body) Per RECIST 1.1 Per BIRC Assessment [43 months]

    Overall response rate ORR is defined as the percentage of participants with a best overall confirmed response of complete response (CR) or partial response (PR) in the whole body as assessed per RECIST 1.1 by BIRC. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.

20. Disease Control Rate (DCR) (Whole Body) Per RECIST 1.1 Per BIRC Assessment [43 months]

    DCR: defined as percentage of participants with a best overall response of CR, PR or stable disease (SD) in the whole body, per RECIST 1.1 by BIRC. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed and non-target lesions are not in progression or in complete response. SD: Neither sufficient shrinkage in the target lesion to qualify for PR or CR nor an increase in lesions which would qualify for PD & non-target lesions are not in unequivocal progression.

21. Time to Tumor Response (TTR) (Whole Body) Per RECIST 1.1 Per Investigator Assessment [43 months]

    TTR was defined as the time from the date of the first dose of ceritinib to the date of the first documented response (CR or PR) in the whole body as assessed per RECIST 1.1 criteria per Investigator. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.

22. Time to Tumor Response (TTR) (Whole Body) Per RECIST 1.1 Per BIRC Assessment [43 months]

    TTR was defined as the time from the date of the first dose of ceritinib to the date of the first documented response (CR or PR) in the whole body as assessed by RECIST 1.1 criteria per BIRC assessment. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.

23. Duration of Response (DOR) (Whole Body) Per RECIST 1.1 Per Investigator Assessment [43 months]

    DOR was defined as the time from the first documented response (PR or CR) to the date of the first documented disease progression or death due to any cause, amongst patients with a confirmed response (PR or CR) in the whole body per RECIST 1.1 per Investigator. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.

24. Duration of Response (DOR) (Whole Body) Per RECIST 1.1 Per BIRC Assessment [43 months]

    DOR was defined as the time from the first documented response (PR or CR) to the date of the first documented disease progression or death due to any cause, amongst patients with a confirmed response (PR or CR) in the whole body per RECIST 1.1 per BIRC. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.

25. Progression Free Survival (PFS) (Whole Body) Per RECIST 1.1 Per Investigator & BIRC Assessment [43 months]

    PFS was defined as the time from the date of the first dose of ceritinib to the date of the first radiologically documented disease progression in the whole body per RECIST 1.1 or death due to any cause. A patient who had not progressed or died at the date of the analysis was censored at the time of the last adequate tumor evaluation on or before the cut-off date.

26. Overall Survival (OS) [24 weeks]

    OS was defined as time from the date of first dose of ceritinib to the date of death due to any cause. The OS time for patients who were alive at the end of the study or were lost to follow-up was censored at the date of last contact.

27. Pharmacokinetics (PK) of Ceritinib in Study Population: Cmax & Cmin (Trough) [Cmax: Cycle 2 Day 1 (C2D1); Cmin: C1D1, C1D8, C1D15, C2D1, C3D1, C4D1, C5D1, C6D1 - all 0hr (pre dose)]

    Cmax is the maximum (peak) concentration of drug in plasma. Cmin is the minimum (trough) concentration of drug in plasma. Sparse blood samples for ceritinib PK evaluation in plasma were collected on C1D1 up to C6D1 from all patients who received at least one dose of investigational study treatment.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically or cytologically confirmed diagnosis of metastatic NSCLC according to the 7th edition of the AJCC Cancer Staging Manual. In addition, the NSCLC must harbor an ALK rearrangement, as assessed using the FDA approved Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular Inc.) test and scoring algorithm (including positivity criteria). If documentation of ALK rearrangement as described above was not locally available, a test to confirm ALK rearrangement was to be performed by a Novartis designated central laboratory. Patients had to wait for the central laboratory result of the ALK rearrangement status before initiating treatment with ceritinib

• At least one extracranial measurable lesion as defined by RECIST 1.1. A previously irradiated site lesion could only be counted as a target lesion if there was clear sign of progression since the irradiation.

• Patients could or could not have neurological symptoms but must have been able to swallow and retain oral medication.

• Patients had to be neurologically stable within at least 1 week prior to the first dose of study drug.

• Patients could have received prior chemotherapy, crizotinib (other ALK inhibitors were not allowed), biologic therapy or other investigational agents.

• Patients must have recovered from all toxicities related to prior anticancer therapies to grade ≤ 1 (CTCAE v 4.03). Patients with any grade of alopecia were allowed to enter the study.

• Patient had life expectancy ≥ 6 weeks.

• Patient had a WHO performance status 0-2.

Patients in Arm 1 to 4 had to also meet the following inclusion criteria:

• Patients had to have active brain metastases from NSCLC, confirmed by Gadolinium-enhanced MRI without concomitant leptomeningeal carcinomatosis. Dose of steroids had to be stable for 5 days before the baseline brain MRI.

Patients in Arm 5 had to also meet the following inclusion criteria:

• Patients must have been diagnosed with leptomeningeal carcinomatosis.

Exclusion Criteria:

• Patients who needed whole brain radiation to control the brain metastases. Patients were not eligible unless treated brain lesions were progressive or new brain lesions were observed since the post whole brain radiation therapy MRI.

• Planning of any brain local treatment (including but not limited to surgery, stereotactic radiosurgery, whole brain radiation, intrathecal chemotherapy) following the administration of the first dose of study drug.

• Patient with a concurrent malignancy or history of a malignant disease other than NSCLC that had been diagnosed and/or required therapy within the past 3 years. Exceptions to this exclusion included the following: completely resected basal cell and squamous cell skin cancers, and completely resected carcinoma in situ of any type.

• Patient had impairment of GI function or GI disease that could significantly alter the absorption of ceritinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome).

• Patient was receiving unstable or increasing doses of corticosteroids.

• Patient had other severe, acute, or chronic medical conditions including uncontrolled diabetes mellitus or psychiatric conditions or laboratory abnormalities that in the opinion of the investigator could increase the risk associated with study participation, or that could interfere with the interpretation of study results.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	USC Kenneth Norris Comprehensive Cancer Center SC-3	Los Angeles	California	United States	90033
2	Stanford Universtiy Medical Center SC-5	Stanford	California	United States	94304
3	Memorial Hospital of South Bend	South Bend	Indiana	United States	46601
4	Dana Farber Cancer Institute SC-12	Boston	Massachusetts	United States	02215
5	The Ohio State University Comprehensive Cancer Center Ohio State University	Columbus	Ohio	United States	43221
6	Southwestern Regional Medical Center	Tulsa	Oklahoma	United States	74133
7	Seattle Cancer Care Alliance	Seattle	Washington	United States	98105
8	Novartis Investigative Site	Auckland		Australia
9	Novartis Investigative Site	Leuven		Belgium	3000
10	Novartis Investigative Site	Salvador	Bahia	Brazil	41253-190
11	Novartis Investigative Site	Porto Alegre	Rio Grande Do Sul	Brazil	90610-000
12	Novartis Investigative Site	Natal	RN	Brazil	59075 740
13	Novartis Investigative Site	Itajai	SC	Brazil	88301-229
14	Novartis Investigative Site	Barretos	SP	Brazil	14784 400
15	Novartis Investigative Site	Sao Paulo	SP	Brazil	01246 000
16	Novartis Investigative Site	Sao Paulo		Brazil	01236 030
17	Novartis Investigative Site	Toronto	Ontario	Canada	M5G 2M9
18	Novartis Investigative Site	Marseille cedex 20	Bouches Du Rhone	France	13915
19	Novartis Investigative Site	Paris		France	75970
20	Novartis Investigative Site	Rennes		France	35043
21	Novartis Investigative Site	Saint-Herblain Cédex		France	44805
22	Novartis Investigative Site	Strasbourg Cedex		France	67091
23	Novartis Investigative Site	Villejuif Cedex		France	94805
24	Novartis Investigative Site	Bad Berka		Germany	99437
25	Novartis Investigative Site	Koeln		Germany	50937
26	Novartis Investigative Site	Pokfulam		Hong Kong
27	Novartis Investigative Site	Livorno	LI	Italy	57124
28	Novartis Investigative Site	Monza	MB	Italy	20900
29	Novartis Investigative Site	Messina	ME	Italy	98158
30	Novartis Investigative Site	Milano	MI	Italy	20133
31	Novartis Investigative Site	Milano	MI	Italy	20141
32	Novartis Investigative Site	Perugia	PG	Italy	06129
33	Novartis Investigative Site	Aviano	PN	Italy	33081
34	Novartis Investigative Site	Parma	PR	Italy	43100
35	Novartis Investigative Site	Roma	RM	Italy	00155
36	Novartis Investigative Site	Orbassano	TO	Italy	10043
37	Novartis Investigative Site	Verona	VR	Italy	37126
38	Novartis Investigative Site	Napoli		Italy	80131
39	Novartis Investigative Site	Seoul	Korea	Korea, Republic of	05505
40	Novartis Investigative Site	Seoul		Korea, Republic of	03080
41	Novartis Investigative Site	Seoul		Korea, Republic of	06351
42	NKI-AVL, Department of Thoracic-Oncology	Amsterdam		Netherlands	1066 CX
43	Novartis Investigative Site	Saint Petersburg		Russian Federation	192148
44	Novartis Investigative Site	Singapore		Singapore	169610
45	Novartis Investigative Site	Malaga	Andalucia	Spain	29010
46	Novartis Investigative Site	Barcelona		Spain	08041
47	Novartis Investigative Site	Madrid		Spain	28034
48	Novartis Investigative Site	Madrid		Spain	28040
49	Novartis Investigative Site	Madrid		Spain	28222
50	Novartis Investigative Site	Tainan	Taiwan ROC	Taiwan	70403
51	Novartis Investigative Site	Taipei		Taiwan	10002
52	Novartis Investigative Site	Taipei		Taiwan	11217
53	Novartis Investigative Site	Istanbul	TUR	Turkey	34098
54	Novartis Investigative Site	Ankara		Turkey	06100
55	Novartis Investigative Site	Sutton	Surrey	United Kingdom	SM2 5PT
56	Novartis Investigative Site	Birmingham		United Kingdom	B9 5SS
57	Novartis Investigative Site	London		United Kingdom	SE1 9RT

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

• Statistical Analysis Plan - Mar 11, 2019
• Study Protocol - May 16, 2018

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02336451
• Other Study ID Numbers: CLDK378A2205; 2014-000578-20
• First Posted: Jan 13, 2015
• Last Update Posted: Apr 21, 2020
• Last Verified: Apr 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: ALK-positive; NSCLC; non-small cell lung cancer; brain metastasis; metastatic to the brain and/or to leptomeninges; ceritinib; LDK378; NSCLC metastatic to the brain; leptomeninges harboring a confirmed ALK rearrangement
• Additional relevant MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Ceritinib

Study Results

Participant Flow

Recruitment Details	A total of 156 patients were enrolled and treated with ceritinib. The FAS (N=156) included all patients who received at least one dose of ceritinib with 42, 40, 12, 44 and 18 patients in arms 1 to 5 respectively. The Safety set was identical to full analysis set in this study.
Pre-assignment Detail	Approximately 160 patients were planned to be enrolled.

Arm/Group Title	Arm 1 (PrALKi=Y, PrBRad=Y)	Arm 2 (PrALKi=Y, PrBRad=N)	Arm 3 (PrALKi=N, PrBRad=Y)	Arm 4 (PrALKi=N, PrBRad=N)	Arm 5 (LepDis)
Arm/Group Description	Participants with metastases in the brain without evidence of leptomeningeal carcinomatosis (LC), previously treated with radiation to the brain and with prior exposure to an Anaplastic lymphoma kinase inhibitor (ALK-I). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain but with prior exposure to an ALK-I. Previous treatment with ALK-I other than crizotinib was not allowed in this arm 2 as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously treated with radiation to the brain but with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain and with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants had LC with or without evidence of active lesion at the baseline Gadolinium-enhanced brain magnetic resonance imaging (MRI). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3.
Period Title: Overall Study
STARTED	42	40	12	44	18
COMPLETED	0	0	0	0	0
NOT COMPLETED	42	40	12	44	18

Baseline Characteristics

Arm/Group Title	Arm 1 (PrALKi=Y, PrBRad=Y)	Arm 2 (PrALKi=Y, PrBRad=N)	Arm 3 (PrALKi=N, PrBRad=Y)	Arm 4 (PrALKi=N, PrBRad=N)	Arm 5 (LepDis)	Total
Arm/Group Description	Participants with metastases in the brain without evidence of leptomeningeal carcinomatosis (LC), previously treated with radiation to the brain and with prior exposure to an Anaplastic lymphoma kinase inhibitor (ALK-I). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain but with prior exposure to an ALK-I. Previous treatment with ALK-I other than crizotinib was not allowed in this arm 2 as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously treated with radiation to the brain but with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain and with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants had LC with or without evidence of active lesion at the baseline Gadolinium-enhanced brain magnetic resonance imaging (MRI). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3.	Total of all reporting groups
Overall Participants	42	40	12	44	18	156
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	48.6 (11.37)	54.5 (12.32)	50.0 (9.67)	51.8 (11.21)	49.9 (11.38)	51.3 (11.53)
Sex: Female, Male (Count of Participants)
Female	21 50%	19 47.5%	6 50%	27 61.4%	9 50%	82 52.6%
Male	21 50%	21 52.5%	6 50%	17 38.6%	9 50%	74 47.4%
Race/Ethnicity, Customized (Number) [Number]
Asian	18 42.9%	11 27.5%	7 58.3%	8 18.2%	3 16.7%	47 30.1%
Black	0 0%	0 0%	0 0%	1 2.3%	0 0%	1 0.6%
Caucasian	24 57.1%	27 67.5%	4 33.3%	32 72.7%	15 83.3%	102 65.4%
Other	0 0%	2 5%	1 8.3%	2 4.5%	0 0%	5 3.2%
Unknown	0 0%	0 0%	0 0%	1 2.3%	0 0%	1 0.6%

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate (ORR) Per Investigator Assessment
Description	Overall response rate (ORR) is defined as the percentage of participants with a best overall confirmed response of complete response (CR) or partial response (PR) in the whole body as assessed per RECIST 1.1 by the investigator. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.
Time Frame	43 months

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) comprised of all patients who received at least one dose of ceritinib.

Arm/Group Title	Arm 1 (PrALKi=Y, PrBRad=Y)	Arm 2 (PrALKi=Y, PrBRad=N)	Arm 3 (PrALKi=N, PrBRad=Y)	Arm 4 (PrALKi=N, PrBRad=N)	Arm 5 (LepDis)
Arm/Group Description	Participants with metastases in the brain without evidence of leptomeningeal carcinomatosis (LC), previously treated with radiation to the brain and with prior exposure to an Anaplastic lymphoma kinase inhibitor (ALK-I). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain but with prior exposure to an ALK-I. Previous treatment with ALK-I other than crizotinib was not allowed in this arm 2 as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously treated with radiation to the brain but with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain and with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants had LC with or without evidence of active lesion at the baseline Gadolinium-enhanced brain magnetic resonance imaging (MRI). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3.
Measure Participants	42	40	12	44	18
Number (95% Confidence Interval) [Percentage of participants]	35.7 85%	30.0 75%	50.0 416.7%	59.1 134.3%	16.7 92.8%

2. Secondary Outcome

Title	Disease Control Rate (DCR) Per Investigator Assessment
Description	DCR: percentage of parts. with best overall response of CR, PR or stable disease (SD) in the whole body, as assessed per RECIST 1.1 by investigator. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed and non-target lesions are not in progression or in complete response. SD: Neither sufficient shrinkage in the target lesion to qualify for PR or CR nor an increase in lesions which would qualify for PD & non-target lesions are not in unequivocal progression.
Time Frame	43 months

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) comprised of all patients who received at least one dose of ceritinib.

Arm/Group Title	Arm 1 (PrALKi=Y, PrBRad=Y)	Arm 2 (PrALKi=Y, PrBRad=N)	Arm 3 (PrALKi=N, PrBRad=Y)	Arm 4 (PrALKi=N, PrBRad=N)	Arm 5 (LepDis)
Arm/Group Description	Participants with metastases in the brain without evidence of leptomeningeal carcinomatosis (LC), previously treated with radiation to the brain and with prior exposure to an Anaplastic lymphoma kinase inhibitor (ALK-I). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain but with prior exposure to an ALK-I. Previous treatment with ALK-I other than crizotinib was not allowed in this arm 2 as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously treated with radiation to the brain but with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain and with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants had LC with or without evidence of active lesion at the baseline Gadolinium-enhanced brain magnetic resonance imaging (MRI). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3.
Measure Participants	42	40	12	44	18
Number (95% Confidence Interval) [Percentage of participants]	66.7 158.8%	82.5 206.3%	66.7 555.8%	70.5 160.2%	66.7 370.6%

3. Secondary Outcome

Title	Overall Intracranial Response Rate (OIRR) Per Modified RECIST 1.1 Per Investigator Assessment
Description	OIRR was calculated based on response assessments in the brain for patients having measurable brain metastases at baseline. OIRR was defined as the percentage of participants with a best overall confirmed response of CR or PR in the brain as assessed per modified RECIST 1.1. This was applied to the brain only. CR: Disappearance of all non-nodal target & non-target lesions. All lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or decreased by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) & non-target lesions are not in progression or in complete response.
Time Frame	43 months

Outcome Measure Data

Analysis Population Description

A subset of FAS (comprised of all patients who received at least one dose of ceritinib) where participants had measurable brain metastases at baseline.

Arm/Group Title	Arm 1 (PrALKi=Y, PrBRad=Y)	Arm 2 (PrALKi=Y, PrBRad=N)	Arm 3 (PrALKi=N, PrBRad=Y)	Arm 4 (PrALKi=N, PrBRad=N)	Arm 5 (LepDis)
Arm/Group Description	Participants with metastases in the brain without evidence of leptomeningeal carcinomatosis (LC), previously treated with radiation to the brain and with prior exposure to an Anaplastic lymphoma kinase inhibitor (ALK-I). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain but with prior exposure to an ALK-I. Previous treatment with ALK-I other than crizotinib was not allowed in this arm 2 as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously treated with radiation to the brain but with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain and with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants had LC with or without evidence of active lesion at the baseline Gadolinium-enhanced brain magnetic resonance imaging (MRI). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3.
Measure Participants	28	29	7	33	8
Number (95% Confidence Interval) [Percentage of participants]	39.3 93.6%	27.6 69%	28.6 238.3%	51.5 117%	12.5 69.4%

4. Secondary Outcome

Title	Overall Intracranial Response Rate (OIRR) Per Modified RECIST 1.1 Per Blinded Independent Review Committee (BIRC) Assessment
Description	OIRR was calculated based on response assessments in the brain for patients having measurable brain metastases at baseline. OIRR was defined as the percentage of participants with a best overall confirmed response of CR or PR in the brain as assessed per modified RECIST 1.1. This was applied to the brain only. CR: Disappearance of all non-nodal target & non-target lesions. All lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or decreased by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) & non-target lesions are not in progression or in complete response.
Time Frame	43 months

Outcome Measure Data

Analysis Population Description

A subset of FAS (comprised of all patients who received at least one dose of ceritinib) where participants had measurable brain metastases at baseline.

Arm/Group Title	Arm 1 (PrALKi=Y, PrBRad=Y)	Arm 2 (PrALKi=Y, PrBRad=N)	Arm 3 (PrALKi=N, PrBRad=Y)	Arm 4 (PrALKi=N, PrBRad=N)	Arm 5 (LepDis)
Arm/Group Description	Participants with metastases in the brain without evidence of leptomeningeal carcinomatosis (LC), previously treated with radiation to the brain and with prior exposure to an Anaplastic lymphoma kinase inhibitor (ALK-I). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain but with prior exposure to an ALK-I. Previous treatment with ALK-I other than crizotinib was not allowed in this arm 2 as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously treated with radiation to the brain but with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain and with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants had LC with or without evidence of active lesion at the baseline Gadolinium-enhanced brain magnetic resonance imaging (MRI). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3.
Measure Participants	30	29	6	34	10
Number (95% Confidence Interval) [Percentage of participants]	33.3 79.3%	24.1 60.3%	33.3 277.5%	58.8 133.6%	20.0 111.1%

5. Secondary Outcome

Title	Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per Investigator Assessment at Weeks 8 & 16
Description	IDCR overall: percentage of participants with a best overall response of CR, PR, SD or non-CR/non-PD in the brain, as assessed per modified RECIST 1.1 by the Investigator. This was applied to the brain only. CR: Disappearance of all non-nodal target & non-target lesions. All lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response. SD: Neither sufficient shrinkage in the target lesion to qualify for PR or CR nor an increase in lesions which would qualify for PD & non-target lesions are not in unequivocal progression.
Time Frame	Week 8 and Week 16

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) comprised of all patients who received at least one dose of ceritinib.

Arm/Group Title	Arm 1 (PrALKi=Y, PrBRad=Y)	Arm 2 (PrALKi=Y, PrBRad=N)	Arm 3 (PrALKi=N, PrBRad=Y)	Arm 4 (PrALKi=N, PrBRad=N)	Arm 5 (LepDis)
Arm/Group Description	Participants with metastases in the brain without evidence of leptomeningeal carcinomatosis (LC), previously treated with radiation to the brain and with prior exposure to an Anaplastic lymphoma kinase inhibitor (ALK-I). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain but with prior exposure to an ALK-I. Previous treatment with ALK-I other than crizotinib was not allowed in this arm 2 as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously treated with radiation to the brain but with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain and with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants had LC with or without evidence of active lesion at the baseline Gadolinium-enhanced brain magnetic resonance imaging (MRI). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3.
Measure Participants	42	40	12	44	18
IDCR at Week 8	71.4 170%	75.0 187.5%	58.3 485.8%	68.2 155%	66.7 370.6%
IDCR at Week 16	59.5 141.7%	62.5 156.3%	58.3 485.8%	65.9 149.8%	50.0 277.8%

6. Secondary Outcome

Title	Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per Investigator Assessment - Overall
Description	IDCR overall: percentage of participants with a best overall response of CR, PR, SD or non-CR/non-PD in the brain, as assessed per modified RECIST 1.1 by the Investigator. This was applied to the brain only. CR: Disappearance of all non-nodal target & non-target lesions. All lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response. SD: Neither sufficient shrinkage in the target lesion to qualify for PR or CR nor an increase in lesions which would qualify for PD & non-target lesions are not in unequivocal progression.
Time Frame	43 months

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) comprised of all patients who received at least one dose of ceritinib.

Arm/Group Title	Arm 1 (PrALKi=Y, PrBRad=Y)	Arm 2 (PrALKi=Y, PrBRad=N)	Arm 3 (PrALKi=N, PrBRad=Y)	Arm 4 (PrALKi=N, PrBRad=N)	Arm 5 (LepDis)
Arm/Group Description	Participants with metastases in the brain without evidence of leptomeningeal carcinomatosis (LC), previously treated with radiation to the brain and with prior exposure to an Anaplastic lymphoma kinase inhibitor (ALK-I). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain but with prior exposure to an ALK-I. Previous treatment with ALK-I other than crizotinib was not allowed in this arm 2 as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously treated with radiation to the brain but with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain and with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants had LC with or without evidence of active lesion at the baseline Gadolinium-enhanced brain magnetic resonance imaging (MRI). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3.
Measure Participants	42	40	12	44	18
Number (95% Confidence Interval) [Percentage of participants]	71.4 170%	85.0 212.5%	75.0 625%	75.0 170.5%	66.7 370.6%

7. Secondary Outcome

Title	Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per BIRC Assessment at Weeks 8 & 16
Description	IDCR overall: percentage of participants with a best overall response of CR, PR, SD or non-CR/non-PD in the brain, as assessed per modified RECIST 1.1 by Investigator. This was applied to the brain only. CR: Disappearance of all non-nodal target & non-target lesions. All lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response. SD: Neither sufficient shrinkage in the target lesion to qualify for PR or CR nor an increase in lesions which would qualify for PD & non-target lesions are not in unequivocal progression.
Time Frame	Week 8 and Week 16

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) comprised of all patients who received at least one dose of ceritinib.

Arm/Group Title	Arm 1 (PrALKi=Y, PrBRad=Y)	Arm 2 (PrALKi=Y, PrBRad=N)	Arm 3 (PrALKi=N, PrBRad=Y)	Arm 4 (PrALKi=N, PrBRad=N)	Arm 5 (LepDis)
Arm/Group Description	Participants with metastases in the brain without evidence of leptomeningeal carcinomatosis (LC), previously treated with radiation to the brain and with prior exposure to an Anaplastic lymphoma kinase inhibitor (ALK-I). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain but with prior exposure to an ALK-I. Previous treatment with ALK-I other than crizotinib was not allowed in this arm 2 as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously treated with radiation to the brain but with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain and with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants had LC with or without evidence of active lesion at the baseline Gadolinium-enhanced brain magnetic resonance imaging (MRI). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3.
Measure Participants	42	40	12	44	18
IDCR at 8 weeks	76.2 181.4%	80.0 200%	58.3 485.8%	68.2 155%	66.7 370.6%
IDCR at 16 weeks	69.0 164.3%	62.5 156.3%	58.3 485.8%	68.2 155%	38.9 216.1%

8. Secondary Outcome

Title	Intracranial Disease Control Rate (IDCR) Per Modified RECIST 1.1 Per BIRC Assessment - Overall
Description	IDCR overall: percentage of participants with a best overall response of CR, PR, SD or non-CR/non-PD in the brain, as assessed per modified RECIST 1.1 by Investigator. This was applied to the brain only. CR: Disappearance of all non-nodal target & non-target lesions. All lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response. SD: Neither sufficient shrinkage in the target lesion to qualify for PR or CR nor an increase in lesions which would qualify for PD & non-target lesions are not in unequivocal progression.
Time Frame	43 months

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) comprised of all patients who received at least one dose of ceritinib.

Arm/Group Title	Arm 1 (PrALKi=Y, PrBRad=Y)	Arm 2 (PrALKi=Y, PrBRad=N)	Arm 3 (PrALKi=N, PrBRad=Y)	Arm 4 (PrALKi=N, PrBRad=N)	Arm 5 (LepDis)
Arm/Group Description	Participants with metastases in the brain without evidence of leptomeningeal carcinomatosis (LC), previously treated with radiation to the brain and with prior exposure to an Anaplastic lymphoma kinase inhibitor (ALK-I). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain but with prior exposure to an ALK-I. Previous treatment with ALK-I other than crizotinib was not allowed in this arm 2 as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously treated with radiation to the brain but with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain and with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants had LC with or without evidence of active lesion at the baseline Gadolinium-enhanced brain magnetic resonance imaging (MRI). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3.
Measure Participants	42	40	12	44	18
Number (95% Confidence Interval) [Percentage of participants]	73.8 175.7%	85.0 212.5%	66.7 555.8%	75.0 170.5%	66.7 370.6%

9. Secondary Outcome

Title	Time to Intracranial Tumor Response (TTIR) Per Modified RECIST 1.1 Per Investigator Assessment
Description	TTIR was defined as the time from the date of the first dose of ceritinib to the date of the first documented response (CR or PR) in the brain as assessed per modified RECIST 1.1 criteria for patients with measurable brain metastases at baseline. This was applied to the brain only. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.
Time Frame	43 months

Outcome Measure Data

Analysis Population Description

A subset of FAS (comprised of all patients who received at least one dose of ceritinib) where participants had measurable brain metastases at baseline and confirmed CR or PR.

Arm/Group Title	Arm 1 (PrALKi=Y, PrBRad=Y)	Arm 2 (PrALKi=Y, PrBRad=N)	Arm 3 (PrALKi=N, PrBRad=Y)	Arm 4 (PrALKi=N, PrBRad=N)	Arm 5 (LepDis)
Arm/Group Description	Participants with metastases in the brain without evidence of leptomeningeal carcinomatosis (LC), previously treated with radiation to the brain and with prior exposure to an Anaplastic lymphoma kinase inhibitor (ALK-I). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain but with prior exposure to an ALK-I. Previous treatment with ALK-I other than crizotinib was not allowed in this arm 2 as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously treated with radiation to the brain but with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain and with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants had LC with or without evidence of active lesion at the baseline Gadolinium-enhanced brain magnetic resonance imaging (MRI). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3.
Measure Participants	11	8	2	17	1
Median (Full Range) [months]	1.87	1.84	3.56	1.77	1.80

10. Secondary Outcome

Title	Time to Intracranial Tumor Response (TTIR) Per Modified RECIST 1.1 Per BIRC Assessment
Description	TTIR was defined as the time from the date of the first dose of ceritinib to the date of the first documented response (CR or PR) in the brain as assessed per modified RECIST 1.1 criteria for patients with measurable brain metastases at baseline. This was applied to the brain only. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.
Time Frame	43 months

Outcome Measure Data

Analysis Population Description

A subset of FAS (comprised of all patients who received at least one dose of ceritinib) where participants had measurable brain metastases at baseline and confirmed CR or PR.

Arm/Group Title	Arm 1 (PrALKi=Y, PrBRad=Y)	Arm 2 (PrALKi=Y, PrBRad=N)	Arm 3 (PrALKi=N, PrBRad=Y)	Arm 4 (PrALKi=N, PrBRad=N)	Arm 5 (LepDis)
Arm/Group Description	Participants with metastases in the brain without evidence of leptomeningeal carcinomatosis (LC), previously treated with radiation to the brain and with prior exposure to an Anaplastic lymphoma kinase inhibitor (ALK-I). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain but with prior exposure to an ALK-I. Previous treatment with ALK-I other than crizotinib was not allowed in this arm 2 as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously treated with radiation to the brain but with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain and with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants had LC with or without evidence of active lesion at the baseline Gadolinium-enhanced brain magnetic resonance imaging (MRI). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3.
Measure Participants	10	7	2	20	2
Median (Full Range) [months]	1.91	1.68	6.31	1.81	1.22

11. Secondary Outcome

Title	Duration of Intracranial Response (DOIR) by Modified RECIST 1.1 Per Investigator Assessment
Description	Defined as the time from the first documented response (PR or CR) in the brain to the date of the first documented disease progression in the brain or death due to any cause, amongst participants with measurable brain metastases at baseline and a confirmed response (PR or CR) in the brain as per modified RECIST 1.1. This was applied to the brain only. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.
Time Frame	43 months

Outcome Measure Data

Analysis Population Description

A subset of FAS (comprised of all patients who received at least one dose of ceritinib) where participants had measurable brain metastases at baseline and confirmed CR or PR.

Arm/Group Title	Arm 1 (PrALKi=Y, PrBRad=Y)	Arm 2 (PrALKi=Y, PrBRad=N)	Arm 3 (PrALKi=N, PrBRad=Y)	Arm 4 (PrALKi=N, PrBRad=N)	Arm 5 (LepDis)
Arm/Group Description	Participants with metastases in the brain without evidence of leptomeningeal carcinomatosis (LC), previously treated with radiation to the brain and with prior exposure to an Anaplastic lymphoma kinase inhibitor (ALK-I). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain but with prior exposure to an ALK-I. Previous treatment with ALK-I other than crizotinib was not allowed in this arm 2 as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously treated with radiation to the brain but with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain and with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants had LC with or without evidence of active lesion at the baseline Gadolinium-enhanced brain magnetic resonance imaging (MRI). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3.
Measure Participants	11	8	2	17	1
Median (95% Confidence Interval) [months]	9.2	10.1	NA	7.5	5.5

12. Secondary Outcome

Title	Duration of Intracranial Response (DOIR) by Modified RECIST 1.1 Per BIRC Assessment
Description	Defined as the time from the first documented response (PR or CR) in the brain to the date of the first documented disease progression in the brain or death due to any cause, amongst participants with measurable brain metastases at baseline and a confirmed response (PR or CR) in the brain as per modified RECIST 1.1. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.
Time Frame	43 months

Outcome Measure Data

Analysis Population Description

A subset of FAS (comprised of all patients who received at least one dose of ceritinib) where participants had measurable brain metastases at baseline and confirmed CR or PR.

Arm/Group Title	Arm 1 (PrALKi=Y, PrBRad=Y)	Arm 2 (PrALKi=Y, PrBRad=N)	Arm 3 (PrALKi=N, PrBRad=Y)	Arm 4 (PrALKi=N, PrBRad=N)	Arm 5 (LepDis)
Arm/Group Description	Participants with metastases in the brain without evidence of leptomeningeal carcinomatosis (LC), previously treated with radiation to the brain and with prior exposure to an Anaplastic lymphoma kinase inhibitor (ALK-I). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain but with prior exposure to an ALK-I. Previous treatment with ALK-I other than crizotinib was not allowed in this arm 2 as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously treated with radiation to the brain but with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain and with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants had LC with or without evidence of active lesion at the baseline Gadolinium-enhanced brain magnetic resonance imaging (MRI). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3.
Measure Participants	10	7	2	20	2
Median (95% Confidence Interval) [months]	11.0	4.6	NA	9.2	3.4

13. Secondary Outcome

Title	Overall Extracranial Response Rate (OERR) Per RECIST 1.1 Per Investigator & BIRC Assessment
Description	OERR was defined as the percentage of participants with a best overall confirmed response of CR or PR outside of the brain, as assessed per RECIST 1.1. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.
Time Frame	43 months

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) comprised of all patients who received at least one dose of ceritinib.

Arm/Group Title	Arm 1 (PrALKi=Y, PrBRad=Y)	Arm 2 (PrALKi=Y, PrBRad=N)	Arm 3 (PrALKi=N, PrBRad=Y)	Arm 4 (PrALKi=N, PrBRad=N)	Arm 5 (LepDis)
Arm/Group Description	Participants with metastases in the brain without evidence of leptomeningeal carcinomatosis (LC), previously treated with radiation to the brain and with prior exposure to an Anaplastic lymphoma kinase inhibitor (ALK-I). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain but with prior exposure to an ALK-I. Previous treatment with ALK-I other than crizotinib was not allowed in this arm 2 as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously treated with radiation to the brain but with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain and with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants had LC with or without evidence of active lesion at the baseline Gadolinium-enhanced brain magnetic resonance imaging (MRI). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3.
Measure Participants	42	40	12	44	18
OERR per Investigator assessment	31.0 73.8%	42.5 106.3%	41.7 347.5%	61.4 139.5%	22.2 123.3%
OERR per BIRC assessment	26.2 62.4%	25.0 62.5%	50.0 416.7%	61.4 139.5%	16.7 92.8%

14. Secondary Outcome

Title	Extracranial Disease Control Rate (EDCR) Per RECIST 1.1 Per Investigator & BIRC Assessment - Overall
Description	EDCR overall was defined as the percentage of participants with a best overall response of CR, PR or SD outside of the brain as assessed per RECIST 1.1. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed and non-target lesions are not in progression or in complete response. SD: Neither sufficient shrinkage in the target lesion to qualify for PR or CR nor an increase in lesions which would qualify for PD & non-target lesions are not in unequivocal progression.
Time Frame	43 months

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) comprised of all patients who received at least one dose of ceritinib.

Arm/Group Title	Arm 1 (PrALKi=Y, PrBRad=Y)	Arm 2 (PrALKi=Y, PrBRad=N)	Arm 3 (PrALKi=N, PrBRad=Y)	Arm 4 (PrALKi=N, PrBRad=N)	Arm 5 (LepDis)
Arm/Group Description	Participants with metastases in the brain without evidence of leptomeningeal carcinomatosis (LC), previously treated with radiation to the brain and with prior exposure to an Anaplastic lymphoma kinase inhibitor (ALK-I). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain but with prior exposure to an ALK-I. Previous treatment with ALK-I other than crizotinib was not allowed in this arm 2 as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously treated with radiation to the brain but with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain and with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants had LC with or without evidence of active lesion at the baseline Gadolinium-enhanced brain magnetic resonance imaging (MRI). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3.
Measure Participants	42	40	12	44	18
EDCR per Investigator assessment	69.0 164.3%	92.5 231.3%	66.7 555.8%	72.7 165.2%	72.2 401.1%
EDCR per BIRC assessment	64.3 153.1%	80.0 200%	66.7 555.8%	68.2 155%	72.2 401.1%

15. Secondary Outcome

Title	Extracranial Disease Control Rate (EDCR) Per RECIST 1.1 Per Investigator & BIRC Assessment at Weeks 8 & 16
Description	EDCR at weeks 8 & 16: defined as percentage of parts. with CR, PR or SD outside of the brain at Wk 8 & 16 extracranial tumor evaluations respectively, per RECIST 1.1. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed and non-target lesions are not in progression or in complete response. SD: Neither sufficient shrinkage in the target lesion to qualify for PR or CR nor an increase in lesions which would qualify for PD & non-target lesions are not in unequivocal progression.
Time Frame	Week 8 and Week 16

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) comprised of all patients who received at least one dose of ceritinib.

Arm/Group Title	Arm 1 (PrALKi=Y, PrBRad=Y)	Arm 2 (PrALKi=Y, PrBRad=N)	Arm 3 (PrALKi=N, PrBRad=Y)	Arm 4 (PrALKi=N, PrBRad=N)	Arm 5 (LepDis)
Arm/Group Description	Participants with metastases in the brain without evidence of leptomeningeal carcinomatosis (LC), previously treated with radiation to the brain and with prior exposure to an Anaplastic lymphoma kinase inhibitor (ALK-I). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain but with prior exposure to an ALK-I. Previous treatment with ALK-I other than crizotinib was not allowed in this arm 2 as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously treated with radiation to the brain but with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain and with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants had LC with or without evidence of active lesion at the baseline Gadolinium-enhanced brain magnetic resonance imaging (MRI). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3.
Measure Participants	42	40	12	44	18
EDCR per Investigator @ Week 8	69.0 164.3%	82.5 206.3%	58.3 485.8%	63.6 144.5%	72.2 401.1%
EDCR per Investigator @ Week 16	57.1 136%	82.5 206.3%	66.7 555.8%	65.9 149.8%	50.0 277.8%
EDCR per BIRC @ Week 8	66.7 158.8%	72.5 181.3%	58.3 485.8%	61.4 139.5%	72.2 401.1%
EDCR per BIRC @ Week 16	54.8 130.5%	70.0 175%	66.7 555.8%	68.2 155%	44.4 246.7%

16. Secondary Outcome

Title	Time to Extracranial Tumor Response (TTER) Per RECIST 1.1 Per Investigator Assessment
Description	TTER was defined as the time from the date of the first dose of ceritinib to the date of the first documented response (CR or PR) outside of the brain as assessed per RECIST 1.1 criteria. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.
Time Frame	43 months

Outcome Measure Data

Analysis Population Description

A subset of FAS (comprised of all patients who received at least one dose of ceritinib) where participants had confirmed CR or PR.

Arm/Group Title	Arm 1 (PrALKi=Y, PrBRad=Y)	Arm 2 (PrALKi=Y, PrBRad=N)	Arm 3 (PrALKi=N, PrBRad=Y)	Arm 4 (PrALKi=N, PrBRad=N)	Arm 5 (LepDis)
Arm/Group Description	Participants with metastases in the brain without evidence of leptomeningeal carcinomatosis (LC), previously treated with radiation to the brain and with prior exposure to an Anaplastic lymphoma kinase inhibitor (ALK-I). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain but with prior exposure to an ALK-I. Previous treatment with ALK-I other than crizotinib was not allowed in this arm 2 as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously treated with radiation to the brain but with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain and with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants had LC with or without evidence of active lesion at the baseline Gadolinium-enhanced brain magnetic resonance imaging (MRI). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3.
Measure Participants	13	17	5	27	4
Median (Full Range) [months]	1.87	1.87	1.81	1.77	2.73

17. Secondary Outcome

Title	Time to Extracranial Tumor Response (TTER) Per RECIST 1.1 Per BIRC Assessment
Description	TTER was defined as the time from the date of the first dose of ceritinib to the date of the first documented response (CR or PR) outside of the brain as assessed per RECIST 1.1 criteria. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.
Time Frame	43 months

Outcome Measure Data

Analysis Population Description

A subset of FAS (comprised of all patients who received at least one dose of ceritinib) where participants had confirmed CR or PR.

Arm/Group Title	Arm 1 (PrALKi=Y, PrBRad=Y)	Arm 2 (PrALKi=Y, PrBRad=N)	Arm 3 (PrALKi=N, PrBRad=Y)	Arm 4 (PrALKi=N, PrBRad=N)	Arm 5 (LepDis)
Arm/Group Description	Participants with metastases in the brain without evidence of leptomeningeal carcinomatosis (LC), previously treated with radiation to the brain and with prior exposure to an Anaplastic lymphoma kinase inhibitor (ALK-I). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain but with prior exposure to an ALK-I. Previous treatment with ALK-I other than crizotinib was not allowed in this arm 2 as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously treated with radiation to the brain but with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain and with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants had LC with or without evidence of active lesion at the baseline Gadolinium-enhanced brain magnetic resonance imaging (MRI). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3.
Measure Participants	10	6	4	27	4
Median (Full Range) [months]	1.81	1.86	2.66	1.77	1.81

18. Secondary Outcome

Title	Duration of Extracranial Response (DOER) Per RECIST 1.1 Per Investigator Assessment
Description	DOER was defined as the time from the first documented response (PR or CR) outside of the brain to the date of the first documented disease progression outside of the brain or death due to any cause, amongst patients with a confirmed response (PR or CR) outside of the brain per RECIST 1.1. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.
Time Frame	43 months

Outcome Measure Data

Analysis Population Description

A subset of FAS (comprised of all patients who received at least one dose of ceritinib) where participants had confirmed CR or PR.

Arm/Group Title	Arm 1 (PrALKi=Y, PrBRad=Y)	Arm 2 (PrALKi=Y, PrBRad=N)	Arm 3 (PrALKi=N, PrBRad=Y)	Arm 4 (PrALKi=N, PrBRad=N)	Arm 5 (LepDis)
Arm/Group Description	Participants with metastases in the brain without evidence of leptomeningeal carcinomatosis (LC), previously treated with radiation to the brain and with prior exposure to an Anaplastic lymphoma kinase inhibitor (ALK-I). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain but with prior exposure to an ALK-I. Previous treatment with ALK-I other than crizotinib was not allowed in this arm 2 as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously treated with radiation to the brain but with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain and with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants had LC with or without evidence of active lesion at the baseline Gadolinium-enhanced brain magnetic resonance imaging (MRI). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3.
Measure Participants	13	17	5	27	4
Median (95% Confidence Interval) [months]	18.4	19.3	NA	NA	4.6

19. Secondary Outcome

Title	Duration of Extracranial Response (DOER) Per RECIST 1.1 Per BIRC Assessment
Description	DOER was defined as the time from the first documented response (PR or CR) outside of the brain to the date of the first documented disease progression outside of the brain or death due to any cause, amongst patients with a confirmed response (PR or CR) outside of the brain per RECIST 1.1. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.
Time Frame	43 months

Outcome Measure Data

Analysis Population Description

A subset of FAS (comprised of all patients who received at least one dose of ceritinib) where participants had confirmed CR or PR.

Arm/Group Title	Arm 1 (PrALKi=Y, PrBRad=Y)	Arm 2 (PrALKi=Y, PrBRad=N)	Arm 3 (PrALKi=N, PrBRad=Y)	Arm 4 (PrALKi=N, PrBRad=N)	Arm 5 (LepDis)
Arm/Group Description	Participants with metastases in the brain without evidence of leptomeningeal carcinomatosis (LC), previously treated with radiation to the brain and with prior exposure to an Anaplastic lymphoma kinase inhibitor (ALK-I). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain but with prior exposure to an ALK-I. Previous treatment with ALK-I other than crizotinib was not allowed in this arm 2 as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously treated with radiation to the brain but with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain and with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants had LC with or without evidence of active lesion at the baseline Gadolinium-enhanced brain magnetic resonance imaging (MRI). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3.
Measure Participants	11	10	6	27	3
Median (95% Confidence Interval) [months]	NA	6.0	NA	NA	5.5

20. Secondary Outcome

Title	Overall Response Rate (ORR) (Whole Body) Per RECIST 1.1 Per BIRC Assessment
Description	Overall response rate ORR is defined as the percentage of participants with a best overall confirmed response of complete response (CR) or partial response (PR) in the whole body as assessed per RECIST 1.1 by BIRC. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.
Time Frame	43 months

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) comprised of all patients who received at least one dose of ceritinib.

Arm/Group Title	Arm 1 (PrALKi=Y, PrBRad=Y)	Arm 2 (PrALKi=Y, PrBRad=N)	Arm 3 (PrALKi=N, PrBRad=Y)	Arm 4 (PrALKi=N, PrBRad=N)	Arm 5 (LepDis)
Arm/Group Description	Participants with metastases in the brain without evidence of leptomeningeal carcinomatosis (LC), previously treated with radiation to the brain and with prior exposure to an Anaplastic lymphoma kinase inhibitor (ALK-I). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain but with prior exposure to an ALK-I. Previous treatment with ALK-I other than crizotinib was not allowed in this arm 2 as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously treated with radiation to the brain but with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain and with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants had LC with or without evidence of active lesion at the baseline Gadolinium-enhanced brain magnetic resonance imaging (MRI). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3.
Measure Participants	42	40	12	44	18
Number (95% Confidence Interval) [Percentage of participants]	23.8 56.7%	15.0 37.5%	33.3 277.5%	61.4 139.5%	11.1 61.7%

21. Secondary Outcome

Title	Disease Control Rate (DCR) (Whole Body) Per RECIST 1.1 Per BIRC Assessment
Description	DCR: defined as percentage of participants with a best overall response of CR, PR or stable disease (SD) in the whole body, per RECIST 1.1 by BIRC. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed and non-target lesions are not in progression or in complete response. SD: Neither sufficient shrinkage in the target lesion to qualify for PR or CR nor an increase in lesions which would qualify for PD & non-target lesions are not in unequivocal progression.
Time Frame	43 months

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) comprised of all patients who received at least one dose of ceritinib.

Arm/Group Title	Arm 1 (PrALKi=Y, PrBRad=Y)	Arm 2 (PrALKi=Y, PrBRad=N)	Arm 3 (PrALKi=N, PrBRad=Y)	Arm 4 (PrALKi=N, PrBRad=N)	Arm 5 (LepDis)
Arm/Group Description	Participants with metastases in the brain without evidence of leptomeningeal carcinomatosis (LC), previously treated with radiation to the brain and with prior exposure to an Anaplastic lymphoma kinase inhibitor (ALK-I). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain but with prior exposure to an ALK-I. Previous treatment with ALK-I other than crizotinib was not allowed in this arm 2 as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously treated with radiation to the brain but with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain and with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants had LC with or without evidence of active lesion at the baseline Gadolinium-enhanced brain magnetic resonance imaging (MRI). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3.
Measure Participants	42	40	12	44	18
Number (95% Confidence Interval) [Percentage of participants]	61.9 147.4%	80.0 200%	66.7 555.8%	68.2 155%	72.2 401.1%

22. Secondary Outcome

Title	Time to Tumor Response (TTR) (Whole Body) Per RECIST 1.1 Per Investigator Assessment
Description	TTR was defined as the time from the date of the first dose of ceritinib to the date of the first documented response (CR or PR) in the whole body as assessed per RECIST 1.1 criteria per Investigator. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.
Time Frame	43 months

Outcome Measure Data

Analysis Population Description

A subset of FAS (comprised of all patients who received at least one dose of ceritinib) where participants had confirmed CR or PR.

Arm/Group Title	Arm 1 (PrALKi=Y, PrBRad=Y)	Arm 2 (PrALKi=Y, PrBRad=N)	Arm 3 (PrALKi=N, PrBRad=Y)	Arm 4 (PrALKi=N, PrBRad=N)	Arm 5 (LepDis)
Arm/Group Description	Participants with metastases in the brain without evidence of leptomeningeal carcinomatosis (LC), previously treated with radiation to the brain and with prior exposure to an Anaplastic lymphoma kinase inhibitor (ALK-I). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain but with prior exposure to an ALK-I. Previous treatment with ALK-I other than crizotinib was not allowed in this arm 2 as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously treated with radiation to the brain but with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain and with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants had LC with or without evidence of active lesion at the baseline Gadolinium-enhanced brain magnetic resonance imaging (MRI). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3.
Measure Participants	15	12	6	26	3
Median (Full Range) [months]	1.87	2.00	1.82	1.81	1.91

23. Secondary Outcome

Title	Time to Tumor Response (TTR) (Whole Body) Per RECIST 1.1 Per BIRC Assessment
Description	TTR was defined as the time from the date of the first dose of ceritinib to the date of the first documented response (CR or PR) in the whole body as assessed by RECIST 1.1 criteria per BIRC assessment. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.
Time Frame	43 months

Outcome Measure Data

Analysis Population Description

A subset of FAS (comprised of all patients who received at least one dose of ceritinib) where participants had confirmed CR or PR.

Arm/Group Title	Arm 1 (PrALKi=Y, PrBRad=Y)	Arm 2 (PrALKi=Y, PrBRad=N)	Arm 3 (PrALKi=N, PrBRad=Y)	Arm 4 (PrALKi=N, PrBRad=N)	Arm 5 (LepDis)
Arm/Group Description	Participants with metastases in the brain without evidence of leptomeningeal carcinomatosis (LC), previously treated with radiation to the brain and with prior exposure to an Anaplastic lymphoma kinase inhibitor (ALK-I). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain but with prior exposure to an ALK-I. Previous treatment with ALK-I other than crizotinib was not allowed in this arm 2 as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously treated with radiation to the brain but with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain and with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants had LC with or without evidence of active lesion at the baseline Gadolinium-enhanced brain magnetic resonance imaging (MRI). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3.
Measure Participants	10	6	4	27	2
Median (Full Range) [months]	2.00	1.76	1.82	1.81	1.86

24. Secondary Outcome

Title	Duration of Response (DOR) (Whole Body) Per RECIST 1.1 Per Investigator Assessment
Description	DOR was defined as the time from the first documented response (PR or CR) to the date of the first documented disease progression or death due to any cause, amongst patients with a confirmed response (PR or CR) in the whole body per RECIST 1.1 per Investigator. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.
Time Frame	43 months

Outcome Measure Data

Analysis Population Description

A subset of FAS (comprised of all patients who received at least one dose of ceritinib) where participants had confirmed CR or PR.

Arm/Group Title	Arm 1 (PrALKi=Y, PrBRad=Y)	Arm 2 (PrALKi=Y, PrBRad=N)	Arm 3 (PrALKi=N, PrBRad=Y)	Arm 4 (PrALKi=N, PrBRad=N)	Arm 5 (LepDis)
Arm/Group Description	Participants with metastases in the brain without evidence of leptomeningeal carcinomatosis (LC), previously treated with radiation to the brain and with prior exposure to an Anaplastic lymphoma kinase inhibitor (ALK-I). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain but with prior exposure to an ALK-I. Previous treatment with ALK-I other than crizotinib was not allowed in this arm 2 as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously treated with radiation to the brain but with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain and with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants had LC with or without evidence of active lesion at the baseline Gadolinium-enhanced brain magnetic resonance imaging (MRI). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3.
Measure Participants	15	12	6	26	3
Median (95% Confidence Interval) [months]	10.8	12.8	NA	9.2	5.5

25. Secondary Outcome

Title	Duration of Response (DOR) (Whole Body) Per RECIST 1.1 Per BIRC Assessment
Description	DOR was defined as the time from the first documented response (PR or CR) to the date of the first documented disease progression or death due to any cause, amongst patients with a confirmed response (PR or CR) in the whole body per RECIST 1.1 per BIRC. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.
Time Frame	43 months

Outcome Measure Data

Analysis Population Description

A subset of FAS (comprised of all patients who received at least one dose of ceritinib) where participants had confirmed CR or PR.

Arm/Group Title	Arm 1 (PrALKi=Y, PrBRad=Y)	Arm 2 (PrALKi=Y, PrBRad=N)	Arm 3 (PrALKi=N, PrBRad=Y)	Arm 4 (PrALKi=N, PrBRad=N)	Arm 5 (LepDis)
Arm/Group Description	Participants with metastases in the brain without evidence of leptomeningeal carcinomatosis (LC), previously treated with radiation to the brain and with prior exposure to an Anaplastic lymphoma kinase inhibitor (ALK-I). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain but with prior exposure to an ALK-I. Previous treatment with ALK-I other than crizotinib was not allowed in this arm 2 as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously treated with radiation to the brain but with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain and with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants had LC with or without evidence of active lesion at the baseline Gadolinium-enhanced brain magnetic resonance imaging (MRI). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3.
Measure Participants	10	6	4	27	2
Median (95% Confidence Interval) [months]	11.0	10.6	NA	9.2	5.7

26. Secondary Outcome

Title	Progression Free Survival (PFS) (Whole Body) Per RECIST 1.1 Per Investigator & BIRC Assessment
Description	PFS was defined as the time from the date of the first dose of ceritinib to the date of the first radiologically documented disease progression in the whole body per RECIST 1.1 or death due to any cause. A patient who had not progressed or died at the date of the analysis was censored at the time of the last adequate tumor evaluation on or before the cut-off date.
Time Frame	43 months

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) comprised of all patients who received at least one dose of ceritinib

Arm/Group Title	Arm 1 (PrALKi=Y, PrBRad=Y)	Arm 2 (PrALKi=Y, PrBRad=N)	Arm 3 (PrALKi=N, PrBRad=Y)	Arm 4 (PrALKi=N, PrBRad=N)	Arm 5 (LepDis)
Arm/Group Description	Participants with metastases in the brain without evidence of leptomeningeal carcinomatosis (LC), previously treated with radiation to the brain and with prior exposure to an Anaplastic lymphoma kinase inhibitor (ALK-I). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain but with prior exposure to an ALK-I. Previous treatment with ALK-I other than crizotinib was not allowed in this arm 2 as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously treated with radiation to the brain but with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain and with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants had LC with or without evidence of active lesion at the baseline Gadolinium-enhanced brain magnetic resonance imaging (MRI). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3.
Measure Participants	42	40	12	44	18
PFS per Investigator assessment	7.2	5.6	NA	7.9	5.2
PFS per BIRC assessment	5.0	5.5	15.5	7.7	3.6

27. Secondary Outcome

Title	Overall Survival (OS)
Description	OS was defined as time from the date of first dose of ceritinib to the date of death due to any cause. The OS time for patients who were alive at the end of the study or were lost to follow-up was censored at the date of last contact.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) comprised of all patients who received at least one dose of ceritinib

Arm/Group Title	Arm 1 (PrALKi=Y, PrBRad=Y)	Arm 2 (PrALKi=Y, PrBRad=N)	Arm 3 (PrALKi=N, PrBRad=Y)	Arm 4 (PrALKi=N, PrBRad=N)	Arm 5 (LepDis)
Arm/Group Description	Participants with metastases in the brain without evidence of leptomeningeal carcinomatosis (LC), previously treated with radiation to the brain and with prior exposure to an Anaplastic lymphoma kinase inhibitor (ALK-I). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain but with prior exposure to an ALK-I. Previous treatment with ALK-I other than crizotinib was not allowed in this arm 2 as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously treated with radiation to the brain but with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain and with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).	Participants had LC with or without evidence of active lesion at the baseline Gadolinium-enhanced brain magnetic resonance imaging (MRI). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3.
Measure Participants	42	40	12	44	18
Median (95% Confidence Interval) [months]	24.0	NA	NA	NA	7.2

28. Secondary Outcome

Title	Pharmacokinetics (PK) of Ceritinib in Study Population: Cmax & Cmin (Trough)
Description	Cmax is the maximum (peak) concentration of drug in plasma. Cmin is the minimum (trough) concentration of drug in plasma. Sparse blood samples for ceritinib PK evaluation in plasma were collected on C1D1 up to C6D1 from all patients who received at least one dose of investigational study treatment.
Time Frame	Cmax: Cycle 2 Day 1 (C2D1); Cmin: C1D1, C1D8, C1D15, C2D1, C3D1, C4D1, C5D1, C6D1 - all 0hr (pre dose)

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic Analysis Set (PAS) comprised of all the patients who received at least one (full or partial) dose of ceritinib and provided at least one evaluable PK blood sample.

Arm/Group Title	Ceritinib 750mg
Arm/Group Description	Participants all received a dose of 750 mg orally in fasted state
Measure Participants	145
Cmin C1D1: 0hr. (pre dose)	0 (0.0)
Cmin C1D8: 0hr. (pre dose)	658 (59.2)
Cmin C1D15: 0hr. (pre dose)	846 (52.9)
Cmin C2D1: 0hr. (pre dose)	1000 (50.0)
Cmax C2D1: 4 - 10 hrs. (post dose)	1100 (47.8)
Cmin C3D1: 0hr. (pre dose)	982 (59.1)
Cmin C4D1: 0hr. (pre dose)	978 (75.4)
Cmin C5D1: 0hr. (pre dose)	885 (75.5)
Cmin C6D1: 0hr. (pre dose)	785 (120.4)

Adverse Events

Time Frame	Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 168 weeks.
Adverse Event Reporting Description	Adverse Event (AE): Any sign or symptom that occurs during the study treatment plus 30 days post treatment.
Arm/Group Title	Arm 1 (PrALKi=Y, PrBRad=Y)		Arm 2 (PrALKi=Y, PrBRad=N)		Arm 3 (PrALKi=N, PrBRad=Y)		Arm 4 (PrALKi=N, PrBRad=N)		Arm 5 (LepDis)		All Participants
Arm/Group Description	Participants with metastases in the brain without evidence of leptomeningeal carcinomatosis (LC), previously treated with radiation to the brain and with prior exposure to an Anaplastic lymphoma kinase inhibitor (ALK-I). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).		Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain but with prior exposure to an ALK-I. Previous treatment with ALK-I other than crizotinib was not allowed in this arm 2 as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).		Participants with metastases in the brain without evidence of LC, previously treated with radiation to the brain but with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).		Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain and with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation		Participants had LC with or without evidence of active lesion at the baseline Gadolinium-enhanced brain magnetic resonance imaging (MRI). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3.		All participants who participated in the study and received at least one (full or partial) dose of ceritinib and provided at least one evaluable PK blood sample
All Cause Mortality
	Arm 1 (PrALKi=Y, PrBRad=Y)		Arm 2 (PrALKi=Y, PrBRad=N)		Arm 3 (PrALKi=N, PrBRad=Y)		Arm 4 (PrALKi=N, PrBRad=N)		Arm 5 (LepDis)		All Participants
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/42 (19%)		5/40 (12.5%)		3/12 (25%)		6/44 (13.6%)		9/18 (50%)		31/156 (19.9%)
Serious Adverse Events
	Arm 1 (PrALKi=Y, PrBRad=Y)		Arm 2 (PrALKi=Y, PrBRad=N)		Arm 3 (PrALKi=N, PrBRad=Y)		Arm 4 (PrALKi=N, PrBRad=N)		Arm 5 (LepDis)		All Participants
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	28/42 (66.7%)		17/40 (42.5%)		4/12 (33.3%)		15/44 (34.1%)		11/18 (61.1%)		75/156 (48.1%)
Blood and lymphatic system disorders
Lymphadenopathy	0/42 (0%)		0/40 (0%)		0/12 (0%)		1/44 (2.3%)		0/18 (0%)		1/156 (0.6%)
Cardiac disorders
Atrial fibrillation	1/42 (2.4%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		0/18 (0%)		1/156 (0.6%)
Left ventricular dysfunction	0/42 (0%)		1/40 (2.5%)		0/12 (0%)		0/44 (0%)		0/18 (0%)		1/156 (0.6%)
Pericardial effusion	2/42 (4.8%)		0/40 (0%)		0/12 (0%)		1/44 (2.3%)		0/18 (0%)		3/156 (1.9%)
Pericarditis	2/42 (4.8%)		2/40 (5%)		0/12 (0%)		0/44 (0%)		0/18 (0%)		4/156 (2.6%)
Tachycardia	2/42 (4.8%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		0/18 (0%)		2/156 (1.3%)
Eye disorders
Keratitis	0/42 (0%)		1/40 (2.5%)		0/12 (0%)		0/44 (0%)		0/18 (0%)		1/156 (0.6%)
Gastrointestinal disorders
Abdominal pain	0/42 (0%)		0/40 (0%)		0/12 (0%)		1/44 (2.3%)		0/18 (0%)		1/156 (0.6%)
Nausea	0/42 (0%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		1/156 (0.6%)
Oesophagopleural fistula	1/42 (2.4%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		0/18 (0%)		1/156 (0.6%)
Salivary hypersecretion	1/42 (2.4%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		0/18 (0%)		1/156 (0.6%)
Small intestinal obstruction	0/42 (0%)		0/40 (0%)		0/12 (0%)		1/44 (2.3%)		0/18 (0%)		1/156 (0.6%)
Subileus	0/42 (0%)		1/40 (2.5%)		0/12 (0%)		0/44 (0%)		0/18 (0%)		1/156 (0.6%)
Upper gastrointestinal haemorrhage	1/42 (2.4%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		0/18 (0%)		1/156 (0.6%)
Vomiting	0/42 (0%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		1/156 (0.6%)
General disorders
Adverse drug reaction	0/42 (0%)		0/40 (0%)		0/12 (0%)		1/44 (2.3%)		0/18 (0%)		1/156 (0.6%)
Disease progression	0/42 (0%)		1/40 (2.5%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		2/156 (1.3%)
General physical health deterioration	0/42 (0%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		1/156 (0.6%)
Hyperthermia	0/42 (0%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		1/156 (0.6%)
Non-cardiac chest pain	0/42 (0%)		1/40 (2.5%)		0/12 (0%)		1/44 (2.3%)		0/18 (0%)		2/156 (1.3%)
Pyrexia	1/42 (2.4%)		1/40 (2.5%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		3/156 (1.9%)
Sudden death	1/42 (2.4%)		0/40 (0%)		0/12 (0%)		1/44 (2.3%)		0/18 (0%)		2/156 (1.3%)
Hepatobiliary disorders
Hepatitis	0/42 (0%)		0/40 (0%)		0/12 (0%)		1/44 (2.3%)		0/18 (0%)		1/156 (0.6%)
Infections and infestations
Colonic abscess	0/42 (0%)		0/40 (0%)		0/12 (0%)		1/44 (2.3%)		0/18 (0%)		1/156 (0.6%)
Herpes zoster	1/42 (2.4%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		0/18 (0%)		1/156 (0.6%)
Lower respiratory tract infection	0/42 (0%)		1/40 (2.5%)		0/12 (0%)		0/44 (0%)		0/18 (0%)		1/156 (0.6%)
Lung infection	0/42 (0%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		1/156 (0.6%)
Lung infection pseudomonal	1/42 (2.4%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		0/18 (0%)		1/156 (0.6%)
Nocardia sepsis	0/42 (0%)		0/40 (0%)		0/12 (0%)		1/44 (2.3%)		0/18 (0%)		1/156 (0.6%)
Pneumonia	4/42 (9.5%)		4/40 (10%)		1/12 (8.3%)		1/44 (2.3%)		2/18 (11.1%)		12/156 (7.7%)
Respiratory tract infection	0/42 (0%)		1/40 (2.5%)		0/12 (0%)		0/44 (0%)		0/18 (0%)		1/156 (0.6%)
Septic shock	1/42 (2.4%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		0/18 (0%)		1/156 (0.6%)
Staphylococcal bacteraemia	1/42 (2.4%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		0/18 (0%)		1/156 (0.6%)
Staphylococcal infection	0/42 (0%)		0/40 (0%)		1/12 (8.3%)		0/44 (0%)		0/18 (0%)		1/156 (0.6%)
Urinary tract infection	0/42 (0%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		1/156 (0.6%)
Injury, poisoning and procedural complications
Post procedural complication	0/42 (0%)		0/40 (0%)		0/12 (0%)		1/44 (2.3%)		0/18 (0%)		1/156 (0.6%)
Investigations
Blood creatinine increased	0/42 (0%)		0/40 (0%)		1/12 (8.3%)		0/44 (0%)		0/18 (0%)		1/156 (0.6%)
General physical condition abnormal	0/42 (0%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		1/156 (0.6%)
Hepatic enzyme increased	0/42 (0%)		0/40 (0%)		0/12 (0%)		1/44 (2.3%)		0/18 (0%)		1/156 (0.6%)
Inflammatory marker increased	0/42 (0%)		1/40 (2.5%)		0/12 (0%)		0/44 (0%)		0/18 (0%)		1/156 (0.6%)
Platelet count decreased	1/42 (2.4%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		0/18 (0%)		1/156 (0.6%)
Metabolism and nutrition disorders
Dehydration	0/42 (0%)		0/40 (0%)		0/12 (0%)		1/44 (2.3%)		0/18 (0%)		1/156 (0.6%)
Hyperglycaemia	2/42 (4.8%)		0/40 (0%)		1/12 (8.3%)		3/44 (6.8%)		1/18 (5.6%)		7/156 (4.5%)
Hyponatraemia	0/42 (0%)		0/40 (0%)		1/12 (8.3%)		1/44 (2.3%)		0/18 (0%)		2/156 (1.3%)
Musculoskeletal and connective tissue disorders
Bone pain	0/42 (0%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		1/156 (0.6%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm progression	0/42 (0%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		1/156 (0.6%)
Nervous system disorders
Aphasia	0/42 (0%)		0/40 (0%)		0/12 (0%)		1/44 (2.3%)		1/18 (5.6%)		2/156 (1.3%)
Ataxia	0/42 (0%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		1/156 (0.6%)
Cerebral haemorrhage	0/42 (0%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		1/156 (0.6%)
Dizziness	0/42 (0%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		1/156 (0.6%)
Dysarthria	0/42 (0%)		1/40 (2.5%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		2/156 (1.3%)
Dysmetria	0/42 (0%)		0/40 (0%)		0/12 (0%)		1/44 (2.3%)		0/18 (0%)		1/156 (0.6%)
Epilepsy	1/42 (2.4%)		1/40 (2.5%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		3/156 (1.9%)
Extrapyramidal disorder	0/42 (0%)		0/40 (0%)		0/12 (0%)		1/44 (2.3%)		0/18 (0%)		1/156 (0.6%)
Haemorrhage intracranial	1/42 (2.4%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		0/18 (0%)		1/156 (0.6%)
Headache	0/42 (0%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		1/156 (0.6%)
Hemiparesis	1/42 (2.4%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		0/18 (0%)		1/156 (0.6%)
Loss of consciousness	1/42 (2.4%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		0/18 (0%)		1/156 (0.6%)
Memory impairment	0/42 (0%)		1/40 (2.5%)		0/12 (0%)		0/44 (0%)		0/18 (0%)		1/156 (0.6%)
Partial seizures	1/42 (2.4%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		0/18 (0%)		1/156 (0.6%)
Seizure	3/42 (7.1%)		0/40 (0%)		0/12 (0%)		2/44 (4.5%)		1/18 (5.6%)		6/156 (3.8%)
Spinal cord compression	1/42 (2.4%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		0/18 (0%)		1/156 (0.6%)
Psychiatric disorders
Bradyphrenia	0/42 (0%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		1/156 (0.6%)
Confusional state	0/42 (0%)		0/40 (0%)		0/12 (0%)		1/44 (2.3%)		1/18 (5.6%)		2/156 (1.3%)
Delirium	0/42 (0%)		0/40 (0%)		0/12 (0%)		1/44 (2.3%)		0/18 (0%)		1/156 (0.6%)
Renal and urinary disorders
Acute kidney injury	0/42 (0%)		0/40 (0%)		1/12 (8.3%)		0/44 (0%)		0/18 (0%)		1/156 (0.6%)
Nephrolithiasis	1/42 (2.4%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		0/18 (0%)		1/156 (0.6%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	1/42 (2.4%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		0/18 (0%)		1/156 (0.6%)
Dyspnoea	1/42 (2.4%)		1/40 (2.5%)		0/12 (0%)		1/44 (2.3%)		0/18 (0%)		3/156 (1.9%)
Interstitial lung disease	1/42 (2.4%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		0/18 (0%)		1/156 (0.6%)
Lung disorder	0/42 (0%)		0/40 (0%)		0/12 (0%)		1/44 (2.3%)		0/18 (0%)		1/156 (0.6%)
Pleural effusion	0/42 (0%)		1/40 (2.5%)		0/12 (0%)		1/44 (2.3%)		0/18 (0%)		2/156 (1.3%)
Pneumonia aspiration	0/42 (0%)		0/40 (0%)		1/12 (8.3%)		0/44 (0%)		0/18 (0%)		1/156 (0.6%)
Pneumothorax	1/42 (2.4%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		0/18 (0%)		1/156 (0.6%)
Pulmonary embolism	1/42 (2.4%)		0/40 (0%)		1/12 (8.3%)		0/44 (0%)		0/18 (0%)		2/156 (1.3%)
Respiratory failure	2/42 (4.8%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		0/18 (0%)		2/156 (1.3%)
Skin and subcutaneous tissue disorders
Vascular purpura	1/42 (2.4%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		0/18 (0%)		1/156 (0.6%)
Vascular disorders
Aortic aneurysm rupture	0/42 (0%)		0/40 (0%)		0/12 (0%)		1/44 (2.3%)		0/18 (0%)		1/156 (0.6%)
Embolism	0/42 (0%)		1/40 (2.5%)		0/12 (0%)		0/44 (0%)		0/18 (0%)		1/156 (0.6%)
Peripheral ischaemia	0/42 (0%)		0/40 (0%)		0/12 (0%)		1/44 (2.3%)		0/18 (0%)		1/156 (0.6%)
Thrombosis	0/42 (0%)		0/40 (0%)		0/12 (0%)		1/44 (2.3%)		0/18 (0%)		1/156 (0.6%)
Other (Not Including Serious) Adverse Events
	Arm 1 (PrALKi=Y, PrBRad=Y)		Arm 2 (PrALKi=Y, PrBRad=N)		Arm 3 (PrALKi=N, PrBRad=Y)		Arm 4 (PrALKi=N, PrBRad=N)		Arm 5 (LepDis)		All Participants
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	42/42 (100%)		40/40 (100%)		11/12 (91.7%)		43/44 (97.7%)		18/18 (100%)		154/156 (98.7%)
Blood and lymphatic system disorders
Anaemia	8/42 (19%)		6/40 (15%)		0/12 (0%)		5/44 (11.4%)		3/18 (16.7%)		22/156 (14.1%)
Neutropenia	1/42 (2.4%)		1/40 (2.5%)		1/12 (8.3%)		2/44 (4.5%)		2/18 (11.1%)		7/156 (4.5%)
Thrombocytopenia	0/42 (0%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		1/156 (0.6%)
Cardiac disorders
Bradycardia	0/42 (0%)		1/40 (2.5%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		2/156 (1.3%)
Palpitations	1/42 (2.4%)		3/40 (7.5%)		0/12 (0%)		0/44 (0%)		0/18 (0%)		4/156 (2.6%)
Sinus bradycardia	3/42 (7.1%)		1/40 (2.5%)		0/12 (0%)		0/44 (0%)		0/18 (0%)		4/156 (2.6%)
Ear and labyrinth disorders
Vertigo	4/42 (9.5%)		0/40 (0%)		1/12 (8.3%)		2/44 (4.5%)		0/18 (0%)		7/156 (4.5%)
Endocrine disorders
Cushingoid	0/42 (0%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		1/156 (0.6%)
Eye disorders
Vitreous detachment	0/42 (0%)		0/40 (0%)		1/12 (8.3%)		0/44 (0%)		0/18 (0%)		1/156 (0.6%)
Gastrointestinal disorders
Abdominal discomfort	5/42 (11.9%)		4/40 (10%)		1/12 (8.3%)		1/44 (2.3%)		0/18 (0%)		11/156 (7.1%)
Abdominal pain	7/42 (16.7%)		12/40 (30%)		4/12 (33.3%)		6/44 (13.6%)		4/18 (22.2%)		33/156 (21.2%)
Abdominal pain upper	6/42 (14.3%)		6/40 (15%)		1/12 (8.3%)		10/44 (22.7%)		2/18 (11.1%)		25/156 (16%)
Bowel movement irregularity	0/42 (0%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		1/156 (0.6%)
Constipation	10/42 (23.8%)		9/40 (22.5%)		2/12 (16.7%)		7/44 (15.9%)		4/18 (22.2%)		32/156 (20.5%)
Diarrhoea	27/42 (64.3%)		34/40 (85%)		8/12 (66.7%)		32/44 (72.7%)		6/18 (33.3%)		107/156 (68.6%)
Dyspepsia	7/42 (16.7%)		6/40 (15%)		1/12 (8.3%)		2/44 (4.5%)		0/18 (0%)		16/156 (10.3%)
Dysphagia	3/42 (7.1%)		1/40 (2.5%)		1/12 (8.3%)		0/44 (0%)		0/18 (0%)		5/156 (3.2%)
Epigastric discomfort	2/42 (4.8%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		3/156 (1.9%)
Faecaloma	0/42 (0%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		1/156 (0.6%)
Ileus	0/42 (0%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		1/156 (0.6%)
Mouth ulceration	3/42 (7.1%)		0/40 (0%)		1/12 (8.3%)		1/44 (2.3%)		0/18 (0%)		5/156 (3.2%)
Nausea	23/42 (54.8%)		29/40 (72.5%)		8/12 (66.7%)		19/44 (43.2%)		8/18 (44.4%)		87/156 (55.8%)
Stomatitis	3/42 (7.1%)		2/40 (5%)		0/12 (0%)		1/44 (2.3%)		0/18 (0%)		6/156 (3.8%)
Vomiting	22/42 (52.4%)		24/40 (60%)		4/12 (33.3%)		13/44 (29.5%)		9/18 (50%)		72/156 (46.2%)
General disorders
Asthenia	11/42 (26.2%)		9/40 (22.5%)		4/12 (33.3%)		9/44 (20.5%)		5/18 (27.8%)		38/156 (24.4%)
Fatigue	13/42 (31%)		14/40 (35%)		3/12 (25%)		9/44 (20.5%)		3/18 (16.7%)		42/156 (26.9%)
Feeling cold	0/42 (0%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		1/156 (0.6%)
Gait disturbance	4/42 (9.5%)		0/40 (0%)		0/12 (0%)		1/44 (2.3%)		1/18 (5.6%)		6/156 (3.8%)
General physical health deterioration	0/42 (0%)		1/40 (2.5%)		1/12 (8.3%)		1/44 (2.3%)		0/18 (0%)		3/156 (1.9%)
Hyperthermia	1/42 (2.4%)		0/40 (0%)		1/12 (8.3%)		0/44 (0%)		0/18 (0%)		2/156 (1.3%)
Influenza like illness	2/42 (4.8%)		0/40 (0%)		0/12 (0%)		3/44 (6.8%)		0/18 (0%)		5/156 (3.2%)
Malaise	0/42 (0%)		3/40 (7.5%)		1/12 (8.3%)		0/44 (0%)		1/18 (5.6%)		5/156 (3.2%)
Non-cardiac chest pain	9/42 (21.4%)		7/40 (17.5%)		1/12 (8.3%)		3/44 (6.8%)		0/18 (0%)		20/156 (12.8%)
Oedema peripheral	8/42 (19%)		6/40 (15%)		1/12 (8.3%)		2/44 (4.5%)		2/18 (11.1%)		19/156 (12.2%)
Pain	1/42 (2.4%)		0/40 (0%)		0/12 (0%)		1/44 (2.3%)		2/18 (11.1%)		4/156 (2.6%)
Pyrexia	6/42 (14.3%)		14/40 (35%)		0/12 (0%)		3/44 (6.8%)		1/18 (5.6%)		24/156 (15.4%)
Infections and infestations
Influenza	1/42 (2.4%)		2/40 (5%)		1/12 (8.3%)		2/44 (4.5%)		0/18 (0%)		6/156 (3.8%)
Mucosal infection	2/42 (4.8%)		1/40 (2.5%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		4/156 (2.6%)
Nasopharyngitis	0/42 (0%)		2/40 (5%)		1/12 (8.3%)		3/44 (6.8%)		0/18 (0%)		6/156 (3.8%)
Oral candidiasis	2/42 (4.8%)		3/40 (7.5%)		0/12 (0%)		1/44 (2.3%)		1/18 (5.6%)		7/156 (4.5%)
Pneumonia	1/42 (2.4%)		1/40 (2.5%)		1/12 (8.3%)		0/44 (0%)		2/18 (11.1%)		5/156 (3.2%)
Respiratory tract infection	0/42 (0%)		1/40 (2.5%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		2/156 (1.3%)
Tuberculosis	0/42 (0%)		0/40 (0%)		1/12 (8.3%)		0/44 (0%)		0/18 (0%)		1/156 (0.6%)
Upper respiratory tract infection	3/42 (7.1%)		2/40 (5%)		2/12 (16.7%)		4/44 (9.1%)		0/18 (0%)		11/156 (7.1%)
Urinary tract infection	3/42 (7.1%)		4/40 (10%)		0/12 (0%)		2/44 (4.5%)		2/18 (11.1%)		11/156 (7.1%)
Vulvovaginal candidiasis	0/42 (0%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		1/156 (0.6%)
Injury, poisoning and procedural complications
Procedural dizziness	0/42 (0%)		0/40 (0%)		1/12 (8.3%)		0/44 (0%)		0/18 (0%)		1/156 (0.6%)
Subcutaneous haematoma	0/42 (0%)		0/40 (0%)		1/12 (8.3%)		0/44 (0%)		0/18 (0%)		1/156 (0.6%)
Investigations
Alanine aminotransferase increased	18/42 (42.9%)		24/40 (60%)		3/12 (25%)		23/44 (52.3%)		6/18 (33.3%)		74/156 (47.4%)
Amylase increased	2/42 (4.8%)		2/40 (5%)		1/12 (8.3%)		3/44 (6.8%)		1/18 (5.6%)		9/156 (5.8%)
Aspartate aminotransferase increased	18/42 (42.9%)		19/40 (47.5%)		2/12 (16.7%)		13/44 (29.5%)		4/18 (22.2%)		56/156 (35.9%)
Bilirubin conjugated increased	0/42 (0%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		1/156 (0.6%)
Blood alkaline phosphatase increased	3/42 (7.1%)		8/40 (20%)		1/12 (8.3%)		6/44 (13.6%)		2/18 (11.1%)		20/156 (12.8%)
Blood bilirubin increased	0/42 (0%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		1/156 (0.6%)
Blood creatinine increased	4/42 (9.5%)		4/40 (10%)		2/12 (16.7%)		10/44 (22.7%)		2/18 (11.1%)		22/156 (14.1%)
Blood lactate dehydrogenase increased	0/42 (0%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		1/156 (0.6%)
Blood phosphorus decreased	0/42 (0%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		1/156 (0.6%)
Cardiac murmur	0/42 (0%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		1/156 (0.6%)
Electrocardiogram QT prolonged	6/42 (14.3%)		1/40 (2.5%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		8/156 (5.1%)
Gamma-glutamyltransferase increased	8/42 (19%)		13/40 (32.5%)		2/12 (16.7%)		9/44 (20.5%)		3/18 (16.7%)		35/156 (22.4%)
Lipase increased	3/42 (7.1%)		0/40 (0%)		0/12 (0%)		8/44 (18.2%)		2/18 (11.1%)		13/156 (8.3%)
Neutrophil count decreased	0/42 (0%)		0/40 (0%)		1/12 (8.3%)		1/44 (2.3%)		0/18 (0%)		2/156 (1.3%)
Weight decreased	6/42 (14.3%)		8/40 (20%)		4/12 (33.3%)		2/44 (4.5%)		3/18 (16.7%)		23/156 (14.7%)
Weight increased	0/42 (0%)		2/40 (5%)		0/12 (0%)		1/44 (2.3%)		1/18 (5.6%)		4/156 (2.6%)
Metabolism and nutrition disorders
Decreased appetite	21/42 (50%)		14/40 (35%)		3/12 (25%)		6/44 (13.6%)		6/18 (33.3%)		50/156 (32.1%)
Hypercalcaemia	0/42 (0%)		0/40 (0%)		1/12 (8.3%)		0/44 (0%)		0/18 (0%)		1/156 (0.6%)
Hyperglycaemia	4/42 (9.5%)		2/40 (5%)		1/12 (8.3%)		5/44 (11.4%)		4/18 (22.2%)		16/156 (10.3%)
Hypoalbuminaemia	2/42 (4.8%)		2/40 (5%)		1/12 (8.3%)		2/44 (4.5%)		1/18 (5.6%)		8/156 (5.1%)
Hypocalcaemia	1/42 (2.4%)		0/40 (0%)		0/12 (0%)		2/44 (4.5%)		1/18 (5.6%)		4/156 (2.6%)
Hypokalaemia	8/42 (19%)		1/40 (2.5%)		0/12 (0%)		1/44 (2.3%)		4/18 (22.2%)		14/156 (9%)
Hypomagnesaemia	0/42 (0%)		1/40 (2.5%)		1/12 (8.3%)		0/44 (0%)		1/18 (5.6%)		3/156 (1.9%)
Hypophagia	1/42 (2.4%)		0/40 (0%)		1/12 (8.3%)		0/44 (0%)		1/18 (5.6%)		3/156 (1.9%)
Hypophosphataemia	4/42 (9.5%)		1/40 (2.5%)		0/12 (0%)		1/44 (2.3%)		1/18 (5.6%)		7/156 (4.5%)
Musculoskeletal and connective tissue disorders
Arthralgia	5/42 (11.9%)		5/40 (12.5%)		2/12 (16.7%)		3/44 (6.8%)		0/18 (0%)		15/156 (9.6%)
Back pain	9/42 (21.4%)		8/40 (20%)		1/12 (8.3%)		1/44 (2.3%)		0/18 (0%)		19/156 (12.2%)
Coccydynia	0/42 (0%)		1/40 (2.5%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		2/156 (1.3%)
Flank pain	0/42 (0%)		1/40 (2.5%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		2/156 (1.3%)
Joint swelling	0/42 (0%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		1/156 (0.6%)
Muscle hypertrophy	0/42 (0%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		1/156 (0.6%)
Muscle spasms	3/42 (7.1%)		5/40 (12.5%)		0/12 (0%)		4/44 (9.1%)		0/18 (0%)		12/156 (7.7%)
Muscular weakness	4/42 (9.5%)		3/40 (7.5%)		0/12 (0%)		0/44 (0%)		3/18 (16.7%)		10/156 (6.4%)
Musculoskeletal chest pain	3/42 (7.1%)		1/40 (2.5%)		0/12 (0%)		2/44 (4.5%)		1/18 (5.6%)		7/156 (4.5%)
Musculoskeletal discomfort	0/42 (0%)		0/40 (0%)		1/12 (8.3%)		0/44 (0%)		0/18 (0%)		1/156 (0.6%)
Musculoskeletal pain	6/42 (14.3%)		1/40 (2.5%)		1/12 (8.3%)		2/44 (4.5%)		1/18 (5.6%)		11/156 (7.1%)
Myalgia	0/42 (0%)		2/40 (5%)		1/12 (8.3%)		2/44 (4.5%)		0/18 (0%)		5/156 (3.2%)
Myopathy	0/42 (0%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		1/156 (0.6%)
Neck pain	0/42 (0%)		1/40 (2.5%)		1/12 (8.3%)		1/44 (2.3%)		0/18 (0%)		3/156 (1.9%)
Pain in extremity	2/42 (4.8%)		2/40 (5%)		1/12 (8.3%)		1/44 (2.3%)		1/18 (5.6%)		7/156 (4.5%)
Nervous system disorders
Amnesia	0/42 (0%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		2/18 (11.1%)		2/156 (1.3%)
Aphasia	0/42 (0%)		0/40 (0%)		0/12 (0%)		1/44 (2.3%)		1/18 (5.6%)		2/156 (1.3%)
Balance disorder	0/42 (0%)		0/40 (0%)		1/12 (8.3%)		1/44 (2.3%)		0/18 (0%)		2/156 (1.3%)
Dizziness	6/42 (14.3%)		8/40 (20%)		1/12 (8.3%)		4/44 (9.1%)		3/18 (16.7%)		22/156 (14.1%)
Dysarthria	1/42 (2.4%)		3/40 (7.5%)		1/12 (8.3%)		1/44 (2.3%)		3/18 (16.7%)		9/156 (5.8%)
Dysgeusia	0/42 (0%)		0/40 (0%)		0/12 (0%)		5/44 (11.4%)		1/18 (5.6%)		6/156 (3.8%)
Headache	12/42 (28.6%)		13/40 (32.5%)		3/12 (25%)		10/44 (22.7%)		4/18 (22.2%)		42/156 (26.9%)
Memory impairment	4/42 (9.5%)		1/40 (2.5%)		0/12 (0%)		1/44 (2.3%)		1/18 (5.6%)		7/156 (4.5%)
Paraesthesia	4/42 (9.5%)		1/40 (2.5%)		0/12 (0%)		3/44 (6.8%)		1/18 (5.6%)		9/156 (5.8%)
Partial seizures	0/42 (0%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		1/156 (0.6%)
Seizure	2/42 (4.8%)		4/40 (10%)		0/12 (0%)		2/44 (4.5%)		3/18 (16.7%)		11/156 (7.1%)
Somnolence	1/42 (2.4%)		1/40 (2.5%)		0/12 (0%)		1/44 (2.3%)		2/18 (11.1%)		5/156 (3.2%)
Tremor	1/42 (2.4%)		3/40 (7.5%)		0/12 (0%)		1/44 (2.3%)		0/18 (0%)		5/156 (3.2%)
Psychiatric disorders
Aggression	0/42 (0%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		1/156 (0.6%)
Agitation	3/42 (7.1%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		4/156 (2.6%)
Anxiety	1/42 (2.4%)		1/40 (2.5%)		1/12 (8.3%)		1/44 (2.3%)		0/18 (0%)		4/156 (2.6%)
Bradyphrenia	0/42 (0%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		1/156 (0.6%)
Depression	3/42 (7.1%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		0/18 (0%)		3/156 (1.9%)
Disorientation	0/42 (0%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		1/156 (0.6%)
Hallucination, auditory	0/42 (0%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		1/156 (0.6%)
Hallucinations, mixed	0/42 (0%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		1/156 (0.6%)
Insomnia	3/42 (7.1%)		4/40 (10%)		1/12 (8.3%)		4/44 (9.1%)		1/18 (5.6%)		13/156 (8.3%)
Renal and urinary disorders
Acute kidney injury	0/42 (0%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		1/156 (0.6%)
Proteinuria	0/42 (0%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		1/156 (0.6%)
Urinary incontinence	1/42 (2.4%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		2/156 (1.3%)
Reproductive system and breast disorders
Pelvic pain	0/42 (0%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		1/156 (0.6%)
Respiratory, thoracic and mediastinal disorders
Cough	10/42 (23.8%)		8/40 (20%)		1/12 (8.3%)		6/44 (13.6%)		4/18 (22.2%)		29/156 (18.6%)
Dyspnoea	4/42 (9.5%)		8/40 (20%)		2/12 (16.7%)		5/44 (11.4%)		2/18 (11.1%)		21/156 (13.5%)
Dyspnoea exertional	1/42 (2.4%)		1/40 (2.5%)		1/12 (8.3%)		1/44 (2.3%)		0/18 (0%)		4/156 (2.6%)
Haemoptysis	3/42 (7.1%)		0/40 (0%)		0/12 (0%)		3/44 (6.8%)		0/18 (0%)		6/156 (3.8%)
Oropharyngeal pain	1/42 (2.4%)		0/40 (0%)		1/12 (8.3%)		1/44 (2.3%)		1/18 (5.6%)		4/156 (2.6%)
Pleural effusion	1/42 (2.4%)		3/40 (7.5%)		0/12 (0%)		1/44 (2.3%)		0/18 (0%)		5/156 (3.2%)
Productive cough	3/42 (7.1%)		1/40 (2.5%)		1/12 (8.3%)		4/44 (9.1%)		1/18 (5.6%)		10/156 (6.4%)
Skin and subcutaneous tissue disorders
Alopecia	0/42 (0%)		2/40 (5%)		1/12 (8.3%)		0/44 (0%)		0/18 (0%)		3/156 (1.9%)
Dry skin	2/42 (4.8%)		0/40 (0%)		0/12 (0%)		4/44 (9.1%)		0/18 (0%)		6/156 (3.8%)
Eczema	1/42 (2.4%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		2/156 (1.3%)
Hyperhidrosis	1/42 (2.4%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		2/156 (1.3%)
Pruritus	3/42 (7.1%)		3/40 (7.5%)		2/12 (16.7%)		1/44 (2.3%)		0/18 (0%)		9/156 (5.8%)
Rash	4/42 (9.5%)		6/40 (15%)		4/12 (33.3%)		7/44 (15.9%)		1/18 (5.6%)		22/156 (14.1%)
Rash maculo-papular	3/42 (7.1%)		0/40 (0%)		0/12 (0%)		2/44 (4.5%)		0/18 (0%)		5/156 (3.2%)
Skin fissures	0/42 (0%)		0/40 (0%)		1/12 (8.3%)		0/44 (0%)		0/18 (0%)		1/156 (0.6%)
Skin striae	0/42 (0%)		0/40 (0%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		1/156 (0.6%)
Vascular disorders
Hypertension	1/42 (2.4%)		3/40 (7.5%)		1/12 (8.3%)		1/44 (2.3%)		1/18 (5.6%)		7/156 (4.5%)
Hypotension	0/42 (0%)		1/40 (2.5%)		0/12 (0%)		0/44 (0%)		1/18 (5.6%)		2/156 (1.3%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.