Study of Capmatinib and Spartalizumab Combination Therapy vs Docetaxel in Non-small Cell Lung Cancer

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03647488
• Collaborator: (none)
• Enrollment: 18
• Locations: 8
• Arms: 3
• Actual Duration (Months): 20.4
• Patients Per Site: 2.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this trial was to evaluate the safety and efficacy of capmatinib in combination with spartalizumab in adult participants with epidermal growth factor receptor (EGFR) wild type (for exon 19 deletions and exon 21 L858R substitution mutations), anaplastic lymphoma kinase (ALK) rearrangement negative in locally advanced (stage IIIB, not eligible for definitive chemo-radiation) or metastatic (stage IV) Non-small cell lung cancer (NSCLC) after failure of platinum doublet and checkpoint inhibitor treatment.

Condition or Disease	Intervention/Treatment	Phase
Carcinoma, Non-Small-Cell Lung	Drug: Capmatinib; Drug: Spartalizumab; Drug: Docetaxel	Phase 2

Detailed Description

This was a two-part prospectively designed, multicenter, open-label, randomized phase II study.

Part 1: Run-in. Prior to the randomized part of the study, a run-in to assess the safety and tolerability as well as preliminary efficacy of the capmatinib and spartalizumab combination was conducted. Participants were treated with capmatinib 400 mg twice daily (BID) and spartalizumab 400 mg intravenously (i.v.) once every 28 days. A review was planned to take place after all participants had at least 24 weeks of follow-up. The decision to expand the study to the randomized part was to be based on the safety, tolerability, and preliminary efficacy of the capmatinib and spartalizumab combination.

Part 2: Randomized. Subjects were planned to be randomized to one of the following arms in a 2:1 ratio: 1) combination of capmatinib 400 mg BID and spartalizumab 400 mg i.v. once every 28 days; 2) docetaxel 75 mg/m2 i.v. following local guidelines as per standard of care and product labels. Based on the results obtained in the run-in part of the study, the randomized part was not opened.

For the run-in part of the study, the treatment period began on Cycle 1 Day 1 and continued in 28-day cycles until disease progression, unacceptable toxicity, withdrawal of informed consent, pregnancy, lost to follow-up, or death irrespective of start of new anti-neoplastic therapy. After treatment discontinuation, all subjects were followed for safety evaluations during the safety follow-up period, and the subject's status was collected every 8 weeks as part of the survival follow-up

Study Design

• Study Type: Interventional
• Actual Enrollment: 18 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: Run-in part was single group. Randomized part (parallel design) was not opened.Run-in part was single group. Randomized part (parallel design) was not opened.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Multicenter Randomized Two-arm Study of Capmatinib and Spartalizumab Combination Therapy vs Docetaxel in Pretreated Adult Patients With EGFR Wild-type ALK Rearrangement Negative Advanced/Metastatic Non-small Cell Lung Cancer
• Actual Study Start Date: Dec 26, 2018
• Actual Primary Completion Date: Sep 7, 2020
• Actual Study Completion Date: Sep 7, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Run-in part: capmatinib + spartalizumab Participants (enrolled in the run-in part) were treated with capmatinib 400 mg twice daily (BID) and spartalizumab 400 mg intravenously (i.v.) once every 28 days	Drug: Capmatinib; Capmatinib 400 mg (tablets) orally taken twice daily; Other Names: INC280 ; Drug: Spartalizumab; Spartalizumab 400 mg via intravenous infusion once every 28 days; Other Names: PDR001
Experimental: Randomized part: capmatinib+spartalizumab Participants (enrolled in the randomized part) treated with capmatinib 400 mg twice daily (BID) and spartalizumab 400 mg intravenously (i.v.) once every 28 days	Drug: Capmatinib; Capmatinib 400 mg (tablets) orally taken twice daily; Other Names: INC280 ; Drug: Spartalizumab; Spartalizumab 400 mg via intravenous infusion once every 28 days; Other Names: PDR001
Active Comparator: Randomized part: docetaxel Participants (enrolled in the randomized part) treated with docetaxel 75mg/m2 i.v. following local guidelines as per standard of care and product labels once every 21 days	Drug: Docetaxel; Docetaxel 75mg/m2 i.v. following local guidelines as per standard of care and product labels once every 21 days

Outcome Measures

Primary Outcome Measures

1. Run-in Part: Percentage of Participants With Dose Limiting Toxicities (DLTs) [From the day of the first dose of study medication up to 56 days]

   A DLT was defined as an adverse event or abnormal laboratory value assessed as unrelated to disease progression, inter-current illness, or concomitant medications that met certain criteria as defined in the protocol.

2. Run-in Part: Percentage of Participants With Adverse Events (AEs) [From the day of the first dose of study medication to 150 days after the last dose of spartalizumab, or 30 days after the last dose of capmatinib (whichever is later) up to maximum duration of approximately 1.7 years]

   Percentage of participants with AEs, including changes from baseline in vital signs and laboratory results qualifying and reported as AEs. AEs were assessed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0: Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences; Grade 5: Death

3. Run-in Part: Percentage of Participants With at Least One Dose Reduction. [From the day of the first dose of study medication to end of treatment, assessed up to maximum duration of 68 weeks]

   Percentage of participants with at least one dose reduction. Dose reductions were only allowed for capmatinib

4. Run-in Part: Percentage of Participants With at Least One Dose Interruption [From the day of the first dose of study medication to end of treatment, assessed up to maximum duration of 68 weeks]

   Percentage of participants with at least one dose interruption. Dose interruptions were allowed for capmatinib and spartalizumab.

5. Run-in Part: Relative Dose Intensity Received by Participants [From the day of the first dose of study medication to end of treatment, assessed up to maximum duration of 68 weeks]

   The relative dose intensity of capmatinib and spartalizumab is computed as the ratio of dose intensity and planned dose intensity, multiplied by 100.

6. Randomized Part: Overall Survival (OS) [From start of treatment to death due to any cause, assessed until the end of the study (up to a planned duration of 18 months)]

   OS is defined as the time from date of start of treatment to date of death due to any cause. If a participant was not known to have died, survival was censored at the date of last known date patient alive. Results are not available because randomized part never started.

Secondary Outcome Measures

1. Objective Response Rate (ORR) Based on RECIST 1.1 and as Per Investigator Assessment [From start of treatment until end of treatment, assessed up to 68 weeks (run-in part)]

   ORR is defined as the percentage of subjects with best overall response (BOR) of complete response (CR) or partial response (PR) based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and as per investigator assessment. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. ORR results for randomized part are not available because randomized part never started.

2. Disease Control Rate (DCR) Based on RECIST 1.1 and as Per Investigator Assessment [From start of treatment until end of treatment, assessed up to 68 weeks (run-in part)]

   DCR is defined as the percentage of subjects with best overall response of CR or PR or stable disease based on RECIST 1.1 and as per investigator assessment. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. Stable disease: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progression. DCR results for randomized part are not available because randomized part never started.

3. Progression Free Survival (PFS) [From start of treatment until the first documented radiological progression or death, whichever comes first, assessed up to 68 weeks (run-in part)]

   PFS is defined as the time from the date of start of treatment to the date of the first documented radiological progression or death due to any cause. For participants who had not progressed or died at the analysis cut-off date, PFS was censored at the date of the last adequate tumor evaluation date. An adequate tumour assessment is a tumour assessment with an overall response other than unknown. Progression is defined using RECIST 1.1 and as per investigator assessment as at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. PFS results for randomized part are not available because randomized part never started.

4. Time to Response (TTR) Based on RECIST 1.1 and as Per Investigator Assessment [From start of treatment to the first documented response of either complete response or partial response, assessed up to 68 weeks (run-in part)]

   TTR is defined as the time from the date of start of treatment to the first documented response of either CR or PR, which must be subsequently confirmed. TTR was evaluated according to RECIST 1.1 and as per investigator assessment. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. For run-in part, TTR results are not available because there were no participants achieving response (CR or PR) For randomized part , TTR results are not available because randomized part never started.

5. Duration of Response (DOR) Based on RECIST 1.1 and as Per Investigator Assessment [From first documented response (CR or PR) to first documented progression or death, whichever came first, assessed up to 68 weeks (run-in part)]

   DOR is the time between the date of first documented response(CR or PR) and the date of first documented progression or death due to underlying cancer based on RECIST1.1 and as per investigator assessment. If progression or death has not occurred, the subject is censored at the date of last adequate tumor assessment. CR: Disappearance of all non-nodal target lesions and any pathological lymph nodes assigned as target lesions must have a reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. Progression: at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. The sum must also demonstrate an absolute increase of at least 5 mm. Results are not available because there were no participants achieving response in the run-in part and randomized part never started

6. AUClast of Capmatinib [Cycle 3 day 1 at predose, 0.5 hours (h), 1h, 2h, 4h and 8h postdose. Each Cycle is 28 days]

   AUClast is the area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration. AUClast was calculated using non-compartmental methods.

7. AUCtau of Capmatinib [Cycle 3 day 1 at predose, 0.5 hours (h), 1h, 2h, 4h and 8h postdose. Each Cycle is 28 days]

   AUCtau is the area under the plasma concentration-time curve from time zero to the end of the dosing interval Tau. AUCtau was calculated using non-compartmental methods.

8. Maximum Plasma Concentration (Cmax) of Capmatinib [Cycle 3 day 1 at predose, 0.5 hours (h), 1h, 2h, 4h and 8h postdose. Each Cycle is 28 days]

   The maximum (peak) observed plasma concentration after single dose administration. Cmax was calculated using non-compartmental methods.

9. Time to Reach Maximum (Tmax) Plasma Concentration of Capmatinib [Cycle 3 day 1 at predose, 0.5 hours (h), 1h, 2h, 4h and 8h postdose. Each Cycle is 28 days]

   Tmax is the time to reach maximum (peak) plasma concentration of capmatinib after single dose administration (time). Tmax was calculated using non-compartmental methods.

10. AUClast of Spartlizumab [CCycle 3 day 1 at predose and 1 hour postdose (up to 1.53 hours postdose), cycle 3 day 4 (=72 hours postdose), cycle 3 day 8 (=168 hours postdose) and cycle 3 day 15 (=336 hours postdose). Each Cycle is 28 days]

    AUClast is the area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration. AUClast was calculated using non-compartmental methods.

11. AUCtau of Spartlizumab [Cycle 3 day 1 at predose and 1 hour postdose (up to 1.53 hours postdose), cycle 3 day 4 (=72 hours postdose), cycle 3 day 8 (=168 hours postdose) and cycle 3 day 15 (=336 hours postdose). Each Cycle is 28 days]

    AUCtau is the area under the plasma concentration-time curve from time zero to the end of the dosing interval Tau. AUCtau was calculated using non-compartmental methods.

12. Maximum Plasma Concentration (Cmax) of Spartlizumab [Cycle 3 day 1 at predose and 1 hour postdose (up to 1.53 hours postdose), cycle 3 day 4 (=72 hours postdose), cycle 3 day 8 (=168 hours postdose) and cycle 3 day 15 (=336 hours postdose). Each Cycle is 28 days]

    The maximum (peak) observed plasma concentration after single dose administration. Cmax was calculated using non-compartmental methods.

13. Time to Reach Maximum (Tmax) Plasma Concentration of Spartlizumab [Cycle 3 day 1 at predose and 1 hour postdose (up to 1.53 hours postdose), cycle 3 day 4 (=72 hours postdose), cycle 3 day 8 (=168 hours postdose) and cycle 3 day 15 (=336 hours postdose). Each Cycle is 28 days]

    Tmax is the time to reach maximum (peak) plasma concentration of spartlizumab after single dose administration (time). Tmax was calculated using non-compartmental methods.

14. Spartalizumab Antidrug Antibodies (ADA) Prevalence at Baseline [Cycle 1 Day 1 at predose. Each Cycle is 28 days]

    ADA prevalence at baseline was calculated as the proportion of participants who had an ADA positive result at baseline

15. Spartalizumab ADA Incidence On-treatment [Predose at Cycle (C)1 Day (D)1, C2D1, C3D1, C4D1, C6D1, C8D1, C10D1, C12D1, thereafter every 6 cycles until discontinuation, and end of treatment (EOT), 30-day and 150-day after EOT]

    ADA incidence on treatment was calculated as the proportion of participants who were treatment-induced ADA positive (post-baseline ADA positive with ADA-negative sample at baseline) and treatment-boosted ADA positive (post-baseline ADA positive with titer that is at least the fold titer change greater than the ADA-positive baseline titer)

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Histologically confirmed locally advanced/metastatic (stage IIIB/IV), EGFR wild-type, ALK rearrangement negative, non-small cell lung cancer

• Subject had demonstrated progression following one prior platinum doublet and one prior PD-(L)1 checkpoint inhibitor (either alone or in combination, the most recent treatment regimen must have contained a PD-(L)1 checkpoint inhibitor)

• Subjects must be candidates for single agent docetaxel

• Subjects must have at least one lesion evaluable by RECIST 1.1

Exclusion Criteria:

• Prior treatment with a MET inhibitor or HGF (Hepatocyte growth factor) targeting therapy

• Any untreated central nervous system (CNS) lesion

• Use of any live vaccines against infectious diseases within 12 weeks of initiation of study treatment.

Other protocol-defined inclusion/exclusion criteria might apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Highlands Oncology Group	Fayetteville	Arkansas	United States	72703
2	Novartis Investigative Site	Leuven		Belgium	3000
3	Novartis Investigative Site	Grenoble		France	38043
4	Novartis Investigative Site	LILLE Cédex		France	59037
5	Novartis Investigative Site	Koeln		Germany	50937
6	Novartis Investigative Site	Tel Aviv		Israel	6423906
7	Novartis Investigative Site	Barcelona	Catalunya	Spain	08036
8	Novartis Investigative Site	Madrid		Spain	28009

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Jul 16, 2018
• Statistical Analysis Plan - Oct 5, 2020

More Information

Additional Information:

• Plain language trial summaries are available on this link

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03647488
• Other Study ID Numbers: CINC280D2201; 2018-001420-19
• First Posted: Aug 27, 2018
• Last Update Posted: Jan 24, 2022
• Last Verified: Jan 1, 2022

• 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: Non-small-cell lung carcinoma; Non-small-cell lung cancer; NSCLC; epidermal growth factor receptor wild type; EGFRwt; Anaplastic lymphoma kinase negative; ALK-; INC280; capmatinib and spartalizumab; combination therapy; docetaxel
• Additional relevant MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Docetaxel; Spartalizumab

Study Results

Participant Flow

Pre-assignment Detail	Based on preliminary results of run-in part, the decision was not to open randomized part of the study. Therefore, no participants were enrolled in randomized part.

Arm/Group Title	Run-in Part: Capmatinib + Spartalizumab	Randomized Part: Capmatinib + Spartalizumab	Randomized Part: Docetaxel
Arm/Group Description	Participants (enrolled in the run-in part) were treated with capmatinib 400 mg twice daily (BID) and spartalizumab 400 mg intravenously (i.v.) once every 28 days	Participants (enrolled in the randomized part) treated with capmatinib 400 mg twice daily (BID) and spartalizumab 400 mg intravenously (i.v.) once every 28 days	Participants (enrolled in the randomized part) treated with docetaxel 75mg/m2 i.v. following local guidelines as per standard of care and product labels once every 21 days
Period Title: Overall Study
STARTED	18	0	0
COMPLETED	0	0	0
NOT COMPLETED	18	0	0

Baseline Characteristics

Arm/Group Title	Run-in Part: Capmatinib + Spartalizumab	Randomized Part: Capmatinib + Spartalizumab	Randomized Part: Docetaxel	Total
Arm/Group Description	Participants (enrolled in the run-in part) were treated with capmatinib 400 mg twice daily (BID) and spartalizumab 400 mg intravenously (i.v.) once every 28 days	Participants (enrolled in the randomized part) treated with capmatinib 400 mg twice daily (BID) and spartalizumab 400 mg intravenously (i.v.) once every 28 days	Participants (enrolled in the randomized part) treated with docetaxel 75mg/m2 i.v. following local guidelines as per standard of care and product labels once every 21 days	Total of all reporting groups
Overall Participants	18	0	0	18
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	61.2 (10.52)	61.2 (10.52)
Sex: Female, Male (Count of Participants)
Female	7 38.9%	0 NaN	0 NaN	7 38.9%
Male	11 61.1%	0 NaN	0 NaN	11 61.1%
Race/Ethnicity, Customized (Count of Participants)
White	17 94.4%	0 NaN	0 NaN	17 94.4%
Missing	1 5.6%	0 NaN	0 NaN	1 5.6%

Outcome Measures

1. Primary Outcome

Title	Run-in Part: Percentage of Participants With Dose Limiting Toxicities (DLTs)
Description	A DLT was defined as an adverse event or abnormal laboratory value assessed as unrelated to disease progression, inter-current illness, or concomitant medications that met certain criteria as defined in the protocol.
Time Frame	From the day of the first dose of study medication up to 56 days

Outcome Measure Data

Analysis Population Description

All participants from the Safety Set in the run-in who experienced DLT during the first 8 weeks of dosing or met the minimum exposure criterion (subject received at least 1 infusion of spartalizumab and took at least 50% of the planned dose of capmatinib within the first 8 weeks of treatment) and had sufficient safety evaluations (subjects were observed for ≥56 days following the first dose, and are considered to have enough safety data to conclude that a DLT did not occur).

Arm/Group Title	Run-in Part: Capmatinib + Spartalizumab
Arm/Group Description	Participants (enrolled in the run-in part) were treated with capmatinib 400 mg twice daily (BID) and spartalizumab 400 mg intravenously (i.v.) once every 28 days
Measure Participants	18
Count of Participants [Participants]	1 5.6%

2. Primary Outcome

Title	Run-in Part: Percentage of Participants With Adverse Events (AEs)
Description	Percentage of participants with AEs, including changes from baseline in vital signs and laboratory results qualifying and reported as AEs. AEs were assessed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0: Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences; Grade 5: Death
Time Frame	From the day of the first dose of study medication to 150 days after the last dose of spartalizumab, or 30 days after the last dose of capmatinib (whichever is later) up to maximum duration of approximately 1.7 years

Outcome Measure Data

Analysis Population Description

All participants in the run-in who received at least one dose of study treatment (i.e. at least one dose of spartalizumab [including incomplete infusion] or of capmatinib).

Arm/Group Title	Run-in Part: Capmatinib + Spartalizumab
Arm/Group Description	Participants (enrolled in the run-in part) were treated with capmatinib 400 mg twice daily (BID) and spartalizumab 400 mg intravenously (i.v.) once every 28 days
Measure Participants	18
AEs- All grades	18 100%
AEs- Grade ≥3	11 61.1%
Treatment-related AEs- All grades	14 77.8%
Treatment related AEs- Grade ≥3	1 5.6%
Serious AEs (SAEs)- All grades	10 55.6%
SAEs- Grade ≥3	7 38.9%
Treatment-related SAEs- All grades	3 16.7%
Treatment-related SAEs- Grade ≥3	0 0%
Fatal SAEs- All grades	1 5.6%
Fatal SAEs- Grade ≥3	1 5.6%
AEs leading to discontinuation- All grades	5 27.8%
AEs leading to discontinuation- Grade ≥3	3 16.7%
Treatment-related AEs leading to discontinuation- All grades	3 16.7%
Treatment-related AEs leading to discontinuation- Grade ≥3	1 5.6%
AEs leading to dose adjustment/interruption- All grades	9 50%
AEs leading to dose adjustment/interruption- Grade ≥3	5 27.8%
AEs requiring additional therapy- All grades	16 88.9%
AEs requiring additional therapy- Grade ≥3	8 44.4%

3. Primary Outcome

Title	Run-in Part: Percentage of Participants With at Least One Dose Reduction.
Description	Percentage of participants with at least one dose reduction. Dose reductions were only allowed for capmatinib
Time Frame	From the day of the first dose of study medication to end of treatment, assessed up to maximum duration of 68 weeks

Outcome Measure Data

Analysis Population Description

All participants in the run-in who received at least one dose of study treatment (i.e. at least one dose of spartalizumab [including incomplete infusion] or of capmatinib).

Arm/Group Title	Run-in Part: Capmatinib + Spartalizumab
Arm/Group Description	Participants (enrolled in the run-in part) were treated with capmatinib 400 mg twice daily (BID) and spartalizumab 400 mg intravenously (i.v.) once every 28 days
Measure Participants	18
Count of Participants [Participants]	6 33.3%

4. Primary Outcome

Title	Run-in Part: Percentage of Participants With at Least One Dose Interruption
Description	Percentage of participants with at least one dose interruption. Dose interruptions were allowed for capmatinib and spartalizumab.
Time Frame	From the day of the first dose of study medication to end of treatment, assessed up to maximum duration of 68 weeks

Outcome Measure Data

Analysis Population Description

All participants in the run-in who received at least one dose of study treatment (i.e. at least one dose of spartalizumab [including incomplete infusion] or of capmatinib).

Arm/Group Title	Run-in Part: Capmatinib + Spartalizumab
Arm/Group Description	Participants (enrolled in the run-in part) were treated with capmatinib 400 mg twice daily (BID) and spartalizumab 400 mg intravenously (i.v.) once every 28 days
Measure Participants	18
Capmatinib	8 44.4%
Spartalizumab	3 16.7%

5. Primary Outcome

Title	Run-in Part: Relative Dose Intensity Received by Participants
Description	The relative dose intensity of capmatinib and spartalizumab is computed as the ratio of dose intensity and planned dose intensity, multiplied by 100.
Time Frame	From the day of the first dose of study medication to end of treatment, assessed up to maximum duration of 68 weeks

Outcome Measure Data

Analysis Population Description

All participants in the run-in who received at least one dose of study treatment (i.e. at least one dose of spartalizumab [including incomplete infusion] or of capmatinib).

Arm/Group Title	Run-in Part: Capmatinib + Spartalizumab
Arm/Group Description	Participants (enrolled in the run-in part) were treated with capmatinib 400 mg twice daily (BID) and spartalizumab 400 mg intravenously (i.v.) once every 28 days
Measure Participants	18
Capmatinib	99.6
Spartalizumab	100.0

6. Primary Outcome

Title	Randomized Part: Overall Survival (OS)
Description	OS is defined as the time from date of start of treatment to date of death due to any cause. If a participant was not known to have died, survival was censored at the date of last known date patient alive. Results are not available because randomized part never started.
Time Frame	From start of treatment to death due to any cause, assessed until the end of the study (up to a planned duration of 18 months)

Outcome Measure Data

Analysis Population Description

Data was not collected as no participants were enrolled in randomized part.

Arm/Group Title	Randomized Part: Capmatinib + Spartalizumab	Randomized Part: Docetaxel
Arm/Group Description	Participants (enrolled in the randomized part) treated with capmatinib 400 mg twice daily (BID) and spartalizumab 400 mg intravenously (i.v.) once every 28 days	Participants (enrolled in the randomized part) treated with docetaxel 75mg/m2 i.v. following local guidelines as per standard of care and product labels once every 21 days
Measure Participants	0	0

7. Secondary Outcome

Title	Objective Response Rate (ORR) Based on RECIST 1.1 and as Per Investigator Assessment
Description	ORR is defined as the percentage of subjects with best overall response (BOR) of complete response (CR) or partial response (PR) based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and as per investigator assessment. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. ORR results for randomized part are not available because randomized part never started.
Time Frame	From start of treatment until end of treatment, assessed up to 68 weeks (run-in part)

Outcome Measure Data

Analysis Population Description

All participants in the run-in who received at least one dose of any component of study treatment.

Arm/Group Title	Run-in Part: Capmatinib + Spartalizumab
Arm/Group Description	Participants (enrolled in the run-in part) were treated with capmatinib 400 mg twice daily (BID) and spartalizumab 400 mg intravenously (i.v.) once every 28 days
Measure Participants	18
Number (95% Confidence Interval) [Percentage of participants]	0 0%

8. Secondary Outcome

Title	Disease Control Rate (DCR) Based on RECIST 1.1 and as Per Investigator Assessment
Description	DCR is defined as the percentage of subjects with best overall response of CR or PR or stable disease based on RECIST 1.1 and as per investigator assessment. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. Stable disease: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progression. DCR results for randomized part are not available because randomized part never started.
Time Frame	From start of treatment until end of treatment, assessed up to 68 weeks (run-in part)

Outcome Measure Data

Analysis Population Description

All participants in the run-in who received at least one dose of any component of study treatment.

Arm/Group Title	Run-in Part: Capmatinib + Spartalizumab
Arm/Group Description	Participants (enrolled in the run-in part) were treated with capmatinib 400 mg twice daily (BID) and spartalizumab 400 mg intravenously (i.v.) once every 28 days
Measure Participants	18
Number (95% Confidence Interval) [Percentage of participants]	27.8 154.4%

9. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	PFS is defined as the time from the date of start of treatment to the date of the first documented radiological progression or death due to any cause. For participants who had not progressed or died at the analysis cut-off date, PFS was censored at the date of the last adequate tumor evaluation date. An adequate tumour assessment is a tumour assessment with an overall response other than unknown. Progression is defined using RECIST 1.1 and as per investigator assessment as at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. PFS results for randomized part are not available because randomized part never started.
Time Frame	From start of treatment until the first documented radiological progression or death, whichever comes first, assessed up to 68 weeks (run-in part)

Outcome Measure Data

Analysis Population Description

All participants in the run-in who received at least one dose of any component of study treatment.

Arm/Group Title	Run-in Part: Capmatinib + Spartalizumab
Arm/Group Description	Participants (enrolled in the run-in part) were treated with capmatinib 400 mg twice daily (BID) and spartalizumab 400 mg intravenously (i.v.) once every 28 days
Measure Participants	18
Median (95% Confidence Interval) [Months]	1.9

10. Secondary Outcome

Title	Time to Response (TTR) Based on RECIST 1.1 and as Per Investigator Assessment
Description	TTR is defined as the time from the date of start of treatment to the first documented response of either CR or PR, which must be subsequently confirmed. TTR was evaluated according to RECIST 1.1 and as per investigator assessment. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. For run-in part, TTR results are not available because there were no participants achieving response (CR or PR) For randomized part , TTR results are not available because randomized part never started.
Time Frame	From start of treatment to the first documented response of either complete response or partial response, assessed up to 68 weeks (run-in part)

Outcome Measure Data

Analysis Population Description

No data available as no participants had event

Arm/Group Title	Run-in Part: Capmatinib + Spartalizumab
Arm/Group Description	Participants (enrolled in the run-in part) were treated with capmatinib 400 mg twice daily (BID) and spartalizumab 400 mg intravenously (i.v.) once every 28 days
Measure Participants	0

11. Secondary Outcome

Title	Duration of Response (DOR) Based on RECIST 1.1 and as Per Investigator Assessment
Description	DOR is the time between the date of first documented response(CR or PR) and the date of first documented progression or death due to underlying cancer based on RECIST1.1 and as per investigator assessment. If progression or death has not occurred, the subject is censored at the date of last adequate tumor assessment. CR: Disappearance of all non-nodal target lesions and any pathological lymph nodes assigned as target lesions must have a reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. Progression: at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. The sum must also demonstrate an absolute increase of at least 5 mm. Results are not available because there were no participants achieving response in the run-in part and randomized part never started
Time Frame	From first documented response (CR or PR) to first documented progression or death, whichever came first, assessed up to 68 weeks (run-in part)

Outcome Measure Data

Analysis Population Description

No data available as no participants had event

Arm/Group Title	Run-in Part: Capmatinib + Spartalizumab
Arm/Group Description	Participants (enrolled in the run-in part) were treated with capmatinib 400 mg twice daily (BID) and spartalizumab 400 mg intravenously (i.v.) once every 28 days
Measure Participants	0

12. Secondary Outcome

Title	AUClast of Capmatinib
Description	AUClast is the area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration. AUClast was calculated using non-compartmental methods.
Time Frame	Cycle 3 day 1 at predose, 0.5 hours (h), 1h, 2h, 4h and 8h postdose. Each Cycle is 28 days

Outcome Measure Data

Analysis Population Description

The capmatinib pharmacokinetic (PK) analysis set included all participants in the run-in phase who provided at least one evaluable capmatinib PK concentration. Only those participants with data available for this endpoint at specified data points were analyzed.

Arm/Group Title	Run-in Part: Capmatinib + Spartalizumab
Arm/Group Description	Participants (enrolled in the run-in part) were treated with capmatinib 400 mg twice daily (BID) and spartalizumab 400 mg intravenously (i.v.) once every 28 days
Measure Participants	8
Geometric Mean (Geometric Coefficient of Variation) [nanogram*hour/milliliter (ng*hr/mL)]	11500 (47.3)

13. Secondary Outcome

Title	AUCtau of Capmatinib
Description	AUCtau is the area under the plasma concentration-time curve from time zero to the end of the dosing interval Tau. AUCtau was calculated using non-compartmental methods.
Time Frame	Cycle 3 day 1 at predose, 0.5 hours (h), 1h, 2h, 4h and 8h postdose. Each Cycle is 28 days

Outcome Measure Data

Analysis Population Description

The capmatinib pharmacokinetic (PK) analysis set included all participants in the run-in phase who provided at least one evaluable capmatinib PK concentration. Only those participants with data available for this endpoint at specified data points were analyzed.

Arm/Group Title	Run-in Part: Capmatinib + Spartalizumab
Arm/Group Description	Participants (enrolled in the run-in part) were treated with capmatinib 400 mg twice daily (BID) and spartalizumab 400 mg intravenously (i.v.) once every 28 days
Measure Participants	5
Geometric Mean (Geometric Coefficient of Variation) [nanogram*hour/milliliter (ng*hr/mL)]	12800 (48.5)

14. Secondary Outcome

Title	Maximum Plasma Concentration (Cmax) of Capmatinib
Description	The maximum (peak) observed plasma concentration after single dose administration. Cmax was calculated using non-compartmental methods.
Time Frame	Cycle 3 day 1 at predose, 0.5 hours (h), 1h, 2h, 4h and 8h postdose. Each Cycle is 28 days

Outcome Measure Data

Analysis Population Description

The capmatinib pharmacokinetic (PK) analysis set included all participants in the run-in phase who provided at least one evaluable capmatinib PK concentration. Only those participants with data available for this endpoint at specified data points were analyzed.

Arm/Group Title	Run-in Part: Capmatinib + Spartalizumab
Arm/Group Description	Participants (enrolled in the run-in part) were treated with capmatinib 400 mg twice daily (BID) and spartalizumab 400 mg intravenously (i.v.) once every 28 days
Measure Participants	8
Geometric Mean (Geometric Coefficient of Variation) [nanogram/milliliter (ng/mL)]	3260 (44.6)

15. Secondary Outcome

Title	Time to Reach Maximum (Tmax) Plasma Concentration of Capmatinib
Description	Tmax is the time to reach maximum (peak) plasma concentration of capmatinib after single dose administration (time). Tmax was calculated using non-compartmental methods.
Time Frame	Cycle 3 day 1 at predose, 0.5 hours (h), 1h, 2h, 4h and 8h postdose. Each Cycle is 28 days

Outcome Measure Data

Analysis Population Description

The capmatinib pharmacokinetic (PK) analysis set included all participants in the run-in phase who provided at least one evaluable capmatinib PK concentration. Only those participants with data available for this endpoint at specified data points were analyzed.

Arm/Group Title	Run-in Part: Capmatinib + Spartalizumab
Arm/Group Description	Participants (enrolled in the run-in part) were treated with capmatinib 400 mg twice daily (BID) and spartalizumab 400 mg intravenously (i.v.) once every 28 days
Measure Participants	8
Median (Full Range) [hour (h)]	1.42

16. Secondary Outcome

Title	AUClast of Spartlizumab
Description	AUClast is the area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration. AUClast was calculated using non-compartmental methods.
Time Frame	CCycle 3 day 1 at predose and 1 hour postdose (up to 1.53 hours postdose), cycle 3 day 4 (=72 hours postdose), cycle 3 day 8 (=168 hours postdose) and cycle 3 day 15 (=336 hours postdose). Each Cycle is 28 days

Outcome Measure Data

Analysis Population Description

The spartlizumab pharmacokinetic (PK) analysis set included all participants in the run-in phase who provided at least one evaluable spartlizumab PK concentration. Only those participants with data available for this endpoint at specified data points were analyzed.

Arm/Group Title	Run-in Part: Capmatinib + Spartalizumab
Arm/Group Description	Participants (enrolled in the run-in part) were treated with capmatinib 400 mg twice daily (BID) and spartalizumab 400 mg intravenously (i.v.) once every 28 days
Measure Participants	7
Geometric Mean (Geometric Coefficient of Variation) [microgram*day/milliliter (μg*day/mL)]	1720 (64.5)

17. Secondary Outcome

Title	AUCtau of Spartlizumab
Description	AUCtau is the area under the plasma concentration-time curve from time zero to the end of the dosing interval Tau. AUCtau was calculated using non-compartmental methods.
Time Frame	Cycle 3 day 1 at predose and 1 hour postdose (up to 1.53 hours postdose), cycle 3 day 4 (=72 hours postdose), cycle 3 day 8 (=168 hours postdose) and cycle 3 day 15 (=336 hours postdose). Each Cycle is 28 days

Outcome Measure Data

Analysis Population Description

The spartlizumab pharmacokinetic (PK) analysis set included all participants in the run-in phase who provided at least one evaluable spartlizumab PK concentration. Only those participants with data available for this endpoint at specified data points were analyzed.

Arm/Group Title	Run-in Part: Capmatinib + Spartalizumab
Arm/Group Description	Participants (enrolled in the run-in part) were treated with capmatinib 400 mg twice daily (BID) and spartalizumab 400 mg intravenously (i.v.) once every 28 days
Measure Participants	7
Geometric Mean (Geometric Coefficient of Variation) [microgram*day/milliliter (μg*day/mL)]	2110 (35.1)

18. Secondary Outcome

Title	Maximum Plasma Concentration (Cmax) of Spartlizumab
Description	The maximum (peak) observed plasma concentration after single dose administration. Cmax was calculated using non-compartmental methods.
Time Frame	Cycle 3 day 1 at predose and 1 hour postdose (up to 1.53 hours postdose), cycle 3 day 4 (=72 hours postdose), cycle 3 day 8 (=168 hours postdose) and cycle 3 day 15 (=336 hours postdose). Each Cycle is 28 days

Outcome Measure Data

Analysis Population Description

The spartlizumab pharmacokinetic (PK) analysis set included all participants in the run-in phase who provided at least one evaluable spartlizumab PK concentration. Only those participants with data available for this endpoint at specified data points were analyzed.

Arm/Group Title	Run-in Part: Capmatinib + Spartalizumab
Arm/Group Description	Participants (enrolled in the run-in part) were treated with capmatinib 400 mg twice daily (BID) and spartalizumab 400 mg intravenously (i.v.) once every 28 days
Measure Participants	8
Geometric Mean (Geometric Coefficient of Variation) [microgram/milliliter (μg/mL)]	138 (23.2)

19. Secondary Outcome

Title	Time to Reach Maximum (Tmax) Plasma Concentration of Spartlizumab
Description	Tmax is the time to reach maximum (peak) plasma concentration of spartlizumab after single dose administration (time). Tmax was calculated using non-compartmental methods.
Time Frame	Cycle 3 day 1 at predose and 1 hour postdose (up to 1.53 hours postdose), cycle 3 day 4 (=72 hours postdose), cycle 3 day 8 (=168 hours postdose) and cycle 3 day 15 (=336 hours postdose). Each Cycle is 28 days

Outcome Measure Data

Analysis Population Description

The spartlizumab pharmacokinetic (PK) analysis set included all participants in the run-in phase who provided at least one evaluable spartlizumab PK concentration. Only those participants with data available for this endpoint at specified data points were analyzed.

Arm/Group Title	Run-in Part: Capmatinib + Spartalizumab
Arm/Group Description	Participants (enrolled in the run-in part) were treated with capmatinib 400 mg twice daily (BID) and spartalizumab 400 mg intravenously (i.v.) once every 28 days
Measure Participants	8
Median (Full Range) [hour (h)]	1.13

20. Secondary Outcome

Title	Spartalizumab Antidrug Antibodies (ADA) Prevalence at Baseline
Description	ADA prevalence at baseline was calculated as the proportion of participants who had an ADA positive result at baseline
Time Frame	Cycle 1 Day 1 at predose. Each Cycle is 28 days

Outcome Measure Data

Analysis Population Description

immunogenicity (IG) prevalence set includes all subjects in the Full analysis set with a determinant baseline IG sample or at least one determinant post-baseline sample. Determinant sample: sample that is neither ADA-inconclusive nor unevaluable

Arm/Group Title	Run-in Part: Capmatinib + Spartalizumab
Arm/Group Description	Participants (enrolled in the run-in part) were treated with capmatinib 400 mg twice daily (BID) and spartalizumab 400 mg intravenously (i.v.) once every 28 days
Measure Participants	17
Count of Participants [Participants]	3 16.7%

21. Secondary Outcome

Title	Spartalizumab ADA Incidence On-treatment
Description	ADA incidence on treatment was calculated as the proportion of participants who were treatment-induced ADA positive (post-baseline ADA positive with ADA-negative sample at baseline) and treatment-boosted ADA positive (post-baseline ADA positive with titer that is at least the fold titer change greater than the ADA-positive baseline titer)
Time Frame	Predose at Cycle (C)1 Day (D)1, C2D1, C3D1, C4D1, C6D1, C8D1, C10D1, C12D1, thereafter every 6 cycles until discontinuation, and end of treatment (EOT), 30-day and 150-day after EOT

Outcome Measure Data

Analysis Population Description

The IG incidence set includes all subjects in the IG prevalence set with a determinant baseline IG sample and at least one determinant post-baseline IG sample. Determinant sample: sample that is neither ADA-inconclusive nor unevaluable.

Arm/Group Title	Run-in Part: Capmatinib + Spartalizumab
Arm/Group Description	Participants (enrolled in the run-in part) were treated with capmatinib 400 mg twice daily (BID) and spartalizumab 400 mg intravenously (i.v.) once every 28 days
Measure Participants	14
Count of Participants [Participants]	3 16.7%

22. Post-Hoc Outcome

Title	All Collected Deaths
Description	On-treatment deaths due to any cause were collected from first dose of study medication to 150 days after the last dose of spartalizumab, or 30 days after the last dose of capmatinib, whichever is later, up to a maximum duration of approximately 1.7 years. Total deaths were collected from first dose of study treatment until end of post-treatment efficacy or survival follow, up to maximum duration of approximately 1.7 years
Time Frame	On-treatment deaths: up to approximately 1.7 years. All deaths: up to approximately 1.7 years

Outcome Measure Data

Analysis Population Description

Safety Set consisted of all participants who received at least one dose of study treatment, i.e. at least one dose of spartalizumab [including incomplete infusion] or of capmatinib.

Arm/Group Title	Run-in Part: Capmatinib + Spartalizumab
Arm/Group Description	Participants (enrolled in the run-in part) were treated with capmatinib 400 mg twice daily (BID) and spartalizumab 400 mg intravenously (i.v.) once every 28 days
Measure Participants	18
Total Deaths	12 66.7%
Deaths on-treatment	5 27.8%

Adverse Events

Time Frame	On-treatment deaths due to any cause and adverse events were collected from first dose of study medication to 150 days after the last dose of spartalizumab, or 30 days after the last dose of capmatinib, whichever is later, up to a maximum duration of approximately 1.7 years.
Adverse Event Reporting Description	Any sign or symptom that occurs during the study treatment plus 150 days after the last dose of spartalizumab or 30 days after the last dose of capmatinib (on-treatment). Total number of deaths are captured in Outcome Measure 22 (post-hoc: all-cause mortality). Analysis performed on the safety set in the run-in part: all participants who received at least one dose of spartalizumab [including incomplete infusion] or of capmatinib. No safety data is available for part 2 because it was not opened.
Arm/Group Title	Run-in Part: Capmatinib + Spartalizumab
Arm/Group Description	Participants (enrolled in the run-in part) were treated with capmatinib 400 mg twice daily (BID) and spartalizumab 400 mg intravenously (i.v.) once every 28 days
All Cause Mortality
	Run-in Part: Capmatinib + Spartalizumab
	Affected / at Risk (%)	# Events
Total	5/18 (27.8%)
Serious Adverse Events
	Run-in Part: Capmatinib + Spartalizumab
	Affected / at Risk (%)	# Events
Total	10/18 (55.6%)
Cardiac disorders
Cardiac failure congestive	1/18 (5.6%)
Ventricular arrhythmia	1/18 (5.6%)
General disorders
Fatigue	3/18 (16.7%)
General physical health deterioration	1/18 (5.6%)
Pyrexia	1/18 (5.6%)
Immune system disorders
Anaphylactic reaction	1/18 (5.6%)
Drug hypersensitivity	1/18 (5.6%)
Infections and infestations
Abdominal infection	1/18 (5.6%)
Pneumonia	1/18 (5.6%)
Respiratory tract infection	1/18 (5.6%)
Metabolism and nutrition disorders
Decreased appetite	1/18 (5.6%)
Respiratory, thoracic and mediastinal disorders
Bronchial obstruction	1/18 (5.6%)
Dyspnoea	1/18 (5.6%)
Haemoptysis	1/18 (5.6%)
Respiratory failure	1/18 (5.6%)
Vascular disorders
Deep vein thrombosis	1/18 (5.6%)
Other (Not Including Serious) Adverse Events
	Run-in Part: Capmatinib + Spartalizumab
	Affected / at Risk (%)	# Events
Total	18/18 (100%)
Blood and lymphatic system disorders
Anaemia	2/18 (11.1%)
Cardiac disorders
Pericardial effusion	1/18 (5.6%)
Stress cardiomyopathy	1/18 (5.6%)
Eye disorders
Eyelid oedema	1/18 (5.6%)
Gastrointestinal disorders
Abdominal pain	1/18 (5.6%)
Cheilitis	1/18 (5.6%)
Constipation	2/18 (11.1%)
Diarrhoea	5/18 (27.8%)
Dry mouth	1/18 (5.6%)
Dyspepsia	1/18 (5.6%)
Dysphagia	2/18 (11.1%)
Nausea	7/18 (38.9%)
Stomatitis	1/18 (5.6%)
Vomiting	5/18 (27.8%)
General disorders
Asthenia	4/18 (22.2%)
Axillary pain	1/18 (5.6%)
Chest pain	2/18 (11.1%)
Fatigue	4/18 (22.2%)
Oedema peripheral	4/18 (22.2%)
Pain	1/18 (5.6%)
Pyrexia	4/18 (22.2%)
Infections and infestations
Herpes zoster	1/18 (5.6%)
Osteomyelitis	1/18 (5.6%)
Pneumonia	1/18 (5.6%)
Investigations
Alanine aminotransferase increased	2/18 (11.1%)
Amylase increased	1/18 (5.6%)
Aspartate aminotransferase increased	2/18 (11.1%)
Blood alkaline phosphatase increased	1/18 (5.6%)
Blood creatinine increased	5/18 (27.8%)
Blood magnesium decreased	1/18 (5.6%)
C-reactive protein increased	2/18 (11.1%)
Creatinine renal clearance decreased	1/18 (5.6%)
Gamma-glutamyltransferase increased	1/18 (5.6%)
Lipase increased	2/18 (11.1%)
Lymphocyte count decreased	2/18 (11.1%)
Weight decreased	3/18 (16.7%)
Metabolism and nutrition disorders
Decreased appetite	2/18 (11.1%)
Dehydration	1/18 (5.6%)
Hyperglycaemia	1/18 (5.6%)
Hypoalbuminaemia	1/18 (5.6%)
Hypomagnesaemia	1/18 (5.6%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/18 (5.6%)
Muscle spasms	1/18 (5.6%)
Musculoskeletal chest pain	1/18 (5.6%)
Pain in extremity	1/18 (5.6%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain	1/18 (5.6%)
Nervous system disorders
Dizziness	1/18 (5.6%)
Dysgeusia	1/18 (5.6%)
Headache	1/18 (5.6%)
Lethargy	1/18 (5.6%)
Somnolence	1/18 (5.6%)
Psychiatric disorders
Anxiety	2/18 (11.1%)
Confusional state	1/18 (5.6%)
Depression	1/18 (5.6%)
Sleep disorder	1/18 (5.6%)
Renal and urinary disorders
Renal pain	1/18 (5.6%)
Reproductive system and breast disorders
Nipple pain	1/18 (5.6%)
Respiratory, thoracic and mediastinal disorders
Bronchospasm	1/18 (5.6%)
Cough	1/18 (5.6%)
Dysphonia	1/18 (5.6%)
Dyspnoea	5/18 (27.8%)
Dyspnoea exertional	1/18 (5.6%)
Pleural effusion	2/18 (11.1%)
Productive cough	1/18 (5.6%)
Skin and subcutaneous tissue disorders
Hyperhidrosis	1/18 (5.6%)
Pruritus	2/18 (11.1%)
Rash macular	1/18 (5.6%)
Vascular disorders
Hypotension	1/18 (5.6%)

Limitations/Caveats

[Not Specified]

More Information

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 (ie, data from all sites) in the clinical trial.