NSCLC: Multicenter Study of Rociletinib Administered to Patients With Previously Treated Mutant EGFR Non-small Cell Lung Cancer

• Sponsor: Clovis Oncology, Inc. (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02147990
• Collaborator: (none)
• Enrollment: 318
• Locations: 91
• Arms: 3
• Actual Duration (Months): 62.4
• Patients Per Site: 3.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the safety and anti-tumor effect of rociletinib. The trial is open-ended, which means patients will continue to take rociletinib until the study doctor determines it is no longer beneficial for them.

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

Detailed Description

This is a Phase 2, single arm, open-label, dual cohort, multicenter study evaluating the safety and efficacy of rociletinib administered orally to patients with previously treated mutant EGFR NSCLC.

Patients will be enrolled into 2 cohorts. Cohort A will enroll approximately 125 eligible patients who are centrally confirmed T790M-positive. Cohort B will be a continuation of the study and will enroll up to approximately 100 eligible patients who will be either centrally confirmed T790M-positive or T790M-negative.

All patients (for Cohort A and B) should have experienced disease progression while on treatment with the first single-agent EGFR-directed TKI (EGFR-TKI) for advanced/metastatic NSCLC. One line of chemotherapy prior to the EGFR-TKI treatment is permissible.

The study (Cohorts A and B) will consist of a screening phase to establish study eligibility and document baseline measurements, an open-label treatment phase, in which the patient will receive rociletinib to ascertain safety and efficacy until disease progression as defined by RECIST Version 1.1, clinical tumor progression, or unacceptable toxicity as assessed by the investigator. For patients with clinical progression, radiographic assessment should be performed to document evidence of radiographic progression.

Study Design

• Study Type: Interventional
• Actual Enrollment: 318 participants
• Allocation: Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: TIGER-2: A Phase 2, Open-label, Multicenter, Safety and Efficacy Study of Oral CO-1686 as 2nd Line EGFR-directed TKI in Patients With Mutant EGFR Non-small Cell Lung Cancer (NSCLC)
• Actual Study Start Date: Jun 16, 2014
• Actual Primary Completion Date: Jul 30, 2019
• Actual Study Completion Date: Aug 27, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Rociletinib Mono-Therapy, T790M +ve (625mg BID) Starting dose of 625mg rociletinib, taken orally twice daily, with 8 oz (240 mL) of water and with a meal or within 30 minutes after a meal. Tablets should be swallowed whole. Treatment with rociletinib is continuous and each cycle will comprise of 28 days.	Drug: Rociletinib; Rociletinib will be administered to patients orally; Other Names: CO-1686
Experimental: Rociletinib Mono-Therapy, T790M +ve (500mg BID) Starting dose of 500mg rociletinib, taken orally twice daily, with 8 oz (240 mL) of water and with a meal or within 30 minutes after a meal. Tablets should be swallowed whole. Treatment with rociletinib is continuous and each cycle will comprise of 28 days.	Drug: Rociletinib; Rociletinib will be administered to patients orally; Other Names: CO-1686
Experimental: Rociletinib Mono-Therapy, T790M -ve (500mg BID) Starting dose of 500mg rociletinib, taken twice daily, with 8 oz (240 mL) of water and with a meal or within 30 minutes after a meal. Tablets should be swallowed whole. Treatment with rociletinib is continuous and each cycle will comprise of 28 days.	Drug: Rociletinib; Rociletinib will be administered to patients orally; Other Names: CO-1686

Outcome Measures

Primary Outcome Measures

1. Objective Response Rate (ORR) According to RECIST Version 1.1 as Determined by Investigator Assessment [Cycle 1 Day 1 to End of Treatment, up to approximately 57 months.]

   ORR is defined as the percentage of patients with a best overall confirmed response of partial response (PR) or complete response (CR) recorded from the start of the treatment until disease progression. For patients who continued treatment post-progression, the first date of progression was used for the analysis. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions, defined by and assessed as: Complete Response (CR), is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR), at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter.

Secondary Outcome Measures

1. Duration of Response (DOR) in T790M Positive Patients According to RECIST Version 1.1 as Determined by Investigator Assessment [From Cycle 1 Day 1 until disease progression or end of treatment, whichever came first, assessed up to 54 months]

   DOR in patients with a T790M mutation (determined by central lab) with confirmed response per investigator. The DOR for complete response (CR) and partial response (PR) was measured from the date that any of these best responses is first recorded until the first date that progressive disease (PD) is objectively documented. For patients who continue treatment post-progression, the first date of progression was used for the analysis.

2. Disease Control Rate (DCR) by RECIST v1.1 as Determined by Investigator Assessment [From Cycle 1 Day 1 until disease progression or end of treatment, whichever came first, assessed up to 57 months]

   DCR is defined as the percentage of patients who have achieved CR, PR, and SD lasting at least 12 weeks. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions, defined by and assessed as: Complete Response (CR), is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR), at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter. Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum longest diameter since the treatment started.

3. Progression-free Survival (PFS) in T790M Positive Patients by RECIST v1.1 as Determined by Investigator Assessment [From Cycle 1 Day 1 until disease progression or end of treatment, whichever came first, assessed up to 57 months]

   PFS was calculated as 1+ the number of days from the first dose of study drug to documented radiographic progression or death due to any cause, whichever occurs first. Patients without a documented event of radiographic progression were censored on the date of their last adequate tumor assessment (i.e., radiologic assessment) or date of first dose of study drug if no tumor assessments were performed. For patients who continued treatment post-progression, the first date of progression was used for the analysis of PFS. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression.

4. Overall Survival (OS) Determined by Investigator Assessment [Cycle 1 Day 1 to date of death, assessed up to 57 months]

   OS was calculated as 1+ the number of days from the first dose of study drug to death due to any cause. Patients without a documented date of death will be censored on the date the patient was last known to be alive.

5. Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Cancer (EORTC QLQ-C30) Global Health Status Quality of Life Scale [Baseline (Day 0), Months 5, 10 and EOT]

   EORTC QLC-C30 is a 30-item questionnaire to assess the quality of life in cancer patients. EORTC QLQ-C30 includes functional scales (physical, role, cognitive, emotional, social), global health status, symptom scales (fatigue, pain, nausea/vomiting), and other (dyspnoea, appetite loss, insomnia, constipation/diarrhea, financial difficulties). Most questions used 4-point scale (1 'Not at All' to 4 'Very Much'); two used 7-point scale (1 'Very Poor' to 7 'Excellent'). Scores are averaged, and transformed to 0-100 scale; higher score = better quality of life.

6. Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in Dermatology Life Quality Index (DLQI) [Baseline (Day 0), Months 5, 10 and EOT]

   Dermatology Life Quality Index (DLQI) score is a participant-reported outcome consisting of a set of 10 questions regarding the degree to which the participant's skin has affected certain behaviors and quality of life over the last week. Responses to each are: very much (score of 3), a lot, a little, or not at all (score of 0). The DLQI score ranges from 0 (best) to 30 (worst); the higher the score, the more quality of life is impaired.

7. Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in EORTC QLQ-LC-13 Alopecia Scale [Baseline (Day 0), Months 5, 10 and EOT]

   EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms.

8. Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in EORTC QLQ-LC-13 Coughing Scale [Baseline (Day 0), Months 5, 10 and EOT]

   EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms.

9. Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in EORTC QLQ-LC-13 Dysphagia Scale [Baseline (Day 0), Months 5, 10 and EOT]

   EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms.

10. Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in EORTC QLQ-LC-13 Dyspnoea Scale [Baseline (Day 0), Months 5, 10 and EOT]

    EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms.

11. Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in EORTC QLQ-LC-13 Haemoptysis Scale [Baseline (Day 0), Months 5, 10 and EOT]

    EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms.

12. Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in EORTC QLQ-LC-13 Pain in Arm or Shoulder Scale [Baseline (Day 0), Months 5, 10 and EOT]

    EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms.

13. Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in EORTC QLQ-LC-13 Pain in Chest Scale [Baseline (Day 0), Months 5, 10 and EOT]

    EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms.

14. Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in EORTC QLQ-LC-13 Medicine for Pain Scale [Baseline (Day 0), Months 5, 10 and EOT]

    EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms.

15. Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in EORTC QLQ-LC-13 Pain in Other Parts Scale [Baseline (Day 0), Months 5, 10 and EOT]

    EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms.

16. Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in EORTC QLQ-LC-13 Peripheral Neuropathy Scale [Baseline (Day 0), Months 5, 10 and EOT]

    EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms.

17. Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in EORTC QLQ-LC-13 Sore Mouth Scale [Baseline (Day 0), Months 5, 10 and EOT]

    EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms.

18. Population PK (POPPK) and Exposure-Response (ER) Analysis of Rociletinib [Every 4 weeks for approximately 6 months (Day 1 of Cycles 2 to 7 inclusive)]

    Sparse blood sampling for POPPK and ER analyses in all patients treated with rociletinib.

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 metastatic or unresectable locally advanced NSCLC

• Documented evidence of a tumor with 1 or more EGFR mutations excluding exon 20 insertion

• Disease progression confirmed by radiologic assessment while receiving treatment with the first single agent EGFR-TKI

• EGFR TKI treatment discontinued less than or equal to 30 days prior to planned initiation of rociletinib

• The washout period for an EGFR inhibitor is a minimum of 3 days

• No intervening treatment between cessation of single agent EGFR TKI and planned initiation of rociletinib

• Previous treatment with less than or equal to 1 prior chemotherapy (excluding prior neo-adjuvant or adjuvant chemotherapy or chemoradiotherapy with curative intent)

• Any toxicity related to prior EGFR inhibitor treatment must have resolved to Grade 1 or less

• Central laboratory confirmation of the presence of the T790M mutation in tumor tissue in Cohort A and the presence or absence of the T790M mutation in tumor tissue in Cohort B. Centrally indeterminate, unknown or invalid specimens are not acceptable. Biopsy material obtained from either primary or metastatic tumor tissue and sent to the central laboratory must be within 60 prior to dosing study drug but following disease progression on the first EGFR TKI

• Measurable disease according to RECIST Version 1.1

• Life expectancy of at least 3 months

• ECOG performance status of 0 to 1

• Minimum Age 18 years (in certain territories, the minimum age requirement may be higher eg age 20 years in Japan and Taiwan)

• Adequate hematological and biological function, confirmed by defined laboratory values

• Written consent on an IRB/IEC-approved Informed Consent Form (ICF) prior to any study specific evaluation

Exclusion Criteria

• Documented evidence of an exon 20 insertion activating mutation in the EGFR gene

• Active second malignancy i.e. patient known to have potentially fatal cancer present for which he/she may be (but not necessarily) currently receiving treatment

• Patients with a history of malignancy that has been completely treated, with no evidence of that cancer currently, are permitted to enrol in the trial provided all chemotherapy was completed greater than 6 months prior and/or bone marrow transplant greater than 2 years prior

• Known pre-existing interstitial lung disease

• Cohort A only: Patients with leptomeningeal carcinomatosis are excluded. Other central nervous system (CNS) metastases are only permitted if treated, asymptomatic, and stable (not requiring steroid for at least 4 weeks prior to the start of study treatment). Cohort B only: Patients with CNS metastases or leptomeningeal carcinomatosis are excluded.

• Treatment with prohibited medications less than or equal to 14 days prior to treatment with rociletinib

• Patients who are currently receiving treatment with any medications that have the potential to prolong the QT interval and the treatment cannot be either discontinued or switched to a different medication before starting rociletinib

• Prior treatment with rociletinib, or other drugs that target T790M positive mutant EGFR with sparing of wild type EGFR

• Any of the following cardiac abnormalities or history

• Clinically significant abnormal 12-lead ECG, QT interval corrected using Fridericia's method (QTCF) greater than 450 msec

• Inability to measure QT interval on ECG

• Personal or family history of long QT syndrome

• Implantable pacemaker or implantable cardioverter defibrillator

• Resting bradycardia less than 55 beats/min

• Non-study related surgical procedures less than or equal to 7 days prior to administration of rociletinib. In all cases, the patient must be sufficiently recovered and stable before treatment administration

• Females who are pregnant or breastfeeding

• Refusal to use adequate contraception for fertile patients (females and males) while on treatment and for 12 weeks after the last dose of rociletinib

• Presence of any serious or unstable concomitant systemic disorder incompatible with the clinical study

• Any other reason the investigator considers the patient should not participate in the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCLA Medical Center	Alhambra	California	United States	91801
2	Comprehensive Blood and Cancer Center	Bakersfield	California	United States	93309
3	Saint Jude Heritage Healthcare	Fullerton	California	United States	92835
4	University of California San Diego Moores Cancer Center	La Jolla	California	United States	92093
5	Northridge Hospital Medical Center	Northridge	California	United States	91328
6	Cancer Care Associates	Redondo Beach	California	United States	90277
7	University of California Davis Medical Center	Sacramento	California	United States	95817
8	University of California San Francisco	San Francisco	California	United States	94115
9	Coastal Integrative Cancer Care	San Luis Obispo	California	United States	93401
10	Saint Mary's Regional Cancer Center	Grand Junction	Colorado	United States	81501-6132
11	Rocky Mountain Cancer Centers, LLP	Lone Tree	Colorado	United States	80218
12	Yale University School of Medicine	New Haven	Connecticut	United States	32135
13	Advanced Medical Specialties	Miami	Florida	United States	33176
14	Cleveland Clinic Florida	Weston	Florida	United States	33331
15	Northwestern University Feinberg School of Medicine	Chicago	Illinois	United States	60611
16	University of Illinois Chicago	Chicago	Illinois	United States	60612
17	Illinois Cancer Specialists	Niles	Illinois	United States	60714
18	Beth Israel Comprehensive Cancer Center	Boston	Massachusetts	United States	02215
19	Lahey Hospital and Medical Center	Burlington	Massachusetts	United States	01805
20	Minnesota Oncology Hematology, P.A	Minneapolis	Minnesota	United States	55404
21	Mayo Clinic - Rochester	Rochester	Minnesota	United States	55905
22	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
23	Montefiore Medical Center	Bronx	New York	United States	10461
24	New York Oncology Hematology, PC	Latham	New York	United States	12110-2188
25	University of Rochester	Rochester	New York	United States	14642
26	University Hospitals of Cleveland	Cleveland	Ohio	United States	44106
27	Cleveland Clinic	Cleveland	Ohio	United States	44195
28	Fox Chase Cancer Center	Philadelphia	Pennsylvania	United States	19111
29	Tennessee Oncology, PLLC	Nashville	Tennessee	United States	37203
30	Texas Oncology P.A.	Amarillo	Texas	United States	79106
31	USO - Texas Oncology P.A.	Arlington	Texas	United States	76014
32	Texas Oncology-Austin Central	Austin	Texas	United States	78705
33	Texas Oncology-Beaumont	Beaumont	Texas	United States	77702
34	Texas Oncology P.A.	Bedford	Texas	United States	76022
35	Texas Oncology P.A.	Dallas	Texas	United States	75246
36	Texas Oncology P.A.	Flower Mound	Texas	United States	75028
37	The Methodist Hospital	Houston	Texas	United States	77030
38	Texas Oncology - Plano East	Plano	Texas	United States	75075-7787
39	Virginia Cancer Specialists	Fairfax	Virginia	United States	22031
40	Northwest Cancer Specialists, P.C.	Vancouver	Washington	United States	98686
41	Yakima Valley Memorial Hospital, North Star Lodge	Yakima	Washington	United States	98902
42	Icon Cancer Centre	South Brisbane	New South Wales	Australia	4101
43	Royal North Shore Hospital	Sydney	New South Wales	Australia	2065
44	Westmead Hospital	Westmead	New South Wales	Australia	2145
45	Flinders Medical Centre	Bedford Park	South Australia	Australia	5042
46	Princess Margaret Hospital	Toronto	Ontario	Canada	M5G 2L7
47	Centre Hospitalier Regional Universitaire (CHRU) de Besancon - L'Hopital Jean Minjoz	Besançon	Franche-comte	France	25030 cedex
48	Hôpital Tenon	Paris	Ile-de-france	France	75020
49	Institut Gustave Roussy	Villejuif	Ile-de-France	France	94805
50	Institut de Cancérologie de l'Ouest - René Gauducheau	Saint Herblain cedex	PAYS DE LA Loire	France
51	Centre Hospitalier Lyon Sud	Pierre Bénité cedex	Rhone-alpes	France	69495
52	Centre Hospitalier Universitaire Côte de Nacre	Caen		France
53	Centre Hospitalier Universitaire Hôpital Nord	Marseille Cedex 20		France	13915
54	Asklepios Fachkliniken München-Gauting	Gauting	Bayern	Germany	82131
55	Klinikum Innenstadt LMU	München	Bayern	Germany	80336
56	Goethe-Universität Frankfurt am Main	Frankfurt am Main	Hessen	Germany	60590
57	Pius Hospital Oldenburg	Oldenburg	Niedersachsen	Germany	26121
58	Universitaetsklinikum Bonn - Zentrum fuer Innere Medizin - Medizinische Klinik und Poliklink III	Bonn	Nordrhein-westfalen	Germany	53127
59	Universitätsklinikum Essen	Essen	Nordrhein-westfalen	Germany	45122
60	Universitätsklinikum Köln	Köln	Nordrhein-westfalen	Germany	50937
61	LungenClinic Großhansdorf GmbH	Großhansdorf	Schleswig-holstein	Germany	22927
62	Evangelische Lungenklinik Berlin	Berlin		Germany	13125
63	Queen Mary Hospital	Hong Kong		Hong Kong
64	Chungbuk National University Hospital	Chungju	Chungcheongbuk-do	Korea, Republic of
65	National Cancer Center	Goyang-si	Gyeonggi-do	Korea, Republic of
66	Gachon University Gil Medical Center	Incheon	Gyeonggi-do	Korea, Republic of	405-760
67	Dong-A University Hospital	Busan		Korea, Republic of
68	Inha University Hospital	Incheon		Korea, Republic of	400-711
69	Samsung Medical Center	Seoul		Korea, Republic of	135-710
70	Asan Medical Center	Seoul		Korea, Republic of
71	Seoul National University Hospital	Seoul		Korea, Republic of
72	Seoul Saint Mary's Hospital	Seoul		Korea, Republic of
73	Severance Hospital, Yonsei University Health System	Seoul		Korea, Republic of
74	Antoni van Leeuwenhoek Hospital	Amsterdam	Noord-holland	Netherlands	1066 CX
75	Vrije Universiteit Medisch Centrum	Amsterdam		Netherlands	1081 HV
76	Hospital Universitario Virgen del Rocio	Seville	Sevilla	Spain	41013
77	Hospital Universitari Germans Trias i Pujol	Badalona		Spain
78	Hospital Vall d´Hebrón	Barcelona		Spain	08035
79	Hospital Universitario Quirón Dexeus	Barcelona		Spain
80	Hospital Universitario La Paz	Madrid		Spain
81	Centre Hospitalier Universitaire Vaudoise	Lausanne	Vaud	Switzerland	1011
82	Taipei Veterans General Hospital	Taipei	Taipei CITY	Taiwan	11217
83	Chang Gung Memorial Hospital Linkou	Taoyuan	Tao-Yuan	Taiwan	33305
84	China Medical University Hospital	Taichung		Taiwan	40447
85	Taichung Veterans General Hospital	Taichung		Taiwan	40705
86	National Taiwan University Hospital	Taipei		Taiwan	100
87	Cambridge University Hospitals NHS Foundation Trust	Cambridge	England	United Kingdom	CB2 0QQ
88	Guy's and Saint Thomas NHS Foundation Trust	London	Greater London	United Kingdom	SE1 9RT
89	Royal Marsden Hospital	London	Greater London	United Kingdom	SW3 6JJ
90	Royal Marsden NHS Trust	Sutton	Surrey	United Kingdom	SM2 5PT
91	University College Hospital	London		United Kingdom	NW1 2PQ

Sponsors and Collaborators

• Clovis Oncology, Inc.

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Aug 16, 2016
• Statistical Analysis Plan - Jun 12, 2015

More Information

Publications

None provided.

• Responsible Party: Clovis Oncology, Inc.
• ClinicalTrials.gov Identifier: NCT02147990
• Other Study ID Numbers: CO-1686-019 (TIGER-2)
• First Posted: May 28, 2014
• Last Update Posted: Aug 12, 2020
• Last Verified: Jul 1, 2020

• Keywords provided by Clovis Oncology, Inc.: cancer; metastatic; locally advanced; lung; non-small cell lung cancer; NSCLC; epidermal growth factor receptor; EGFR; T790M; CO-1686; unresectable; recurrent; EGFR-directed therapy; irreversible EGFR inhibitor; TIGER; Rociletinib
• Additional relevant MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung

Study Results

Participant Flow

Recruitment Details	318 patients were enrolled at 67 study sites in North America, Europe, Asia and Australia. One patient was not included in the Safety Population due to failure of the study site to provide any dosing data in electronic data capture (EDC) before the site was closed.

Arm/Group Title	Rociletinib 625 mg BID T790M+	Rociletinib 500 mg BID T790M+	Rociletinib 500 mg BID T790M-
Arm/Group Description	Rociletinib 625 mg BID in patients with T790M-positive tumor status	Rociletinib 500 mg BID in patients with T790M-positive tumor status	Rociletinib 500 mg BID in patients with T790M-negative tumor status
Period Title: Overall Study
STARTED	154	100	63
COMPLETED	154	100	63
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Rociletinib 625 mg BID T790M+	Rociletinib 500 mg BID T790M+	Rociletinib 500 mg BID T790M-	Total
Arm/Group Description	Rociletinib 625 mg BID in patients with T790M-positive tumor status	Rociletinib 500 mg BID in patients with T790M-positive tumor status	Rociletinib 500 mg BID in patients with T790M-negative tumor status	Total of all reporting groups
Overall Participants	154	100	63	317
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.8 (10.67)	65.3 (9.93)	64.1 (10.01)	63.8 (10.34)
Sex: Female, Male (Count of Participants)
Female	105 68.2%	69 69%	41 65.1%	215 67.8%
Male	49 31.8%	31 31%	22 34.9%	102 32.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 1.3%	2 2%	3 4.8%	7 2.2%
Not Hispanic or Latino	131 85.1%	93 93%	55 87.3%	279 88%
Unknown or Not Reported	21 13.6%	5 5%	5 7.9%	31 9.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.6%	0 0%	0 0%	1 0.3%
Asian	59 38.3%	34 34%	32 50.8%	125 39.4%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	6 3.9%	5 5%	2 3.2%	13 4.1%
White	74 48.1%	58 58%	23 36.5%	155 48.9%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	14 9.1%	3 3%	6 9.5%	23 7.3%
T790M Status (Count of Participants)
T790M Negative	1 0.6%	0 0%	62 98.4%	63 19.9%
T790M Positive	153 99.4%	100 100%	0 0%	253 79.8%
Missing	0 0%	0 0%	1 1.6%	1 0.3%

Outcome Measures

1. Primary Outcome

Title	Objective Response Rate (ORR) According to RECIST Version 1.1 as Determined by Investigator Assessment
Description	ORR is defined as the percentage of patients with a best overall confirmed response of partial response (PR) or complete response (CR) recorded from the start of the treatment until disease progression. For patients who continued treatment post-progression, the first date of progression was used for the analysis. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions, defined by and assessed as: Complete Response (CR), is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR), at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter.
Time Frame	Cycle 1 Day 1 to End of Treatment, up to approximately 57 months.

Outcome Measure Data

Analysis Population Description

Investigator Tumor Evaluable Population - defined as all patients who received at least 1 dose of rociletinib, have at least 1 measureable tumor lesion at baseline, and have at least 1 post-baseline tumor assessment as determined by the investigator.

Arm/Group Title	Rociletinib 625 mg BID T790M+	Rociletinib 500 mg BID T790M+	Rociletinib 500 mg BID T790M-
Arm/Group Description	Rociletinib 625 mg BID in patients with T790M-positive tumor status	Rociletinib 500 mg BID in patients with T790M-positive tumor status	Rociletinib 500 mg BID in patients with T790M-negative tumor status
Measure Participants	153	97	61
Number (95% Confidence Interval) [percentage of participants]	34.6 22.5%	34.0 34%	18.0 28.6%

2. Secondary Outcome

Title	Duration of Response (DOR) in T790M Positive Patients According to RECIST Version 1.1 as Determined by Investigator Assessment
Description	DOR in patients with a T790M mutation (determined by central lab) with confirmed response per investigator. The DOR for complete response (CR) and partial response (PR) was measured from the date that any of these best responses is first recorded until the first date that progressive disease (PD) is objectively documented. For patients who continue treatment post-progression, the first date of progression was used for the analysis.
Time Frame	From Cycle 1 Day 1 until disease progression or end of treatment, whichever came first, assessed up to 54 months

Outcome Measure Data

Analysis Population Description

Centrally-confirmed T790M-positive subset of the Investigator Tumor Evaluable Population - defined as all patients who received at least 1 dose of rociletinib, have at least 1 measureable tumor lesion at baseline, and have at least 1 post-baseline tumor assessment as determined by the investigator.

Arm/Group Title	Rociletinib 625 mg BID T790M+	Rociletinib 500 mg BID T790M+	All T790M+
Arm/Group Description	Rociletinib 625 mg BID in patients with T790M-positive tumor status	Rociletinib 500 mg BID in patients with T790M-positive tumor status	All Rociletinib 500 mg BID and 625 mg BID patients with T790M-positive tumor status
Measure Participants	53	33	86
Median (95% Confidence Interval) [months]	7.4	9.1	7.6

3. Secondary Outcome

Title	Disease Control Rate (DCR) by RECIST v1.1 as Determined by Investigator Assessment
Description	DCR is defined as the percentage of patients who have achieved CR, PR, and SD lasting at least 12 weeks. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions, defined by and assessed as: Complete Response (CR), is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR), at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter. Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum longest diameter since the treatment started.
Time Frame	From Cycle 1 Day 1 until disease progression or end of treatment, whichever came first, assessed up to 57 months

Outcome Measure Data

Analysis Population Description

Investigator Tumor Evaluable Population - defined as all patients who received at least 1 dose of rociletinib, have at least 1 measureable tumor lesion at baseline, and have at least 1 post-baseline tumor assessment as determined by the investigator.

Arm/Group Title	Rociletinib 625 mg BID T790M+	Rociletinib 500 mg BID T790M+	Rociletinib 500 mg BID T790M-
Arm/Group Description	Rociletinib 625 mg BID in patients with T790M-positive tumor status	Rociletinib 500 mg BID in patients with T790M-positive tumor status	Rociletinib 500 mg BID in patients with T790M-negative tumor status
Measure Participants	153	97	61
Number (95% Confidence Interval) [percentage of patients]	67.3	76.3	59.0

4. Secondary Outcome

Title	Progression-free Survival (PFS) in T790M Positive Patients by RECIST v1.1 as Determined by Investigator Assessment
Description	PFS was calculated as 1+ the number of days from the first dose of study drug to documented radiographic progression or death due to any cause, whichever occurs first. Patients without a documented event of radiographic progression were censored on the date of their last adequate tumor assessment (i.e., radiologic assessment) or date of first dose of study drug if no tumor assessments were performed. For patients who continued treatment post-progression, the first date of progression was used for the analysis of PFS. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression.
Time Frame	From Cycle 1 Day 1 until disease progression or end of treatment, whichever came first, assessed up to 57 months

Outcome Measure Data

Analysis Population Description

Centrally-confirmed T790M-positive subset of the Intent-to-treat (ITT) population defined as all patients who received at least 1 dose of rociletinib.

Arm/Group Title	Rociletinib 625 mg BID T790M+	Rociletinib 500 mg BID T790M+	All T790M+
Arm/Group Description	Rociletinib 625 mg BID in patients with T790M-positive tumor status	Rociletinib 500 mg BID in patients with T790M-positive tumor status	All Rociletinib 500 mg BID and 625 mg BID patients with T790M-positive tumor status
Measure Participants	154	100	254
Median (95% Confidence Interval) [months]	5.5	5.9	5.5

5. Secondary Outcome

Title	Overall Survival (OS) Determined by Investigator Assessment
Description	OS was calculated as 1+ the number of days from the first dose of study drug to death due to any cause. Patients without a documented date of death will be censored on the date the patient was last known to be alive.
Time Frame	Cycle 1 Day 1 to date of death, assessed up to 57 months

Outcome Measure Data

Analysis Population Description

Centrally-confirmed T790M-positive subset of the Intent-to-treat (ITT) population defined as all patients who received at least 1 dose of rociletinib.

Arm/Group Title	Rociletinib 625 mg BID T790M+	Rociletinib 500 mg BID T790M+	All T790M+
Arm/Group Description	Rociletinib 625 mg BID in patients with T790M-positive tumor status	Rociletinib 500 mg BID in patients with T790M-positive tumor status	All Rociletinib 500 mg BID and 625 mg BID patients with T790M-positive tumor status
Measure Participants	154	100	254
Median (95% Confidence Interval) [months]	18.8	29.8	23.7

6. Secondary Outcome

Title	Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Cancer (EORTC QLQ-C30) Global Health Status Quality of Life Scale
Description	EORTC QLC-C30 is a 30-item questionnaire to assess the quality of life in cancer patients. EORTC QLQ-C30 includes functional scales (physical, role, cognitive, emotional, social), global health status, symptom scales (fatigue, pain, nausea/vomiting), and other (dyspnoea, appetite loss, insomnia, constipation/diarrhea, financial difficulties). Most questions used 4-point scale (1 'Not at All' to 4 'Very Much'); two used 7-point scale (1 'Very Poor' to 7 'Excellent'). Scores are averaged, and transformed to 0-100 scale; higher score = better quality of life.
Time Frame	Baseline (Day 0), Months 5, 10 and EOT

Outcome Measure Data

Analysis Population Description

Safety population - defined as all patients who received at least 1 dose of rociletinib.

Arm/Group Title	Rociletinib 625 mg BID T790M+	Rociletinib 500 mg BID T790M+	Rociletinib 500 mg BID T790M-
Arm/Group Description	Rociletinib 625 mg BID in patients with T790M-positive tumor status	Rociletinib 500 mg BID in patients with T790M-positive tumor status	Rociletinib 500 mg BID in patients with T790M-negative tumor status
Measure Participants	154	100	63
Baseline (Day 0)	62.18 (22.245)	59.76 (22.495)	54.63 (24.629)
Cycle 5 (approximately month 5)	-2.48 (22.470)	-0.56 (23.763)	5.56 (28.842)
Cycle 10 (approximately month 10)	-2.21 (22.294)	-3.81 (21.422)	3.57 (23.956)
End of Treatment	-4.82 (23.381)	-9.65 (18.481)	-10.42 (35.158)

7. Secondary Outcome

Title	Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in Dermatology Life Quality Index (DLQI)
Description	Dermatology Life Quality Index (DLQI) score is a participant-reported outcome consisting of a set of 10 questions regarding the degree to which the participant's skin has affected certain behaviors and quality of life over the last week. Responses to each are: very much (score of 3), a lot, a little, or not at all (score of 0). The DLQI score ranges from 0 (best) to 30 (worst); the higher the score, the more quality of life is impaired.
Time Frame	Baseline (Day 0), Months 5, 10 and EOT

Outcome Measure Data

Analysis Population Description

Safety population - defined as all patients who received at least 1 dose of rociletinib.

Arm/Group Title	Rociletinib 625 mg BID T790M+	Rociletinib 500 mg BID T790M+	Rociletinib 500 mg BID T790M-
Arm/Group Description	Rociletinib 625 mg BID in patients with T790M-positive tumor status	Rociletinib 500 mg BID in patients with T790M-positive tumor status	Rociletinib 500 mg BID in patients with T790M-negative tumor status
Measure Participants	154	100	63
Baseline (Day 0)	2.10 (3.408)	2.42 (4.706)	2.74 (4.763)
Cycle 5 (approximately month 5)	-0.82 (3.240)	-1.29 (3.499)	-1.63 (3.731)
Cycle 10 (approximately month 10)	-1.02 (2.810)	-1.64 (3.531)	-0.79 (2.751)
End of Treatment	-0.77 (3.191)	-0.22 (2.157)	-1.14 (4.204)

8. Secondary Outcome

Title	Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in EORTC QLQ-LC-13 Alopecia Scale
Description	EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms.
Time Frame	Baseline (Day 0), Months 5, 10 and EOT

Outcome Measure Data

Analysis Population Description

Safety population - defined as all patients who received at least 1 dose of rociletinib.

Arm/Group Title	Rociletinib 625 mg BID T790M+	Rociletinib 500 mg BID T790M+	Rociletinib 500 mg BID T790M-
Arm/Group Description	Rociletinib 625 mg BID in patients with T790M-positive tumor status	Rociletinib 500 mg BID in patients with T790M-positive tumor status	Rociletinib 500 mg BID in patients with T790M-negative tumor status
Measure Participants	154	100	63
Baseline (Day 0)	9.96 (21.264)	9.43 (20.779)	19.05 (29.154)
Cycle 5 (approximately month 5)	-4.62 (27.499)	-2.69 (27.855)	-10.10 (19.516)
Cycle 10 (approximately month 10)	-2.00 (21.728)	-6.67 (25.309)	-2.56 (21.350)
End of Treatment	4.50 (33.483)	3.51 (44.298)	0.00 (39.841)

9. Secondary Outcome

Title	Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in EORTC QLQ-LC-13 Coughing Scale
Description	EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms.
Time Frame	Baseline (Day 0), Months 5, 10 and EOT

Outcome Measure Data

Analysis Population Description

Safety population - defined as all patients who received at least 1 dose of rociletinib.

Arm/Group Title	Rociletinib 625 mg BID T790M+	Rociletinib 500 mg BID T790M+	Rociletinib 500 mg BID T790M-
Arm/Group Description	Rociletinib 625 mg BID in patients with T790M-positive tumor status	Rociletinib 500 mg BID in patients with T790M-positive tumor status	Rociletinib 500 mg BID in patients with T790M-negative tumor status
Measure Participants	154	100	63
Baseline (Day 0)	33.12 (26.540)	29.97 (25.862)	38.62 (23.346)
Cycle 5 (approximately month 5)	-7.92 (26.728)	-9.29 (26.619)	-12.12 (27.409)
Cycle 10 (approximately month 10)	-6.67 (23.328)	-17.14 (30.648)	2.56 (21.350)
End of Treatment	-5.41 (27.793)	0.00 (36.851)	6.67 (25.820)

10. Secondary Outcome

Title	Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in EORTC QLQ-LC-13 Dysphagia Scale
Description	EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms.
Time Frame	Baseline (Day 0), Months 5, 10 and EOT

Outcome Measure Data

Analysis Population Description

Safety population - defined as all patients who received at least 1 dose of rociletinib.

Arm/Group Title	Rociletinib 625 mg BID T790M+	Rociletinib 500 mg BID T790M+	Rociletinib 500 mg BID T790M-
Arm/Group Description	Rociletinib 625 mg BID in patients with T790M-positive tumor status	Rociletinib 500 mg BID in patients with T790M-positive tumor status	Rociletinib 500 mg BID in patients with T790M-negative tumor status
Measure Participants	154	100	63
Baseline (Day 0)	5.19 (15.306)	7.41 (17.532)	5.82 (17.495)
Cycle 5 (approximately month 5)	1.65 (12.803)	-0.54 (17.589)	7.07 (21.663)
Cycle 10 (approximately month 10)	-3.27 (13.752)	-3.81 (15.700)	2.56 (9.245)
End of Treatment	3.60 (17.184)	7.41 (31.427)	6.67 (28.730)

11. Secondary Outcome

Title	Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in EORTC QLQ-LC-13 Dyspnoea Scale
Description	EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms.
Time Frame	Baseline (Day 0), Months 5, 10 and EOT

Outcome Measure Data

Analysis Population Description

Safety population - defined as all patients who received at least 1 dose of rociletinib.

Arm/Group Title	Rociletinib 625 mg BID T790M+	Rociletinib 500 mg BID T790M+	Rociletinib 500 mg BID T790M-
Arm/Group Description	Rociletinib 625 mg BID in patients with T790M-positive tumor status	Rociletinib 500 mg BID in patients with T790M-positive tumor status	Rociletinib 500 mg BID in patients with T790M-negative tumor status
Measure Participants	154	100	63
Baseline (Day 0)	21.79 (21.554)	22.56 (21.441)	30.34 (26.415)
Cycle 5 (approximately month 5)	6.11 (21.681)	-1.25 (18.777)	-3.70 (23.516)
Cycle 10 (approximately month 10)	2.83 (19.606)	1.90 (14.879)	6.84 (22.923)
End of Treatment	8.41 (22.892)	8.77 (18.362)	0.00 (28.172)

12. Secondary Outcome

Title	Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in EORTC QLQ-LC-13 Haemoptysis Scale
Description	EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms.
Time Frame	Baseline (Day 0), Months 5, 10 and EOT

Outcome Measure Data

Analysis Population Description

Safety population - defined as all patients who received at least 1 dose of rociletinib.

Arm/Group Title	Rociletinib 625 mg BID T790M+	Rociletinib 500 mg BID T790M+	Rociletinib 500 mg BID T790M-
Arm/Group Description	Rociletinib 625 mg BID in patients with T790M-positive tumor status	Rociletinib 500 mg BID in patients with T790M-positive tumor status	Rociletinib 500 mg BID in patients with T790M-negative tumor status
Measure Participants	154	100	63
Baseline (Day 0)	2.38 (8.613)	1.68 (11.039)	4.76 (13.194)
Cycle 5 (approximately month 5)	-1.98 (7.919)	-1.61 (9.404)	-5.21 (14.930)
Cycle 10 (approximately month 10)	-0.65 (8.138)	-0.95 (5.634)	-5.13 (18.490)
End of Treatment	-0.90 (12.389)	0.00 (0.000)	-2.22 (8.607)

13. Secondary Outcome

Title	Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in EORTC QLQ-LC-13 Pain in Arm or Shoulder Scale
Description	EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms.
Time Frame	Baseline (Day 0), Months 5, 10 and EOT

Outcome Measure Data

Analysis Population Description

Safety population - defined as all patients who received at least 1 dose of rociletinib.

Arm/Group Title	Rociletinib 625 mg BID T790M+	Rociletinib 500 mg BID T790M+	Rociletinib 500 mg BID T790M-
Arm/Group Description	Rociletinib 625 mg BID in patients with T790M-positive tumor status	Rociletinib 500 mg BID in patients with T790M-positive tumor status	Rociletinib 500 mg BID in patients with T790M-negative tumor status
Measure Participants	154	100	63
Baseline (Day 0)	19.91 (26.271)	16.67 (26.325)	28.42 (34.338)
Cycle 5 (approximately month 5)	-5.94 (32.110)	-2.69 (25.819)	-7.29 (35.655)
Cycle 10 (approximately month 10)	-1.31 (31.242)	-2.86 (27.262)	8.33 (28.868)
End of Treatment	5.41 (29.932)	0.00 (35.136)	4.44 (33.014)

14. Secondary Outcome

Title	Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in EORTC QLQ-LC-13 Pain in Chest Scale
Description	EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms.
Time Frame	Baseline (Day 0), Months 5, 10 and EOT

Outcome Measure Data

Analysis Population Description

Safety population - defined as all patients who received at least 1 dose of rociletinib.

Arm/Group Title	Rociletinib 625 mg BID T790M+	Rociletinib 500 mg BID T790M+	Rociletinib 500 mg BID T790M-
Arm/Group Description	Rociletinib 625 mg BID in patients with T790M-positive tumor status	Rociletinib 500 mg BID in patients with T790M-positive tumor status	Rociletinib 500 mg BID in patients with T790M-negative tumor status
Measure Participants	154	100	63
Baseline (Day 0)	19.91 (25.429)	12.79 (22.691)	25.40 (32.635)
Cycle 5 (approximately month 5)	-4.62 (25.399)	-5.38 (20.194)	-8.08 (28.904)
Cycle 10 (approximately month 10)	-3.27 (24.272)	-6.86 (19.728)	2.56 (39.585)
End of Treatment	1.80 (34.198)	7.02 (13.962)	-4.44 (30.516)

15. Secondary Outcome

Title	Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in EORTC QLQ-LC-13 Medicine for Pain Scale
Description	EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms.
Time Frame	Baseline (Day 0), Months 5, 10 and EOT

Outcome Measure Data

Analysis Population Description

Safety population - defined as all patients who received at least 1 dose of rociletinib.

Arm/Group Title	Rociletinib 625 mg BID T790M+	Rociletinib 500 mg BID T790M+	Rociletinib 500 mg BID T790M-
Arm/Group Description	Rociletinib 625 mg BID in patients with T790M-positive tumor status	Rociletinib 500 mg BID in patients with T790M-positive tumor status	Rociletinib 500 mg BID in patients with T790M-negative tumor status
Measure Participants	154	100	63
Baseline (Day 0)	60.47 (27.302)	66.67 (27.766)	53.17 (23.350)
Cycle 5 (approximately month 5)	6.67 (35.450)	8.89 (23.458)	-4.76 (36.648)
Cycle 10 (approximately month 10)	4.76 (12.105)	-4.17 (27.817)	22.22 (19.245)
End of Treatment	3.92 (20.008)	0.00 (30.861)	-5.56 (38.968)

16. Secondary Outcome

Title	Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in EORTC QLQ-LC-13 Pain in Other Parts Scale
Description	EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms.
Time Frame	Baseline (Day 0), Months 5, 10 and EOT

Outcome Measure Data

Analysis Population Description

Safety population - defined as all patients who received at least 1 dose of rociletinib.

Arm/Group Title	Rociletinib 625 mg BID T790M+	Rociletinib 500 mg BID T790M+	Rociletinib 500 mg BID T790M-
Arm/Group Description	Rociletinib 625 mg BID in patients with T790M-positive tumor status	Rociletinib 500 mg BID in patients with T790M-positive tumor status	Rociletinib 500 mg BID in patients with T790M-negative tumor status
Measure Participants	154	100	63
Baseline (Day 0)	28.41 (30.848)	30.58 (33.219)	31.69 (29.456)
Cycle 5 (approximately month 5)	2.46 (34.464)	-1.13 (29.664)	-7.78 (33.543)
Cycle 10 (approximately month 10)	-3.47 (28.550)	-6.67 (31.102)	-2.78 (22.285)
End of Treatment	20.59 (31.798)	0.00 (26.352)	6.67 (44.006)

17. Secondary Outcome

Title	Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in EORTC QLQ-LC-13 Peripheral Neuropathy Scale
Description	EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms.
Time Frame	Baseline (Day 0), Months 5, 10 and EOT

Outcome Measure Data

Analysis Population Description

Safety population - defined as all patients who received at least 1 dose of rociletinib.

Arm/Group Title	Rociletinib 625 mg BID T790M+	Rociletinib 500 mg BID T790M+	Rociletinib 500 mg BID T790M-
Arm/Group Description	Rociletinib 625 mg BID in patients with T790M-positive tumor status	Rociletinib 500 mg BID in patients with T790M-positive tumor status	Rociletinib 500 mg BID in patients with T790M-negative tumor status
Measure Participants	154	100	63
Baseline (Day 0)	11.90 (22.117)	6.40 (17.611)	17.20 (29.409)
Cycle 5 (approximately month 5)	0.00 (25.386)	3.76 (23.458)	4.17 (31.395)
Cycle 10 (approximately month 10)	4.58 (25.837)	2.86 (18.737)	0.00 (20.101)
End of Treatment	2.70 (21.341)	7.02 (26.244)	2.22 (15.258)

18. Secondary Outcome

Title	Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in EORTC QLQ-LC-13 Sore Mouth Scale
Description	EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms.
Time Frame	Baseline (Day 0), Months 5, 10 and EOT

Outcome Measure Data

Analysis Population Description

Safety population - defined as all patients who received at least 1 dose of rociletinib.

Arm/Group Title	Rociletinib 625 mg BID T790M+	Rociletinib 500 mg BID T790M+	Rociletinib 500 mg BID T790M-
Arm/Group Description	Rociletinib 625 mg BID in patients with T790M-positive tumor status	Rociletinib 500 mg BID in patients with T790M-positive tumor status	Rociletinib 500 mg BID in patients with T790M-negative tumor status
Measure Participants	154	100	63
Baseline (Day 0)	5.19 (13.273)	7.41 (17.532)	10.58 (21.440)
Cycle 5 (approximately month 5)	1.98 (18.149)	-2.19 (21.832)	-2.02 (27.562)
Cycle 10 (approximately month 10)	0.65 (19.425)	-1.90 (24.176)	2.56 (21.350)
End of Treatment	4.50 (21.026)	12.28 (29.836)	2.22 (36.659)

19. Secondary Outcome

Title	Population PK (POPPK) and Exposure-Response (ER) Analysis of Rociletinib
Description	Sparse blood sampling for POPPK and ER analyses in all patients treated with rociletinib.
Time Frame	Every 4 weeks for approximately 6 months (Day 1 of Cycles 2 to 7 inclusive)

Outcome Measure Data

Analysis Population Description

Population PK (PPK) and exposure-response (ER) analysis were listed as a secondary objective. These analyses were conducted based on pooled data from multiple rociletinib trials (including TIGER2), thus no PPK or ER report was generated specifically for this study.

Arm/Group Title	Rociletinib 625 mg BID T790M+	Rociletinib 500 mg BID T790M+	Rociletinib 500 mg BID T790M-
Arm/Group Description	Rociletinib 625 mg BID in patients with T790M-positive tumor status	Rociletinib 500 mg BID in patients with T790M-positive tumor status	Rociletinib 500 mg BID in patients with T790M-negative tumor status
Measure Participants	0	0	0

Adverse Events

Time Frame	Adverse events were reported from the date of first dose of study drug and within 28 days after last dose of study drug, or up to approximately 62 months. In addition, study procedure-related AEs that occurred after signing of the informed consent form and before first dose of study drug were expected to be reported.
Arm/Group Title	Rociletinib 625 mg BID T790M+		Rociletinib 500 mg BID T790M+		Rociletinib 500 mg BID T790M-
Arm/Group Description	Rociletinib 625 mg BID in patients with T790M-positive tumor status		Rociletinib 500 mg BID in patients with T790M-positive tumor status		Rociletinib 500 mg BID in patients with T790M-negative tumor status
All Cause Mortality
	Rociletinib 625 mg BID T790M+		Rociletinib 500 mg BID T790M+		Rociletinib 500 mg BID T790M-
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	27/154 (17.5%)		7/100 (7%)		9/63 (14.3%)
Serious Adverse Events
	Rociletinib 625 mg BID T790M+		Rociletinib 500 mg BID T790M+		Rociletinib 500 mg BID T790M-
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	77/154 (50%)		48/100 (48%)		34/63 (54%)
Blood and lymphatic system disorders
Anemia	3/154 (1.9%)		0/100 (0%)		1/63 (1.6%)
Lymphadenitis	1/154 (0.6%)		0/100 (0%)		0/63 (0%)
Thrombocytopenia	2/154 (1.3%)		0/100 (0%)		1/63 (1.6%)
Cardiac disorders
Acute coronary syndrome	0/154 (0%)		1/100 (1%)		0/63 (0%)
Atrial fibrillation	1/154 (0.6%)		0/100 (0%)		2/63 (3.2%)
Bradycardia	2/154 (1.3%)		0/100 (0%)		0/63 (0%)
Cardiac arrest	1/154 (0.6%)		0/100 (0%)		0/63 (0%)
Pericardial effusion	0/154 (0%)		0/100 (0%)		1/63 (1.6%)
Pericarditis	2/154 (1.3%)		0/100 (0%)		0/63 (0%)
Ventricular fibrillation	1/154 (0.6%)		0/100 (0%)		0/63 (0%)
Eye disorders
Angle closure glaucoma	0/154 (0%)		2/100 (2%)		0/63 (0%)
Cataract	2/154 (1.3%)		2/100 (2%)		4/63 (6.3%)
Diplopia	1/154 (0.6%)		0/100 (0%)		0/63 (0%)
Gastrointestinal disorders
Abdominal pain	2/154 (1.3%)		0/100 (0%)		1/63 (1.6%)
Abdominal pain upper	1/154 (0.6%)		0/100 (0%)		0/63 (0%)
Colitis	0/154 (0%)		1/100 (1%)		0/63 (0%)
Constipation	3/154 (1.9%)		2/100 (2%)		0/63 (0%)
Diarrhoea	3/154 (1.9%)		4/100 (4%)		0/63 (0%)
Duodenal ulcer	1/154 (0.6%)		1/100 (1%)		0/63 (0%)
Gastrointestinal haemorrhage	0/154 (0%)		1/100 (1%)		0/63 (0%)
Haemorrhoidal haemorrhage	0/154 (0%)		1/100 (1%)		0/63 (0%)
Ileus paralytic	0/154 (0%)		1/100 (1%)		0/63 (0%)
Lower gastrointestinal haemorrhage	0/154 (0%)		0/100 (0%)		1/63 (1.6%)
Melaena	1/154 (0.6%)		0/100 (0%)		0/63 (0%)
Nausea	6/154 (3.9%)		2/100 (2%)		2/63 (3.2%)
Pancreatitis	5/154 (3.2%)		0/100 (0%)		1/63 (1.6%)
Pancreatitis acute	1/154 (0.6%)		0/100 (0%)		0/63 (0%)
Upper gastrointestinal haemorrhage	1/154 (0.6%)		0/100 (0%)		0/63 (0%)
Vomiting	4/154 (2.6%)		3/100 (3%)		3/63 (4.8%)
General disorders
Chest pain	2/154 (1.3%)		2/100 (2%)		0/63 (0%)
Death	1/154 (0.6%)		0/100 (0%)		0/63 (0%)
Euthanasia	0/154 (0%)		1/100 (1%)		0/63 (0%)
Fatigue	0/154 (0%)		2/100 (2%)		0/63 (0%)
Malaise	0/154 (0%)		0/100 (0%)		1/63 (1.6%)
Non-cardiac chest pain	1/154 (0.6%)		0/100 (0%)		0/63 (0%)
Oedema	0/154 (0%)		0/100 (0%)		1/63 (1.6%)
Oedema peripheral	0/154 (0%)		0/100 (0%)		1/63 (1.6%)
Peripheral swelling	0/154 (0%)		0/100 (0%)		1/63 (1.6%)
Pyrexia	1/154 (0.6%)		3/100 (3%)		1/63 (1.6%)
Sudden death	0/154 (0%)		0/100 (0%)		1/63 (1.6%)
Hepatobiliary disorders
Bile duct obstruction	1/154 (0.6%)		0/100 (0%)		0/63 (0%)
Cholecystitis	0/154 (0%)		0/100 (0%)		2/63 (3.2%)
Cholecystitis acute	1/154 (0.6%)		2/100 (2%)		0/63 (0%)
Gallbladder obstruction	0/154 (0%)		1/100 (1%)		0/63 (0%)
Hepatic function abnormal	0/154 (0%)		1/100 (1%)		0/63 (0%)
Hepatitis	1/154 (0.6%)		0/100 (0%)		0/63 (0%)
Infections and infestations
Biliary tract infection	1/154 (0.6%)		0/100 (0%)		0/63 (0%)
Cellulitis	1/154 (0.6%)		0/100 (0%)		0/63 (0%)
Clostridium difficile infection	1/154 (0.6%)		0/100 (0%)		0/63 (0%)
Cystitis	1/154 (0.6%)		0/100 (0%)		0/63 (0%)
Diverticulitis	0/154 (0%)		1/100 (1%)		0/63 (0%)
Enterocolitis infectious	0/154 (0%)		0/100 (0%)		1/63 (1.6%)
Gastroenteritis viral	0/154 (0%)		1/100 (1%)		0/63 (0%)
Herpes zoster	1/154 (0.6%)		0/100 (0%)		0/63 (0%)
Influenza	0/154 (0%)		1/100 (1%)		0/63 (0%)
Listeria sepsis	0/154 (0%)		0/100 (0%)		1/63 (1.6%)
Lower respiratory tract infection	1/154 (0.6%)		0/100 (0%)		0/63 (0%)
Lung infection	1/154 (0.6%)		0/100 (0%)		2/63 (3.2%)
Pneumonia	3/154 (1.9%)		5/100 (5%)		2/63 (3.2%)
Pneumonia bacterial	0/154 (0%)		1/100 (1%)		0/63 (0%)
Pyelonephritis acute	0/154 (0%)		2/100 (2%)		0/63 (0%)
Sepsis	0/154 (0%)		1/100 (1%)		1/63 (1.6%)
Urinary tract infection	0/154 (0%)		3/100 (3%)		0/63 (0%)
Injury, poisoning and procedural complications
Postoperative ileus	0/154 (0%)		1/100 (1%)		0/63 (0%)
Spinal fracture	0/154 (0%)		1/100 (1%)		0/63 (0%)
Traumatic fracture	1/154 (0.6%)		1/100 (1%)		0/63 (0%)
Investigations
Blood creatinine increased	1/154 (0.6%)		0/100 (0%)		2/63 (3.2%)
Electrocardiogram QT prolonged	2/154 (1.3%)		0/100 (0%)		0/63 (0%)
Haemoglobin decreased	1/154 (0.6%)		0/100 (0%)		0/63 (0%)
Transaminases increased	1/154 (0.6%)		0/100 (0%)		0/63 (0%)
Metabolism and nutrition disorders
Decreased appetite	1/154 (0.6%)		0/100 (0%)		0/63 (0%)
Dehydration	4/154 (2.6%)		2/100 (2%)		0/63 (0%)
Diabetic ketoacidosis	0/154 (0%)		1/100 (1%)		0/63 (0%)
Hyperglycaemia	10/154 (6.5%)		6/100 (6%)		1/63 (1.6%)
Hypoglycaemia	0/154 (0%)		1/100 (1%)		0/63 (0%)
Hypokalaemia	1/154 (0.6%)		1/100 (1%)		0/63 (0%)
Hyponatraemia	1/154 (0.6%)		1/100 (1%)		0/63 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/154 (0%)		0/100 (0%)		1/63 (1.6%)
Back pain	3/154 (1.9%)		1/100 (1%)		0/63 (0%)
Bursitis	1/154 (0.6%)		0/100 (0%)		0/63 (0%)
Flank pain	0/154 (0%)		1/100 (1%)		0/63 (0%)
Muscular weakness	0/154 (0%)		2/100 (2%)		1/63 (1.6%)
Musculoskeletal pain	1/154 (0.6%)		0/100 (0%)		1/63 (1.6%)
Osteonecrosis of jaw	1/154 (0.6%)		0/100 (0%)		0/63 (0%)
Pathological fracture	1/154 (0.6%)		1/100 (1%)		1/63 (1.6%)
Spinal column stenosis	0/154 (0%)		1/100 (1%)		0/63 (0%)
Spinal pain	0/154 (0%)		1/100 (1%)		0/63 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm progression	23/154 (14.9%)		4/100 (4%)		7/63 (11.1%)
Malignant pleural effusion	1/154 (0.6%)		0/100 (0%)		0/63 (0%)
Metastases to meninges	1/154 (0.6%)		1/100 (1%)		0/63 (0%)
Myelodysplastic syndrome	0/154 (0%)		1/100 (1%)		0/63 (0%)
Nervous system disorders
Cerebral infarction	0/154 (0%)		0/100 (0%)		1/63 (1.6%)
Cerebrovascular accident	0/154 (0%)		1/100 (1%)		0/63 (0%)
Cognitive disorder	0/154 (0%)		1/100 (1%)		0/63 (0%)
Epilepsy	1/154 (0.6%)		0/100 (0%)		0/63 (0%)
Headache	0/154 (0%)		1/100 (1%)		1/63 (1.6%)
Hypoaesthesia	0/154 (0%)		0/100 (0%)		1/63 (1.6%)
Leukoencephalopathy	1/154 (0.6%)		0/100 (0%)		0/63 (0%)
Partial seizures	1/154 (0.6%)		0/100 (0%)		0/63 (0%)
Seizure	2/154 (1.3%)		1/100 (1%)		0/63 (0%)
Syncope	1/154 (0.6%)		0/100 (0%)		0/63 (0%)
Psychiatric disorders
Agitation	0/154 (0%)		1/100 (1%)		0/63 (0%)
Confusional state	2/154 (1.3%)		1/100 (1%)		0/63 (0%)
Renal and urinary disorders
Acute kidney injury	0/154 (0%)		0/100 (0%)		1/63 (1.6%)
Bladder perforation	1/154 (0.6%)		0/100 (0%)		0/63 (0%)
Cystitis interstitial	1/154 (0.6%)		0/100 (0%)		0/63 (0%)
Haematuria	0/154 (0%)		0/100 (0%)		1/63 (1.6%)
Respiratory, thoracic and mediastinal disorders
Chylothorax	1/154 (0.6%)		0/100 (0%)		0/63 (0%)
Dyspnoea	1/154 (0.6%)		4/100 (4%)		3/63 (4.8%)
Dyspnoea exertional	0/154 (0%)		1/100 (1%)		0/63 (0%)
Hypoxia	1/154 (0.6%)		0/100 (0%)		0/63 (0%)
Pleural effusion	0/154 (0%)		1/100 (1%)		2/63 (3.2%)
Pneumonitis	1/154 (0.6%)		0/100 (0%)		0/63 (0%)
Pneumothorax	1/154 (0.6%)		2/100 (2%)		0/63 (0%)
Pulmonary artery thrombosis	1/154 (0.6%)		0/100 (0%)		0/63 (0%)
Pulmonary embolism	1/154 (0.6%)		1/100 (1%)		0/63 (0%)
Vascular disorders
Deep vein thrombosis	1/154 (0.6%)		0/100 (0%)		0/63 (0%)
Embolism	1/154 (0.6%)		0/100 (0%)		0/63 (0%)
Hypertension	0/154 (0%)		1/100 (1%)		0/63 (0%)
Shock haemorrhagic	1/154 (0.6%)		0/100 (0%)		0/63 (0%)
Other (Not Including Serious) Adverse Events
	Rociletinib 625 mg BID T790M+		Rociletinib 500 mg BID T790M+		Rociletinib 500 mg BID T790M-
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	153/154 (99.4%)		100/100 (100%)		63/63 (100%)
Blood and lymphatic system disorders
Anaemia	32/154 (20.8%)		13/100 (13%)		10/63 (15.9%)
Neutropenia	3/154 (1.9%)		5/100 (5%)		2/63 (3.2%)
Thromobcytopenia	11/154 (7.1%)		1/100 (1%)		1/63 (1.6%)
Eye disorders
Cataract	28/154 (18.2%)		18/100 (18%)		7/63 (11.1%)
Vision blurred	7/154 (4.5%)		8/100 (8%)		2/63 (3.2%)
Gastrointestinal disorders
Abdominal pain	24/154 (15.6%)		15/100 (15%)		6/63 (9.5%)
Abdominal pain upper	18/154 (11.7%)		9/100 (9%)		1/63 (1.6%)
Constipation	38/154 (24.7%)		35/100 (35%)		21/63 (33.3%)
Diarrhoea	91/154 (59.1%)		59/100 (59%)		30/63 (47.6%)
Dry mouth	18/154 (11.7%)		13/100 (13%)		2/63 (3.2%)
Dyspepsia	13/154 (8.4%)		4/100 (4%)		7/63 (11.1%)
Gastrooesophageal reflux disease	16/154 (10.4%)		8/100 (8%)		5/63 (7.9%)
Mouth ulceration	2/154 (1.3%)		2/100 (2%)		5/63 (7.9%)
Nausea	86/154 (55.8%)		58/100 (58%)		31/63 (49.2%)
Stomatitis	9/154 (5.8%)		5/100 (5%)		1/63 (1.6%)
Vomiting	62/154 (40.3%)		35/100 (35%)		21/63 (33.3%)
Abdominal distension	6/154 (3.9%)		6/100 (6%)		0/63 (0%)
General disorders
Asthenia	19/154 (12.3%)		6/100 (6%)		6/63 (9.5%)
Chest pain	11/154 (7.1%)		13/100 (13%)		3/63 (4.8%)
Fatigue	57/154 (37%)		48/100 (48%)		29/63 (46%)
Influenza like illness	8/154 (5.2%)		5/100 (5%)		2/63 (3.2%)
Malaise	4/154 (2.6%)		2/100 (2%)		4/63 (6.3%)
Mucosal inflammation	6/154 (3.9%)		7/100 (7%)		3/63 (4.8%)
Non-cardiac chest pain	8/154 (5.2%)		1/100 (1%)		2/63 (3.2%)
Oedema peripheral	16/154 (10.4%)		6/100 (6%)		8/63 (12.7%)
Pyrexia	21/154 (13.6%)		11/100 (11%)		5/63 (7.9%)
Infections and infestations
Paronychia	2/154 (1.3%)		5/100 (5%)		0/63 (0%)
Pneumonia	7/154 (4.5%)		5/100 (5%)		5/63 (7.9%)
Upper respiratory tract infection	13/154 (8.4%)		8/100 (8%)		4/63 (6.3%)
Urinary tract infection	22/154 (14.3%)		15/100 (15%)		6/63 (9.5%)
Investigations
Alanine aminotransferase increased	21/154 (13.6%)		9/100 (9%)		6/63 (9.5%)
Aspartate aminotransferase increased	18/154 (11.7%)		5/100 (5%)		5/63 (7.9%)
Blood alkaline phosphatase increased	10/154 (6.5%)		6/100 (6%)		4/63 (6.3%)
Blood bilirubin increased	15/154 (9.7%)		3/100 (3%)		2/63 (3.2%)
Blood creatinine increased	12/154 (7.8%)		7/100 (7%)		5/63 (7.9%)
Electrocardiogram QT prolonged	62/154 (40.3%)		29/100 (29%)		19/63 (30.2%)
Platelet count decreased	6/154 (3.9%)		2/100 (2%)		4/63 (6.3%)
Weight decreased	43/154 (27.9%)		28/100 (28%)		15/63 (23.8%)
Metabolism and nutrition disorders
Decreased appetite	62/154 (40.3%)		42/100 (42%)		25/63 (39.7%)
Dehydration	16/154 (10.4%)		5/100 (5%)		2/63 (3.2%)
Hyperglycaemia	97/154 (63%)		64/100 (64%)		33/63 (52.4%)
Hypoalbuminaemia	8/154 (5.2%)		3/100 (3%)		3/63 (4.8%)
Hypokalaemia	18/154 (11.7%)		9/100 (9%)		8/63 (12.7%)
Hypomagnesaemia	12/154 (7.8%)		7/100 (7%)		3/63 (4.8%)
Hyponatraemia	8/154 (5.2%)		8/100 (8%)		3/63 (4.8%)
Musculoskeletal and connective tissue disorders
Arthralgia	22/154 (14.3%)		18/100 (18%)		5/63 (7.9%)
Back pain	16/154 (10.4%)		19/100 (19%)		9/63 (14.3%)
Muscle spasms	35/154 (22.7%)		23/100 (23%)		10/63 (15.9%)
Musculoskeletal chest pain	11/154 (7.1%)		7/100 (7%)		4/63 (6.3%)
Musculoskeletal pain	13/154 (8.4%)		7/100 (7%)		4/63 (6.3%)
Myalgia	15/154 (9.7%)		4/100 (4%)		1/63 (1.6%)
Neck pain	4/154 (2.6%)		5/100 (5%)		2/63 (3.2%)
Pain in extremity	8/154 (5.2%)		7/100 (7%)		3/63 (4.8%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm progression	27/154 (17.5%)		7/100 (7%)		9/63 (14.3%)
Nervous system disorders
Dizziness	21/154 (13.6%)		18/100 (18%)		7/63 (11.1%)
Dysgeusia	10/154 (6.5%)		9/100 (9%)		5/63 (7.9%)
Headache	45/154 (29.2%)		19/100 (19%)		14/63 (22.2%)
Lethargy	3/154 (1.9%)		2/100 (2%)		4/63 (6.3%)
Psychiatric disorders
Anxiety	7/154 (4.5%)		4/100 (4%)		4/63 (6.3%)
Confusional state	8/154 (5.2%)		3/100 (3%)		2/63 (3.2%)
Depression	5/154 (3.2%)		6/100 (6%)		3/63 (4.8%)
Insomnia	13/154 (8.4%)		10/100 (10%)		6/63 (9.5%)
Respiratory, thoracic and mediastinal disorders
Cough	35/154 (22.7%)		25/100 (25%)		18/63 (28.6%)
Dysphonia	2/154 (1.3%)		6/100 (6%)		2/63 (3.2%)
Dyspnoea	28/154 (18.2%)		24/100 (24%)		15/63 (23.8%)
Dyspnoea exertional	5/154 (3.2%)		6/100 (6%)		1/63 (1.6%)
Haemoptysis	4/154 (2.6%)		0/100 (0%)		4/63 (6.3%)
Pleural effusion	7/154 (4.5%)		6/100 (6%)		6/63 (9.5%)
Productive cough	8/154 (5.2%)		4/100 (4%)		4/63 (6.3%)
Rhinorrhoea	2/154 (1.3%)		5/100 (5%)		0/63 (0%)
Skin and subcutaneous tissue disorders
Dry skin	11/154 (7.1%)		8/100 (8%)		2/63 (3.2%)
Pruritus	8/154 (5.2%)		5/100 (5%)		7/63 (11.1%)
Rash	9/154 (5.8%)		9/100 (9%)		2/63 (3.2%)
Vascular disorders
Hypertension	9/154 (5.8%)		4/100 (4%)		3/63 (4.8%)
Hypotension	5/154 (3.2%)		5/100 (5%)		0/63 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

All parties agree to submit all manuscripts or abstracts to all other parties 30 days prior to submission. This will enable all parties to protect proprietary information and to provide comments based on information that may not yet be available to other parties. The sponsor may request a delay in publication if there are important intellectual property concerns relating to publication, but does not have the right to suppress publication of the study results indefinitely.