GeoMETry-III: Study of Capmatinib Efficacy in Comparison With Docetaxel in Previously Treated Participants With Non-small Cell Lung Cancer Harboring MET Exon 14 Skipping Mutation

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04427072

Collaborator

(none)

Enrollment

Locations

Arms

54.9

Anticipated Duration (Months)

1.3

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of the study is to learn whether the study drug (capmatinib) helps to control lung cancer better compared to a single agent chemotherapy (docetaxel) and whether it is safe when given to patients suffering from a particular type of lung cancer. This type of cancer is called non-small cell lung cancer (NSCLC) with certain specific genetic alterations (called mutations) of a gene called MET, within a specific part of the gene called exon 14.

Condition or Disease	Intervention/Treatment	Phase
Carcinoma, Non-Small-Cell Lung	Drug: Capmatinib Drug: Docetaxel	Phase 3

Detailed Description

Approximately 90 patients with advanced or metastatic lung cancer, with these specific mutations in the MET gene but without changes in their epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genes, will be enrolled in this study. Participants will be randomly assigned to get either capmatinib or docetaxel in a 2 to 1 ratio. The randomization will be stratified by prior lines of systemic therapy received for advanced/metastatic disease (one line vs. two lines).

During treatment, visits will be scheduled every 21 days.

For all participants, the respective treatment (either with capmatinib or docetaxel) may be continued beyond initial disease progression as per RECIST 1.1 (as assessed by the investigator and confirmed by BIRC) if, in the judgment of the investigator, there is evidence of clinical benefit, and the participant wishes to continue on the study treatment. After treatment discontinuation, all participants will be followed for safety evaluations during the safety follow-up period, and the participant's status will be collected every 12 weeks as part of the survival follow-up.

Participants randomized to docetaxel treatment will be eligible to crossover to receive capmatinib treatment after BIRC-confirmed, RECIST 1.1-defined progressive disease and after meeting the eligibility criteria prior to crossover.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

90 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Participants randomized to docetaxel treatment will be eligible to crossover to receive capmatinib treatment after blinded independent review committee (BIRC)-confirmed, RECIST 1.1- defined disease progression.Participants randomized to docetaxel treatment will be eligible to crossover to receive capmatinib treatment after blinded independent review committee (BIRC)-confirmed, RECIST 1.1- defined disease progression.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase III, Randomized, Controlled, Open-label, Multicenter, Global Study of Capmatinib Versus SoC Docetaxel Chemotherapy in Previously Treated Patients With EGFR wt, ALK Negative, Locally Advanced or Metastatic (Stage IIIB/IIIC or IV) NSCLC Harboring MET Exon 14 Skipping Mutation (METΔex14).

Actual Study Start Date :

Sep 25, 2020

Anticipated Primary Completion Date :

Apr 22, 2025

Anticipated Study Completion Date :

Apr 22, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Capmatinib 400mg of capmatinib tablets, administered orally twice daily	Drug: Capmatinib 400mg of capmatinib tablets administered orally twice daily Other Names: INC280
Active Comparator: Docetaxel Docetaxel 75 mg/m2 solution administered by intravenous infusion on Day 1 of every 21-day cycle	Drug: Docetaxel Docetaxel 75 mg/m2 by intravenous infusion every 21 days

Arm

Intervention/Treatment

Experimental: Capmatinib

400mg of capmatinib tablets, administered orally twice daily

Drug: Capmatinib

400mg of capmatinib tablets administered orally twice daily

Other Names:

INC280

Active Comparator: Docetaxel

Docetaxel 75 mg/m2 solution administered by intravenous infusion on Day 1 of every 21-day cycle

Drug: Docetaxel

Docetaxel 75 mg/m2 by intravenous infusion every 21 days

Outcome Measures

Primary Outcome Measures

Progression free survival (PFS) per blinded independent review committee (BIRC) using RECIST v1.1 [From randomization to the date of first documented progression or death from any cause, whichever comes first, assessed up to approximately 21 months]
Progression free survival is defined as the time from the date of randomization to the date of the first documented progression assessed by BIRC according to RECIST 1.1, or death due to any cause

Secondary Outcome Measures

Overall response (ORR) per RECIST 1.1 by BIRC [Up to approximately 21 months]
Percentage of participants with confirmed best overall response (BOR) of complete response (CR) or partial response (PR), assessed by BIRC according to RECIST 1.1.
Overall response (ORR) per RECIST 1.1 by investigator [Up to approximately 21 months]
Percentage of participants with confirmed BOR of CR or PR, assessed by local review according to RECIST 1.1.
Time to response (TTR) per RECIST 1.1 by BIRC [From date of randomization to first documented response of either CR or PR, assessed up to approximately 21 months]
Time from date of randomization to first documented response of either CR or PR, which must be subsequently confirmed, assessed by BIRC according to RECIST 1.1.
Time to response (TTR) per RECIST 1.1 by investigator [From date of randomization to first documented response of either CR or PR, assessed up to approximately 21 months]
Time from date of randomization to first documented response of either CR or PR, which must be subsequently confirmed, assessed by local review according to RECIST 1.1.
Duration of response (DOR) per RECIST 1.1 by BIRC [From first documented response to first documented progression or death due to any cause, whichever comes first, assessed up to approximately 21 months]
Time from the date of first documented response (CR or PR) to the first documented progression by BIRC per RECIST 1.1 or death due to any cause.
Duration of response (DOR) per RECIST 1.1 by investigator [From first documented response to first documented progression or death due to any cause, whichever comes first, assessed up to approximately 21 months]
Time from the date of first documented response (CR or PR) to the first documented progression by local review per RECIST 1.1 or death due to any cause.
Disease Control Rate (DCR) per RECIST 1.1 by BIRC [Up to approximately 21 months]
Percentage of participants with a BOR of confirmed CR, PR and stable disease (SD) assessed by BIRC according to RECIST 1.1
Disease Control Rate (DCR) per RECIST 1.1 by investigator [Up to approximately 21 months]
Percentage of participants with a BOR of confirmed CR, PR and SD assessed by local review according to RECIST 1.1
Progression free survival (PFS) per investigator using RECIST v1.1 [From randomization to the date of first documented progression or death from any cause, whichever comes first, assessed up to approximately 21 months]
Time from the date of randomization to the date of the first documented progression assessed by local review according to RECIST 1.1, or death due to any cause
Overall survival (OS) [From randomization to death due to any cause, assessed up to approximately 42 months]
OS is defined as the time from the date of randomization to the date of death due to any cause.
Overall intracranial response rate (OIRR) [Up to approximately 21 months]
Percentage of participants with confirmed best overall intracranial response (BOIR) of CR or partial response (PR), as assessed by BIRC review per RANO-BM criteria.
Duration of intracranial response (DOIR) [From date of first documented intracranial response (CR or PR) to first documented intracranial progression, assessed up to approximately 21 months]
Time from date of first documented intracranial response (CR or PR) to first documented intracranial progression per RANO-BM assessed by BIRC or date of death due to underlying cause of cancer.
Time to intracranial response (TTIR) [From date of randomization to first documented intracranial response of either CR or PR, assessed up to approximately 21 months]
Time from date of randomization to first documented intracranial response of either CR or PR, per RANO-BM criteria and assessed by BIRC, which must be subsequently confirmed.
Intracranial disease control rate (IDCR) [Up to approximately 21 months]
Percentage of participants with a BOR of confirmed CR, PR and stable disease (SD) (or non-CR/non-PD) per RANO-BM, assessed by BIRC.
Plasma capmatinib concentration [Cycle (C) 1 Day (D) 15 pre-dose, 1 and 4 hours post-dose, C3 D1 pre-dose. Each cycle duration is 21 days.]
Plasma concentrations of capmatinib. Blood samples will be collected at indicated time points for pharmacokinetic analysis.
Change from baseline in score as per European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 [Cycle (C) 1 Day (D) 1, C3 D1 and then every 6 weeks up to approximately 21 months, end of treatment and 6, 12 , 18 weeks post treatment . Each cycle duration is 21 days.]
EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. The questionnaire is composed of both multi-item scales and single-item measures based on the participants experience over the past week. These include five domains (physical, role, emotional, cognitive and social functioning), three symptom scales (fatigue, nausea/vomiting, and pain), six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial impact) and a global health status/HRQoL scale. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. Change from baseline in EORTC QLQ-C30 scores will be assessed
Change from baseline in score as per European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Lung Cancer Module (QLQ-LC13) [Cycle (C) 1 Day (D) 1, C3 D1 and then every 6 weeks up to approximately 21 months, end of treatment and 6, 12 , 18 weeks post treatment . Each cycle duration is 21 days.]
EORTC QLQ-LC13 is a 13-item lung cancer specific questionnaire. The five domains of the questionnaire include pain, dyspnea, coughing and hemoptysis, and are based on their presence over the past week. All but the pain domain are scored on a 4 point Likert scale ranging from "not at all" to "very much". Pain is score based on its presence, hence yes or no. A higher score indicates a higher presence of symptoms. Change from baseline in EORTC QLQ-LC13 scores will be assessed
Change from baseline in score as per European Quality of Life 5-Dimension 5-Level (EQ-5D-5L) questionnaire [Cycle (C) 1 Day (D) 1, C3 D1 and then every 6 weeks up to approximately 21 months, end of treatment and 6, 12 , 18 weeks post treatment . Each cycle duration is 21 days.]
EQ-5D-5L is a standardized measure to assess the overall health-related quality of life in patients. The EQ-5D-5L consists of 2 parts- the descriptive system and the EQ visual analogue scale (EQ VAS). The descriptive system comprises 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each with 5 levels: from 1 (no problems) to 5 (extreme problems). The EQ VAS is a self-perceived health score assessed using a visual analogue scale that ranges from 0 (the worst imaginable health) to 100 (the best imaginable health), with higher scores indicating higher health utility. Change from baseline in EQ-5D-5L scores will be assessed
Time to symptom deterioration for chest pain, cough and dyspnea assessed using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Lung Cancer Module (QLQ-LC13) [Cycle (C) 1 Day (D) 1, C3 D1 and then every 6 weeks up to approximately 21 months, end of treatment and 6, 12 , 18 weeks post treatment. Each cycle duration is 21 days.]
EORTC QLQ-LC13 is a 13-item lung cancer specific questionnaire. The five domains of the questionnaire include pain, dyspnea, coughing and hemoptysis, and are based on their presence over the past week. All but the pain domain are scored on a 4 point Likert scale ranging from "not at all" to "very much". Pain is score based on its presence, hence yes or no. A higher score indicates a higher presence of symptoms. Time to symptom deterioration for chest pain, cough and dyspnea will be assessed
Time to deterioration for global health status /QoL assessed using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 [Cycle (C) 1 Day (D) 1, C3 D1 and then every 6 weeks up to approximately 21 months, end of treatment and 6, 12 , 18 weeks post treatment. Each cycle duration is 21 days.]
EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. The questionnaire is composed of both multi-item scales and single-item measures based on the participants experience over the past week. These include five domains (physical, role, emotional, cognitive and social functioning), three symptom scales (fatigue, nausea/vomiting, and pain), six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial impact) and a global health status/HRQoL scale. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. Time to deterioration in QoL from EORTC-QLQ-C30 will be assessed.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Key Inclusion Criteria:

Stage IIIB/IIIC (not amenable to surgery, radiation or multi modality therapy) or IV NSCLC (according to Version 8 of the American Joint Committee on Cancer (AJCC) Staging Manual) at the time of study entry.
Histologically or cytologically confirmed diagnosis of NSCLC that is:

EGFR wt. Assessed as part of participant's standard of care by a validated test for EGFR mutations as per local guidelines. The EGFR wt status (for EGFR mutations that predict sensitivity to EGFR therapy, including, but not limited to exon 19 deletions and exon 21 L858R substitution mutations.
AND ALK rearrangement negative. Assessed as part of participant's standard of care by a validated test.
AND has METΔex14 mutation as determined by Novartis-designated central laboratory or by locally performed, tissue-based test, validated according to local regulation, from a Clinical Laboratory Improvement Amendments (CLIA)-certified US laboratory or an accredited local laboratory outside of the US. The positive METΔex14 mutation result as determined per local test must be documented in the participant's source documents and in the CRF prior to entering main screening.

Mandatory provision of a formalin-fixed, paraffin embedded tumor tissue sample (archival tumor block or slides, or a newly obtained tumor sample) with quality and quantity sufficient to allow assessment of METΔex14 mutation status (as defined in the study [laboratory manual]). This pertains to all participants, including those who have a METΔex14 mutation result from a local test. Tumor samples must contain at least 10% tumor content.

Participants must have progressed on one or two prior lines of

Progressed on one or two prior lines of systemic therapy for advanced/metastatic disease (stage IIIB/IIIC [not candidates for surgery, radiation or multi modality therapy] or IV NSCLC) and must be docetaxel naïve and candidates for single agent chemotherapy (docetaxel). Treatment failure is defined as documented disease progression or intolerance to treatment., however participants must have progressed on or after the last therapy before study entry.
At least one measurable lesion as defined by RECIST 1.1
Adequate organ function
Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.
Participants must have a life expectancy of at least 3 months.

Key Exclusion Criteria:

Prior treatment with any MET inhibitor or HGF-targeting therapy.
Participants with symptomatic central nervous system (CNS) metastases who are neurologically unstable or have required increasing doses of steroids within the 2 weeks prior to study entry to manage CNS symptoms.
Participants with known druggable molecular alterations (such as ROS1and RET rearrangement, BRAF mutation, KRAS mutation, NTRK fusion, etc.) which might be a candidate for alternative targeted therapies.
Presence or history of interstitial lung disease or interstitial pneumonitis, including clinically significant radiation pneumonitis (i.e., affecting activities of daily living or requiring therapeutic intervention).
Substance abuse, active infection or other severe, acute, or chronic medical or psychotic conditions or laboratory abnormalities that in the opinion of the investigator may increase the risk associated with study participation

Other protocol-defined inclusion/exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Melbourne	Victoria	Australia	3000
2	Novartis Investigative Site	Leuven		Belgium	3000
3	Novartis Investigative Site	Roeselare		Belgium	8800
4	Novartis Investigative Site	Barretos	SP	Brazil	14784 400
5	Novartis Investigative Site	Sao Paulo	SP	Brazil	01246 000
6	Novartis Investigative Site	Sao Paulo	SP	Brazil	04014-002
7	Novartis Investigative Site	Pleven		Bulgaria	5800
8	Novartis Investigative Site	Sofia		Bulgaria	1303
9	Novartis Investigative Site	Sofia		Bulgaria	1407
10	Novartis Investigative Site	Le Mans	Cedex 09	France	72037
11	Novartis Investigative Site	Angers Cedex 9		France	49933
12	Novartis Investigative Site	Bordeaux		France	33076
13	Novartis Investigative Site	Caen Cedex		France	14021
14	Novartis Investigative Site	Clermont-Ferrand		France	63011
15	Novartis Investigative Site	Paris		France	75231
16	Novartis Investigative Site	Paris		France	75877
17	Novartis Investigative Site	Pierre Benite Cedex		France	69495
18	Novartis Investigative Site	Rennes		France	35043
19	Novartis Investigative Site	Regensburg	Bavaria	Germany	93053
20	Novartis Investigative Site	Gauting	Bayern	Germany	82131
21	Novartis Investigative Site	Berlin		Germany	13125
22	Novartis Investigative Site	Berlin		Germany	14165
23	Novartis Investigative Site	Frankfurt		Germany	60488
24	Novartis Investigative Site	Gottingen		Germany	37075
25	Novartis Investigative Site	Grosshansdorf		Germany	22947
26	Novartis Investigative Site	Koeln		Germany	50937
27	Novartis Investigative Site	Oldenburg		Germany	26121
28	Novartis Investigative Site	Ulm		Germany	89081
29	Novartis Investigative Site	Torokbalint	Pest	Hungary	2045
30	Novartis Investigative Site	Budapest		Hungary	1121
31	Novartis Investigative Site	New Delhi	Delhi	India	110076
32	Novartis Investigative Site	Pune	Maharashtra	India	411013
33	Novartis Investigative Site	Vellore	Tamil Nadu	India	632 004
34	Novartis Investigative Site	Bologna	BO	Italy	40138
35	Novartis Investigative Site	Meldola	FC	Italy	47014
36	Novartis Investigative Site	Genova	GE	Italy	16132
37	Novartis Investigative Site	Milano	MI	Italy	20141
38	Novartis Investigative Site	Milano	MI	Italy	20162
39	Novartis Investigative Site	Padova	PD	Italy	35100
40	Novartis Investigative Site	Aviano	PN	Italy	33081
41	Novartis Investigative Site	Parma	PR	Italy	43100
42	Novartis Investigative Site	Reggio Emilia	RE	Italy	42123
43	Novartis Investigative Site	Roma	RM	Italy	00128
44	Novartis Investigative Site	Gyeonggi do	Korea	Korea, Republic of	10408
45	Novartis Investigative Site	Seoul		Korea, Republic of	05505
46	Novartis Investigative Site	Vilnius		Lithuania	LT-08660
47	Novartis Investigative Site	Kuantan	Pahang	Malaysia	25100
48	Novartis Investigative Site	Kuala Lumpur	Wilayah Persekutuan	Malaysia	50586
49	Novartis Investigative Site	Pulau Pinang		Malaysia	10990
50	Novartis Investigative Site	Nijmegen		Netherlands	6500 HB
51	Novartis Investigative Site	Lisboa		Portugal	1769-001
52	Novartis Investigative Site	Matosinhos		Portugal	4454 513
53	Novartis Investigative Site	Porto		Portugal	4200-072
54	Novartis Investigative Site	Arkhangelsk		Russian Federation	163045
55	Novartis Investigative Site	Chelyabinsk		Russian Federation	454048
56	Novartis Investigative Site	Nizhniy Novgorod		Russian Federation	603081
57	Novartis Investigative Site	Omsk		Russian Federation	644013
58	Novartis Investigative Site	Pushkin Saint Petersburg		Russian Federation	196603
59	Novartis Investigative Site	St- Petersburg		Russian Federation	197022
60	Novartis Investigative Site	Port Elizabeth	Western Cape	South Africa	6045
61	Novartis Investigative Site	Cape Town		South Africa	7500
62	Novartis Investigative Site	Malaga	Andalucia	Spain	29010
63	Novartis Investigative Site	Oviedo	Asturias	Spain	33011
64	Novartis Investigative Site	Hospitalet de LLobregat	Catalunya	Spain	08907
65	Novartis Investigative Site	Valencia	Comunidad Valenciana	Spain	46026
66	Novartis Investigative Site	La Coruna	Galicia	Spain	15006
67	Novartis Investigative Site	Madrid		Spain	28009
68	Novartis Investigative Site	Madrid		Spain	28041
69	Novartis Investigative Site	Songkhla	Hat Yai	Thailand	90110
70	Novartis Investigative Site	Bangkok		Thailand	10700
71	Novartis Investigative Site	Hanoi		Vietnam	100000