Study of Oral cMET Inhibitor INC280 in Patients With EGFR Wild-type (wt), Advanced Non-small Cell Lung Cancer (NSCLC) (Geometry Mono-1)

NCT ID: NCT02414139

Last Updated: 2024-03-20

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 373 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-06-11
• Study Completion Date: 2023-05-16

Brief Summary

Study to evaluate the efficacy and safety of capmatinib as a single-agent treatment for subjects with advanced/metastatic (stage IIIB or IV) non-small cell lung cancer (NSCLC) who had wild-type epidermal growth factor receptor (EGFR wt) (for exon 19 deletions and exon 21 L858R substitution mutations), anaplastic lymphoma kinase (ALK)-negative rearrangement, and mesenchymal epithelial transition (MET) mutations leading to exon 14 deletion (referred to as MET mutation hereafter) and/or MET amplification.

Detailed Description

This was a Phase II, multicenter, open-label study. Patients were enrolled in different cohorts based on their MET status (amplification and/or mutation) and prior treatment status: Cohort 1a, Cohort 1b, Cohort 2, Cohort 3, Cohort 4, Cohort 5a, Cohort 5b, Cohort 6, and Cohort 7. MET mutation (by RT-PCR) and/or MET amplification status by gene copy number (GCN, by FISH) was determined by central laboratory.

Patients in Cohorts 1, 2, 3, and 4 had previously failed 1 or 2 prior lines of systemic therapy, while patients enrolled in Cohorts 5 and 7 were treatment-naïve for advanced disease/metastatic disease. Patients enrolled in Cohort 6 had failed 1 prior line of systemic therapy for advanced/ metastatic disease.

Patients with MET mutation were enrolled in Cohort 4 (pre-treated), Cohort 5b (treatment naïve) or Cohort 7 (treatment naïve expansion cohort of Cohort 5b), irrespective of their MET GCN. The enrollment in expansion Cohort 7 started after the completion of enrollment in Cohort 5b.

Patients without MET mutation, were enrolled in Cohorts 1a, 1b, 2, 3 (pre-treated) or 5a (treatment naïve), based on their MET GCN. Patients enrolled in Cohort 6 (expansion cohort of Cohort 1a and Cohort 4) had either MET GCN ≥10 without MET mutation (Cohort 6.1) or MET mutation, irrespective to their MET GCN (Cohort 6.2). The enrollment in Cohort 6 started upon enrollment completion of the respective Cohort 1a or Cohort 4.

All participants in the study received oral capmatinib 400 mg twice daily. A treatment cycle was defined as 21 days. Treatment with capmatinib continued until patient experienced any of the following: disease progression according to RECIST 1.1 as determined by investigator and confirmed by Blinded Independent Review Committee (BIRC), unacceptable toxicity that precluded further treatment, treatment discontinuation at the discretion of the Investigator or patient, lost to follow-up, or death. Treatment with capmatinib was allowed beyond RECIST 1.1-defined disease progression (as determined by investigator and confirmed by BIRC) if, in the judgment of the investigator, there was evidence of clinical benefit and the patient wished to continue on the study treatment. All patients continued to have safety evaluations for 30 days after the last dose of study treatment.

Patients who discontinued treatment with capmatinib for any reason other than disease progression, as determined by the investigator and confirmed by BIRC, death, withdrawal of consent for further assessments, or being lost to follow-up, continued to have tumor assessments (post-treatment efficacy follow-up) until disease progression confirmed by BIRC, death, withdrawal of consent for further assessments, or lost to follow-up.

All patients who discontinued treatment with capmatinib were followed for survival (post-treatment survival follow-up) until death, loss to follow-up, withdrawal of consent to survival follow-up, or the end of the study.

Conditions

Carcinoma, Non-Small-Cell Lung

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Cohort 1a: Pre-treated patients with MET GCN ≥ 10 (2/3L)

Pre-treated patients with MET GCN ≥ 10 treated with INC280 at 400mg BID as second or third line (2/3L)

Group Type: EXPERIMENTAL

Capmatinib

Intervention Type: DRUG

Capmatinib was administered orally, at a dose of 400 mg on a continuous twice daily dosing schedule.

Capmatinib was administered to participants in Cohorts 1a, 1b, 2, 3, 4, 5a and 5b in a fasted state. For Cohorts 6.1. 6.2 and 7, capmatinib was administered either with or without food.

Cohort 1b:Pre-treated patients with MET GCN ≥ 6 and < 10 (2/3L)

Pre-treated patients with MET GCN ≥ 6 and \< 10 treated with INC280 at 400 mg BID as second or third line (2/3L)

Group Type: EXPERIMENTAL

Capmatinib

Intervention Type: DRUG

Capmatinib was administered orally, at a dose of 400 mg on a continuous twice daily dosing schedule.

Capmatinib was administered to participants in Cohorts 1a, 1b, 2, 3, 4, 5a and 5b in a fasted state. For Cohorts 6.1. 6.2 and 7, capmatinib was administered either with or without food.

Cohort 2: Pre-treated patients with MET GCN ≥ 4 and < 6 (2/3L)

Pre-treated patients with MET GCN ≥ 4 and \< 6 treated with INC280 at 400mg BID as second or third line (2/3L)

Group Type: EXPERIMENTAL

Capmatinib

Intervention Type: DRUG

Capmatinib was administered orally, at a dose of 400 mg on a continuous twice daily dosing schedule.

Capmatinib was administered to participants in Cohorts 1a, 1b, 2, 3, 4, 5a and 5b in a fasted state. For Cohorts 6.1. 6.2 and 7, capmatinib was administered either with or without food.

Cohort 3: Pre-treated patients with MET GCN < 4 (2/3L)

Pre-treated patients with MET GCN \< 4 treated with INC280 at 400mg BID as second or third line (2/3L)

Group Type: EXPERIMENTAL

Capmatinib

Intervention Type: DRUG

Capmatinib was administered orally, at a dose of 400 mg on a continuous twice daily dosing schedule.

Capmatinib was administered to participants in Cohorts 1a, 1b, 2, 3, 4, 5a and 5b in a fasted state. For Cohorts 6.1. 6.2 and 7, capmatinib was administered either with or without food.

Cohort 4: Pre-treated patients with MET mutation regardless of MET GCN (2/3L)

Pre-treated patients with MET mutation regardless of MET GCN treated with INC280 at 400mg BID as second or third line (2/3L)

Group Type: EXPERIMENTAL

Capmatinib

Intervention Type: DRUG

Capmatinib was administered orally, at a dose of 400 mg on a continuous twice daily dosing schedule.

Capmatinib was administered to participants in Cohorts 1a, 1b, 2, 3, 4, 5a and 5b in a fasted state. For Cohorts 6.1. 6.2 and 7, capmatinib was administered either with or without food.

Cohort 5a: Treatment-naïve patients with MET GCN ≥10 (1L)

Treatment-naïve patients with MET GCN ≥10 treated with INC280 at 400mg BID as first-line (1L)

Group Type: EXPERIMENTAL

Capmatinib

Intervention Type: DRUG

Capmatinib was administered orally, at a dose of 400 mg on a continuous twice daily dosing schedule.

Capmatinib was administered to participants in Cohorts 1a, 1b, 2, 3, 4, 5a and 5b in a fasted state. For Cohorts 6.1. 6.2 and 7, capmatinib was administered either with or without food.

Cohort 5b: Treatment-naïve patients with MET mutation regardless of MET GCN (1L)

Treatment-naïve patients with MET mutation regardless of MET GCN treated with INC280 at 400mg BID as first line (1L)

Group Type: EXPERIMENTAL

Capmatinib

Intervention Type: DRUG

Capmatinib was administered orally, at a dose of 400 mg on a continuous twice daily dosing schedule.

Capmatinib was administered to participants in Cohorts 1a, 1b, 2, 3, 4, 5a and 5b in a fasted state. For Cohorts 6.1. 6.2 and 7, capmatinib was administered either with or without food.

Cohort 6.1 (expansion of Cohort 1a): Pre-treated patients MET GCN ≥ 10 without MET mutation (2L)

Pre-treated patients with MET GCN ≥ 10 without MET mutation treated with INC280 at 400 mg BID as second line (2L) (expansion cohort of Cohort 1a)

Group Type: EXPERIMENTAL

Capmatinib

Intervention Type: DRUG

Capmatinib was administered orally, at a dose of 400 mg on a continuous twice daily dosing schedule.

Capmatinib was administered to participants in Cohorts 1a, 1b, 2, 3, 4, 5a and 5b in a fasted state. For Cohorts 6.1. 6.2 and 7, capmatinib was administered either with or without food.

Cohort 6.2 (expansion of Cohort 4): Pre-treated patients with MET mutation (2L)

Pre-treated patients with MET mutation regardless of MET GCN treated with INC280 at 400 mg BID as second line (2L)(expansion of Cohort 4)

Group Type: EXPERIMENTAL

Capmatinib

Intervention Type: DRUG

Capmatinib was administered orally, at a dose of 400 mg on a continuous twice daily dosing schedule.

Capmatinib was administered to participants in Cohorts 1a, 1b, 2, 3, 4, 5a and 5b in a fasted state. For Cohorts 6.1. 6.2 and 7, capmatinib was administered either with or without food.

Cohort 7 (expansion of Cohort 5b): Treatment-naïve with MET mutation regardless of MET GCN (1L)

Treatment-naïve patients with MET mutation regardless of MET GCN treated with INC280 at 400mg BID as first line (1L) (expansion cohort of Cohort 5b)

Group Type: EXPERIMENTAL

Capmatinib

Intervention Type: DRUG

Capmatinib was administered orally, at a dose of 400 mg on a continuous twice daily dosing schedule.

Capmatinib was administered to participants in Cohorts 1a, 1b, 2, 3, 4, 5a and 5b in a fasted state. For Cohorts 6.1. 6.2 and 7, capmatinib was administered either with or without food.

Interventions

Capmatinib

Capmatinib was administered orally, at a dose of 400 mg on a continuous twice daily dosing schedule.

Capmatinib was administered to participants in Cohorts 1a, 1b, 2, 3, 4, 5a and 5b in a fasted state. For Cohorts 6.1. 6.2 and 7, capmatinib was administered either with or without food.

Intervention Type: DRUG

Other Intervention Names

INC280

Eligibility Criteria

Inclusion Criteria

• Subjects with Stage IIIB or IV NSCLC (any histology) at the time of study entry
• Subjects with histologically or cytologically confirmed diagnosis of NSCLC that is:

1. EGFR wt status (for exon 19 deletions and exon 21 L858R substitution mutations)

2. and ALK rearrangement-negative

3. and MET-mutation and/or amplification status (as defined in the protocol).

• For Cohorts 1a, 1b, 2, 3, 4 subjects must have failed one or two prior lines of systemic therapy for advanced disease (stage IIIB or IV NSCLC). For Cohort 6, subjects must have failed one prior line of systemic therapy for advanced disease (stage IIIB or IV NSCLC).
• For Cohorts 5a, 5b, and 7, subjects must not have received any systemic therapy for advanced disease (stage IIIB or IV NSCLC).
• Subjects with at least one measurable lesion as defined by RECIST 1.1. A previously irradiated site lesion may only be counted as a target lesion if there was clear sign of progression since the irradiation.
• Subjects who recovered from all toxicities related to prior anticancer therapies to grade ≤ 1 (Common Terminology Criteria for Adverse Events [CTCAE] v 4.03). Subjects with any grade of alopecia were allowed to enter the study.
• Subjects with adequate organ function
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1

Exclusion Criteria

• Prior treatment with crizotinib, or any other MET or HGF inhibitor
• Characterized EGFR mutations that predict sensitivity to EGFR therapy, including, but not limited to exon 19 deletions and exon 21 mutations.
• Characterized ALK-positive rearrangement.
• 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.
• Clinically significant, uncontrolled heart diseases
• Thoracic radiotherapy to lung fields ≤ 4 weeks prior to starting capmatinib or subjects who had not recovered from radiotherapy-related toxicities. For all other anatomic sites (including radiotherapy to thoracic vertebrae and ribs), radiotherapy ≤ 2 weeks prior to starting capmatinib or subjects who had not recovered from radiotherapy-related toxicities.

Palliative radiotherapy for bone lesions ≤ 2 weeks prior to starting capmatinib was allowed.

• Receiving treatment with strong inducers of CYP3A4 and/or any enzyme-inducing anticonvulsant and could not be discontinued ≥ 1 week prior to the start of treatment with capmatinib and for the duration of the study.
• Receiving treatment with unstable or increasing doses of corticosteroids.
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of capmatinib.
• Applicable to Cohorts 1-4 and Cohort 6 only: previous anticancer and investigational agents within 4 weeks or ≤ 5 × half-life of the agent (whichever was longer) before first dose of- capmatinib. If previous treatment was a monoclonal antibody, then the treatment must have been discontinued ≥ 4 weeks before first dose of capmatinib. If previous treatment was an oral targeted agent, then the treatment must have been discontinued ≥ 5 × half-life of the agent before the first dose of capmatinib.
• Pregnant or nursing (lactating) women.
• Women of child-bearing potential, unless they are using highly effective methods of contraception during dosing and for 7 days after stopping treatment
• Sexually active males unless they used a condom during intercourse while taking drug and for 7 days after stopping treatment and should not father a child in this period.
• 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).

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Novartis Pharmaceuticals

Role: STUDY_DIRECTOR

Novartis Pharmaceuticals

Locations

Novartis Investigative Site

Amsterdam, , Netherlands

Novartis Investigative Site

Groningen, , Netherlands

Pacific Shores Medical Group SC

Long Beach, California, United States

University Of California Los Angeles Dept of Onc

Los Angeles, California, United States

University of California Irvine Medical Center Chao Family Chao Family Comp Cancer Center

Orange, California, United States

H Lee Moffitt Cancer Center and Research Institute .

Tampa, Florida, United States

University of Iowa Hospitals and Clinics SC-3

Iowa City, Iowa, United States

Massachusetts General Hospital MGH Cancer Center

Boston, Massachusetts, United States

VA Ann Arbor Health System VA Ann Arbor Health System

Ann Arbor, Michigan, United States

Mayo Clinic Rochester .

Rochester, Minnesota, United States

Oregon Health and Science University SC

Portland, Oregon, United States

Lehigh Valley Health Network SC

Allentown, Pennsylvania, United States

Andrew and Patel Associates

Camp Hill, Pennsylvania, United States

Mays Cancer Ctr Uthsa Mdacc SC-5

San Antonio, Texas, United States

University of Utah / Huntsman Cancer Institute Oncology

Salt Lake City, Utah, United States

Novartis Investigative Site

CABA, Buenos Aires, Argentina

Novartis Investigative Site

Buenos Aires, Buenos Aires F.D., Argentina

Novartis Investigative Site

La Rioja, , Argentina

Novartis Investigative Site

Vienna, , Austria

Novartis Investigative Site

Leuven, , Belgium

Novartis Investigative Site

Marseille, Bouches Du Rhone, France

Novartis Investigative Site

Dijon, Cote D Or, France

Novartis Investigative Site

Clermont-Ferrand, , France

Novartis Investigative Site

La Tronche, , France

Novartis Investigative Site

Lille, , France

Novartis Investigative Site

Marseille, , France

Novartis Investigative Site

Paris, , France

Novartis Investigative Site

Pierre-Bénite, , France

Novartis Investigative Site

Rennes, , France

Novartis Investigative Site

Strasbourg, , France

Novartis Investigative Site

Heidelberg, Baden-Wurttemberg, Germany

Novartis Investigative Site

Berlin, , Germany

Novartis Investigative Site

Cologne, , Germany

Novartis Investigative Site

Frankfurt, , Germany

Novartis Investigative Site

Göttingen, , Germany

Novartis Investigative Site

Halle, , Germany

Novartis Investigative Site

Hamburg, , Germany

Novartis Investigative Site

Hanover, , Germany

Novartis Investigative Site

Homburg, , Germany

Novartis Investigative Site

München, , Germany

Novartis Investigative Site

Nuremberg, , Germany

Novartis Investigative Site

Ravensburg, , Germany

Novartis Investigative Site

Tübingen, , Germany

Novartis Investigative Site

Ulm, , Germany

Novartis Investigative Site

Ramat Gan, , Israel

Novartis Investigative Site

Tel Aviv, , Israel

Novartis Investigative Site

Bologna, BO, Italy

Novartis Investigative Site

Brescia, BS, Italy

Novartis Investigative Site

Catania, CT, Italy

Novartis Investigative Site

Catanzaro, CZ, Italy

Novartis Investigative Site

Meldola, FC, Italy

Novartis Investigative Site

Florence, FI, Italy

Novartis Investigative Site

Monza, MB, Italy

Novartis Investigative Site

Milan, MI, Italy

Novartis Investigative Site

Milan, MI, Italy

Novartis Investigative Site

Modena, MO, Italy

Novartis Investigative Site

Roma, RM, Italy

Novartis Investigative Site

Verona, VR, Italy

Novartis Investigative Site

Napoli, , Italy

Novartis Investigative Site

Nagoya, Aichi-ken, Japan

Novartis Investigative Site

Nagoya, Aichi-ken, Japan

Novartis Investigative Site

Fukuoka, Fukuoka, Japan

Novartis Investigative Site

Akashi, Hyōgo, Japan

Novartis Investigative Site

Sendai, Miyagi, Japan

Novartis Investigative Site

Okayama, Okayama-ken, Japan

Novartis Investigative Site

Ōsaka-sayama, Osaka, Japan

Novartis Investigative Site

Chuo Ku, Tokyo, Japan

Novartis Investigative Site

Koto Ku, Tokyo, Japan

Novartis Investigative Site

Ube, Yamaguchi, Japan

Novartis Investigative Site

El Achrafiyé, , Lebanon

Novartis Investigative Site

Mexico City, Mexico City, Mexico

Novartis Investigative Site

Maastricht, , Netherlands

Novartis Investigative Site

Rotterdam, , Netherlands

Novartis Investigative Site

Oslo, , Norway

Novartis Investigative Site

Moscow, , Russia

Novartis Investigative Site

Saint Petersburg, , Russia

Novartis Investigative Site

Tambov, , Russia

Novartis Investigative Site

Singapore, , Singapore

Novartis Investigative Site

Singapore, , Singapore

Novartis Investigative Site

Bundang Gu, Gyeonggi-do, South Korea

Novartis Investigative Site

Gyeonggi-do, Korea, South Korea

Novartis Investigative Site

Seoul, , South Korea

Novartis Investigative Site

Seville, Andalusia, Spain

Novartis Investigative Site

Barcelona, Catalonia, Spain

Novartis Investigative Site

Barcelona, Catalonia, Spain

Novartis Investigative Site

A Coruña, Galicia, Spain

Novartis Investigative Site

Oviedo, Principality of Asturias, Spain

Novartis Investigative Site

Madrid, , Spain

Novartis Investigative Site

Madrid, , Spain

Novartis Investigative Site

Stockholm, , Sweden

Novartis Investigative Site

Kaohsiung City, , Taiwan

Novartis Investigative Site

Taipei, , Taiwan

Novartis Investigative Site

Taoyuan District, , Taiwan

Novartis Investigative Site

Birmingham, , United Kingdom

Novartis Investigative Site

London, , United Kingdom

Countries

United States; Argentina; Austria; Belgium; France; Germany; Israel; Italy; Japan; Lebanon; Mexico; Netherlands; Norway; Russia; Singapore; South Korea; Spain; Sweden; Taiwan; United Kingdom

References

Wolf J, Hochmair M, Han JY, Reguart N, Souquet PJ, Smit EF, Orlov SV, Vansteenkiste J, Nishio M, de Jonge M, Akerley W, Garon EB, Groen HJM, Tan DSW, Seto T, Frampton GM, Robeva A, Carbini M, Le Mouhaer S, Yovine A, Boran A, Bossen C, Yang Y, Ji L, Fairchild L, Heist RS. Capmatinib in MET exon 14-mutated non-small-cell lung cancer: final results from the open-label, phase 2 GEOMETRY mono-1 trial. Lancet Oncol. 2024 Oct;25(10):1357-1370. doi: 10.1016/S1470-2045(24)00441-8.

Reference Type: DERIVED

PMID: 39362249 (View on PubMed)

Wolf J, Garon EB, Groen HJM, Tan DSW, Gilloteau I, Le Mouhaer S, Hampe M, Cai C, Chassot-Agostinho A, Reynolds M, Sherif B, Heist RS. Patient-reported outcomes in capmatinib-treated patients with METex14-mutated advanced NSCLC: Results from the GEOMETRY mono-1 study. Eur J Cancer. 2023 Apr;183:98-108. doi: 10.1016/j.ejca.2022.10.030. Epub 2022 Dec 10.

Reference Type: DERIVED

PMID: 36822130 (View on PubMed)

Wolf J, Seto T, Han JY, Reguart N, Garon EB, Groen HJM, Tan DSW, Hida T, de Jonge M, Orlov SV, Smit EF, Souquet PJ, Vansteenkiste J, Hochmair M, Felip E, Nishio M, Thomas M, Ohashi K, Toyozawa R, Overbeck TR, de Marinis F, Kim TM, Laack E, Robeva A, Le Mouhaer S, Waldron-Lynch M, Sankaran B, Balbin OA, Cui X, Giovannini M, Akimov M, Heist RS; GEOMETRY mono-1 Investigators. Capmatinib in MET Exon 14-Mutated or MET-Amplified Non-Small-Cell Lung Cancer. N Engl J Med. 2020 Sep 3;383(10):944-957. doi: 10.1056/NEJMoa2002787.

Reference Type: DERIVED

PMID: 32877583 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

https://www.novctrd.com/ctrdweb/trialresult/trialresults/pdf?trialResultId=17663

For interim results on this study, please click the link below to the NovartisClinicalTrial.com website

Other Identifiers

2014-003850-15

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CINC280A2201

Identifier Type: -

Identifier Source: org_study_id