Clinical trial NCT04427072: Study of Capmatinib Efficacy in Comparison With Docetaxel in Previously Treated Participants With Non-small Cell Lung Cancer Harboring MET Exon 14 Skipping Mutation
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).
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Carcinoma, Non-Small-Cell Lung
Keywords: Non small cell lung cancer
Non small cell lung carcinoma
NSCLC
INC280
capmatinib
MET mutation
MET exon14
MET exon14 skipping
MET exon14 deletion
METex14
METex14del
MET∆ex14
EGFRwt
Epidermal growth factor receptor wild type
ALK negative
docetaxel
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2020-06-11
Enrollment: 22
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
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.
Primary purpose: TREATMENT

Brief summary: The purpose of the study was 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.

Detailed description: Twenty-two 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, were enrolled in this study. Participants were randomly assigned to get either capmatinib or docetaxel in a 2 to 1 ratio. The randomization was stratified by prior lines of systemic therapy received for advanced/metastatic disease (one line vs. two lines).

During treatment, visits were scheduled every 21 days.

For all participants, the respective treatment (either with capmatinib or docetaxel) could 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 was evidence of clinical benefit, and the participant wished to continue on the study treatment. After treatment discontinuation, all participants were followed for safety evaluations during the safety follow-up period, and the participant's status was collected every 12 weeks as part of the survival follow-up.

Participants randomized to docetaxel treatment were eligible to cross over to receive capmatinib treatment after BIRC-confirmed, RECIST 1.1-defined progressive disease and after meeting the eligibility criteria prior to crossover. This was the extension treatment phase.

Eligibility criteria: 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 was:

  1. 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.
  2. AND ALK rearrangement negative. Assessed as part of participant's standard of care by a validated test.
  3. AND had 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 have been 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 pertained to all participants, including those who had a METΔex14 mutation result from a local test. Tumor samples must have contained at least 10% tumor content.

  6. Participants must have 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 have been docetaxel naïve and candidates for single agent chemotherapy (docetaxel). Treatment failure was 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.
* 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 were neurologically unstable or had 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 ROS1 and RET rearrangement, BRAF mutation, KRAS mutation, NTRK fusion, etc.) which might have been 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 have increased the risk associated with study participation.

Primary outcomes:
measure: Progression-free Survival (PFS) Per Blinded Independent Review Committee (BIRC) Using RECIST v1.1
timeFrame: From randomization to the date of first documented progression or death from any cause, whichever came first, assessed up to approximately 21 months
Secondary outcomes:
measure: Overall Response (ORR) Per RECIST 1.1 by BIRC
timeFrame: Up to approximately 21 months
measure: Overall Response Rate (ORR) Per RECIST 1.1 by Investigator
timeFrame: Up to approximately 21 months
measure: Time to Response (TTR) Per RECIST 1.1 by BIRC
timeFrame: From date of randomization to first documented response of either CR or PR, assessed up to approximately 21 months
measure: Time to Response (TTR) Per RECIST 1.1 by Investigator
timeFrame: From date of randomization to first documented response of either CR or PR, assessed up to approximately 21 months
measure: Duration of Response (DOR) Per RECIST 1.1 by BIRC
timeFrame: From first documented response to first documented progression or death due to any cause, whichever came first, assessed up to approximately 21 months
measure: Duration of Response (DOR) Per RECIST 1.1 by Investigator
timeFrame: From first documented response to first documented progression or death due to any cause, whichever came first, assessed up to approximately 21 months
measure: Disease Control Rate (DCR) Per RECIST 1.1 by BIRC
timeFrame: Up to approximately 21 months
measure: Disease Control Rate (DCR) Per RECIST 1.1 by Investigator
timeFrame: Up to approximately 21 months
measure: Progression-free Survival (PFS) Per Investigator Using RECIST v1.1
timeFrame: From randomization to the date of first documented progression or death from any cause, whichever came first, assessed up to approximately 21 months
measure: Overall Survival (OS)
timeFrame: From randomization to death due to any cause, assessed up to approximately 36 months
measure: Overall Intracranial Response Rate (OIRR)
timeFrame: Up to approximately 21 months
measure: Duration of Intracranial Response (DOIR)
timeFrame: From date of first documented intracranial response (CR or PR) to first documented intracranial progression, assessed up to approximately 21 months
measure: Time to Intracranial Response (TTIR)
timeFrame: From date of randomization to first documented intracranial response of either CR or PR, assessed up to approximately 21 months
measure: Intracranial Disease Control Rate (IDCR)
timeFrame: Up to approximately 21 months
measure: Plasma Capmatinib Concentration
timeFrame: Cycle (C) 1 Day (D) 15 pre-dose, 1 and 4 hours post-dose, C3 D1 pre-dose. Each cycle duration was 21 days.
measure: Change From Baseline in Score as Per European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30
timeFrame: Baseline, Cycle (C) 3, Day (D) 1 and then every 6 weeks up to approximately 21 months, end of treatment. Each cycle duration was 21 days.
measure: Change From Baseline in Score as Per European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Lung Cancer Module (QLQ-LC13)
timeFrame: Baseline, Cycle (C) 3, Day (D) 1 and then every 6 weeks up to approximately 21 months, end of treatment. Each cycle duration was 21 days.
measure: Change From Baseline in Score as Per European Quality of Life 5-Dimension 5-Level (EQ-5D-5L) Questionnaire
timeFrame: Baseline, Cycle (C) 3, Day (D) 1 and then every 6 weeks up to approximately 21 months, end of treatment. Each cycle duration was 21 days.
measure: 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)
timeFrame: 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 was 21 days.
measure: 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
timeFrame: 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 was 21 days.
Other outcomes:
Locations:
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Barretos
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Pleven
country: Bulgaria
facility: Novartis Investigative Site
city: Sofia
country: Bulgaria
facility: Novartis Investigative Site
city: Sofia
country: Bulgaria
facility: Novartis Investigative Site
city: Caen
country: France
facility: Novartis Investigative Site
city: Paris
country: France
facility: Novartis Investigative Site
city: Pierre Benite
country: France
facility: Novartis Investigative Site
city: Regensburg
country: Germany
facility: Novartis Investigative Site
state: Bavaria
city: Gauting
country: Germany
facility: Novartis Investigative Site
state: Bayern
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Koeln
country: Germany
facility: Novartis Investigative Site
city: Oldenburg
country: Germany
facility: Novartis Investigative Site
city: Torokbalint
country: Hungary
facility: Novartis Investigative Site
state: Pest
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: New Delhi
country: India
facility: Novartis Investigative Site
state: Delhi
city: Pune
country: India
facility: Novartis Investigative Site
state: Maharashtra
city: Vellore
country: India
facility: Novartis Investigative Site
state: Tamil Nadu
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Vilnius
country: Lithuania
facility: Novartis Investigative Site
city: Kuantan
country: Malaysia
facility: Novartis Investigative Site
state: Pahang
city: Kuala Lumpur
country: Malaysia
facility: Novartis Investigative Site
state: Wilayah Persekutuan
city: Pulau Pinang
country: Malaysia
facility: Novartis Investigative Site
city: Nijmegen
country: Netherlands
facility: Novartis Investigative Site
city: Lisboa
country: Portugal
facility: Novartis Investigative Site
city: Matosinhos
country: Portugal
facility: Novartis Investigative Site
city: Nizhniy Novgorod
country: Russian Federation
facility: Novartis Investigative Site
city: Omsk
country: Russian Federation
facility: Novartis Investigative Site
city: Pushkin Saint Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: St- Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Port Elizabeth
country: South Africa
facility: Novartis Investigative Site
state: Western Cape
city: Malaga
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Oviedo
country: Spain
facility: Novartis Investigative Site
state: Asturias
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Valencia
country: Spain
facility: Novartis Investigative Site
city: Songkhla
country: Thailand
facility: Novartis Investigative Site
state: Hat Yai
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Hanoi
country: Vietnam
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: