Clinical trial NCT04816214: Study Evaluating Efficacy and Safety of Capmatinib in Combination With Osimertinib in Adult Subjects With Non-small Cell Lung Cancers as Second Line Therapy
Official title: A Phase III Randomized, Controlled, Open-label, Multicenter, Global Study of Capmatinib in Combination With Osimertinib Versus Platinum - Pemetrexed Based Doublet Chemotherapy in Patients With Locally Advanced or Metastatic NSCLC Harboring EGFR Activating Mutations Who Have Progressed on Prior Generation EGFR-TKI Therapy and Whose Tumors Are T790M Mutation Negative and Harbor MET Amplification (GEOMETRY-E)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Carcinoma, Non-Small-Cell Lung
Keywords: INC280
capmatinib
osimertinib
pemetrexed
platinum-based chemotherapy
NSCLC
Non-Small Cell Lung Cancer
Carcinoma
EGFR Mutation
T790M negative
MET amplification
second line therapy
GEOMETRY
GEOMETRY-E
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2021-03-25
Enrollment: 6
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The study was terminated early based on Sponsor's decision unrelated to any safety concerns and the randomized part of the study was not initiated
Primary purpose: TREATMENT

Brief summary: This study aimed to evaluate the anticancer activity of capmatinib in combination with osimertinib compared to platinum-pemetrexed based doublet chemotherapy as second line treatment in patients with advanced or metastatic non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation, T790M negative, mesenchymal-to-epithelial transition factor (MET) amplified who progressed following EGFR tyrosine kinase inhibitors (TKIs).

Detailed description: This was a multicenter, open-label, randomized, active-controlled, global phase III study that enrolled adult participants with locally advanced or metastatic NSCLC with epidermal growth factor receptor (EGFR) activating mutation, T790M negative, mesenchymal-to-epithelial transition factor (MET) amplified who had progressed following EGFR tyrosine kinase inhibitors (TKIs).

The study was conducted in two parts. The initial part was a safety run-in part, which aimed at assessing the safety and tolerability of capmatinib in combination with osimertinib and at determining the recommended dosage for the subsequent randomized part. The randomized part compared the efficacy and safety of capmatinib in combination with osimertinib to a platinum-based doublet chemotherapy regimen using either cisplatin or carboplatin, combined with pemetrexed, as second-line treatment.The randomized part was not initiated.

In the randomized part (if initiated), participants were to receive their assigned treatment (either capmatinib in combination with osimertinib or platinum-pemetrexed based doublet chemotherapy) until they experienced any of the following: documented disease progression according to the Response Evaluation Criteria In Solid Tumors 1.1 (RECIST 1.1) as assessed by the investigator during the run-in part and confirmed by a blinded independent review committee (BIRC) during the randomized part, withdrawal of consent, pregnancy, lost to follow-up, or death. Participants who progressed in the platinum-pemetrexed arm were to be permitted to switch to capmatinib in combination with osimertinib therapy after BIRC-confirmed, RECIST 1.1-defined progressive disease. If, in the judgment of the investigator, there was evidence of clinical benefit and the participant wished to continue, study treatment could be continued beyond the initial disease progression according to RECIST 1.1 criteria. After treatment discontinuation, all participants were to be followed for safety evaluations during the safety follow-up period.

On 11-May-2022, Novartis decided to halt enrollment for this study due to a business consideration unrelated to any safety concerns. Ongoing patients in the run-in part were allowed to continue treatment through other post-trial drug supply options, as applicable. On 27-Dec-2022 the last patient was transitioned off the study, and following the study protocol this date was declared the Global end of trial date. Randomized part was not initiated.

Eligibility criteria: Key Inclusion Criteria:

* Histologically or cytologically confirmed diagnosis of NSCLC with EGFR mutations known to be associated with EGFR TKI sensitivity, EGFR T790M negative and MET gene amplification
* Stage IIIB/IIIC or IV NSCLC
* Participants must have progressed on one prior line of therapy (1st/2nd generation EGFR TKIs, osimertinib or other third generation EGFR TKIs) for advanced/metastatic disease (stage IIIB/IIIC and must be candidates for platinum (cisplatin or carboplatin) - pemetrexed doublet based chemotherapy
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1
* Participants must have recovered from all toxicities related to prior systemic therapy to grade ≤ 1 Common Terminology Criteria Adverse Event 5.0 (CTCAE v 5.0)
* At least one measurable lesion as defined by RECIST 1.1
* Participants must have adequate organ function

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
* Carcinomatous meningitis
* Presence or history of a malignant disease other than NSCLC that had been diagnosed and/or required therapy within the past 3 years
* Presence or history of interstitial lung disease or interstitial pneumonitis, including clinically significant radiation pneumonitis
* Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome
* Clinically significant, uncontrolled heart diseases
* known druggable molecular alterations that may render participants eligible for alternative targeted therapies

Primary outcomes:
measure: Run-in Part: Number of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: Up to 21 Days
measure: Randomized Part: Progression Free Survival (PFS) Based on BIRC Assessment
timeFrame: From randomization to first documented progression or deaths, planned to be assessed up to 37 months
Secondary outcomes:
measure: Run-in Part: Number of Participants With at Least One Dose Interruption and Dose Reduction of Each Study Drug
timeFrame: From the first dose until last dose of study treatment, assessed up to 39 weeks
measure: Run-in Part: Dose Intensity of Each Study Drug
timeFrame: From the first dose until last dose of study treatment, assessed up to 39 weeks
measure: Run-in Part: Median Duration of Exposure to Each Study Drug
timeFrame: From the first dose until last dose of study treatment, assessed up to 39 weeks
measure: Run-in Part: Maximum Plasma Concentration (Cmax) of Capmatinib
timeFrame: Pre-dose, 0.5, 1, 2, 3, 4, 6, and 8 hours post-dose on Days 1 and 15 of Cycle 1 (Cycle = 21 days)
measure: Run-in Part: Maximum Plasma Concentration (Cmax) of Osimertinib and Its Metabolites (AZ5104 and AZ7550)
timeFrame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8 and 24 hours post-dose on Days 1 and 15 of Cycle 1 (Cycle = 21 days)
measure: Run-in Part: Time to Maximum Plasma Concentration (Tmax) of Capmatinib
timeFrame: Pre-dose, 0.5, 1, 2, 3, 4, 6, and 8 hours post-dose on Days 1 and 15 of Cycle 1 (Cycle = 21 days)
measure: Run-in Part: Time to Maximum Plasma Concentration (Tmax) of Osimertinib and Its Metabolites (AZ5104 and AZ7550)
timeFrame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8 and 24 hours post-dose on Days 1 and 15 of Cycle 1 (Cycle = 21 days)
measure: Run-in Part: Area Under the Curve to the Last Measurable Concentration (AUClast) of Capmatinib
timeFrame: Pre-dose, 0.5, 1, 2, 3, 4, 6, and 8 hours post-dose on Days 1 and 15 of Cycle 1 (Cycle = 21 days)
measure: Run-in Part: Area Under the Curve to the Last Measurable Concentration (AUClast) of Osimertinib and Its Metabolites (AZ5104 and AZ7550)
timeFrame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8 and 24 hours post-dose on Days 1 and 15 of Cycle 1 (Cycle = 21 days)
measure: Run-in Part: Overall Response Rate (ORR) as Per Investigator Assessment
timeFrame: Up to end of study, assessed up to 39 weeks
measure: Run-in Part: Duration of Response (DOR) as Per Investigator Assessment
timeFrame: Up to disease progression or death or end of study, assessed up to 39 weeks
measure: Run-in Part: Time to Response (TTR) as Per Investigator Assessment
timeFrame: From first dose of treatment up to end of study, assessed up to 39 weeks
measure: Run-in Part: Disease Control Rate (DCR) as Per Investigator Assessment
timeFrame: From randomization up to end of study, assessed up to 39 weeks
measure: Run-in Part: Progression-Free Survival (PFS) as Per Investigator Assessment
timeFrame: From first dose of treatment until first documented progression or death or end of study, assessed up to 39 weeks
measure: Randomized Part: Overall Response Rate (ORR) as Per BIRC Assessment
timeFrame: Planned to be assessed up to 37 months
measure: Randomized Part: Overall Intracranial Response Rate (OIRR) as Per BIRC Assessment
timeFrame: Planned to be assessed up to 37 months
measure: Randomized Part: Duration of Response (DOR) as Per BIRC Assessment
timeFrame: From first documented response to first documented progression or death, planned to be assessed up to 37 months
measure: Randomized Part: Time to Response (TTR) as Per BIRC Assessment
timeFrame: From randomization to first documented response, planned to be assessed up to 37 months
measure: Randomized Part: Disease Control Rate (DCR) as Per BIRC Assessment
timeFrame: Planned to be assessed up to 37 months
measure: Randomized Part: Progression-Free Survival After Next Line of Treatment (PFS2) as Per Investigator Assessment
timeFrame: Planned to be assessed up to 37 months
measure: Randomized Part: Maximum Plasma Concentration (Cmax) of Capmatinib
timeFrame: Pre-dose on Day 1 of Cycles 1, 2, 3, 4 and 6 (Cycle = 21 days)
measure: Randomized Part: Maximum Plasma Concentration (Cmax) of Osimertinib and Its Metabolites
timeFrame: Pre-dose on Day 1 of Cycles 1, 2, 3, 4 and 6 (Cycle = 21 days)
measure: Randomized Part: Overall Survival (OS)
timeFrame: From randomization to date of death, planned to be assessed up to 37 months
measure: Randomized Part: Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire (EORTC QLQ-C30) Score
timeFrame: Cycle 1 Day 1, Cycle 3 Day 1, then every 6 weeks for the 18 months after Cycle 1 Day 1 and every 12 weeks thereafter, until end of treatment, end of treatment and 6, 12 and 18 weeks post-progression (Cycle = 21 days)
measure: Randomized Part: Change From Baseline in the EORTC QLQ Lung Cancer Module (EORTC QLQ-LC13) Score
timeFrame: Cycle 1 Day 1, Cycle 3 Day 1, then every 6 weeks for the 18 months after Cycle 1 Day 1 and every 12 weeks thereafter, until end of treatment, end of treatment and 6, 12 and 18 weeks post-progression (Cycle = 21 days)
measure: Randomized Part: Change From Baseline in the EuroQoL-5 Dimension-5 Level (EQ-5D-5L) Score
timeFrame: Cycle 1 Day 1, Cycle 3 Day 1, then every 6 weeks for the 18 months after Cycle 1 Day 1 and every 12 weeks thereafter, until end of treatment, end of treatment and 6, 12 and 18 weeks post-progression (Cycle = 21 days)
measure: Randomized Part: Change From Baseline in the National Comprehensive Cancer Network Functional Assessment of Cancer Therapy (NCCN FACT)-Brain Symptom Index Version 2.0 (FBrSI)
timeFrame: Cycle 1 Day 1, Cycle 3 Day 1, then every 6 weeks for the 18 months after Cycle 1 Day 1 and every 12 weeks thereafter, until end of treatment, end of treatment and 6, 12 and 18 weeks post-progression (Cycle = 21 days)
measure: Randomized Part: Time to Symptom Deterioration for EORTC QLQ-C30 Questionnaire
timeFrame: From baseline to symptom deterioration, planned to be assessed up to 37 months
measure: Randomized Part: Time to Symptom Deterioration for EORTC QLQ-LC13 Questionnaire
timeFrame: From baseline to symptom deterioration, planned to be assessed up to 37 months
measure: Randomized Part: Time to Symptom Deterioration for NCCN FBrSl Questionnaire
timeFrame: From baseline to symptom deterioration, planned to be assessed up to 37 months
measure: Randomized Part: Duration of Intracranial Response (DOIR) Based on BIRC
timeFrame: From the date of first documented intracranial response to first documented intracranial progression or death, planned to be assessed up to 37 months
measure: Randomized Part: Time to Intracranial Response (TTIR) Based on BIRC
timeFrame: From randomization to first documented response, planned to be assessed up to 37 months
measure: Randomized Part: Intracranial Disease Control Rate (IDCR) Based on BIRC
timeFrame: Planned to be assessed up to 37 months
Other outcomes:
Locations:
city: Kashiwa
country: Japan
facility: Novartis Investigative Site
state: Chiba
city: Sunto Gun
country: Japan
facility: Novartis Investigative Site
state: Shizuoka
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: