GEOMETRY-E: Study Evaluating Efficacy and Safety of Capmatinib in Combination With Osimertinib in Adult Subjects With Non-small Cell Lung Cancers as Second Line Therapy
Study Details
Study Description
Brief Summary
This phase III study is designed 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). The randomized part will be preceded by a safety run-in part in which the recommended dose of the combination of capmatinib and osimertinib will be confirmed.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 3 |
Detailed Description
This is a multicenter, open-label, randomized, active-controlled, global phase III study that will enroll adult participants with locally advanced or metastatic NSCLC with EGFR activating mutation, T790M negative, MET amplified who have progressed following EGFR TKIs.
The study will consist of an initial safety run-in part to evaluate the safety and tolerability of capmatinib in combination with osimertinib and to confirm the recommended dose for the randomized part, and a randomized part that will evaluate the efficacy and safety of capmatinib in combination with osimertinib compared to platinum (cisplatin or carboplatin) - pemetrexed doublet based chemotherapy as second line treatment.
Participant's respective treatment (either with capmatinib in combination with osimertinib, or with platinum (cisplatin or carboplatin) - pemetrexed based doublet chemotherapy) will be continued until participant experiences any of the following: documented disease progression by Response Evaluation Criteria In Solid Tumors 1.1 (RECIST 1.1) (as assessed by the investigator in the run-in part, and as assessed by the investigator confirmed by blinded independent review committee (BIRC) in the randomization part), withdrawal of consent, pregnancy, lost to follow-up, or death. Participants who progressed in the platinum-pemetrexed arm will be allowed to crossover to capmatinib in combination with osimertinib therapy after BIRC confirmed, RECIST 1.1-defined progressive disease. Study treatment may be continued beyond initial disease progression as per RECIST 1.1 if, in the judgement 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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Combination of capmatinib + osimertinib (run-in part) For run-in part: Up to 2 dose levels of capmatinib in combination with osimertinib may be investigated. The starting dose of combination is capmatinib 400 mg orally twice daily (b.i.d) and osimertinib 80 mg orally once per day (q.d). If a dose de-escalation is required, a lower dose level is defined as capmatinib 400 mg orally twice a day (b.i.d) and osimertinib 40 mg orally once per day (q.d.) |
Drug: capmatinib
film-coated tablet for oral use
Other Names:
Drug: osimertinib
tablet for oral use
Other Names:
|
| Experimental: Combination of capmatinib + osimertinib (randomized part) For randomized part: capmatinib in combination with osimertinib administered at the recommended Phase III regimen (defined in the safety run-in part). |
Drug: capmatinib
film-coated tablet for oral use
Other Names:
Drug: osimertinib
tablet for oral use
Other Names:
|
| Active Comparator: Platinum + pemetrexed based doublet chemotherapy (randomized part) For randomized part: following local guidelines as per standard of care and products labels Participants randomized to platinum-pemetrexed based doublet chemotherapy arm will be allowed to crossover to receive capmatinib in combination with osimertinib |
Drug: pemetrexed
concentrate for solution for intravenous use
Other Names:
Drug: cisplatin
concentrate for solution for intravenous use
Drug: carboplatin
concentrate for solution for intravenous use
|
Outcome Measures
Primary Outcome Measures
- Run-in part: Incidence of dose limiting toxicities (DLTs) [3 weeks]
Incidence of Dose Limiting Toxicities (DLT) during the first 21 days (3 weeks) of treatment for each dose level associated with administration of capmatinib in combination with osimertinib
- Randomized part: Progression free survival (PFS) [37 months]
Progression free survival (PFS) per Blinded Independent Review Committee (BIRC) according to Response Evaluation Criteria In Solid Tumors 1.1 (RECIST 1.1)
Secondary Outcome Measures
- Run-in part: Percentage of participants with dose adjustments (reductions, interruptions or permanent discontinuation) [6 months]
To define the percentage of participants with dose adjustments (reductions, interruption, or permanent discontinuation) and the reasons by treatment arm
- Run-in part: Dose intensity of each study drug [6 months]
Dose intensity will be computed as the ratio of actual cumulative dose received and actual duration of exposure
- Run-in part: Median Duration of exposure to each study drug [6 months]
Median duration of exposure to capmatinib and osimertinib where duration of exposure is defined as the time between the first and last dose of treatment
- Run-in part: Maximum plasma concentration (Cmax) of capmatinib [pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post-dose on Cycle 1 Day 1 and Day 15 (one cycle is 21 days)]
The Cmax values are based on the plasma concentration-time profile of capmatinib. To characterize the pharmacokinetics of capmatinib
- Run-in part: Maximum plasma concentration (Cmax) of osimertinib and its metabolites [pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post-dose on Cycle 1 Day 1 and Day 15 (one cycle is 21 days), and also 24 hours post-dose on Cycle 1 Day 1.]
The Cmax values are based on the plasma concentration-time profile of osimertinib and its metabolites. To characterize the pharmacokinetics of osimertinib and its metabolites in combination setting
- Run-in part: Time to maximum plasma concentration (Tmax) of capmatinib [pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post-dose on Cycle 1 Day 1 and Day 15 (one cycle is 21 days)]
The Tmax values are based on the plasma concentration-time profile of capmatinib. To characterize the pharmacokinetics of capmatinib
- Run-in part: Time to maximum plasma concentration (Tmax) of osimertinib and its metabolites [pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post-dose on Cycle 1 Day 1 and Day 15 (one cycle is 21 days), and also 24 hours post-dose on Cycle 1 Day 1.]
The Tmax values are based on the plasma concentration-time profile of osimertinib and its metabolites. To characterize the pharmacokinetics of osimertinib and its metabolites in combination setting
- Run-in part: Area Under the Curve (AUC) of capmatinib [pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post-dose on Cycle 1 Day 1 and Day 15 (one cycle is 21 days)]
The AUC values are based on the plasma concentration-time profile of capmatinib. To characterize the pharmacokinetics of capmatinib
- Run-in part: Area Under the Curve (AUC) of osimertinib and its metabolites [pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post-dose on Cycle 1 Day 1 and Day 15 (one cycle is 21 days), and also 24 hours post-dose on Cycle 1 Day 1.]
The AUC values are based on the plasma concentration-time profile of osimertinib and its metabolites. To characterize the pharmacokinetics of osimertinib and its metabolites
- Run-in part: Duration of response (DOR) [6 months]
Duration of response is defined as the time from first documented response of complete response (CR) or partial response (PR) to date of first documented progression or death as per investigator judgment according to RECIST 1.1
- Run-in part: Overall Response Rate (ORR) [6 months]
ORR is defined as the proportion of subjects with confirmed best overall response of CR or PR, as per investigator judgment according to RECIST 1.1
- Run-in part only: Time to Response (TTR) [6 months]
Time to response (TTR) is defined as duration of time between the date of randomization and the date of first documented response of either CR or PR as per investigator judgment according to RECIST 1.1 criteria
- Run-in part: Disease control rate (DCR) [6 months]
Disease control rate is defined as the proportion of subjects with CR or PR or subjects with stable disease (SD) as per investigator judgment according to RECIST 1.1
- Run-in part: Progression-Free Survival (PFS) [6 months]
Progression-free survival is defined as the time from randomization to the date of the first documented radiological progression as per investigator judgment according to RECIST 1.1 response criteria or death due to any cause
- Randomized part: Overall Response Rate (ORR) [37 months]
ORR is defined as the proportion of subjects with confirmed best overall response of complete response (CR) or partial response (PR), as per BIRC by RECIST 1.1
- Randomized part: overall intracranial response rate (OIRR) [37 months]
OIRR is defined as the proportion of participants with a confirmed best overall intracranial response (BOIR) of CR or PR as per BIRC according to Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria
- Randomized part: Duration of response (DOR) [37 months]
Duration of response is defined as the time from first documented response of CR or PR to date of first documented progression or death as per BIRC according to RECIST 1.1 criteria
- Randomized part: Time to Response (TTR) [37 months]
Time to response (TTR) is defined as duration of time between the date of randomization and the date of first documented response of either CR or PR as per BIRC according to RECIST 1.1 criteria
- Randomized part: Disease control rate (DCR) [37 months]
Disease control rate is defined as the proportion of patients with CR or PR or subjects with SD as per BIRC according to RECIST 1.1 criteria
- Randomized part: Progression-Free Survival after next line of treatment (PFS2) [37 months]
PFS2 is defined as the documented radiological progression after next-line of treatment as per investigator judgment according to RECIST 1.1 response criteria or death due to any cause
- Randomized part: plasma concentration of capmatinib [Pre-dose on Day 1 of Cycles 1, 2, 3, 4 and 6 (one cycle is 21 days)]
Plasma concentration to characterize the pharmacokinetics of capmatinib
- Randomized part: plasma concentration of osimertinib and its metabolites [Pre-dose on Day 1 of Cycles 1, 2, 3, 4 and 6 (one cycle is 21 days)]
Plasma concentration to characterize the pharmacokinetics of osimertinib and its metabolites in combination setting
- Randomized part: Overall Survival (OS) [37 months]
OS is defined as the time from date of randomization/start of treatment to date of death due to any cause
- Randomized part: change from baseline in the EORTC QLQ-C30 score [Baseline, 37 months]
The European Organization for Research and Treatment of Cancer (EORTC) core quality of life questionnaire (EORTC QLQ-C30) is a questionnaire developed to assess the quality of life of cancer patients. It contains 30 items and is composed of both multi-item scales and single-item measures based on the patients experience over the past week. These include five scales (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/quality of life scale (QoL) scale. All of the scales and single-item measures range in score from 0 to 100. A high score for a functional scale represents a high /healthy level of functioning; a high score for the global health status / QoL represents a high QoL, but a high score for a symptom scale / item represents a high level of symptomatology/problems.
- Randomized part: change from baseline in the EORTC QLQ-LC13 score [Baseline, 37 months]
The Lung Cancer module of the EORTC's quality of life questionnaire (EORTC QLQ-LC13) is used in conjunction with the EORTC QLQ-C30 and provides information on an additional 13 items specifically related to lung cancer. The five domains of the LC13 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 score is based on its presence, hence yes or no. A higher score indicates a higher presence of symptoms.
- Randomized part: change from baseline in the EQ-5D-5L score [Baseline, 37 months]
The EuroQoL-5 Dimension-5 Level (EQ-5D-5L) is a standardized measure of health status developed by the EuroQol (EQ) Group in order to provide a simple, generic measure of health for clinical and economic appraisal The EQ-5D-5L consists of 2 pages - 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: no problems, slight problems, moderate problems, severe problems, and extreme problems. The participant is asked to indicate his/her health state by ticking in the box against the most appropriate statement in each of the 5 dimensions. This decision results in a 1-digit number expressing the level selected for that dimension. The EQ VAS records the participant's self-rated health on a 20 cm vertical VAS with endpoints labeled 'the best health you can imagine' at the top and 'the worst health you can imagine' at the bottom.
- Randomized part: change from baseline in the NCCN FACT-Brain Symptom Index [Baseline, 37 months]
The National Comprehensive Cancer Network (NCCN) Functional Assessment of Cancer Therapy (FACT)-Brain Symptom Index version 2.0 (FBrSI) will be used to explore changes in symptoms associated with potential BM in this study. The FBrSI was adapted from the previously developed FACT-Brain module. The symptoms module contains 12 items with a recall period of the past 7 days. The participant responds to 12 statements and indicates to what extent it applies to them on a 5-point Likert response scale from "not at all" to "very much."
- Randomized part: Time to symptom deterioration for EORTC QLQ-C30 questionnaire [37 months]
Time to symptom deterioration from baseline category to one more severe category of the EORTC QLQ-C30 questionnaire
- Randomized part: Time to symptom deterioration for EORTC QLQ-LC13 questionnaire [37 months]
Time to symptom deterioration from baseline category to one more severe category of the EORTC QLQ-LC13 questionnaire
- Randomized part: Time to symptom deterioration for NCCN FBrSl questionnaire [37 months]
Time to symptom deterioration from baseline category to one more severe category of the NCCN FBrSl questionnaire
- Randomized part: Duration of intracranial response (DOIR) [37 months]
Duration of response is defined as the time from first documented response of CR or PR to date of first documented progression or death as per BIRC according to RANO-BM criteria
- Randomized part: Time to intracranial response (TTIR) [37 months]
TTIR is defined as the time from the date of randomization/start of the treatment to the date of the first documented intracranial response of either CR or PR as per BIRC according to RANO-BM criteria
- Randomized part: Intracranial Disease control rate (IDCR) [37 months]
Intracranial Disease control rate is defined as the proportion of patients with CR or PR or subjects with SD as per BIRC according to RANO-BM criteria
Eligibility Criteria
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
-
Patients 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
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
-
Carcinomatous meningitis
-
Presence or history of a malignant disease other than NSCLC that has 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
Other protocol-defined inclusion/exclusion criteria may apply.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Novartis Investigative Site | Kashiwa | Chiba | Japan | 277 8577 |
| 2 | Novartis Investigative Site | Sunto Gun | Shizuoka | Japan | 411 8777 |
| 3 | Novartis Investigative Site | Seoul | Korea, Republic of | 05505 | |
| 4 | Novartis Investigative Site | Singapore | Singapore | 169610 |
Sponsors and Collaborators
- Novartis Pharmaceuticals
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- CINC280L12301
- 2020-003677-21