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)
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 入组人数
- 6
- 试验地点
- 1
- 主要终点
- Randomized Part: Progression Free Survival (PFS) Based on BIRC Assessment
研究概览
简要总结
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).
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Run-in part: Capmatinib + Osimertinib
In the run-in part, up to two dose levels of capmatinib in combination with osimertinib were planned to be investigated. The initial dose level for the combination therapy was capmatinib 400 mg orally twice daily (b.i.d) and osimertinib 80 mg orally once per day (q.d). If a dose de-escalation was necessary, a lower dose level was defined as capmatinib 400 mg orally b.i.d and osimertinib 40 mg orally q.d.
干预措施: Capmatinib (Drug)
Run-in part: Capmatinib + Osimertinib
In the run-in part, up to two dose levels of capmatinib in combination with osimertinib were planned to be investigated. The initial dose level for the combination therapy was capmatinib 400 mg orally twice daily (b.i.d) and osimertinib 80 mg orally once per day (q.d). If a dose de-escalation was necessary, a lower dose level was defined as capmatinib 400 mg orally b.i.d and osimertinib 40 mg orally q.d.
干预措施: Osimertinib (Drug)
Randomized part: Capmatinib + Osimertinib
In the randomized part, capmatinib in combination with osimertinib was to be administered at the recommended Phase III regimen (defined in the safety run-in part).
The study was terminated early based on Sponsor's decision unrelated to safety concerns and the randomized part of the study was not initiated.
干预措施: Capmatinib (Drug)
Randomized part: Capmatinib + Osimertinib
In the randomized part, capmatinib in combination with osimertinib was to be administered at the recommended Phase III regimen (defined in the safety run-in part).
The study was terminated early based on Sponsor's decision unrelated to safety concerns and the randomized part of the study was not initiated.
干预措施: Osimertinib (Drug)
Randomized Part: Platinum + Pemetrexed Based Doublet Chemotherapy
In the randomized part, platinum-pemetrexed based doublet chemotherapy was to follow local guidelines as per standard of care and products labels. Participants randomized to platinum-pemetrexed based doublet chemotherapy arm were to be allowed to crossover to receive capmatinib in combination with osimertinib. The study was terminated early based on Sponsor's decision unrelated to safety concerns and the randomized part of the study was not initiated.
干预措施: Pemetrexed (Drug)
Randomized Part: Platinum + Pemetrexed Based Doublet Chemotherapy
In the randomized part, platinum-pemetrexed based doublet chemotherapy was to follow local guidelines as per standard of care and products labels. Participants randomized to platinum-pemetrexed based doublet chemotherapy arm were to be allowed to crossover to receive capmatinib in combination with osimertinib. The study was terminated early based on Sponsor's decision unrelated to safety concerns and the randomized part of the study was not initiated.
干预措施: Cisplatin (Drug)
Randomized Part: Platinum + Pemetrexed Based Doublet Chemotherapy
In the randomized part, platinum-pemetrexed based doublet chemotherapy was to follow local guidelines as per standard of care and products labels. Participants randomized to platinum-pemetrexed based doublet chemotherapy arm were to be allowed to crossover to receive capmatinib in combination with osimertinib. The study was terminated early based on Sponsor's decision unrelated to safety concerns and the randomized part of the study was not initiated.
干预措施: Carboplatin (Drug)
结局指标
主要结局
Randomized Part: Progression Free Survival (PFS) Based on BIRC Assessment
时间窗: From randomization to first documented progression or deaths, planned to be assessed up to 37 months
PFS was defined as time from date of randomization to the date of first documented disease progression (PD) based on Blinded Independent Review Committee (BIRC) as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), or death from any cause, whichever occurred first. Progression was defined as a ≥20% increase in sum of longest diameters (SLD) compared to smallest SLD in the study, or progression of non-target lesions or new lesions.
Run-in Part: Number of Participants With Dose Limiting Toxicities (DLTs)
时间窗: Up to 21 Days
A DLT was defined as an adverse event (AE) or abnormal laboratory value assessed as unrelated to disease, progressive disease, inter-current illness, or concomitant medications, that despite optimal therapeutic intervention that occurred within the first 21 days of treatment with capmatinib in combination with osimertinib.
次要结局
- Run-in Part: Number of Participants With at Least One Dose Interruption and Dose Reduction of Each Study Drug(From the first dose until last dose of study treatment, assessed up to 39 weeks)
- Run-in Part: Dose Intensity of Each Study Drug(From the first dose until last dose of study treatment, assessed up to 39 weeks)
- Run-in Part: Overall Response Rate (ORR) as Per Investigator Assessment(Up to end of study, assessed up to 39 weeks)
- Run-in Part: Duration of Response (DOR) as Per Investigator Assessment(Up to disease progression or death or end of study, assessed up to 39 weeks)
- Run-in Part: Time to Response (TTR) as Per Investigator Assessment(From first dose of treatment up to end of study, assessed up to 39 weeks)
- Run-in Part: Disease Control Rate (DCR) as Per Investigator Assessment(From randomization up to end of study, assessed up to 39 weeks)
- Randomized Part: Time to Response (TTR) as Per BIRC Assessment(From randomization to first documented response, planned to be assessed up to 37 months)
- Randomized Part: Progression-Free Survival After Next Line of Treatment (PFS2) as Per Investigator Assessment(Planned to be assessed up to 37 months)
- Run-in Part: Maximum Plasma Concentration (Cmax) of Osimertinib and Its Metabolites (AZ5104 and AZ7550)(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))
- 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 Days 1 and 15 of Cycle 1 (Cycle = 21 days))
- Run-in Part: Time to Maximum Plasma Concentration (Tmax) of Osimertinib and Its Metabolites (AZ5104 and AZ7550)(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))
- Run-in Part: Area Under the Curve to the Last Measurable Concentration (AUClast) of Osimertinib and Its Metabolites (AZ5104 and AZ7550)(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))
- Randomized Part: Duration of Response (DOR) as Per BIRC Assessment(From first documented response to first documented progression or death, planned to be assessed up to 37 months)
- Randomized Part: Disease Control Rate (DCR) as Per BIRC Assessment(Planned to be assessed up to 37 months)
- Run-in Part: Area Under the Curve to the Last Measurable Concentration (AUClast) of Capmatinib(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))
- Run-in Part: Progression-Free Survival (PFS) as Per Investigator Assessment(From first dose of treatment until first documented progression or death or end of study, assessed up to 39 weeks)
- Randomized Part: Overall Intracranial Response Rate (OIRR) as Per BIRC Assessment(Planned to be assessed up to 37 months)
- Randomized Part: Change From Baseline in the EORTC QLQ Lung Cancer Module (EORTC QLQ-LC13) Score(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))
- 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)(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))
- Run-in Part: Median Duration of Exposure to Each Study Drug(From the first dose until last dose of study treatment, assessed up to 39 weeks)
- Run-in Part: Maximum Plasma Concentration (Cmax) of Capmatinib(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))
- Randomized Part: Overall Response Rate (ORR) as Per BIRC Assessment(Planned to be assessed up to 37 months)
- Randomized Part: Maximum Plasma Concentration (Cmax) of Capmatinib(Pre-dose on Day 1 of Cycles 1, 2, 3, 4 and 6 (Cycle = 21 days))
- Randomized Part: Overall Survival (OS)(From randomization to date of death, planned to be assessed up to 37 months)
- Randomized Part: Maximum Plasma Concentration (Cmax) of Osimertinib and Its Metabolites(Pre-dose on Day 1 of Cycles 1, 2, 3, 4 and 6 (Cycle = 21 days))
- Randomized Part: Time to Symptom Deterioration for EORTC QLQ-C30 Questionnaire(From baseline to symptom deterioration, planned to be assessed up to 37 months)
- Randomized Part: Time to Symptom Deterioration for EORTC QLQ-LC13 Questionnaire(From baseline to symptom deterioration, planned to be assessed up to 37 months)
- Randomized Part: Time to Symptom Deterioration for NCCN FBrSl Questionnaire(From baseline to symptom deterioration, planned to be assessed up to 37 months)
- 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(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))
- Randomized Part: Change From Baseline in the EuroQoL-5 Dimension-5 Level (EQ-5D-5L) Score(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))
- Randomized Part: Intracranial Disease Control Rate (IDCR) Based on BIRC(Planned to be assessed up to 37 months)
- Randomized Part: Duration of Intracranial Response (DOIR) Based on BIRC(From the date of first documented intracranial response to first documented intracranial progression or death, planned to be assessed up to 37 months)
- Randomized Part: Time to Intracranial Response (TTIR) Based on BIRC(From randomization to first documented response, planned to be assessed up to 37 months)