Clinical Trial Results:
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 EGFR‑TKI therapy and whose tumors are T790M mutation negative and harbor MET amplification (GEOMETRY-E)
Summary
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EudraCT number |
2020-003677-21 |
Trial protocol |
FR DE ES SI PL IT BG HU HR |
Global end of trial date |
27 Dec 2022
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Results information
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Results version number |
v1(current) |
This version publication date |
20 Oct 2023
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First version publication date |
20 Oct 2023
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
CINC280L12301
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT04816214 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Novartis
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Sponsor organisation address |
CH-4002, Basel, Switzerland,
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Public contact |
Study Director, Novartis, +41 6133241111, novartis.email@novartis.com
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Scientific contact |
Study Director, Novartis, +41 6133241111, novartis.email@novartis.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
27 Dec 2022
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
27 Dec 2022
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
The 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 EGFR mutation, T790M negative, MET amplified, who progressed following EGFR tyrosine kinase inhibitors (TKIs). A run-in part was conducted to determine the recommended dose of capmatinib and osimertinib for the randomized part.
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.
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Protection of trial subjects |
The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
22 Sep 2021
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Japan: 2
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Country: Number of subjects enrolled |
Singapore: 2
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Country: Number of subjects enrolled |
Korea, Republic of: 2
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Worldwide total number of subjects |
6
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EEA total number of subjects |
0
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
4
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From 65 to 84 years |
2
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85 years and over |
0
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Recruitment
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Recruitment details |
In the Run-in part, subjects were enrolled at 4 investigative sites in 3 countries. The study was terminated early based on Sponsor's decision unrelated to safety concerns and the randomized part of the study was not initiated. | ||||||||||||||
Pre-assignment
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Screening details |
A total of 23 subjects were screened of which 6 subjects were enrolled in the run-in part of the study. | ||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||
Arms
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Arm title
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Run-in Part: Capmatinib + Osimertinib | ||||||||||||||
Arm description |
Subjects received a starting dose of capmatinib 400 mg, orally, twice daily (BID) in combination with osimertinib 80 mg, orally, once daily (QD) | ||||||||||||||
Arm type |
Experimental | ||||||||||||||
Investigational medicinal product name |
Capmatinib
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Investigational medicinal product code |
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Other name |
INC280
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
400 mg of capmatinib administered BID
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Investigational medicinal product name |
Osimertinib
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Investigational medicinal product code |
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Other name |
Tagrisso, Tagrix
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
80 mg of osimertinib administered QD
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Baseline characteristics reporting groups
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Reporting group title |
Run-in Part: Capmatinib + Osimertinib
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Reporting group description |
Subjects received a starting dose of capmatinib 400 mg, orally, twice daily (BID) in combination with osimertinib 80 mg, orally, once daily (QD) | ||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Run-in Part: Capmatinib + Osimertinib
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Reporting group description |
Subjects received a starting dose of capmatinib 400 mg, orally, twice daily (BID) in combination with osimertinib 80 mg, orally, once daily (QD) |
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End point title |
Run-in Part: Number of Partipants With Dose Limiting Toxicities (DLTs) [1] | ||||||
End point description |
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. FAS included all participants who received any component of the study treatment.
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End point type |
Primary
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End point timeframe |
Up to 21 Days (3 weeks)
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Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive statistical analysis was planned to be reported for this endpoint. |
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No statistical analyses for this end point |
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End point title |
Run-in Part: Number of Participants With at Least One Dose Interruption and Dose Reduction of Each Study Drug | ||||||||||||||
End point description |
Number of participants with at least one dose interruption and dose reduction were reported for each study drug. Safety set included all participants who received at least one dose of study treatment.
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End point type |
Secondary
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End point timeframe |
From the first dose until last dose of study treatment, assessed up to 39 weeks
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No statistical analyses for this end point |
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End point title |
Run-in Part: Dose Intensity of Each Study Drug | ||||||||||||
End point description |
Dose intensity was computed as the ratio of actual cumulative dose (milligrams) received and actual duration of exposure (weeks) to study drug. Safety set included all participants who received at least one dose of study treatment.
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End point type |
Secondary
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End point timeframe |
From the first dose until last dose of study treatment, assessed up to 39 weeks
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No statistical analyses for this end point |
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End point title |
Run-in Part: Median Duration of Exposure to Each Study Drug | ||||||||||||
End point description |
Duration of exposure is defined as the time (in weeks) between the first and the last dose of study treatment. Safety set included all participants who received at least one dose of study treatment.
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End point type |
Secondary
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End point timeframe |
From the first dose until last dose of study treatment, assessed up to 39 weeks
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No statistical analyses for this end point |
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End point title |
Run-in Part: Maximum Plasma Concentration (Cmax) of Capmatinib | ||||||||||||
End point description |
Blood samples were collected. Cmax of capmatinib was calculated from plasma concentration-time data using non-compartmental methods and summarized using descriptive statistics. PK analysis set included all participants who provided at least one evaluable PK concentration. ‘Number of subjects analysed’ indicates the number of participants with data available for endpoint analysis. ‘Number analysed (n)’ indicates the number of participants with data available at specified timepoint.
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End point type |
Secondary
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End point 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)
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No statistical analyses for this end point |
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End point title |
Run-in Part: Maximum Plasma Concentration (Cmax) of Osimertinib and Its Metabolites (AZ5104 and AZ7550) | ||||||||||||||||||||
End point description |
Blood samples were colllected. Cmax of osimertinib and its metabolites (AZ5104 and AZ7550) was calculated from plasma concentration-time data using non-compartmental methods and summarized using descriptive statistics. PK analysis set included all participants who provided at least one evaluable PK concentration. ‘Number of subjects analysed’ indicates the number of participants with data available for endpoint analysis. ‘Number analysed (n)’ indicates the number of participants with data available at specified timepoint.
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End point type |
Secondary
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End point 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)
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No statistical analyses for this end point |
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End point title |
Run-in Part: Time to Maximum Plasma Concentration (Tmax) of Capmatinib | ||||||||||||
End point description |
Blood samples were colllected. Tmax of capmatinib was calculated from plasma concentration-time data using non-compartmental methods and summarized using descriptive statistics. Actual recorded sampling times were considered for the calculations. PK analysis set included all participants who provided at least one evaluable PK concentration. ‘Number of subjects analysed’ indicates the number of participants with data available for endpoint analysis. ‘Number analysed (n)’ indicates the number of participants with data available at specified timepoint.
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End point type |
Secondary
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End point 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)
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No statistical analyses for this end point |
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End point title |
Run-in Part: Time to Maximum Plasma Concentration (Tmax) of Osimertinib and Its Metabolites (AZ5104 and AZ7550) | ||||||||||||||||||||
End point description |
Blood samples were collected. Tmax of osimertinib and its metabolites (AZ5104 and AZ7550) was calculated from plasma concentration-time data using non-compartmental methods and summarized using descriptive statistics.
Actual recorded sampling times were considered for the calculations. PK analysis set included all participants who provided at least one evaluable PK concentration. ‘Number of participants analysed’ indicates the number of subjects with data available for endpoint analysis. ‘Number analysed (n)’ indicates the number of participants with data available at specified timepoint.
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End point type |
Secondary
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End point 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)
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No statistical analyses for this end point |
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End point title |
Run-in Part: Area Under the Curve to the Last Measurable Concentration (AUClast) of Capmatinib | ||||||||||||
End point description |
Blood samples were collected. AUClast of capmatinib was calculated from plasma concentration-time data using non-compartmental methods and summarized using descriptive statistics. PK analysis set included all participants who provided at least one evaluable PK concentration. ‘Number of subjects analysed’ indicates the number of participants with data available for endpoint analysis. ‘Number analysed (n)’ indicates the number of participants with data available at specified timepoint.
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End point type |
Secondary
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End point 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)
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No statistical analyses for this end point |
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End point title |
Run-in Part: Area Under the Curve to the Last Measurable Concentration (AUClast) of Osimertinib and Its Metabolites (AZ5104 and AZ7550) | ||||||||||||||||||||
End point description |
Blood samples were collected. AUClast of osimertinib and its metabolites (AZ5104 and AZ7550) was calculated from plasma concentration-time data using non-compartmental methods and summarized using descriptive statistics. PK analysis set included all participants who provided at least one evaluable PK concentration.‘Number of subjects analysed’ indicates the number of participants with data available for endpoint analysis. ‘Number analysed (n)’ indicates the number of participants with data available at specified timepoint.
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End point type |
Secondary
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End point 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)
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No statistical analyses for this end point |
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End point title |
Run-in Part: Overall Response Rate (ORR) as per investigator assessment | ||||||||
End point description |
ORR was defined as the percentage of participants with a confirmed best overall response (BOR) of complete response (CR) or partial response (PR), as per investigator judgment and according to Response Evaluation Criteria in Solid Tumors 1.1 (RECIST v1.1). Criteria for CR: Disappearance of all lesions and pathologic lymph nodes; PR: ≥30% decrease in the sum of longest diameters (SLD) of the target lesions or no new lesions or no progression of non-target lesions. Full Analysis Set (FAS) included all participants who received any component of the study treatment.
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End point type |
Secondary
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End point timeframe |
Up to end of study, assessed up to 39 weeks
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No statistical analyses for this end point |
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End point title |
Run-in Part: Duration of Response (DOR) as per investigator assessment | ||||||||
End point description |
DOR was defined as the time from first documented response of CR or PR to the date of first documented progressive disease (PD) or death due to any cause. Criteria for CR: Disappearance of all lesions and pathologic lymph nodes; PR: ≥30% decrease in the SLD of the target lesions or no new lesions or no progression of non-target lesions; PD: ≥20% increase in SLD compared to the smallest SLD in the study, or progression of non-target lesions or new lesions. FAS included all participants who received any component of the study treatment. ‘Number of subjects analysed’ indicates the number of participants with CR or PR. 9999= Upper limit of 95% confidence interval (CI) was not estimable due to an insufficient number of subjects with events.
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End point type |
Secondary
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End point timeframe |
Up to disease progression or death or end of study, assessed up to 39 weeks
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No statistical analyses for this end point |
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End point title |
Run-in Part: Time to Response (TTR) as per investigator assessment | ||||||||
End point description |
TTR was defined as the duration of time between the date of first dose of treatment and the date of the first documented response of either CR or PR as per investigator judgment and according to RECIST v1.1 criteria. Criteria for CR: Disappearance of all lesions and pathologic lymph nodes; PR: ≥30% decrease in SLD of the target lesions or no new lesions or no progression of non-target lesions. FAS included all participants who received any component of the study treatment. ‘Number of subjects analysed’ indicates the number of participants with CR or PR. 9999= Median and the upper limit of 95% CI were not estimable due to an insufficient number of participants with events.
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End point type |
Secondary
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End point timeframe |
From first dose of treatment up to end of study, assessed up to 39 weeks
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No statistical analyses for this end point |
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End point title |
Run-in Part: Disease Control Rate (DCR) as per investigator assessment | ||||||||
End point description |
DCR was defined as the percentage of participants with a BOR of CR, PR and stable disease (SD) as per investigator judgment and according to RECIST v1.1. Criteria for CR: Disappearance of all lesions and pathologic lymph nodes; PR: ≥30% decrease in SLD of the target lesions or no new lesions or no progression of non-target lesions; SD: Neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease. FAS included all participants who received any component of the study treatment.
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End point type |
Secondary
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End point timeframe |
From randomisation up to end of study, assessed up to 39 weeks
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No statistical analyses for this end point |
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End point title |
Run-in Part: Progression-Free Survival (PFS) as per investigator assessment | ||||||||
End point description |
PFS was defined as the time (in months) from first dose of treatment to the date of the first documented PD or death due to any cause as per investigator judgment and according to RECIST v1.1. PFS was censored if no PFS event (progression or death) was observed. Progression was defined as a ≥20% increase in SLD compared to smallest SLD in the study, or progression of non-target lesions or new lesions. FAS included all participants who received any component of the study treatment. 9999= The upper limit of 95% CI was not estimable due to an insufficient number of participants with events.
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End point type |
Secondary
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End point timeframe |
From first dose of treatment until first documented progression or death or end of study, assessed up to 39 weeks
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
From first dose of treatment until 30 days after last dose of study treatment, assessed up to 39 weeks
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Adverse event reporting additional description |
Safety set included all participants who received at least one dose of study treatment. Due to early study termination, the randomized part of the study was not conducted. Hence safety data was not collected in the randomized part of the study.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
25.1
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Reporting groups
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Reporting group title |
Run-in Part: Capmatinib + Osimertinib
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Reporting group description |
Subjects received a starting dose of capmatinib 400 mg, orally, BID in combination with osimertinib 80 mg, orally, QD for a maximum of 39 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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14 Sep 2021 |
Amendment 1:
• Revised inclusion and exclusion criteria: Removed the requirements of T790M negative results for subjects previously treated with osimertinib; Allowed subjects who had previously received 3rd generation EGFR TKIs other than osimertinib to participate in this study; Excluded subjects with known druggable molecular alterations, known EGFR T790M positive status, and who received live vaccines within 30 days prior to the first dose of study treatment.
• Updated the biomarker collection schedule for the randomisation part to add one additional time point (Cycle 1 Day 1) and adjusted the schedule of sample collections to start at Cycle 2 instead of Cycle 4. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
The study was terminated as Novartis decided to halt enrolment on 11 May 2022. This was a business decision and not related to any safety concerns. |