A Phase II, Open-Label, Multicenter Study of Capmatinib in Subjects With MET Exon 14 Skipping Mutation Positive, Advanced, NSCLC With Brain Metastases
Primary Purpose
Non-small Cell Lung Carcinoma (NSCLC)
Status
Withdrawn
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
Capmatinib
Sponsored by
About this trial
This is an interventional treatment trial for Non-small Cell Lung Carcinoma (NSCLC) focused on measuring Non-small cell lung carcinoma, Non-small cell lung cancer, NSCLC, Treatment of lung cancer after first metastasi, Lung cancer, Lung adenocarcinoma, Squamous cell lung carcinoma, Large-cell lung carcinoma, Large-cell lung cancer
Eligibility Criteria
Inclusion Criteria:
- Histologically confirmed stage IV (according to Version 8 of the American Joint Committee on Cancer (AJCC)) NSCLC that is EGFR wt, ALK rearrangement negative as assessed by a validated test as part of the participant's standard of care and has MET∆ex14 mutation per Novartis-designated central laboratory or (US only) locally with FoundationOne Companion Diagnostic (F1CDx) .
- Treatment naïve or up to two prior lines of systemic therapy for stage IIIb-IV NSCLC
Measurable intracranial lesions:
- Cohort 1 and Cohort 2 (without leptomeningeal carcinoma): At least 1 measurable intracranial lesion per RANO-BM criteria, documented by a radiologist/neuroradiologist (treated or untreated).
- Cohort 2 (with leptomeningeal carcinoma): participants with leptomeningeal carcinoma may not have measurable lesions. In this circumstance, the participant's disease will be considered to have non-target lesions only at baseline and their response based on descriptive clinical criteria by physician assessment.
- Capable of undergoing magnetic resonance imaging (MRI)
- ECOG performance status of 0 or 1
Exclusion Criteria:
- Only for Cohort 1: any neurological symptoms related to brain metastases
- For participants in Cohort 2 with prior brain therapy: Treatment with stereotactic radiosurgery within 14 days prior to the start of study treatment or treatment with WBRT within 14 days prior to the start of study treatment
- Prior treatment with any MET targeting therapy or HGF inhibitor
- Participants with other known druggable molecular alterations (such as ROS1 translocation or BRAF mutation) who might be candidates to alternative targeted therapies as applicable per local regulations and treatment guidelines
- Presence or history of ILD or interstitial pneumonitis, including clinically significant radiation pneumonitis (i.e., affecting activities of daily living or requiring therapeutic intervention)
- Clinically significant, uncontrolled heart diseases including History of familial long QT syndrome, sudden death or congenital long QT syndrome
Other protocol-defined inclusion/exclusion criteria may apply
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Cohort 1
Cohort 2
Arm Description
Participants who are asymptomatic and without prior brain therapy
Participants who are symptomatic with or without prior brain therapy or asymptomatic with prior brain therapy or with leptomeningeal disease
Outcomes
Primary Outcome Measures
Overall Intracranial Response Rate (OIRR) in Cohort 1 by Blinded Independent Review Committee (BIRC) review
Overall Intracranial Response Rate (OIRR) in Cohort 1, defined as the proportion of participants with a confirmed best intracranial overall response of Complete Response (CR) or Partial Response (PR) per RANO-BM criteria as assessed by BIRC review
Secondary Outcome Measures
Overall Intracranial Response Rate (OIRR) in Cohort 1 by investigator review
Overall Intracranial Response Rate (OIRR) in Cohort 1, defined as the proportion of participants with a confirmed best intracranial overall response of Complete Response (CR) or Partial Response (PR) per RANO-BM criteria as assessed by investigator review
Intracranial Disease Control Rate (IDCR) by investigator and BIRC review
Intracranial Disease Control Rate (IDCR) per RANO-BM criteria as assessed by investigator review and by BIRC review
Time to intracranial tumor Response (TTIR) by investigator and BIRC review
Time to intracranial tumor Response (TTIR) per RANO-BM criteria as assessed by investigator review and by BIRC review
Duration of Intracranial Response (DOIR) by investigator and BIRC review
Duration of Intracranial Response (DOIR) per RANO-BM as assessed by investigator review and by BIRC review
Overall Intracranial Response Rate (OIRR) in Cohort 2 by investigator and BIRC review
Overall Intracranial Response Rate (OIRR) per RANO-BM criteria in Cohort 2 by investigator review and by BIRC review
Overall Extracranial Response Rate (OERR) by investigator and BIRC review
Overall Extracranial Response Rate (OERR) per RECIST 1.1 by investigator review and by BIRC review
Extracranial Disease Control Rate (EDCR) by investigator and BIRC review
Extracranial Disease Control Rate (EDCR) per RECIST 1.1 by investigator and BIRC review
Time to Extracranial Response (TTER) by investigator and BIRC review
Time to Extracranial Response (TTER) per RECIST 1.1 by investigator review and by BIRC review
Duration of Extracranial Response (DOER) by investigator and BIRC review
Duration of Extracranial Response (DOER) per RECIST 1.1 by investigator review and by BIRC review
Overall Response Rate (ORR) per RECIST 1.1 by investigator and BIRC review
Overall Response Rate (ORR) in the whole body per RECIST 1.1 by investigator review and by BIRC review
Time to response (TTR) by investigator and BIRC review
Time to response (TTR) in the whole body per RECIST 1.1 by investigator review and by BIRC review
Duration of response (DOR) by investigator and BIRC review
Duration of response (DOR) in the whole body per RECIST 1.1 by investigator review and by BIRC review
Progression free survival (PFS) by investigator and BIRC review
Progression free survival (PFS) in the whole body per RECIST 1.1 by investigator review and by BIRC review
Overall survival (OS)
Overall survival (OS) is defined as the time from the date of start of treatment to the date of death due to any cause.
Percentage of patients with Adverse Events (AEs) and Serious Adverse Events (SAEs)
Safety profile of capmatinib. Incidence and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs) including any clinically significant lab, vital signs, ECG abnormalities that are captured as an AE
Number of participants with dose interruptions
Tolerability measured by the number of subjects who have interruptions of study treatment
Number of participants with dose reductions
Tolerability measured by the number of subjects who have reductions of study treatment
Dose intensity
Tolerability measured by the dose intensity of study drug computed as the ratio of actual cumulative dose received and actual duration of exposure
Time to deterioration in Functional Assessment of Cancer Therapy (FACT)-Brain Symptom Index (FBrSI) scores in Cohort 1
Time to deterioration in symptoms of brain metastases in Cohort 1 with the Functional Assessment of Cancer Therapy (FACT)-Brain Symptom Index (FBrSI) (a standardized questionnaire developed to assess the quality of life of cancer patients)
Change from baseline in score as per FACT-Brain Symptom Index (FBrSI) in Cohort 2
Change from baseline in symptoms of brain metastases in Cohort 2 with the FACT-Brain Symptom Index (FBrSI) (a standardized questionnaire developed to assess the quality of life of cancer patients)
Change from baseline in score as per European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30
Change from baseline in lung cancer related symptoms, functioning and other domains of HRQoL in both cohorts with the EORTC QLQ-C30 (a 30-item questionnaire developed to assess the quality of life of cancer patients)
Change from baseline in score as per European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Lung Cancer Module (QLQ-LC13)
Change from baseline in lung cancer related symptoms, functioning and other domains of HRQoL in both cohorts with the QLQ-LC13 (a 13-item questionnaire developed to assess the quality of life of cancer patients)
Change from baseline in score as per European Quality of Life 5-Dimension 5-Level (EQ-5D-5L) questionnaire
Change from baseline in lung cancer related symptoms, functioning and other domains of HRQoL in both cohorts with the EQ-5D-5L (a standardized questionnaire developed to assess the quality of life of cancer patients)
Full Information
NCT ID
NCT04460729
First Posted
July 2, 2020
Last Updated
December 1, 2020
Sponsor
Novartis Pharmaceuticals
1. Study Identification
Unique Protocol Identification Number
NCT04460729
Brief Title
A Phase II, Open-Label, Multicenter Study of Capmatinib in Subjects With MET Exon 14 Skipping Mutation Positive, Advanced, NSCLC With Brain Metastases
Official Title
A Phase II, Open-Label, Multicenter Study of Capmatinib in Subjects With MET Exon 14 Skipping Mutation Positive, Advanced, Non Small-Cell Lung Cancer That Has Metastasized to the Brain
Study Type
Interventional
2. Study Status
Record Verification Date
November 2020
Overall Recruitment Status
Withdrawn
Why Stopped
company decision
Study Start Date
November 11, 2020 (Anticipated)
Primary Completion Date
November 17, 2023 (Anticipated)
Study Completion Date
November 17, 2023 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
The purpose of this study is to establish the intracranial efficacy of single agent capmatinib in the population of treatment-naïve or pretreated with one or two prior lines of systemic therapies for advanced stage Non Small-Cell Lung Cancer (NSCLC) with MET exon 14 mutation that has metastasized to the brain.
Cohort 1 (asymptomatic brain metastases (BM) without prior brain therapy) has been selected to identify patients who are most likely to benefit from capmatinib therapy in this setting and to establish a clinically relevant response outcome.
Cohort 2 is a heterogeneous group of patients (symptomatic with and without prior brain therapy, asymptomatic with prior brain therapy, or with leptomeningeal disease.), and the outcomes will be descriptive only
Detailed Description
This is a prospectively designed, multicenter, open-label, two-cohort, phase II study to evaluate the intracranial efficacy of single agent capmatinib in participants with MET exon 14 mutated NSCLC and BM. Participants can be treatment naïve or pretreated with one or two prior lines of systemic therapies for advanced stage (stage IIIb - IV) NSCLC.
Approximately 60 participants will be enrolled globally and allocated to one of two cohorts:
Cohort 1 will enroll approximately 40 participants who are asymptomatic and without prior brain therapy.
Cohort 2 will enroll approximately 20 participants who are symptomatic with or without prior brain therapy or asymptomatic with prior brain therapy or with leptomeningeal disease.
All participants will be pre-screened for MET mutation and presence of BM will be documented at baseline by a radiologist/neuroradiologist.
Intracranial disease will be assessed and response to treatment will be evaluated using the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria every 8 weeks. Extracranial and whole body disease will be assessed and response to treatment will be evaluated using RECIST 1.1 every 8 weeks.
Participants will receive capmatinib 400 mg b.i.d. until they experience any of the following: documented disease progression by RANO-BM criteria and/or RECIST 1.1 (as assessed by the investigator and confirmed by BIRC), withdrawal of consent, pregnancy, lost to follow-up, or death.
For all participants, treatment with capmatinib may be continued beyond initial progression disease (PD) as per RANO-BM criteria and/or RECIST 1.1 (as assessed by the investigator and confirmed by BIRC) if, in the judgment 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, and the participant's status will be collected every 12 weeks as part of the survival follow-up.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Non-small Cell Lung Carcinoma (NSCLC)
Keywords
Non-small cell lung carcinoma, Non-small cell lung cancer, NSCLC, Treatment of lung cancer after first metastasi, Lung cancer, Lung adenocarcinoma, Squamous cell lung carcinoma, Large-cell lung carcinoma, Large-cell lung cancer
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Approximately 60 participants will be enrolled globally and allocated to one of two cohorts based on whether their metastatic brain disease is symptomatic or asymptomatic and with or without prior brain therapy or if they have been diagnosed with leptomeningeal disease
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
0 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Cohort 1
Arm Type
Experimental
Arm Description
Participants who are asymptomatic and without prior brain therapy
Arm Title
Cohort 2
Arm Type
Experimental
Arm Description
Participants who are symptomatic with or without prior brain therapy or asymptomatic with prior brain therapy or with leptomeningeal disease
Intervention Type
Drug
Intervention Name(s)
Capmatinib
Intervention Description
400 mg administered orally twice daily
Primary Outcome Measure Information:
Title
Overall Intracranial Response Rate (OIRR) in Cohort 1 by Blinded Independent Review Committee (BIRC) review
Description
Overall Intracranial Response Rate (OIRR) in Cohort 1, defined as the proportion of participants with a confirmed best intracranial overall response of Complete Response (CR) or Partial Response (PR) per RANO-BM criteria as assessed by BIRC review
Time Frame
Up to 36 months
Secondary Outcome Measure Information:
Title
Overall Intracranial Response Rate (OIRR) in Cohort 1 by investigator review
Description
Overall Intracranial Response Rate (OIRR) in Cohort 1, defined as the proportion of participants with a confirmed best intracranial overall response of Complete Response (CR) or Partial Response (PR) per RANO-BM criteria as assessed by investigator review
Time Frame
Up to 36 months
Title
Intracranial Disease Control Rate (IDCR) by investigator and BIRC review
Description
Intracranial Disease Control Rate (IDCR) per RANO-BM criteria as assessed by investigator review and by BIRC review
Time Frame
Up to 36 months
Title
Time to intracranial tumor Response (TTIR) by investigator and BIRC review
Description
Time to intracranial tumor Response (TTIR) per RANO-BM criteria as assessed by investigator review and by BIRC review
Time Frame
Up to 36 months
Title
Duration of Intracranial Response (DOIR) by investigator and BIRC review
Description
Duration of Intracranial Response (DOIR) per RANO-BM as assessed by investigator review and by BIRC review
Time Frame
Up to 36 months
Title
Overall Intracranial Response Rate (OIRR) in Cohort 2 by investigator and BIRC review
Description
Overall Intracranial Response Rate (OIRR) per RANO-BM criteria in Cohort 2 by investigator review and by BIRC review
Time Frame
Up to 36 months
Title
Overall Extracranial Response Rate (OERR) by investigator and BIRC review
Description
Overall Extracranial Response Rate (OERR) per RECIST 1.1 by investigator review and by BIRC review
Time Frame
Up to 36 months
Title
Extracranial Disease Control Rate (EDCR) by investigator and BIRC review
Description
Extracranial Disease Control Rate (EDCR) per RECIST 1.1 by investigator and BIRC review
Time Frame
Up to 36 months
Title
Time to Extracranial Response (TTER) by investigator and BIRC review
Description
Time to Extracranial Response (TTER) per RECIST 1.1 by investigator review and by BIRC review
Time Frame
Up to 36 months
Title
Duration of Extracranial Response (DOER) by investigator and BIRC review
Description
Duration of Extracranial Response (DOER) per RECIST 1.1 by investigator review and by BIRC review
Time Frame
Up to 36 months
Title
Overall Response Rate (ORR) per RECIST 1.1 by investigator and BIRC review
Description
Overall Response Rate (ORR) in the whole body per RECIST 1.1 by investigator review and by BIRC review
Time Frame
Up to 36 months
Title
Time to response (TTR) by investigator and BIRC review
Description
Time to response (TTR) in the whole body per RECIST 1.1 by investigator review and by BIRC review
Time Frame
Up to 36 months
Title
Duration of response (DOR) by investigator and BIRC review
Description
Duration of response (DOR) in the whole body per RECIST 1.1 by investigator review and by BIRC review
Time Frame
Up to 36 months
Title
Progression free survival (PFS) by investigator and BIRC review
Description
Progression free survival (PFS) in the whole body per RECIST 1.1 by investigator review and by BIRC review
Time Frame
Up to 36 months
Title
Overall survival (OS)
Description
Overall survival (OS) is defined as the time from the date of start of treatment to the date of death due to any cause.
Time Frame
Up to 36 months
Title
Percentage of patients with Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description
Safety profile of capmatinib. Incidence and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs) including any clinically significant lab, vital signs, ECG abnormalities that are captured as an AE
Time Frame
Up to 36 months
Title
Number of participants with dose interruptions
Description
Tolerability measured by the number of subjects who have interruptions of study treatment
Time Frame
Up to 29 months
Title
Number of participants with dose reductions
Description
Tolerability measured by the number of subjects who have reductions of study treatment
Time Frame
Up to 29 months
Title
Dose intensity
Description
Tolerability measured by the dose intensity of study drug computed as the ratio of actual cumulative dose received and actual duration of exposure
Time Frame
Up to 29 months
Title
Time to deterioration in Functional Assessment of Cancer Therapy (FACT)-Brain Symptom Index (FBrSI) scores in Cohort 1
Description
Time to deterioration in symptoms of brain metastases in Cohort 1 with the Functional Assessment of Cancer Therapy (FACT)-Brain Symptom Index (FBrSI) (a standardized questionnaire developed to assess the quality of life of cancer patients)
Time Frame
Day 1 and 15 of Cycle 1, Day 1 of cycles 2 to 11 and then every other cycle until end of treatment (up to 29 months). Cycle=28 days
Title
Change from baseline in score as per FACT-Brain Symptom Index (FBrSI) in Cohort 2
Description
Change from baseline in symptoms of brain metastases in Cohort 2 with the FACT-Brain Symptom Index (FBrSI) (a standardized questionnaire developed to assess the quality of life of cancer patients)
Time Frame
Day 1 and 15 of Cycle 1, Day 1 of cycles 2 to 11 and then every other cycle until end of treatment (up to 29 months). Cycle=28 days
Title
Change from baseline in score as per European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30
Description
Change from baseline in lung cancer related symptoms, functioning and other domains of HRQoL in both cohorts with the EORTC QLQ-C30 (a 30-item questionnaire developed to assess the quality of life of cancer patients)
Time Frame
Day 1 of cycle 1 to 11 and then every other cycle until end of treatment (up to 29 months). Cycle=28 days
Title
Change from baseline in score as per European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Lung Cancer Module (QLQ-LC13)
Description
Change from baseline in lung cancer related symptoms, functioning and other domains of HRQoL in both cohorts with the QLQ-LC13 (a 13-item questionnaire developed to assess the quality of life of cancer patients)
Time Frame
Day 1 of cycle 1 to 11 and then every other cycle until end of treatment (up to 29 months). Cycle=28 days
Title
Change from baseline in score as per European Quality of Life 5-Dimension 5-Level (EQ-5D-5L) questionnaire
Description
Change from baseline in lung cancer related symptoms, functioning and other domains of HRQoL in both cohorts with the EQ-5D-5L (a standardized questionnaire developed to assess the quality of life of cancer patients)
Time Frame
Day 1 of cycle 1 to 11 and then every other cycle until end of treatment (up to 29 months). Cycle=28 days
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Histologically confirmed stage IV (according to Version 8 of the American Joint Committee on Cancer (AJCC)) NSCLC that is EGFR wt, ALK rearrangement negative as assessed by a validated test as part of the participant's standard of care and has MET∆ex14 mutation per Novartis-designated central laboratory or (US only) locally with FoundationOne Companion Diagnostic (F1CDx) .
Treatment naïve or up to two prior lines of systemic therapy for stage IIIb-IV NSCLC
Measurable intracranial lesions:
Cohort 1 and Cohort 2 (without leptomeningeal carcinoma): At least 1 measurable intracranial lesion per RANO-BM criteria, documented by a radiologist/neuroradiologist (treated or untreated).
Cohort 2 (with leptomeningeal carcinoma): participants with leptomeningeal carcinoma may not have measurable lesions. In this circumstance, the participant's disease will be considered to have non-target lesions only at baseline and their response based on descriptive clinical criteria by physician assessment.
Capable of undergoing magnetic resonance imaging (MRI)
ECOG performance status of 0 or 1
Exclusion Criteria:
Only for Cohort 1: any neurological symptoms related to brain metastases
For participants in Cohort 2 with prior brain therapy: Treatment with stereotactic radiosurgery within 14 days prior to the start of study treatment or treatment with WBRT within 14 days prior to the start of study treatment
Prior treatment with any MET targeting therapy or HGF inhibitor
Participants with other known druggable molecular alterations (such as ROS1 translocation or BRAF mutation) who might be candidates to alternative targeted therapies as applicable per local regulations and treatment guidelines
Presence or history of ILD or interstitial pneumonitis, including clinically significant radiation pneumonitis (i.e., affecting activities of daily living or requiring therapeutic intervention)
Clinically significant, uncontrolled heart diseases including History of familial long QT syndrome, sudden death or congenital long QT syndrome
Other protocol-defined inclusion/exclusion criteria may apply
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Novartis Pharmaceuticals
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.
This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com
Learn more about this trial
A Phase II, Open-Label, Multicenter Study of Capmatinib in Subjects With MET Exon 14 Skipping Mutation Positive, Advanced, NSCLC With Brain Metastases
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