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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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ClinicalTrials.gov Identifier: NCT04460729
Recruitment Status : Withdrawn (company decision)
First Posted : July 8, 2020
Last Update Posted : December 3, 2020
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

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


Condition or disease Intervention/treatment Phase
Non-small Cell Lung Carcinoma (NSCLC) Drug: Capmatinib Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention 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)
Primary Purpose: Treatment
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
Estimated Study Start Date : November 11, 2020
Estimated Primary Completion Date : November 17, 2023
Estimated Study Completion Date : November 17, 2023

Resource links provided by the National Library of Medicine

Drug Information available for: Capmatinib

Arm Intervention/treatment
Experimental: Cohort 1
Participants who are asymptomatic and without prior brain therapy
Drug: Capmatinib
400 mg administered orally twice daily

Experimental: Cohort 2
Participants who are symptomatic with or without prior brain therapy or asymptomatic with prior brain therapy or with leptomeningeal disease
Drug: Capmatinib
400 mg administered orally twice daily




Primary Outcome Measures :
  1. Overall Intracranial Response Rate (OIRR) in Cohort 1 by Blinded Independent Review Committee (BIRC) review [ Time Frame: Up to 36 months ]
    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 :
  1. Overall Intracranial Response Rate (OIRR) in Cohort 1 by investigator review [ Time Frame: Up to 36 months ]
    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

  2. Intracranial Disease Control Rate (IDCR) by investigator and BIRC review [ Time Frame: Up to 36 months ]
    Intracranial Disease Control Rate (IDCR) per RANO-BM criteria as assessed by investigator review and by BIRC review

  3. Time to intracranial tumor Response (TTIR) by investigator and BIRC review [ Time Frame: Up to 36 months ]
    Time to intracranial tumor Response (TTIR) per RANO-BM criteria as assessed by investigator review and by BIRC review

  4. Duration of Intracranial Response (DOIR) by investigator and BIRC review [ Time Frame: Up to 36 months ]
    Duration of Intracranial Response (DOIR) per RANO-BM as assessed by investigator review and by BIRC review

  5. Overall Intracranial Response Rate (OIRR) in Cohort 2 by investigator and BIRC review [ Time Frame: Up to 36 months ]
    Overall Intracranial Response Rate (OIRR) per RANO-BM criteria in Cohort 2 by investigator review and by BIRC review

  6. Overall Extracranial Response Rate (OERR) by investigator and BIRC review [ Time Frame: Up to 36 months ]
    Overall Extracranial Response Rate (OERR) per RECIST 1.1 by investigator review and by BIRC review

  7. Extracranial Disease Control Rate (EDCR) by investigator and BIRC review [ Time Frame: Up to 36 months ]
    Extracranial Disease Control Rate (EDCR) per RECIST 1.1 by investigator and BIRC review

  8. Time to Extracranial Response (TTER) by investigator and BIRC review [ Time Frame: Up to 36 months ]
    Time to Extracranial Response (TTER) per RECIST 1.1 by investigator review and by BIRC review

  9. Duration of Extracranial Response (DOER) by investigator and BIRC review [ Time Frame: Up to 36 months ]
    Duration of Extracranial Response (DOER) per RECIST 1.1 by investigator review and by BIRC review

  10. Overall Response Rate (ORR) per RECIST 1.1 by investigator and BIRC review [ Time Frame: Up to 36 months ]
    Overall Response Rate (ORR) in the whole body per RECIST 1.1 by investigator review and by BIRC review

  11. Time to response (TTR) by investigator and BIRC review [ Time Frame: Up to 36 months ]
    Time to response (TTR) in the whole body per RECIST 1.1 by investigator review and by BIRC review

  12. Duration of response (DOR) by investigator and BIRC review [ Time Frame: Up to 36 months ]
    Duration of response (DOR) in the whole body per RECIST 1.1 by investigator review and by BIRC review

  13. Progression free survival (PFS) by investigator and BIRC review [ Time Frame: Up to 36 months ]
    Progression free survival (PFS) in the whole body per RECIST 1.1 by investigator review and by BIRC review

  14. Overall survival (OS) [ Time Frame: Up to 36 months ]
    Overall survival (OS) is defined as the time from the date of start of treatment to the date of death due to any cause.

  15. Percentage of patients with Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to 36 months ]
    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

  16. Number of participants with dose interruptions [ Time Frame: Up to 29 months ]
    Tolerability measured by the number of subjects who have interruptions of study treatment

  17. Number of participants with dose reductions [ Time Frame: Up to 29 months ]
    Tolerability measured by the number of subjects who have reductions of study treatment

  18. Dose intensity [ Time Frame: Up to 29 months ]
    Tolerability measured by the dose intensity of study drug computed as the ratio of actual cumulative dose received and actual duration of exposure

  19. Time to deterioration in Functional Assessment of Cancer Therapy (FACT)-Brain Symptom Index (FBrSI) scores in Cohort 1 [ 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 ]
    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)

  20. Change from baseline in score as per FACT-Brain Symptom Index (FBrSI) in Cohort 2 [ 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 ]
    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)

  21. Change from baseline in score as per European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 [ 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 ]
    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)

  22. Change from baseline in score as per European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Lung Cancer Module (QLQ-LC13) [ 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 ]
    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)

  23. Change from baseline in score as per European Quality of Life 5-Dimension 5-Level (EQ-5D-5L) questionnaire [ 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 ]
    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)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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:

    1. 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).
    2. 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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04460729


Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT04460729    
Other Study ID Numbers: CINC280A2203
First Posted: July 8, 2020    Key Record Dates
Last Update Posted: December 3, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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


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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
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
Additional relevant MeSH terms:
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Carcinoma
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms