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Safety and Pharmacokinetics of Cobimetinib in Pediatric and Young Adult Participants With Previously Treated Solid Tumors (iMATRIXcobi)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02639546
Recruitment Status : Completed
First Posted : December 24, 2015
Results First Posted : March 31, 2022
Last Update Posted : March 31, 2022
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Study Description
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Brief Summary:
This open-label, dose-escalation study is designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of cobimetinib in pediatric and young adult participants with solid tumors with known or potential kinase pathway activation for which standard therapy has proven to be ineffective or intolerable or for which no curative standard-of-care treatment options exist. The study will be conducted in two stages: a dose-escalation stage and an expansion stage at the recommended dose.

Condition or disease Intervention/treatment Phase
Solid Tumors Drug: Cobimetinib Phase 1 Phase 2

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 56 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II, Multicenter, Open-Label, Dose-Escalation Study of the Safety and Pharmacokinetics of Cobimetinib In Pediatric and Young Adult Patients With Previously Treated Solid Tumors
Actual Study Start Date : May 20, 2016
Actual Primary Completion Date : July 21, 2021
Actual Study Completion Date : July 21, 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Cobimetinib

Arms and Interventions
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Arm Intervention/treatment
Experimental: Phase I (Tablet) Cobimetinib (0.6 mg/kg)
Dose-Escalation: Participants received 0.6 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.
 Drug: Cobimetinib
Cobimetinib tablet or suspension will be administered as per the schedule described in arm description.
Other Name: RO5514041, GDC-0973, XL-518
Experimental: Phase I (Tablet) Cobimetinib (0.8 mg/kg)
Dose-Escalation: Participants received 0.8 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.
 Drug: Cobimetinib
Cobimetinib tablet or suspension will be administered as per the schedule described in arm description.
Other Name: RO5514041, GDC-0973, XL-518
Experimental: Phase I (Tablet) Cobimetinib (1 mg/kg)
Dose-Escalation: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.
 Drug: Cobimetinib
Cobimetinib tablet or suspension will be administered as per the schedule described in arm description.
Other Name: RO5514041, GDC-0973, XL-518
Experimental: Phase I (Suspension) Cobimetinib (0.6 mg/kg)
Dose-Escalation: Participants received 0.6 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.
 Drug: Cobimetinib
Cobimetinib tablet or suspension will be administered as per the schedule described in arm description.
Other Name: RO5514041, GDC-0973, XL-518
Experimental: Phase I (Suspension) Cobimetinib (0.8 mg/kg)
Dose-Escalation: Participants received 0.8 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.
 Drug: Cobimetinib
Cobimetinib tablet or suspension will be administered as per the schedule described in arm description.
Other Name: RO5514041, GDC-0973, XL-518
Experimental: Phase I (Suspension) Cobimetinib (1 mg/kg)
Dose-Escalation: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.
 Drug: Cobimetinib
Cobimetinib tablet or suspension will be administered as per the schedule described in arm description.
Other Name: RO5514041, GDC-0973, XL-518
Experimental: Phase I (Suspension) Cobimetinib (1.33 mg/kg)
Dose-Escalation: Participants received 1.33 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.
 Drug: Cobimetinib
Cobimetinib tablet or suspension will be administered as per the schedule described in arm description.
Other Name: RO5514041, GDC-0973, XL-518
Experimental: Phase II (Suspension) Cobimetinib (1 mg/kg)
Dose-Expansion: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.
 Drug: Cobimetinib
Cobimetinib tablet or suspension will be administered as per the schedule described in arm description.
Other Name: RO5514041, GDC-0973, XL-518


Outcome Measures
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Primary Outcome Measures :
  1. Percentage of Participants With Dose-Limiting Toxicities (DLTs) [ Time Frame: Baseline up until 30 days after the last dose of study drug (up to 5 years, 2 months) ]
    Dose-Limiting Toxicities (DLTs) were defined as cobimetinib-related adverse events occurring within the first 28 days of each administration of cobimetinib.

  2. Percentage of Participants With Adverse Events (AEs), Including Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) [ Time Frame: Baseline up until 30 days after the last dose of study drug (up to 5 years, 2 months) ]
    An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including abnormal laboratory values or abnormal clinical test results), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as AEs.

  3. Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) of Cobimetinib [ Time Frame: Cycle 1 Day 1 up to Cycle 1 Day 28 (cycle length=28 days) ]
    A prior dose level was defined as an MTD/MAD if at a certain dose level, there were greater than or equal to (>=) 2 out of 6 participants who had Dose Limiting Toxicities (DLTs).

  4. Percentage of Participants With Objective Response (Complete Response (CR) or Partial Response (PR)) as Determined by the Investigator Using Modified International Neuroblastoma Response Criteria (mINRC) for Participants With Neuroblastoma (Phase I) [ Time Frame: Baseline up to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 months) ]
    Tumor assessment was performed using mINRC for Participants with Neuroblastoma.

  5. Percentage of Participants With Objective Response (CR or PR) as Determined by the Investigator Using RANO Criteria for Participants With High-Grade Glioma (HGG) (Phase I) and RECIST v1.1 for Participants With Low-Grade Glioma (LGG) (Phase I and II) [ Time Frame: Baseline up to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 months) ]
    Tumor assessment was performed using Response Assessment in Neuro-Oncology (RANO) criteria for participants with HGG and Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) for participants with LGG. While the data for LGG in the phase II cohort is presented separately in other parts of the record, it was also considered useful to combine the data for LGG from phase I and phase II, which was done here.

  6. Percentage of Participants With Objective Response (CR or PR) as Determined by the Investigator Using RECIST v1.1 Criteria for Participants With All Other Tumours (Phase I) [ Time Frame: Baseline up to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 months) ]
    Tumor assessment was performed using RECIST v1.1 for Participants with All Other Tumours.

  7. Percentage of Participants With Objective Response (CR or PR) as Determined by the Investigator Using RANO Criteria for Participants With LGG (Phase II) [ Time Frame: Baseline up to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 months) ]
    Tumor assessment will be performed using RANO criteria for LGG.

  8. Progression-Free Survival (PFS) as Determined by the Investigator Using mINRC for Participants With Neuroblastoma (Phase I) [ Time Frame: From the time of cobimetinib study drug initiation to the first documented disease progression, or death due to any cause, whichever occurs first (up to 5 years, 2 months) ]
    Tumor assessment was performed using mINRC for Participants with Neuroblastoma.

  9. PFS as Determined by the Investigator Using RANO Criteria for Participants With HGG (Phase I) and RECIST v1.1 for Partcipants With LGG (Phase I and II) [ Time Frame: From the time of cobimetinib study drug initiation to the first documented disease progression, or death due to any cause, whichever occurs first (up to 5 years, 2 months) ]
    Tumor assessment was performed using RANO for participants with HGG and RECIST v1.1 for participants with LGG. While the data for LGG in the phase II cohort is presented separately in other parts of the record, it was also considered useful to combine the data for LGG from phase I and phase II, which was done here.

  10. PFS as Determined by the Investigator Using RECIST v1.1 Criteria for Participants With All Other Tumours (Phase I) [ Time Frame: From the time of cobimetinib study drug initiation to the first documented disease progression, or death due to any cause, whichever occurs first (up to 5 years, 2 months) ]
    Tumor assessment was performed using RECIST v1.1 for Participants with All Other Tumours.

  11. PFS as Determined by the Investigator Using RANO Criteria for Participants With LGG (Phase II) [ Time Frame: From the time of cobimetinib study drug initiation to the first documented disease progression, or death due to any cause, whichever occurs first (up to 5 years, 2 months) ]
    Tumor assessment was performed using RANO criteria for Participants with LGG.


Secondary Outcome Measures :
  1. Recommended Phase II Dose (RP2D) of Cobimetinib [ Time Frame: Cycle 1 Day 1 up to Cycle 1 Day 28 (cycle length=28 days) ]
    A prior dose level was defined as an RP2D if at a certain dose level, there were greater than or equal to (≥) 2 out of 6 participants who had Dose Limiting Toxicities (DLTs).

  2. Duration of Response (DOR) as Determined by the Investigator Using RECIST v1.1 for Participants With LGG (Phase I and II) [ Time Frame: From first occurrence of objective response to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 months) ]
    Tumor assessment was performed using RECIST v1.1 criteria for participants with LGG. While the data for LGG in the phase II cohort is presented separately in other parts of the record, it was also considered useful to combine the data for LGG from phase I and phase II, which was done here.

  3. DOR as Determined by the Investigator RANO Criteria for Participants With LGG (Phase II) [ Time Frame: From first occurrence of objective response to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 months) ]
    Tumor assessment was performed using RANO criteria for Participants with LGG.

  4. Overall Survival (OS) for Participants With Neuroblastoma (Phase I) [ Time Frame: Baseline until death due to any cause (up to 5 years, 2 months) ]
    OS was defined as the time from initiation of study drug to death from any cause.

  5. OS for Participants With High-Grade Glioma (HGG) (Phase I) and Low-Grade Glioma (LGG) (Phase I and II) [ Time Frame: Baseline until death due to any cause (up to 5 years, 2 months) ]
    OS was defined as the time from initiation of study drug to death from any cause. While the data for LGG in the phase II cohort is presented separately in other parts of the record, it was also considered useful to combine the data for LGG from phase I and phase II, which was done here.

  6. OS for Participants With All Other Tumours (Phase I) [ Time Frame: Baseline until death due to any cause (up to 5 years, 2 months) ]
    OS was defined as the time from initiation of study drug to death from any cause.

  7. Maximum Plasma Concentration Observed (Cmax) of Cobimetinib [ Time Frame: Pre-dose, 2, 4, 6, and 24 hours post-dose on Cycle 1 Days 1 and 21 (predose=within 4 hours prior to dose; cycle length=28 days) ]
    Plasma samples for determination of Cobimetinib concentration were collected prior to dosing and at 2, 4, 6 and 24 hours after dosing on Days 1 and 21 of Cycle 1. The sampling will allow determination of Cmax.

  8. Time to Cmax (Tmax) of Cobimetinib [ Time Frame: Pre-dose, 2, 4, 6, and 24 hours post-dose on Cycle 1 Days 1 and 21 (pre-dose=within 4 hours prior to dose; cycle length=28 days) ]
    Plasma samples for determination of Cobimetinib concentration were collected prior to dosing and at 2, 4, 6 and 24 hours after dosing on Days 1 and 21 of Cycle 1. The sampling will allow determination of Tmax.

  9. Area Under the Concentration-Time Curve From 0 to 24 Hours (AUC0-24) of Cobimetinib [ Time Frame: Pre-dose, 2, 4, 6, and 24 hours post-dose on Cycle 1 Days 1 and 21 (pre-dose=within 4 hours prior to dose; cycle length=28 days) ]
    Plasma samples for determination of Cobimetinib concentration were collected prior to dosing and at 2, 4, 6 and 24 hours after dosing on Days 1 and 21 of Cycle 1. The sampling will allow determination of AUC0-24.

  10. Apparent Clearance (CL/F) of Cobimetinib [ Time Frame: Pre-dose, 2, 4, 6, and 24 hours post-dose on Cycle 1 Days 1 and 21; pre-dose on Cycle 2 Day 1 (pre-dose=within 4 hours prior to dose; cycle length=28 days) ]
    Plasma samples for determination of Cobimetinib concentration were collected prior to dosing and at 2, 4, 6 and 24 hours after dosing on Days 1 and 21 of Cycle 1, and within 4 hours prior to dosing on Day 1 of Cycle 2.


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   6 Months to 30 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • For dose-escalation stage (tablets): age at study entry >= 6 years to < 18 years
  • For dose-escalation stage (suspension): age at study entry >= 6 months to < 18 years. Participants <1 year of age will not be enrolled until >= 6 participants >= 1 year to < 18 years of age have received at least one cycle of therapy with suspension and until safety and pharmacokinetic assessment of these participants have been conducted.
  • For expansion stage: age at study entry to be >= 6 months (>=6 years if suspension is not available) to < 30 years. Participants >= 6 months to < 1 year of age may not be enrolled until >= 6 participants >= 1 year to < 18 years of age have received at least one cycle of therapy with suspension in the dose-escalation phase and until safety and pharmacokinetic assessment of these participants have been conducted.
  • Tumor for which prior treatment has proven to be ineffective or intolerable or for which no standard therapy exists
  • Tumor with known or expected RAS/RAF/MEK/ERK pathway involvement. Diagnosis must be one of the following tumor types:

Central nervous system gliomas, including high- and low-grade gliomas, and diffuse intrinsic pontine glioma (DIPG) Embryonal rhabdomyosarcoma and other non-rhabdomyosarcoma soft tissue sarcomas Neuroblastoma Melanoma Malignant peripheral nerve sheath tumor Rhabdoid tumors, including atypical teratoid/rhabdoid tumor (ATRT) NF1-associated tumor (including plexiform neurofibroma), schwannoma, or RASopathy-associated tumor that in the judgment of the investigator is life threatening, results in severe symptoms (including severe pain), or is in close proximity to vital structures

  • Measurable disease as defined by mINRC, RANO criteria for HGG, RANO criteria for LGG, RECIST v1.1, or evaluable by nuclear medicine techniques, immunocytochemistry, tumor markers, or other reliable measures
  • Availability of tumor tissue at study enrollment
  • Lansky performance status or Karnofsky performance status of >= 50 percent
  • Life expectancy >= 3 months
  • Adequate hematologic, cardiac, and end-organ function
  • Body weight must be >= 20 kilograms (kg) if suspension is not available

Exclusion Criteria:

  • Pregnant or lactating women
  • Close proximity in time to treatment with high-dose chemotherapy, stem-cell rescue, differentiation therapy, immunotherapy, thoracic or mediastinal radiotherapy, hormonal therapy, biologic therapy, herbal cancer therapy, hematopoietic growth factor, investigational therapy, or St. John's wort according to protocol-defined criteria prior to initiation of study drug
  • Inability to swallow oral medications
  • Impaired gastrointestinal absorption
  • History or evidence of retinal pathology according to protocol-defined criteria, including serous retinopathy
  • History of Grade >= 2 central nervous system (CNS) hemorrhage
  • History of CNS hemorrhage within 28 days of study entry. This criterion may be waived at the investigator's request if the CNS hemorrhage was asymptomatic, with approval of the Medical Monitor
  • Known active infection (excluding fungal infection of the nail beds) within 28 days prior to initiation of study drug that has not completely resolved
  • Major surgical procedure or significant traumatic injury within 4 weeks prior to initiation of study drug, or anticipation of need for major surgical procedure during the course of the study
  • Prior allogenic bone marrow transplantation or prior solid organ transplantation
Contacts and Locations
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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): NCT02639546


Locations
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Sponsors and Collaborators
Hoffmann-La Roche
Investigators
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Study Director: Clinical Trials Hoffmann-La Roche
  Study Documents (Full-Text)

Documents provided by Hoffmann-La Roche:
Study Protocol and Statistical Analysis Plan  [PDF] April 11, 2019

More Information
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Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT02639546    
Other Study ID Numbers: GO29665
2014-004685-25 ( EudraCT Number )
First Posted: December 24, 2015    Key Record Dates
Results First Posted: March 31, 2022
Last Update Posted: March 31, 2022
Last Verified: March 2022

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Neoplasms