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

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)
Estimated Enrollment :	50 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
Estimated Primary Completion Date :	February 21, 2023
Estimated Study Completion Date :	February 21, 2023

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Cobimetinib - Dose-Escalation Stage; Participants will receive 0.6 milligrams per kilogram (mg/kg) cobimetinib by mouth once daily on Days 1 to 21 of each 28-day treatment cycle. The dose will be increased by up to approximately 33% of the preceding dose level for each successive cohort until maximum tolerated dose (MTD) or maximum administered dose (MAD) is determined. Once MTD or MAD has been identified in tablets, enrollment of participants using suspension will commence at a minimum of one dose level below MTD or MAD of the tablets.	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: Cobimetinib - Expansion Stage; During the expansion stage, participants will be enrolled in disease-specific cohorts and treated at or below the MTD or MAD determined during the dose-escalation stage for pediatric participants and at the recommended adult dose for participants greater than or equal to (>=) 18 years.	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: Cycle 1 Day 1 up to Cycle 1 Day 28 (cycle length=28 days) ]
2. MTD or MAD of Cobimetinib [ Time Frame: Cycle 1 Day 1 up to Cycle 1 Day 28 (cycle length=28 days) ]
3. Recommended Phase II Dose of Cobimetinib (RP2D) [ Time Frame: Cycle 1 Day 1 up to Cycle 1 Day 28 (cycle length=28 days) ]
4. 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; pre-dose on Cycle 2 Day 1 (predose=within 4 hours prior to dose; cycle length=28 days) ]
5. 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 on Cycle 2 Day 1 (pre-dose=within 4 hours prior to dose; cycle length=28 days) ]
6. 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 on Cycle 2 Day 1 (pre-dose=within 4 hours prior to dose; cycle length=28 days) ]
7. 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) ]
8. Percentage of Participants with Objective Response [ Time Frame: Baseline up to disease progression or death due to any cause, whichever occurs first (up to 6.75 years) ]
   Tumor assessment will be performed using modified International Neuroblastoma Response Criteria (mINRC) for participants with neuroblastoma, Response Assessment in Neuro-Oncology (RANO) criteria for participants with high-grade glioma (HGG), and Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) for participants with other tumors.
9. Progression-Free Survival (PFS) as Determined by the Investigator [ Time Frame: Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 6.75 years) ]
   Tumor assessment will be performed using mINRC for participants with neuroblastoma, RANO criteria for participants with HGG, and RECIST v1.1 for participants with other tumors.

Secondary Outcome Measures :

1. Duration of Response (DOR) as Determined by the Investigator [ Time Frame: From first occurrence of objective response to disease progression or death due to any cause, whichever occurs first (up to 6.75 years) ]
   Tumor assessment will be performed using mINRC for participants with neuroblastoma, RANO criteria for participants with HGG, and RECIST v1.1 for participants with other tumors.
2. Overall Survival [ Time Frame: Baseline until death due to any cause (up to 6.75 years) ]

Eligibility Criteria

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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, 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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Contacts

Contact: Reference Study ID Number: GO29665 www.roche.com/about_roche/roche_worldwide.htm	888-662-6728 (U.S. and Canada)	global-roche-genentech-trials@gene.com

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Sponsors and Collaborators

Hoffmann-La Roche

Investigators

Study Director:	Clinical Trials	Hoffmann-La Roche

More Information

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Responsible Party:	Hoffmann-La Roche
ClinicalTrials.gov Identifier:	NCT02639546 History of Changes
Other Study ID Numbers:	GO29665; 2014-004685-25 ( EudraCT Number )
First Posted:	December 24, 2015
Last Update Posted:	January 12, 2018
Last Verified:	January 2018