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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Solid Tumors

Intervention / Treatment
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* Drug: Cobimetinib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I (Tablet) Cobimetinib (0.6 mg/kg)<br>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<br>* Cobimetinib tablet or suspension will be administered as per the schedule described in arm description.<br>* Other names: RO5514041, GDC-0973, XL-518;|
| Experimental: Phase I (Tablet) Cobimetinib (0.8 mg/kg)<br>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<br>* Cobimetinib tablet or suspension will be administered as per the schedule described in arm description.<br>* Other names: RO5514041, GDC-0973, XL-518;|
| Experimental: Phase I (Tablet) Cobimetinib (1 mg/kg)<br>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<br>* Cobimetinib tablet or suspension will be administered as per the schedule described in arm description.<br>* Other names: RO5514041, GDC-0973, XL-518;|
| Experimental: Phase I (Suspension) Cobimetinib (0.6 mg/kg)<br>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<br>* Cobimetinib tablet or suspension will be administered as per the schedule described in arm description.<br>* Other names: RO5514041, GDC-0973, XL-518;|
| Experimental: Phase I (Suspension) Cobimetinib (0.8 mg/kg)<br>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<br>* Cobimetinib tablet or suspension will be administered as per the schedule described in arm description.<br>* Other names: RO5514041, GDC-0973, XL-518;|
| Experimental: Phase I (Suspension) Cobimetinib (1 mg/kg)<br>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<br>* Cobimetinib tablet or suspension will be administered as per the schedule described in arm description.<br>* Other names: RO5514041, GDC-0973, XL-518;|
| Experimental: Phase I (Suspension) Cobimetinib (1.33 mg/kg)<br>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<br>* Cobimetinib tablet or suspension will be administered as per the schedule described in arm description.<br>* Other names: RO5514041, GDC-0973, XL-518;|
| Experimental: Phase II (Suspension) Cobimetinib (1 mg/kg)<br>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<br>* Cobimetinib tablet or suspension will be administered as per the schedule described in arm description.<br>* Other names: RO5514041, GDC-0973, XL-518;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Dose-Limiting Toxicities (DLTs) | Dose-Limiting Toxicities (DLTs) were defined as cobimetinib-related adverse events occurring within the first 28 days of each administration of cobimetinib. | Baseline up until 30 days after the last dose of study drug (up to 5 years, 2 months) | 
| Percentage of Participants With Adverse Events (AEs), Including Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) | 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. | Baseline up until 30 days after the last dose of study drug (up to 5 years, 2 months) | 
| Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) of Cobimetinib | 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). | Cycle 1 Day 1 up to Cycle 1 Day 28 (cycle length=28 days) | 
| 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) | Tumor assessment was performed using mINRC for Participants with Neuroblastoma. | Baseline up to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 months) | 
| 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) | 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. | Baseline up to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 months) | 
| 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) | Tumor assessment was performed using RECIST v1.1 for Participants with All Other Tumours. | Baseline up to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 months) | 
| Percentage of Participants With Objective Response (CR or PR) as Determined by the Investigator Using RANO Criteria for Participants With LGG (Phase II) | Tumor assessment will be performed using RANO criteria for LGG. | Baseline up to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 months) | 
| Progression-Free Survival (PFS) as Determined by the Investigator Using mINRC for Participants With Neuroblastoma (Phase I) | Tumor assessment was performed using mINRC for Participants with Neuroblastoma. | 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) | 
| 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) | 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. | 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) | 
| PFS as Determined by the Investigator Using RECIST v1.1 Criteria for Participants With All Other Tumours (Phase I) | Tumor assessment was performed using RECIST v1.1 for Participants with All Other Tumours. | 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) | 
| PFS as Determined by the Investigator Using RANO Criteria for Participants With LGG (Phase II) | Tumor assessment was performed using RANO criteria for Participants with LGG. | 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) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended Phase II Dose (RP2D) of Cobimetinib | 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). | Cycle 1 Day 1 up to Cycle 1 Day 28 (cycle length=28 days) | 
| Duration of Response (DOR) as Determined by the Investigator Using RECIST v1.1 for Participants With LGG (Phase I and II) | 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. | From first occurrence of objective response to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 months) | 
| DOR as Determined by the Investigator RANO Criteria for Participants With LGG (Phase II) | Tumor assessment was performed using RANO criteria for Participants with LGG. | From first occurrence of objective response to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 months) | 
| Overall Survival (OS) for Participants With Neuroblastoma (Phase I) | OS was defined as the time from initiation of study drug to death from any cause. | Baseline until death due to any cause (up to 5 years, 2 months) | 
| OS for Participants With High-Grade Glioma (HGG) (Phase I) and Low-Grade Glioma (LGG) (Phase I and II) | 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. | Baseline until death due to any cause (up to 5 years, 2 months) | 
| OS for Participants With All Other Tumours (Phase I) | OS was defined as the time from initiation of study drug to death from any cause. | Baseline until death due to any cause (up to 5 years, 2 months) | 
| Maximum Plasma Concentration Observed (Cmax) of Cobimetinib | 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. | 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) | 
| Time to Cmax (Tmax) of Cobimetinib | 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. | 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) | 
| Area Under the Concentration-Time Curve From 0 to 24 Hours (AUC0-24) of Cobimetinib | 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. | 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) | 
| Apparent Clearance (CL/F) of Cobimetinib | 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. | 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) |