Solid Tumors
Conditions
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.
Interventions
DRUGCobimetinib
Cobimetinib tablet or suspension will be administered as per the schedule described in arm description.
Sponsors
Hoffmann-La Roche
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Months to 30 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| PFS as Determined by the Investigator Using RANO Criteria for Participants With LGG (Phase II) | 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. |
| Percentage of Participants With Dose-Limiting Toxicities (DLTs) | 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. |
| Percentage of Participants With Adverse Events (AEs), Including Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) | 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. |
| Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) of Cobimetinib | 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). |
| 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) | 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. |
| 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) | 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. |
| 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) | 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. |
| Percentage of Participants With Objective Response (CR or PR) as Determined by the Investigator Using RANO Criteria for Participants With LGG (Phase II) | 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. |
| Progression-Free Survival (PFS) as Determined by the Investigator Using mINRC for Participants With Neuroblastoma (Phase I) | 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. |
| 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) | 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. |
| PFS as Determined by the Investigator Using RECIST v1.1 Criteria for Participants With All Other Tumours (Phase I) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Recommended Phase II Dose (RP2D) of Cobimetinib | 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). |
| Duration of Response (DOR) as Determined by the Investigator Using RECIST v1.1 for Participants With LGG (Phase I and II) | 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. |
| Overall Survival (OS) for Participants With Neuroblastoma (Phase I) | 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. |
| OS for Participants With High-Grade Glioma (HGG) (Phase I) and Low-Grade Glioma (LGG) (Phase I and II) | 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. |
| OS for Participants With All Other Tumours (Phase I) | 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. |
| Maximum Plasma Concentration Observed (Cmax) of Cobimetinib | 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. |
| Time to Cmax (Tmax) of Cobimetinib | 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. |
| Area Under the Concentration-Time Curve From 0 to 24 Hours (AUC0-24) of Cobimetinib | 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. |
| Apparent Clearance (CL/F) of Cobimetinib | 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. |
| DOR as Determined by the Investigator RANO Criteria for Participants With LGG (Phase II) | 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. |
Countries
France, Germany, Israel, Italy, Spain, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted at 17 centers in 7 countries.
Pre-assignment details
A total of 63 participants were screened, of which a total of 56 participants were enrolled. Tumor type was not a determinant of cohort assignment for the phase I portion of the study. The phase II portion of the study was restricted to participants with Low-Grade Glioma.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 6 |
| 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. | 6 |
| 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. | 6 |
| 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. | 6 |
| 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. | 7 |
| 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. | 8 |
| 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. | 5 |
| 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. | 12 |
| Total | 56 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Death | 2 | 2 | 1 | 2 | 2 | 2 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 0 | 1 | 1 | 0 | 1 |
| Overall Study | PI, physician decision; no response to trt. | 2 | 0 | 0 | 0 | 0 | 1 | 0 | 1 |
| Overall Study | Study Terminated By Sponsor | 0 | 2 | 3 | 4 | 4 | 3 | 3 | 9 |
| Overall Study | Withdrawal by Subject | 2 | 2 | 1 | 0 | 0 | 1 | 2 | 1 |
Baseline characteristics
| Characteristic | Phase I (Tablet) Cobimetinib (0.6 mg/kg) | Phase I (Tablet) Cobimetinib (0.8 mg/kg) | Phase I (Tablet) Cobimetinib (1 mg/kg) | Phase I (Suspension) Cobimetinib (0.6 mg/kg) | Phase I (Suspension) Cobimetinib (0.8 mg/kg) | Phase I (Suspension) Cobimetinib (1 mg/kg) | Phase I (Suspension) Cobimetinib (1.33 mg/kg) | Phase II (Suspension) Cobimetinib (1 mg/kg) | Total |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 11.8 Years STANDARD_DEVIATION 3.5 | 9.5 Years STANDARD_DEVIATION 3.3 | 9.5 Years STANDARD_DEVIATION 3.4 | 8.5 Years STANDARD_DEVIATION 1.4 | 9.7 Years STANDARD_DEVIATION 5.3 | 8.9 Years STANDARD_DEVIATION 3.1 | 10.2 Years STANDARD_DEVIATION 3.3 | 8.7 Years STANDARD_DEVIATION 7.5 | 9.5 Years STANDARD_DEVIATION 4.6 |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants | 1 Participants | 1 Participants | 4 Participants | 11 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 5 Participants | 3 Participants | 4 Participants | 1 Participants | 2 Participants | 4 Participants | 3 Participants | 7 Participants | 29 Participants |
| Race/Ethnicity, Customized Not Stated | 0 Participants | 0 Participants | 2 Participants | 3 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 8 Participants |
| Race/Ethnicity, Customized Unknown | 1 Participants | 1 Participants | 2 Participants | 5 Participants | 4 Participants | 3 Participants | 1 Participants | 1 Participants | 18 Participants |
| Race/Ethnicity, Customized White | 5 Participants | 4 Participants | 3 Participants | 0 Participants | 2 Participants | 5 Participants | 4 Participants | 11 Participants | 34 Participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 4 Participants | 2 Participants | 0 Participants | 2 Participants | 5 Participants | 7 Participants | 23 Participants |
| Sex: Female, Male Male | 5 Participants | 4 Participants | 2 Participants | 4 Participants | 7 Participants | 6 Participants | 0 Participants | 5 Participants | 33 Participants |
| Tumor Type Dnet In Noonan's Syndrome Tumor With RAS/RAF/MEK/ERK Pathway Activation | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Tumor Type High-Grade Glioma | 3 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 5 Participants |
| Tumor Type Low-Grade Glioma | 1 Participants | 2 Participants | 4 Participants | 5 Participants | 3 Participants | 2 Participants | 3 Participants | 12 Participants | 32 Participants |
| Tumor Type Malignant Peripheral Nerve Sheath Tumor | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Tumor Type Metastatic Mediastinal Yolksac Tumor With RAS/RAF/MEK/ERK Pathway Activation | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Tumor Type Neuroblastoma | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Tumor Type Non-Rhabdomyosarcoma Soft Tissue Sarcoma | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Tumor Type Plexiform Neurofibroma | 1 Participants | 2 Participants | 1 Participants | 1 Participants | 2 Participants | 4 Participants | 1 Participants | 0 Participants | 12 Participants |
| Tumor Type Rhabdoid Tumor/ATRT | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 7 | 0 / 8 | 0 / 5 | 0 / 12 |
| other Total, other adverse events | 6 / 6 | 6 / 6 | 6 / 6 | 6 / 6 | 7 / 7 | 8 / 8 | 5 / 5 | 12 / 12 |
| serious Total, serious adverse events | 2 / 6 | 2 / 6 | 2 / 6 | 2 / 6 | 1 / 7 | 2 / 8 | 2 / 5 | 5 / 12 |
Outcome results
Primary
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).
Time frame: Cycle 1 Day 1 up to Cycle 1 Day 28 (cycle length=28 days)
Population: The safety evaluable population was defined as all participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I (Tablet) Cobimetinib (0.6 mg/kg) | Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) of Cobimetinib | 0.8 mg/kg |
| Phase I (Tablet) Cobimetinib (0.8 mg/kg) | Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) of Cobimetinib | 1 mg/kg |
Primary
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.
Time frame: Baseline up until 30 days after the last dose of study drug (up to 5 years, 2 months)
Population: The safety evaluable population was defined as all participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I (Tablet) Cobimetinib (0.6 mg/kg) | Percentage of Participants With Adverse Events (AEs), Including Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) | AEs | 100.0 Percentage of Participants |
| Phase I (Tablet) Cobimetinib (0.6 mg/kg) | Percentage of Participants With Adverse Events (AEs), Including Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) | AESIs | 33.3 Percentage of Participants |
| Phase I (Tablet) Cobimetinib (0.6 mg/kg) | Percentage of Participants With Adverse Events (AEs), Including Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) | SAEs | 33.3 Percentage of Participants |
| Phase I (Tablet) Cobimetinib (0.8 mg/kg) | Percentage of Participants With Adverse Events (AEs), Including Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) | AESIs | 33.3 Percentage of Participants |
| Phase I (Tablet) Cobimetinib (0.8 mg/kg) | Percentage of Participants With Adverse Events (AEs), Including Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) | SAEs | 33.3 Percentage of Participants |
| Phase I (Tablet) Cobimetinib (0.8 mg/kg) | Percentage of Participants With Adverse Events (AEs), Including Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) | AEs | 100.0 Percentage of Participants |
| Phase I (Tablet) Cobimetinib (1 mg/kg) | Percentage of Participants With Adverse Events (AEs), Including Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) | AESIs | 33.3 Percentage of Participants |
| Phase I (Tablet) Cobimetinib (1 mg/kg) | Percentage of Participants With Adverse Events (AEs), Including Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) | AEs | 100.0 Percentage of Participants |
| Phase I (Tablet) Cobimetinib (1 mg/kg) | Percentage of Participants With Adverse Events (AEs), Including Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) | SAEs | 33.3 Percentage of Participants |
| Phase I (Suspension) Cobimetinib (0.6 mg/kg) | Percentage of Participants With Adverse Events (AEs), Including Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) | AEs | 100.0 Percentage of Participants |
| Phase I (Suspension) Cobimetinib (0.6 mg/kg) | Percentage of Participants With Adverse Events (AEs), Including Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) | SAEs | 33.3 Percentage of Participants |
| Phase I (Suspension) Cobimetinib (0.6 mg/kg) | Percentage of Participants With Adverse Events (AEs), Including Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) | AESIs | 50.0 Percentage of Participants |
| Phase I (Suspension) Cobimetinib (0.8 mg/kg) | Percentage of Participants With Adverse Events (AEs), Including Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) | SAEs | 14.3 Percentage of Participants |
| Phase I (Suspension) Cobimetinib (0.8 mg/kg) | Percentage of Participants With Adverse Events (AEs), Including Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) | AEs | 100.0 Percentage of Participants |
| Phase I (Suspension) Cobimetinib (0.8 mg/kg) | Percentage of Participants With Adverse Events (AEs), Including Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) | AESIs | 42.9 Percentage of Participants |
| Phase I (Suspension) Cobimetinib (1 mg/kg) | Percentage of Participants With Adverse Events (AEs), Including Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) | SAEs | 25.0 Percentage of Participants |
| Phase I (Suspension) Cobimetinib (1 mg/kg) | Percentage of Participants With Adverse Events (AEs), Including Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) | AEs | 100.0 Percentage of Participants |
| Phase I (Suspension) Cobimetinib (1 mg/kg) | Percentage of Participants With Adverse Events (AEs), Including Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) | AESIs | 25.0 Percentage of Participants |
| Phase I (Suspension) Cobimetinib (1.33 mg/kg) | Percentage of Participants With Adverse Events (AEs), Including Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) | SAEs | 40.0 Percentage of Participants |
| Phase I (Suspension) Cobimetinib (1.33 mg/kg) | Percentage of Participants With Adverse Events (AEs), Including Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) | AEs | 100.0 Percentage of Participants |
| Phase I (Suspension) Cobimetinib (1.33 mg/kg) | Percentage of Participants With Adverse Events (AEs), Including Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) | AESIs | 100.0 Percentage of Participants |
| Phase II (Suspension) Cobimetinib (1 mg/kg) | Percentage of Participants With Adverse Events (AEs), Including Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) | AEs | 100.0 Percentage of Participants |
| Phase II (Suspension) Cobimetinib (1 mg/kg) | Percentage of Participants With Adverse Events (AEs), Including Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) | SAEs | 41.7 Percentage of Participants |
| Phase II (Suspension) Cobimetinib (1 mg/kg) | Percentage of Participants With Adverse Events (AEs), Including Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) | AESIs | 58.3 Percentage of Participants |
Primary
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.
Time frame: Baseline up until 30 days after the last dose of study drug (up to 5 years, 2 months)
Population: The safety evaluable population was defined as all participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I (Tablet) Cobimetinib (0.6 mg/kg) | Percentage of Participants With Dose-Limiting Toxicities (DLTs) | 0 Percentage of Participants |
| Phase I (Tablet) Cobimetinib (0.8 mg/kg) | Percentage of Participants With Dose-Limiting Toxicities (DLTs) | 0 Percentage of Participants |
| Phase I (Tablet) Cobimetinib (1 mg/kg) | Percentage of Participants With Dose-Limiting Toxicities (DLTs) | 33.3 Percentage of Participants |
| Phase I (Suspension) Cobimetinib (0.6 mg/kg) | Percentage of Participants With Dose-Limiting Toxicities (DLTs) | 16.7 Percentage of Participants |
| Phase I (Suspension) Cobimetinib (0.8 mg/kg) | Percentage of Participants With Dose-Limiting Toxicities (DLTs) | 0 Percentage of Participants |
| Phase I (Suspension) Cobimetinib (1 mg/kg) | Percentage of Participants With Dose-Limiting Toxicities (DLTs) | 0 Percentage of Participants |
| Phase I (Suspension) Cobimetinib (1.33 mg/kg) | Percentage of Participants With Dose-Limiting Toxicities (DLTs) | 60.0 Percentage of Participants |
| Phase II (Suspension) Cobimetinib (1 mg/kg) | Percentage of Participants With Dose-Limiting Toxicities (DLTs) | 0 Percentage of Participants |
Primary
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.
Time frame: Baseline up to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 months)
Population: The safety evaluable population was defined as all participants who received at least one dose of study drug. Participants enrolled into phase I (Dose-Escalation) cohorts independent of their tumor type. As the same criteria were not used to assess response in all tumor types, the efficacy analyses were broken down by tumor type.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I (Tablet) Cobimetinib (0.6 mg/kg) | 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) | 0 Percentage of Participants |
Primary
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.
Time frame: Baseline up to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 months)
Population: The safety evaluable population was defined as all participants who received at least one dose of study drug. Participants enrolled into phase I (Dose-Escalation) cohorts independent of their tumor type. For phase II, only one tumor type cohort was opened (LGG). As the same criteria were not used to assess response in all tumor types, the efficacy analyses were broken down by tumor type.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I (Tablet) Cobimetinib (0.6 mg/kg) | 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) | 0 Percentage of Participants |
| Phase I (Tablet) Cobimetinib (0.8 mg/kg) | 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) | 9.4 Percentage of Participants |
Primary
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.
Time frame: Baseline up to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 months)
Population: The safety evaluable population was defined as all participants who received at least one dose of study drug. For phase II, only one tumor type cohort was opened (LGG).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I (Tablet) Cobimetinib (0.6 mg/kg) | Percentage of Participants With Objective Response (CR or PR) as Determined by the Investigator Using RANO Criteria for Participants With LGG (Phase II) | 8.3 Percentage of Participants |
Primary
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.
Time frame: Baseline up to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 months)
Population: The safety evaluable population was defined as all participants who received at least one dose of study drug. Participants enrolled into phase I (Dose-Escalation) cohorts independent of their tumor type. As the same criteria were not used to assess response in all tumor types, the efficacy analyses were broken down by tumor type.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I (Tablet) Cobimetinib (0.6 mg/kg) | 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) | 0 Percentage of Participants |
| Phase I (Tablet) Cobimetinib (0.8 mg/kg) | 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) | 0 Percentage of Participants |
| Phase I (Tablet) Cobimetinib (1 mg/kg) | 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) | 0 Percentage of Participants |
| Phase I (Suspension) Cobimetinib (0.6 mg/kg) | 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) | 0 Percentage of Participants |
| Phase I (Suspension) Cobimetinib (0.8 mg/kg) | 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) | 0 Percentage of Participants |
| Phase I (Suspension) Cobimetinib (1 mg/kg) | 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) | 0 Percentage of Participants |
Primary
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.
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)
Population: The safety evaluable population was defined as all participants who received at least one dose of study drug. Participants enrolled into phase I (Dose-Escalation) cohorts independent of their tumor type. For phase II, only one tumor type cohort was opened (LGG). As the same criteria were not used to assess response in all tumor types, the efficacy analyses were broken down by tumor type.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I (Tablet) Cobimetinib (0.6 mg/kg) | 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) | 1.0 Months |
| Phase I (Tablet) Cobimetinib (0.8 mg/kg) | 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) | 22.0 Months |
Primary
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.
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)
Population: The safety evaluable population was defined as all participants who received at least one dose of study drug. For phase II, only one tumor type cohort was opened (LGG).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I (Tablet) Cobimetinib (0.6 mg/kg) | PFS as Determined by the Investigator Using RANO Criteria for Participants With LGG (Phase II) | 18.4 Months |
Primary
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.
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)
Population: The safety evaluable population was defined as all participants who received at least one dose of study drug. Participants enrolled into phase I (Dose-Escalation) cohorts independent of their tumor type. As the same criteria were not used to assess response in all tumor types, the efficacy analyses were broken down by tumor type.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I (Tablet) Cobimetinib (0.6 mg/kg) | PFS as Determined by the Investigator Using RECIST v1.1 Criteria for Participants With All Other Tumours (Phase I) | NA Months |
| Phase I (Tablet) Cobimetinib (0.8 mg/kg) | PFS as Determined by the Investigator Using RECIST v1.1 Criteria for Participants With All Other Tumours (Phase I) | 4.1 Months |
| Phase I (Tablet) Cobimetinib (1 mg/kg) | PFS as Determined by the Investigator Using RECIST v1.1 Criteria for Participants With All Other Tumours (Phase I) | 1.1 Months |
| Phase I (Suspension) Cobimetinib (0.6 mg/kg) | PFS as Determined by the Investigator Using RECIST v1.1 Criteria for Participants With All Other Tumours (Phase I) | 3.4 Months |
| Phase I (Suspension) Cobimetinib (0.8 mg/kg) | PFS as Determined by the Investigator Using RECIST v1.1 Criteria for Participants With All Other Tumours (Phase I) | NA Months |
| Phase I (Suspension) Cobimetinib (1 mg/kg) | PFS as Determined by the Investigator Using RECIST v1.1 Criteria for Participants With All Other Tumours (Phase I) | 0.5 Months |
Primary
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.
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)
Population: The safety evaluable population was defined as all participants who received at least one dose of study drug. Participants enrolled into phase I (Dose-Escalation) cohorts independent of their tumor type. As the same criteria were not used to assess response in all tumor types, the efficacy analyses were broken down by tumor type.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I (Tablet) Cobimetinib (0.6 mg/kg) | Progression-Free Survival (PFS) as Determined by the Investigator Using mINRC for Participants With Neuroblastoma (Phase I) | 1.3 Months |
Secondary
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.
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)
Population: Please note that for this Outcome Measure, the Apparent Clearance of Cobimetinib could not be calculated/estimated as PK samples were collected only up to 24hr post dosing.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Phase I (Tablet) Cobimetinib (0.6 mg/kg) | Apparent Clearance (CL/F) of Cobimetinib | NA L/hr |
| Phase I (Tablet) Cobimetinib (0.8 mg/kg) | Apparent Clearance (CL/F) of Cobimetinib | NA L/hr |
| Phase I (Tablet) Cobimetinib (1 mg/kg) | Apparent Clearance (CL/F) of Cobimetinib | NA L/hr |
| Phase I (Suspension) Cobimetinib (0.6 mg/kg) | Apparent Clearance (CL/F) of Cobimetinib | NA L/hr |
| Phase I (Suspension) Cobimetinib (0.8 mg/kg) | Apparent Clearance (CL/F) of Cobimetinib | NA L/hr |
| Phase I (Suspension) Cobimetinib (1 mg/kg) | Apparent Clearance (CL/F) of Cobimetinib | NA L/hr |
| Phase I (Suspension) Cobimetinib (1.33 mg/kg) | Apparent Clearance (CL/F) of Cobimetinib | NA L/hr |
| Phase II (Suspension) Cobimetinib (1 mg/kg) | Apparent Clearance (CL/F) of Cobimetinib | NA L/hr |
Secondary
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.
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)
Population: The PK population was defined as all participants who received at least 1 dose of Cobimetinib and had evaluable PK data. Only participants for whom data were collected are included in the analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase I (Tablet) Cobimetinib (0.6 mg/kg) | Area Under the Concentration-Time Curve From 0 to 24 Hours (AUC0-24) of Cobimetinib | Cycle 1 Day 1 | 865 hr*ng/mL | Geometric Coefficient of Variation 83 |
| Phase I (Tablet) Cobimetinib (0.6 mg/kg) | Area Under the Concentration-Time Curve From 0 to 24 Hours (AUC0-24) of Cobimetinib | Cycle 1 Day 21 | 836 hr*ng/mL | Geometric Coefficient of Variation 83.5 |
| Phase I (Tablet) Cobimetinib (0.8 mg/kg) | Area Under the Concentration-Time Curve From 0 to 24 Hours (AUC0-24) of Cobimetinib | Cycle 1 Day 1 | 1006 hr*ng/mL | Geometric Coefficient of Variation 100 |
| Phase I (Tablet) Cobimetinib (0.8 mg/kg) | Area Under the Concentration-Time Curve From 0 to 24 Hours (AUC0-24) of Cobimetinib | Cycle 1 Day 21 | 2802 hr*ng/mL | Geometric Coefficient of Variation 111 |
| Phase I (Tablet) Cobimetinib (1 mg/kg) | Area Under the Concentration-Time Curve From 0 to 24 Hours (AUC0-24) of Cobimetinib | Cycle 1 Day 1 | 1432 hr*ng/mL | Geometric Coefficient of Variation 50 |
| Phase I (Tablet) Cobimetinib (1 mg/kg) | Area Under the Concentration-Time Curve From 0 to 24 Hours (AUC0-24) of Cobimetinib | Cycle 1 Day 21 | 2382 hr*ng/mL | Geometric Coefficient of Variation 38.4 |
| Phase I (Suspension) Cobimetinib (0.6 mg/kg) | Area Under the Concentration-Time Curve From 0 to 24 Hours (AUC0-24) of Cobimetinib | Cycle 1 Day 1 | 743 hr*ng/mL | Geometric Coefficient of Variation 67.4 |
| Phase I (Suspension) Cobimetinib (0.6 mg/kg) | Area Under the Concentration-Time Curve From 0 to 24 Hours (AUC0-24) of Cobimetinib | Cycle 1 Day 21 | 1624 hr*ng/mL | Geometric Coefficient of Variation 80.4 |
| Phase I (Suspension) Cobimetinib (0.8 mg/kg) | Area Under the Concentration-Time Curve From 0 to 24 Hours (AUC0-24) of Cobimetinib | Cycle 1 Day 1 | 1111 hr*ng/mL | Geometric Coefficient of Variation 144 |
| Phase I (Suspension) Cobimetinib (0.8 mg/kg) | Area Under the Concentration-Time Curve From 0 to 24 Hours (AUC0-24) of Cobimetinib | Cycle 1 Day 21 | 1805 hr*ng/mL | Geometric Coefficient of Variation 109 |
| Phase I (Suspension) Cobimetinib (1 mg/kg) | Area Under the Concentration-Time Curve From 0 to 24 Hours (AUC0-24) of Cobimetinib | Cycle 1 Day 1 | 1627 hr*ng/mL | Geometric Coefficient of Variation 74 |
| Phase I (Suspension) Cobimetinib (1 mg/kg) | Area Under the Concentration-Time Curve From 0 to 24 Hours (AUC0-24) of Cobimetinib | Cycle 1 Day 21 | 2562 hr*ng/mL | Geometric Coefficient of Variation 104 |
| Phase I (Suspension) Cobimetinib (1.33 mg/kg) | Area Under the Concentration-Time Curve From 0 to 24 Hours (AUC0-24) of Cobimetinib | Cycle 1 Day 21 | 2511 hr*ng/mL | Geometric Coefficient of Variation 104 |
| Phase I (Suspension) Cobimetinib (1.33 mg/kg) | Area Under the Concentration-Time Curve From 0 to 24 Hours (AUC0-24) of Cobimetinib | Cycle 1 Day 1 | 1567 hr*ng/mL | Geometric Coefficient of Variation 33.1 |
| Phase II (Suspension) Cobimetinib (1 mg/kg) | Area Under the Concentration-Time Curve From 0 to 24 Hours (AUC0-24) of Cobimetinib | Cycle 1 Day 1 | 589 hr*ng/mL | Geometric Coefficient of Variation 79.5 |
| Phase II (Suspension) Cobimetinib (1 mg/kg) | Area Under the Concentration-Time Curve From 0 to 24 Hours (AUC0-24) of Cobimetinib | Cycle 1 Day 21 | 1402 hr*ng/mL | Geometric Coefficient of Variation 59 |
Secondary
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.
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)
Population: The safety evaluable population was defined as all participants who received at least one dose of study drug. For phase II, only one tumor type cohort was opened (LGG).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I (Tablet) Cobimetinib (0.6 mg/kg) | DOR as Determined by the Investigator RANO Criteria for Participants With LGG (Phase II) | NA Months |
Secondary
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.
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)
Population: The safety evaluable population was defined as all participants who received at least one dose of study drug. Participants enrolled into phase I (Dose-Escalation) cohorts independent of their tumor type. For phase II, only one tumor type cohort was opened (LGG). As the same criteria were not used to assess response in all tumor types, the efficacy analyses were broken down by tumor type.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I (Tablet) Cobimetinib (0.6 mg/kg) | Duration of Response (DOR) as Determined by the Investigator Using RECIST v1.1 for Participants With LGG (Phase I and II) | NA Months |
Secondary
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.
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)
Population: The PK population was defined as all participants who received at least 1 dose of Cobimetinib and had evaluable PK data. Only participants for whom data were collected are included in the analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase I (Tablet) Cobimetinib (0.6 mg/kg) | Maximum Plasma Concentration Observed (Cmax) of Cobimetinib | Cycle 1 Day 1 | 62.0 ng/mL | Geometric Coefficient of Variation 82.3 |
| Phase I (Tablet) Cobimetinib (0.6 mg/kg) | Maximum Plasma Concentration Observed (Cmax) of Cobimetinib | Cycle 1 Day 21 | 51.1 ng/mL | Geometric Coefficient of Variation 74 |
| Phase I (Tablet) Cobimetinib (0.8 mg/kg) | Maximum Plasma Concentration Observed (Cmax) of Cobimetinib | Cycle 1 Day 1 | 88.3 ng/mL | Geometric Coefficient of Variation 102 |
| Phase I (Tablet) Cobimetinib (0.8 mg/kg) | Maximum Plasma Concentration Observed (Cmax) of Cobimetinib | Cycle 1 Day 21 | 181 ng/mL | Geometric Coefficient of Variation 134 |
| Phase I (Tablet) Cobimetinib (1 mg/kg) | Maximum Plasma Concentration Observed (Cmax) of Cobimetinib | Cycle 1 Day 1 | 144 ng/mL | Geometric Coefficient of Variation 58.6 |
| Phase I (Tablet) Cobimetinib (1 mg/kg) | Maximum Plasma Concentration Observed (Cmax) of Cobimetinib | Cycle 1 Day 21 | 193 ng/mL | Geometric Coefficient of Variation 35 |
| Phase I (Suspension) Cobimetinib (0.6 mg/kg) | Maximum Plasma Concentration Observed (Cmax) of Cobimetinib | Cycle 1 Day 1 | 51.5 ng/mL | Geometric Coefficient of Variation 73.4 |
| Phase I (Suspension) Cobimetinib (0.6 mg/kg) | Maximum Plasma Concentration Observed (Cmax) of Cobimetinib | Cycle 1 Day 21 | 105 ng/mL | Geometric Coefficient of Variation 84.5 |
| Phase I (Suspension) Cobimetinib (0.8 mg/kg) | Maximum Plasma Concentration Observed (Cmax) of Cobimetinib | Cycle 1 Day 1 | 67.4 ng/mL | Geometric Coefficient of Variation 165 |
| Phase I (Suspension) Cobimetinib (0.8 mg/kg) | Maximum Plasma Concentration Observed (Cmax) of Cobimetinib | Cycle 1 Day 21 | 156 ng/mL | Geometric Coefficient of Variation 91.2 |
| Phase I (Suspension) Cobimetinib (1 mg/kg) | Maximum Plasma Concentration Observed (Cmax) of Cobimetinib | Cycle 1 Day 1 | 136 ng/mL | Geometric Coefficient of Variation 80.3 |
| Phase I (Suspension) Cobimetinib (1 mg/kg) | Maximum Plasma Concentration Observed (Cmax) of Cobimetinib | Cycle 1 Day 21 | 179 ng/mL | Geometric Coefficient of Variation 113 |
| Phase I (Suspension) Cobimetinib (1.33 mg/kg) | Maximum Plasma Concentration Observed (Cmax) of Cobimetinib | Cycle 1 Day 21 | 172 ng/mL | Geometric Coefficient of Variation 60.3 |
| Phase I (Suspension) Cobimetinib (1.33 mg/kg) | Maximum Plasma Concentration Observed (Cmax) of Cobimetinib | Cycle 1 Day 1 | 111 ng/mL | Geometric Coefficient of Variation 37 |
| Phase II (Suspension) Cobimetinib (1 mg/kg) | Maximum Plasma Concentration Observed (Cmax) of Cobimetinib | Cycle 1 Day 1 | 44.0 ng/mL | Geometric Coefficient of Variation 69.8 |
| Phase II (Suspension) Cobimetinib (1 mg/kg) | Maximum Plasma Concentration Observed (Cmax) of Cobimetinib | Cycle 1 Day 21 | 116 ng/mL | Geometric Coefficient of Variation 42 |
Secondary
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.
Time frame: Baseline until death due to any cause (up to 5 years, 2 months)
Population: The safety evaluable population was defined as all participants who received at least one dose of study drug. Participants enrolled into phase I (Dose-Escalation) cohorts independent of their tumor type. As the same criteria were not used to assess response in all tumor types, the efficacy analyses were broken down by tumor type.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I (Tablet) Cobimetinib (0.6 mg/kg) | OS for Participants With All Other Tumours (Phase I) | NA Months |
| Phase I (Tablet) Cobimetinib (0.8 mg/kg) | OS for Participants With All Other Tumours (Phase I) | 5.5 Months |
| Phase I (Tablet) Cobimetinib (1 mg/kg) | OS for Participants With All Other Tumours (Phase I) | 1.1 Months |
| Phase I (Suspension) Cobimetinib (0.6 mg/kg) | OS for Participants With All Other Tumours (Phase I) | 6.3 Months |
| Phase I (Suspension) Cobimetinib (0.8 mg/kg) | OS for Participants With All Other Tumours (Phase I) | NA Months |
| Phase I (Suspension) Cobimetinib (1 mg/kg) | OS for Participants With All Other Tumours (Phase I) | 5.1 Months |
Secondary
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.
Time frame: Baseline until death due to any cause (up to 5 years, 2 months)
Population: The safety evaluable population was defined as all participants who received at least one dose of study drug. Participants enrolled into phase I (Dose-Escalation) cohorts independent of their tumor type. For phase II, only one tumor type cohort was opened (LGG). As the same criteria were not used to assess response in all tumor types, the efficacy analyses were broken down by tumor type.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I (Tablet) Cobimetinib (0.6 mg/kg) | OS for Participants With High-Grade Glioma (HGG) (Phase I) and Low-Grade Glioma (LGG) (Phase I and II) | 1.4 Months |
| Phase I (Tablet) Cobimetinib (0.8 mg/kg) | OS for Participants With High-Grade Glioma (HGG) (Phase I) and Low-Grade Glioma (LGG) (Phase I and II) | NA Months |
Secondary
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.
Time frame: Baseline until death due to any cause (up to 5 years, 2 months)
Population: The safety evaluable population was defined as all participants who received at least one dose of study drug. Participants enrolled into phase I (Dose-Escalation) cohorts independent of their tumor type. As the same criteria were not used to assess response in all tumor types, the efficacy analyses were broken down by tumor type.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I (Tablet) Cobimetinib (0.6 mg/kg) | Overall Survival (OS) for Participants With Neuroblastoma (Phase I) | 4.6 Months |
Secondary
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).
Time frame: Cycle 1 Day 1 up to Cycle 1 Day 28 (cycle length=28 days)
Population: The safety evaluable population was defined as all participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I (Tablet) Cobimetinib (0.6 mg/kg) | Recommended Phase II Dose (RP2D) of Cobimetinib | 1 mg/kg |
Secondary
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.
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)
Population: The PK population was defined as all participants who received at least 1 dose of Cobimetinib and had evaluable PK data. Only participants for whom data were collected are included in the analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase I (Tablet) Cobimetinib (0.6 mg/kg) | Time to Cmax (Tmax) of Cobimetinib | Cycle 1 Day 1 | 4 hr |
| Phase I (Tablet) Cobimetinib (0.6 mg/kg) | Time to Cmax (Tmax) of Cobimetinib | Cycle 1 Day 21 | 4 hr |
| Phase I (Tablet) Cobimetinib (0.8 mg/kg) | Time to Cmax (Tmax) of Cobimetinib | Cycle 1 Day 1 | 2 hr |
| Phase I (Tablet) Cobimetinib (0.8 mg/kg) | Time to Cmax (Tmax) of Cobimetinib | Cycle 1 Day 21 | 4 hr |
| Phase I (Tablet) Cobimetinib (1 mg/kg) | Time to Cmax (Tmax) of Cobimetinib | Cycle 1 Day 1 | 3 hr |
| Phase I (Tablet) Cobimetinib (1 mg/kg) | Time to Cmax (Tmax) of Cobimetinib | Cycle 1 Day 21 | 2 hr |
| Phase I (Suspension) Cobimetinib (0.6 mg/kg) | Time to Cmax (Tmax) of Cobimetinib | Cycle 1 Day 1 | 4 hr |
| Phase I (Suspension) Cobimetinib (0.6 mg/kg) | Time to Cmax (Tmax) of Cobimetinib | Cycle 1 Day 21 | 4 hr |
| Phase I (Suspension) Cobimetinib (0.8 mg/kg) | Time to Cmax (Tmax) of Cobimetinib | Cycle 1 Day 1 | 4 hr |
| Phase I (Suspension) Cobimetinib (0.8 mg/kg) | Time to Cmax (Tmax) of Cobimetinib | Cycle 1 Day 21 | 2 hr |
| Phase I (Suspension) Cobimetinib (1 mg/kg) | Time to Cmax (Tmax) of Cobimetinib | Cycle 1 Day 1 | 2 hr |
| Phase I (Suspension) Cobimetinib (1 mg/kg) | Time to Cmax (Tmax) of Cobimetinib | Cycle 1 Day 21 | 3 hr |
| Phase I (Suspension) Cobimetinib (1.33 mg/kg) | Time to Cmax (Tmax) of Cobimetinib | Cycle 1 Day 21 | 4 hr |
| Phase I (Suspension) Cobimetinib (1.33 mg/kg) | Time to Cmax (Tmax) of Cobimetinib | Cycle 1 Day 1 | 5 hr |
| Phase II (Suspension) Cobimetinib (1 mg/kg) | Time to Cmax (Tmax) of Cobimetinib | Cycle 1 Day 1 | 4 hr |
| Phase II (Suspension) Cobimetinib (1 mg/kg) | Time to Cmax (Tmax) of Cobimetinib | Cycle 1 Day 21 | 2 hr |