Clinical trial NCT02639546: Safety and Pharmacokinetics of Cobimetinib in Pediatric and Young Adult Participants With Previously Treated Solid Tumors
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Solid Tumors
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2015-12-24
Enrollment: 56
Sex: ALL
Minimum age (years): 6
Maximum age (years): 30
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.


Eligibility 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

Primary outcomes:
measure: Percentage of Participants With Dose-Limiting Toxicities (DLTs)
timeFrame: Baseline up until 30 days after the last dose of study drug (up to 5 years, 2 months)
measure: Percentage of Participants With Adverse Events (AEs), Including Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs)
timeFrame: Baseline up until 30 days after the last dose of study drug (up to 5 years, 2 months)
measure: Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) of Cobimetinib
timeFrame: Cycle 1 Day 1 up to Cycle 1 Day 28 (cycle length=28 days)
measure: 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)
timeFrame: Baseline up to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 months)
measure: 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)
timeFrame: Baseline up to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 months)
measure: 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)
timeFrame: Baseline up to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 months)
measure: Percentage of Participants With Objective Response (CR or PR) as Determined by the Investigator Using RANO Criteria for Participants With LGG (Phase II)
timeFrame: Baseline up to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 months)
measure: Progression-Free Survival (PFS) as Determined by the Investigator Using mINRC for Participants With Neuroblastoma (Phase I)
timeFrame: 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)
measure: 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)
timeFrame: 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)
measure: PFS as Determined by the Investigator Using RECIST v1.1 Criteria for Participants With All Other Tumours (Phase I)
timeFrame: 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)
measure: PFS as Determined by the Investigator Using RANO Criteria for Participants With LGG (Phase II)
timeFrame: 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 outcomes:
measure: Recommended Phase II Dose (RP2D) of Cobimetinib
timeFrame: Cycle 1 Day 1 up to Cycle 1 Day 28 (cycle length=28 days)
measure: Duration of Response (DOR) as Determined by the Investigator Using RECIST v1.1 for Participants With LGG (Phase I and II)
timeFrame: From first occurrence of objective response to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 months)
measure: DOR as Determined by the Investigator RANO Criteria for Participants With LGG (Phase II)
timeFrame: From first occurrence of objective response to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 months)
measure: Overall Survival (OS) for Participants With Neuroblastoma (Phase I)
timeFrame: Baseline until death due to any cause (up to 5 years, 2 months)
measure: OS for Participants With High-Grade Glioma (HGG) (Phase I) and Low-Grade Glioma (LGG) (Phase I and II)
timeFrame: Baseline until death due to any cause (up to 5 years, 2 months)
measure: OS for Participants With All Other Tumours (Phase I)
timeFrame: Baseline until death due to any cause (up to 5 years, 2 months)
measure: Maximum Plasma Concentration Observed (Cmax) of Cobimetinib
timeFrame: 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)
measure: Time to Cmax (Tmax) of Cobimetinib
timeFrame: 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)
measure: Area Under the Concentration-Time Curve From 0 to 24 Hours (AUC0-24) of Cobimetinib
timeFrame: 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)
measure: Apparent Clearance (CL/F) of Cobimetinib
timeFrame: 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)
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: Arkansas Children'S Hospital
state: Arkansas
city: Orlando
country: United States
facility: Arnold Palmer Hosp-Children
state: Florida
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio
state: Texas
city: Marseille
country: France
facility: Hôpital de la Timone, Oncologie Pédiatrique
city: Paris
country: France
facility: Institut Curie, Oncologie Pédiatrique
city: Villejuif
country: France
facility: Institut Gustave Roussy; Service Pediatrique
city: Muenster
country: Germany
facility: Universitaetsklinikum Muenster
city: Petach-Tikva
country: Israel
facility: Schneider Children's Medical Center
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori; Struttura Complessa di Pediatria Oncologica
state: Lombardia
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital Infantil Universitario Nino Jesus
city: Valencia
country: Spain
facility: Hospital Universitari i Politecnic La Fe de Valencia
city: Liverpool
country: United Kingdom
facility: Alderhey Childrens Trust
city: London
country: United Kingdom
facility: Great Ormond Street Hospital; Dept. Of Pediatric Oncology
city: Newcastle Upon Tyne
country: United Kingdom
facility: The Royal Victoria Infirmary; Paediatric and Adolescent Oncology Unit
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Trippett T, Toledano H, Campbell Hewson Q, Verschuur A, Langevin AM, Aerts I, Howell L, Gallego S, Rossig C, Smith A, Patel D, Pereira LR, Cheeti S, Musib L, Hutchinson KE, Devlin C, Bernardi R, Geoerger B. Cobimetinib in Pediatric and Young Adult Patients with Relapsed or Refractory Solid Tumors (iMATRIX-cobi): A Multicenter, Phase I/II Study. Target Oncol. 2022 May;17(3):283-293. doi: 10.1007/s11523-022-00888-9. Epub 2022 Jun 17.