Solid tumors and primary central nervous system (CNS) tumors MedDRA version: 21.1 Level: LLT Classification code 10065147 Term: Malignant solid tumor System Organ Class: 100000004864 MedDRA version: 21.1 Level: LLT Classification code 10065252 Term: Solid tumor System Organ Class: 100000004864
Conditions
Interventions
Product Name: Entrectinib
Product Code: RO7102122/F03
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: ENTRECTINIB
CAS Number: 1108743-60-7
Current Sponsor code: RO7102122
Concentration unit: m
Sponsors
F. Hoffmann-La Roche Ltd
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: - Age: Male or female from birth to age > 18 years. Disease status: - Phase 1 portion (closed): Patients must have measurable or evaluable disease - Phase 2 portion: – Parts B and D:Patients must have measurable or evaluable disease - Part C (closed): Patients must have measurable or evaluable disease – Part E (closed): Patients must have measurable or evaluable disease and will be assessed according to tumor type - Tumor types included below harboring NTRK1/2/3 or ROS1 gene fusions as determined locally by an appropriately validated assay performed in a Clinical Laboratory Improvement Amendments-certified or equivalently-accredited diagnostic laboratory, or centrally by a Foundation Medicine Clinical Trial Assay or the alternative, approved central laboratory for that region:: o Phase 1 portion: – Part A: Relapsed or refractory extracranial solid tumors o Phase 2 portion: – Part B: Primary brain tumors with NTRK1/2/3 or ROS1 gene fusions – Part D: Extracranial solid tumors with NTRK1/2/3 or ROS1 gene fusions - Histologic/molecular diagnosis of malignancy at diagnosis or the time of relapse - For patients enrolled via local molecular testing, an archival tumor tissue from diagnosis or, preferably, from relapsed disease is required to be submitted for independent central testing at Foundation Medicine, Inc. laboratory or the alternative, approved central assay laboratory for that region - Performance status: Lansky or Karnofsky score >= 60% and minimum life expectancy of at least 4 weeks - Prior therapy: Patient’s must have a a disease that is locally advanced, metastatic, or where surgical resection is likely to result in severe morbidity, and who have no satisfactory treatment options for solid tumors and primary CNS tumors that are neurotrophic tyrosine receptor kinase (NTRK) or ROS1 fusion-positive.Patients must have recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to enrollment - Adequate bone marrow, liver, renal, cardiac and neurologic function - Females of childbearing potential must have a negative serum pregnancy test during screening and be neither breastfeeding nor intending to become pregnant during study participation and in the following 90 days after discontinuation of study treatment - For male patients with a female partner of childbearing potential or a pregnant female partner: Agreement to remain abstinent or use a condom during the treatment period and for at least 3 months after the last dose of study drug - Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures Are the trial subjects under 18? yes Number of subjects for this age range: 50 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 18 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: - Current participation in another therapeutic clinical trial - Known congenital long QT syndrome - History of recent (3 months) symptomatic congestive heart failure or ejection fraction =50% at screening - Known active infections (bacterial, fungal, or viral) - Familial or personal history of congenital bone disorders, bone metabolism alterations or osteopenia - Receiving Enzyme Inducing Antiepileptic Drugs - All Phase 2 patients: Prior treatment with approved or investigational tyrosine receptor kinase inhibitor (TRK) or ROS1 inhibitors - Patients with known hypersensitivity to entrectinib or any of the other excipients of the investigational medicinal product - Patients with NB with bone marrow space-only disease - Incomplete recovery from acute effects of any surgery prior to treatment - Active gastrointestinal disease or other malabsorption syndromes that would impact drug absorption - Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or entrectinib administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry in to this study or could compromise protocol objectives in the opinion of the Investigator and/or Sponsor
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: • To determine the maximum tolerated dose (MTD), or recommended Phase 2 dose (RP2D), of F1 entrectinib formulation in pediatric patients (pediatrics and young adults) with relapsed or refractory solid tumors (Part A) • To confirm RP2D of F06 entrectinib formulation in pediatric patients able to swallow intact capsules and in patients dosed via feeding tube (nasogastric tube or gastric tube) • To confirm RP2D of minitablets/F15 formulation in pediatric patients unable to swallow intact capsules • To evaluate efficacy of entrectinib as assessed by objective response rate (ORR) in patients with primary brain tumors harboring NTRK1/2/3 or ROS1 gene fusions (Part B) using Response Assessment in Neuro-Oncology Criteria (RANO) and in patients with extracranial solid tumors harboring NTRK1/2/3 or ROS1 gene fusions (Part D) using Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1), as assessed by blinded independent central review (BICR);Secondary Objective: •To describe the safety profile of entrectinib •To characterize the PK of entrectinib •To determine the duration of response (DOR), time to response (TTR), clinical benefit rate (CBR), progression-free survival (PFS) and overall survival (OS) in all enrolled patients receiving entrectinib at the RP2D •To determine the intracranial tumor response, DOR, TTR, and CNS-PFS in Parts B and D patients receiving entrectinib at the RP2D and presenting with measurable primary or secondary CNS disease at baseline, using RANO or RANO-BM, as applicable •To describe growth, puberty, neurological and neurocognitive function of patients on treatment •To evaluate the efficacy of entrectinib as assessed by ORR in all patients with NTRK1/2/3 gene fusions, regardless of study phase or cohorts using RANO for CNS tumors or RECIST v1.1 for extra-cranial tumors, as assessed by BICR and by investigators •To characterize palatability and tolerability of the different formulations used in the clinical trial;Prim | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Incidence and severity of adverse events, laboratory and electrocardiogram (ECG) abnormalities 2. Maximal plasma concentration (Cmax) of entrectinib 3. Time of maximal plasma concentration (Tmax) of entrectinib 4. Area under the plasma concentration vs. time curve (AUC) of entrectinib 5. Duration of response in patients with relapsed or refractory extracranial solid tumors 6. Time to response in patients with relapsed or refractory extracranial solid tumors 7. Clinical benefit rate in patients with relapsed or refractory extracranial solid tumors 8. Progression-free survival in patients with relapsed or refractory extracranial solid tumors 9. Intracranial tumor response in Parts B and D patients presenting with measurable primary or secondary CNS disease at baseline 10. Duration of response in Parts B and D patients presenting with measurable primary or secondary CNS disease at baseline 11. Time to response in Parts B and D patients presenting with measurable primary or secondary CNS disease at baseline 12. CNS- Progression-free survival in Parts B and D patients presenting with measurable primary or secondary CNS disease at baseline 13. Overall survival for all patients 14. Objective response rate in all patients 15. Analysis of markers of bone formation and resorption and markers of calcium metabolism including P1NP, osteocalcin, BSAP, CTX-1, Vitamin D, parathyroid hormone) plus tartrate resistant acid phosphatase 5b (TRAP5b), sclerostin and Myostatin (GDF8 16. Assessment of bone growth (serial hand/wrist and knee X-rays) and bone mineral density (BMD) via dual x-ray absorptiometry (DXA) scans in patients 17. Acceptability and palatability assessment for capsules and age-appropriate dosage form;Timepoint(s) of evaluation of this end point: 1. Up to 30 days after last dose and every 3 months until death 2-4. Cycle 1 Day 1 pre-dose and at 1, 2, 4, 6, and 24 hours post-dose; Cycle 1 Days 8, 15 and 22 pre-dose; on Cycle 2 Da | — |
Countries
France, Germany, Italy, Spain, United Kingdom, United States
Contacts
Public ContactTrial Information Support Line-TISL
F. Hoffmann-La Roche Ltd
Outcome results
None listed