Locally Advanced Or Metastatic Solid Or Primary CNS Tumors And/Or Who Have No Satisfactory Treatment Options

This is an open-label, Phase 1/2 multicenter dose escalation study in pediatric patients with relapsed or refractory extracranial solid tumors (Phase 1), with additional expansion cohorts (Phase 2) in patients with primary brain tumors harboring NTRK1/2/3 or ROS1 gene fusions, and extracranial solid tumors harboring NTRK1/2/3 or ROS1 gene fusions.

ENTRECTINIB (RXDX-101)

ENTRECTINIB

tablet
mini tablet

100, 200
50 (20*2.5 mg)

Primary Outcome Measures :
Maximum Tolerated Dose (MTD) [ Time Frame: Approximately 6 months ]
Assessed by National Cancer Institute Common Terminology for Adverse Events Criteria (NCI CTCAE v4.03)

Recommended Phase 2 Dose (RP2D) of F1 Formulation In Pediatric Participants Able To Swallow Intact Capsules [ Time Frame: Approximately 6 months ]
Assessed by NCI CTCAE v4.03

Recommended Phase 2 Dose (RP2D) of F06 Formulation In Pediatric Participants Able To Swallow Intact Capsules [ Time Frame: Approximately 6 months ]
Assessed by NCI CTCAE v4.03

Recommended Phase 2 Dose (RP2D) of F06 Formulation In Pediatric In Participants Dosed Via Feeding Tube (Nasogastric Tube Or Gastric Tube) [ Time Frame: Approximately 6 months ]
Assessed by NCI CTCAE v4.03

Recommended Phase 2 Dose (RP2D) Of Minitablets/F15 Formulation In Pediatric Participants Unable To Swallow Intact Capsules [ Time Frame: Approximately 6 months ]
Assessed by NCI CTCAE v4.03

Objective Response Rate (ORR) [ Time Frame: Approximately 6 months ]
Assessed by RECIST v1.1


Secondary Outcome Measures :
Safety and Tolerability - AE, ECG and Labs assessed by NCI CTCAE v4.03 [ Time Frame: Approximately 24 months ]
AE, ECG and Labs assessed by NCI CTCAE v4.03

Maximum observed plasma drug concentration (Cmax) using F1 Formulation [ Time Frame: Approximately 24 months ]
Assessed by plasma concentrations obtained on Days 1, 2, 8, 15, 22 (Cycle 1), Days 1, 2 (Cycle 2) and on Day 1 of every cycle thereafter

Maximum observed plasma drug concentration (Cmax) using F06 Formulation given intact [ Time Frame: Approximately 24 months ]
Assessed by plasma concentrations obtained on Days 1, 2, 8, 15, 22 (Cycle 1), Days 1, 2 (Cycle 2) and on Day 1 of every cycle thereafter

Maximum observed plasma drug concentration (Cmax) using F06 Formulation administered via feeding tube [ Time Frame: Approximately 24 months ]
Assessed by plasma concentrations obtained on Days 1, 2, 8, 15, 22 (Cycle 1), Days 1, 2 (Cycle 2) and on Day 1 of every cycle thereafter

Maximum observed plasma drug concentration (Cmax) using minitablets/F15 [ Time Frame: Approximately 24 months ]
Assessed by plasma concentrations obtained on Days 1, 2, 8, 15, 22 (Cycle 1), Days 1, 2 (Cycle 2) and on Day 1 of every cycle thereafter

Time to Cmax, by inspection (Tmax) using F1 Formulation [ Time Frame: Approximately 24 months ]
Assessed by plasma concentrations obtained on Days 1, 2, 8, 15, 22 (Cycle 1), Days 1, 2 (Cycle 2) and on Day 1 of every cycle thereafter

Time to Cmax, by inspection (Tmax) using F06 Formulation given intact [ Time Frame: Approximately 24 months ]
Assessed by plasma concentrations obtained on Days 1, 2, 8, 15, 22 (Cycle 1), Days 1, 2 (Cycle 2) and on Day 1 of every cycle thereafter

Time to Cmax, by inspection (Tmax) using F06 Formulation administered via feeding tube [ Time Frame: Approximately 24 months ]
Assessed by plasma concentrations obtained on Days 1, 2, 8, 15, 22 (Cycle 1), Days 1, 2 (Cycle 2) and on Day 1 of every cycle thereafter

Time to Cmax, by inspection (Tmax) using minitablets/F15 [ Time Frame: Approximately 24 months ]
Assessed by plasma concentrations obtained on Days 1, 2, 8, 15, 22 (Cycle 1), Days 1, 2 (Cycle 2) and on Day 1 of every cycle thereafter

AUC at steady state (AUCss) using F1 Formulation [ Time Frame: Approximately 24 months ]
Assessed by plasma concentrations obtained on Days 1, 2, 8, 15, 22 (Cycle 1), Days 1, 2 (Cycle 2) and on Day 1 of every cycle thereafter

AUC at steady state (AUCss) using F06 Formulation given intact [ Time Frame: Approximately 24 months ]
Assessed by plasma concentrations obtained on Days 1, 2, 8, 15, 22 (Cycle 1), Days 1, 2 (Cycle 2) and on Day 1 of every cycle thereafter

AUC at steady state (AUCss) using F06 Formulation administered via feeding tube [ Time Frame: Approximately 24 months ]
Assessed by plasma concentrations obtained on Days 1, 2, 8, 15, 22 (Cycle 1), Days 1, 2 (Cycle 2) and on Day 1 of every cycle thereafter

AUC at steady state (AUCss) using minitablets/F15 [ Time Frame: Approximately 24 months ]
Assessed by plasma concentrations obtained on Days 1, 2, 8, 15, 22 (Cycle 1), Days 1, 2 (Cycle 2) and on Day 1 of every cycle thereafter

Terminal half life (t½) using F1 Formulation [ Time Frame: Approximately 24 months ]
Assessed by plasma concentrations obtained on Days 1, 2, 8, 15, 22 (Cycle 1), Days 1, 2 (Cycle 2) and on Day 1 of every cycle thereafter

Terminal half life (t½) using F06 Formulation given intact [ Time Frame: Approximately 24 months ]
Assessed by plasma concentrations obtained on Days 1, 2, 8, 15, 22 (Cycle 1), Days 1, 2 (Cycle 2) and on Day 1 of every cycle thereafter

Terminal half life (t½) using F06 Formulation administered via feeding tube [ Time Frame: Approximately 24 months ]
Assessed by plasma concentrations obtained on Days 1, 2, 8, 15, 22 (Cycle 1), Days 1, 2 (Cycle 2) and on Day 1 of every cycle thereafter

Terminal half life (t½) using minitablets/F15 [ Time Frame: Approximately 24 months ]
Assessed by plasma concentrations obtained on Days 1, 2, 8, 15, 22 (Cycle 1), Days 1, 2 (Cycle 2) and on Day 1 of every cycle thereafter

Area under the drug concentration by time curve (AUC) using F1 Formulation [ Time Frame: Approximately 24 months ]
Assessed by plasma concentrations obtained on Days 1, 2, 8, 15, 22 (Cycle 1), Days 1, 2 (Cycle 2) and on Day 1 of every cycle thereafter

Area under the drug concentration by time curve (AUC) using F06 Formulation given intact [ Time Frame: Approximately 24 months ]
Assessed by plasma concentrations obtained on Days 1, 2, 8, 15, 22 (Cycle 1), Days 1, 2 (Cycle 2) and on Day 1 of every cycle thereafter

Area under the drug concentration by time curve (AUC) using F06 Formulation administered via feeding tube [ Time Frame: Approximately 24 months ]
Assessed by plasma concentrations obtained on Days 1, 2, 8, 15, 22 (Cycle 1), Days 1, 2 (Cycle 2) and on Day 1 of every cycle thereafter

Area under the drug concentration by time curve (AUC) using minitablets/F15 [ Time Frame: Approximately 24 months ]
Assessed by plasma concentrations obtained on Days 1, 2, 8, 15, 22 (Cycle 1), Days 1, 2 (Cycle 2) and on Day 1 of every cycle thereafter

Progression-free Survival (PFS) [ Time Frame: Approximately 6 months ]
Defined as time from the date of study enrollment to the first occurrence of objective disease progression or date of death due to any cause, whichever occurs first

Overall Survival (OS) [ Time Frame: Approximately 6 months ]
Assessed by RECIST v1.1

Duration of Response (DOR) [ Time Frame: Approximately 6 months ]
Assessed by RECIST v1.1

Time to response (TTR) [ Time Frame: Approximately 6 months ]
Assessed by RECIST v1.1

Clinical Benefit Rate (CBR) [ Time Frame: Approximately 6 months ]
Assessed by RECIST v1.1

Inclusion Criteria:

Disease status:

Phase 1 portion (closed): Participants must have measurable or evaluable disease, as defined by RECIST v1.1
Phase 2 portion:

Part B: Participants must have measurable or evaluable disease, as defined by RANO
Part C (closed): Participants must have measurable or evaluable disease, as defined by RECIST v1.1 ± Curie Scale
Part D: Participants must have measurable or evaluable disease, as defined by RECIST v1.1
Part E (closed): Participants must have measurable or evaluable disease, as defined by RECIST v1.1 ± Curie Scale or RANO
Tumor type:

Phase 1 portion:

* Part A: Relapsed or refractory extracranial solid tumors

Phase 2 portion

Part B: Primary brain tumors with NTRK1/2/3 or ROS1 gene fusions; gene fusions are defined as those predicted to translate into a fusion protein with a functional TRKA/B/C or ROS1 kinase domain, without a concomitant second oncodriver as determined by a nucleic acid-based diagnostic testing method
Part D: Extracranial solid tumors (including NB) with NTRK1/2/3 or ROS1 gene fusions; gene fusions are defined as those predicted to translate into a fusion protein with a functional TRKA/B/C or ROS1 kinase domain, without a concomitant second oncodriver as determined by a nucleic acid-based diagnostic testing method
Histologic/molecular diagnosis of malignancy at diagnosis or the time of relapse
Archival tumor tissue from diagnosis or, preferably, at relapse
Performance status: Lansky or Karnofsky score ≥ 60% and minimum life expectancy of at least 4 weeks
Prior therapy: Participants must have 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
Participants must have recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to enrollment
Adequate organ 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. Agreement to remain abstinent or use use combined contraceptive methods prior to study entry, for the duration of study participation and in the following 90 days after discontinuation of study treatment.
For male participants 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

Exclusion Criteria:

Receiving other experimental therapy
Known congenital long QT syndrome
History of recent (3 months) symptomatic congestive heart failure or ejection fraction ≤50% at screening
Known active infections
Familial or personal history of congenital bone disorders, bone metabolism alterations or osteopenia
Receiving Enzyme Inducing Antiepileptic Drugs (EIAEDs) within 14 days of first dose.
Prior treatment with approved or investigational TRK or ROS1 inhibitors
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 lab abnormality that may increase the risk associated with study participation, drug administration or may interfere with the interpretation of study results.