Clinical trial NCT02650401: Study Of Entrectinib (Rxdx-101) in Children and Adolescents With Locally Advanced Or Metastatic Solid Or Primary CNS Tumors And/Or Who Have No Satisfactory Treatment Options
Official title: A Phase 1/2, Open-Label, Dose-Escalation And Expansion Study Of Entrectinib (Rxdx-101) In Pediatrics With Locally Advanced Or Metastatic Solid Or Primary CNS Tumors And/Or Who Have No Satisfactory Treatment Options
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Solid Tumors
CNS Tumors
Keywords: TRK
Tyrosine kinase
NTRK
NTRK1
NTRK2
NTRK3
ROS1
ALK
Pediatric
Relapsed
Refractory
Solid Tumor
Metastatic Cancer
Gene rearrangement
Neuroblastoma
Infantile fibrosarcoma
Secretory breast cancer
Congenital mesoblastic nephroma
Pontine glioma
Brain tumors
CNS tumors
Sarcoma
Ewing sarcoma
Glial tumors
Salivary Gland Cancer (MASC)
Papillary thyroid cancer
Medulloblastoma
Wilms tumor (anaplastic)
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2016-01-08
Enrollment: 69
Sex: ALL
Minimum age (years): 0
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: Inclusion Criteria:

1. 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
2. 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
3. Histologic/molecular diagnosis of malignancy at diagnosis or the time of relapse
4. Archival tumor tissue from diagnosis or, preferably, at relapse
5. Performance status: Lansky or Karnofsky score ≥ 60% and minimum life expectancy of at least 4 weeks
6. 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
7. Participants must have recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to enrollment
8. Adequate organ and neurologic function
9. 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.
10. 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:

1. Receiving other experimental therapy
2. Known congenital long QT syndrome
3. History of recent (3 months) symptomatic congestive heart failure or ejection fraction ≤50% at screening
4. Known active infections
5. Familial or personal history of congenital bone disorders, bone metabolism alterations or osteopenia
6. Receiving Enzyme Inducing Antiepileptic Drugs (EIAEDs) within 14 days of first dose.
7. Prior treatment with approved or investigational TRK or ROS1 inhibitors
8. Known hypersensitivity to entrectinib or any of the other excipients of the investigational medicinal product
9. Patients with NB with bone marrow space-only disease
10. Incomplete recovery from acute effects of any surgery prior to treatment.
11. Active gastrointestinal disease or other malabsorption syndromes that would impact drug absorption.
12. 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.

Primary outcomes:
measure: Maximum Tolerated Dose (MTD)
timeFrame: Approximately 6 months
measure: Recommended Phase 2 Dose (RP2D) of F1 Formulation In Pediatric Participants Able To Swallow Intact Capsules
timeFrame: Approximately 6 months
measure: Recommended Phase 2 Dose (RP2D) of F06 Formulation In Pediatric Participants Able To Swallow Intact Capsules
timeFrame: Approximately 6 months
measure: Recommended Phase 2 Dose (RP2D) of F06 Formulation In Pediatric In Participants Dosed Via Feeding Tube (Nasogastric Tube Or Gastric Tube)
timeFrame: Approximately 6 months
measure: Recommended Phase 2 Dose (RP2D) Of Minitablets/F15 Formulation In Pediatric Participants Unable To Swallow Intact Capsules
timeFrame: Approximately 6 months
measure: Cohort B: Objective Response Rate (ORR)
timeFrame: Approximately 6 months
measure: Cohort D: ORR
timeFrame: Approximately 6 months
Secondary outcomes:
measure: Safety and Tolerability - AE, ECG and Labs assessed by NCI CTCAE v4.03
timeFrame: Approximately 24 months
measure: Maximum observed plasma drug concentration (Cmax) using F1 Formulation
timeFrame: Approximately 24 months
measure: Maximum observed plasma drug concentration (Cmax) using F06 Formulation given intact
timeFrame: Approximately 24 months
measure: Maximum observed plasma drug concentration (Cmax) using F06 Formulation administered via feeding tube
timeFrame: Approximately 24 months
measure: Maximum observed plasma drug concentration (Cmax) using minitablets/F15
timeFrame: Approximately 24 months
measure: Time to Cmax, by inspection (Tmax) using F1 Formulation
timeFrame: Approximately 24 months
measure: Time to Cmax, by inspection (Tmax) using F06 Formulation given intact
timeFrame: Approximately 24 months
measure: Time to Cmax, by inspection (Tmax) using F06 Formulation administered via feeding tube
timeFrame: Approximately 24 months
measure: Time to Cmax, by inspection (Tmax) using minitablets/F15
timeFrame: Approximately 24 months
measure: AUC at steady state (AUCss) using F1 Formulation
timeFrame: Approximately 24 months
measure: AUC at steady state (AUCss) using F06 Formulation given intact
timeFrame: Approximately 24 months
measure: AUC at steady state (AUCss) using F06 Formulation administered via feeding tube
timeFrame: Approximately 24 months
measure: AUC at steady state (AUCss) using minitablets/F15
timeFrame: Approximately 24 months
measure: Terminal half life (t½) using F1 Formulation
timeFrame: Approximately 24 months
measure: Terminal half life (t½) using F06 Formulation given intact
timeFrame: Approximately 24 months
measure: Terminal half life (t½) using F06 Formulation administered via feeding tube
timeFrame: Approximately 24 months
measure: Terminal half life (t½) using minitablets/F15
timeFrame: Approximately 24 months
measure: Area under the drug concentration by time curve (AUC) using F1 Formulation
timeFrame: Approximately 24 months
measure: Area under the drug concentration by time curve (AUC) using F06 Formulation given intact
timeFrame: Approximately 24 months
measure: Area under the drug concentration by time curve (AUC) using F06 Formulation administered via feeding tube
timeFrame: Approximately 24 months
measure: Area under the drug concentration by time curve (AUC) using minitablets/F15
timeFrame: Approximately 24 months
measure: Cohort A, D, or E: Clinical Benefit Rate (CBR)
timeFrame: Approximately 6 months
measure: Cohort B or E: CBR
timeFrame: Approximately 6 months
measure: Cohort C: CBR
timeFrame: Approximately 6 months
measure: Cohort A, D, or E: Progression-free Survival (PFS)
timeFrame: Approximately 6 months
measure: Cohort B or E: PFS
timeFrame: Approximately 6 months
measure: Cohort C: PFS
timeFrame: Approximately 6 months
measure: Cohort A, D, or E: Overall Survival (OS)
timeFrame: Approximately 6 months
measure: Cohort B or E: OS
timeFrame: Approximately 6 months
measure: Cohort A, D, or E: ORR
timeFrame: Approximately 6 months
measure: Cohort B or E: ORR
timeFrame: Approximately 6 months
measure: Cohort C: ORR
timeFrame: Approximately 6 months
measure: Cohort A, D, or E: Time to response (TTR)
timeFrame: Approximately 6 months
measure: Cohort B or E: TTR
timeFrame: Approximately 6 months
measure: Cohort C: TTR
timeFrame: Approximately 6 months
measure: Cohort A, D, or E: Duration of Response (DOR)
timeFrame: Approximately 6 months
measure: Cohort B or E: DOR
timeFrame: Approximately 6 months
measure: Cohort C: DOR
timeFrame: Approximately 6 months
measure: Phase 2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort B or E): ORR
timeFrame: Approximately 6 months
measure: Phase 2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort D or E): ORR
timeFrame: Approximately 6 months
measure: Phase 1/2 Participants with NTRK1/2/3 gene fusions (Cohort A, D, or E): ORR
timeFrame: Approximately 6 months
measure: Phase 1/2 Participants with NTRK1/2/3 gene fusions (Cohort B or E): ORR
timeFrame: Approximately 6 months
measure: Phase 1/2 Participants with ROS1 gene fusions (Cohort A, D, or E): ORR
timeFrame: Approximately 6 months
measure: Phase 1/2 Participants with ROS1 gene fusions (Cohort B or E): ORR
timeFrame: Approximately 6 months
measure: Phase 1/2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort A, D, or E): ORR
timeFrame: Approximately 6 months
measure: Phase 1/2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort B or E): ORR
timeFrame: Approximately 6 months
measure: Phase 2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort B or E): DOR
timeFrame: Approximately 6 months
measure: Phase 2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort D or E): DOR
timeFrame: Approximately 6 months
measure: Phase 1/2 Participants with NTRK1/2/3 gene fusions (Cohort A, D, or E): DOR
timeFrame: Approximately 6 months
measure: Phase 1/2 Participants with NTRK1/2/3 gene fusions (Cohort B or E): DOR
timeFrame: Approximately 6 months
measure: Phase 1/2 Participants with ROS1 gene fusions (Cohort A, D, or E): DOR
timeFrame: Approximately 6 months
measure: Phase 1/2 Participants with ROS1 gene fusions (Cohort B or E): DOR
timeFrame: Approximately 6 months
measure: Phase 1/2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort A, D, or E): DOR
timeFrame: Approximately 6 months
measure: Phase 1/2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort B or E): DOR
timeFrame: Approximately 6 months
measure: Phase 2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort B or E): TTR
timeFrame: Approximately 6 months
measure: Phase 2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort D or E): TTR
timeFrame: Approximately 6 months
measure: Phase 1/2 Participants with NTRK1/2/3 gene fusions (Cohort A, D, or E): TTR
timeFrame: Approximately 6 months
measure: Phase 1/2 Participants with NTRK1/2/3 gene fusions (Cohort B or E): TTR
timeFrame: Approximately 6 months
measure: Phase 1/2 Participants with ROS1 gene fusions (Cohort A, D, or E): TTR
timeFrame: Approximately 6 months
measure: Phase 1/2 Participants with ROS1 gene fusions (Cohort B or E): TTR
timeFrame: Approximately 6 months
measure: Phase 1/2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort A, D, or E): TTR
timeFrame: Approximately 6 months
measure: Phase 1/2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort B or E): TTR
timeFrame: Approximately 6 months
Other outcomes:
Locations:
city: San Diego
country: United States
facility: Rady Childrens Hospital
state: California
city: San Francisco
country: United States
facility: UCSF Benioff Children's Hospital
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Atlanta
country: United States
facility: Egleston Children's Hospital at Emory University Atlanta
state: Georgia
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University,St. Louis Children's Hospital
state: Missouri
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science Uni
state: Oregon
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Memphis
country: United States
facility: St. Jude Children'S Research Hospital
state: Tennessee
city: Houston
country: United States
facility: Texas Children's Cancer and Hematology Center
state: Texas
city: Salt Lake City
country: United States
facility: Primary Children's Hospital
state: Utah
city: Toronto
country: Canada
facility: The Hospital for Sick Children
state: Ontario
city: Beijing
country: China
facility: Beijing Children's Hospital, Capital Medical University
city: Shanghai
country: China
facility: Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
city: Lyon
country: France
facility: Centre Leon Berard
city: Marseille
country: France
facility: Hôpital de la Timone, Oncologie Pédiatrique
city: Heidelberg
country: Germany
facility: Universitaetsklinikum Heidelberg
state: Baden Wuerttemberg
city: Hong Kong
country: Hong Kong
facility: Hong Kong Children's Hospital
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori
state: Lombardia
city: Madrid
country: Spain
facility: Hospital Infantil Universitario Nino Jesus
city: Newcastle upon Tyne
country: United Kingdom
facility: Royal Victoria Infirmary
city: Sutton
country: United Kingdom
facility: Royal Marsden NHS Foundation Trust
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Desai AV, Robinson GW, Gauvain K, Basu EM, Macy ME, Maese L, Whipple NS, Sabnis AJ, Foster JH, Shusterman S, Yoon J, Weiss BD, Abdelbaki MS, Armstrong AE, Cash T, Pratilas CA, Corradini N, Marshall LV, Farid-Kapadia M, Chohan S, Devlin C, Meneses-Lorente G, Cardenas A, Hutchinson KE, Bergthold G, Caron H, Chow Maneval E, Gajjar A, Fox E. Entrectinib in children and young adults with solid or primary CNS tumors harboring NTRK, ROS1, or ALK aberrations (STARTRK-NG). Neuro Oncol. 2022 Oct 3;24(10):1776-1789. doi: 10.1093/neuonc/noac087.
citation: Doebele RC, Drilon A, Paz-Ares L, Siena S, Shaw AT, Farago AF, Blakely CM, Seto T, Cho BC, Tosi D, Besse B, Chawla SP, Bazhenova L, Krauss JC, Chae YK, Barve M, Garrido-Laguna I, Liu SV, Conkling P, John T, Fakih M, Sigal D, Loong HH, Buchschacher GL Jr, Garrido P, Nieva J, Steuer C, Overbeck TR, Bowles DW, Fox E, Riehl T, Chow-Maneval E, Simmons B, Cui N, Johnson A, Eng S, Wilson TR, Demetri GD; trial investigators. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020 Feb;21(2):271-282. doi: 10.1016/S1470-2045(19)30691-6. Epub 2019 Dec 11.