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 (STARTRK-NG)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

F. Hoffmann-La Roche AG

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

12 Dec 2019 → ongoing

Decision date (initial)

2024-06-24

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

F. Hoffmann-La Roche Ltd

External identifiers

EU CT number

2023-505088-35-00

EudraCT number

2019-001155-39

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Others, Pharmacokinetic, Efficacy

To determine the maximum tolerated dose (MTD), or recommended Phase 2 dose (RP2D), of F1 entrectinib formulation in pediatric patients with relapsed or refractory solid tumors (Cohort 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 minitablet formulation in pediatric patients unable to swallow intact capsules. To evaluate efficacy of entrectinib as assessed by objective response rate (ORR) in the efficacy evaluable patients from Phase II dose expansion (Cohorts B and D) harboring NTRK1/2/3 or ROS1 gene fusions. Responses will be evaluated with use of the Response Assessment in Neuro-Oncology Criteria (RANO) for primary CNS tumors and RECIST v1.1 in patients with extracranial solid tumors, as assessed by blinded independent central review (BICR)

Secondary objectives 8

1. 1. To describe the safety profile of entrectinib
2. 2. To characterize the pharmacokinetic (PK) of entrectinib
3. 3. To evaluate the efficacy of entrectinib as assessed by ORR in subsets of the efficacy evaluable and safety evaluable populations – Patients with NTRK1/2/3 or ROS1 gene fusions in Phase II with use of RANO for CNS tumors (Cohort B or E) and RECIST v1.1 for extracranial tumors (Cohort D or E) as assessed by the investigator – Patients with NTRK1/2/3 gene fusions regardless of study phase or cohorts (Phase I, Cohort B, D, or E) with use of RANO for CNS tumors or RECIST v1.1 for extracranial tumors as assessed by the BICR and the investigator – Patients with ROS1 gene fusions regardless of study phase or cohorts (Phase I, Cohort B, D, or E) with use of RANO for CNS tumors or RECIST v1.1 for extracranial tumors as assessed by the BICR and the investigator – Patients with any fusion type regardless of study phase or cohorts (Phase I, Cohort B, D, or E) with use of RANO for CNS tumors or RECIST v1.1 for extracranial tumors as assessed by the BICR and the investigator
4. 4. To determine the duration of response (DOR) and time to response (TTR) as assessed by BICR and the investigator
5. 5. To evaluate ORR, TTR, DOR, clinical benefit rate (CBR) and progression-free survival (PFS) in the efficacy evaluable and safety evaluable populations as assessed by BICR and the investigator with use of the RECIST v1.1, RANO, and the Curie Scale, as applicable
6. 6. To determine overall survival (OS) in the efficacy evaluable and safety evaluable populations
7. 7. To describe growth (weight, height), puberty (Tanner), neurological and neurocognitive function of patients on treatment
8. 8. To characterize the acceptability and palatability of F06 capsules and minitablet formulations

Conditions and MedDRA coding

Pediatric Solid tumors and primary central nervous system (CNS) tumors

Study design 2 periods

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-002096-PIP01-16

Plan to share IPD

No

IPD plan description

N/A

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Sex and age: male or female aged from birth to age < 18 years
2. Disease status: Phase 1 portion (closed): Patients must have measurable or evaluable disease Phase 2 portion: Cohort B: Patients must have measurable or evaluable disease as defined by RANO Cohort C (closed) and D: Patients must have measurable or evaluable disease as defined per RECIST v1.1±Curie Scale Cohort D: Patients must have measurable or evaluable disease, Cohort E (closed): Patients must have measurable or evaluable disease and be assessed according to tumor type as defined per RECIST v1.1±Curie Scale or RANO
3. 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 (CLIA)-certified or equivalently-accredited diagnostic laboratory, or centrally by a Foundation Medicine Clinical Trial Assay or the alternative, approved central laboratory for that region: Phase 1 portion: Cohort A: Relapsed or refractory extracranial solid tumors Phase 2 portion: Cohort B: Primary brain tumors with NTRK1/2/3 or ROS1 gene fusions Cohort D: Extracranial solid tumors with NTRK1/2/3 or ROS1 gene fusions
4. Histologic/molecular diagnosis of malignancy at diagnosis or the time of relapse
5. 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
6. Performance status: Lansky or Karnofsky score ≥ 60% and minimum life expectancy of at least 4 weeks

Exclusion criteria 6

1. Current participation in another therapeutic clinical trial
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 (bacterial, fungal, or viral)
5. All Phase 2 patients: Prior treatment with approved or investigational tyrosine receptor kinase inhibitor (TRK) or ROS1 inhibitors
6. Incomplete recovery from acute effects of any surgery prior to treatment

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. 1. Dose limiting toxicity DLT during the first cycle (28 days) in pediatric patients with relapsed or refractory solid tumors using the F1 formulation (and subsequently using F06, minitablets). The RP2D will be determined from DLT derived from clinical and laboratory observations in the first treatment cycle according to the NCI CTCAE v4.03 that is related to entrectinib)
2. 2. Objective response rate as assessed by the BICR will be evaluated in the efficacy evaluable population from the Phase II dose expansion cohorts (Cohort B and D)

Secondary endpoints 11

1. 1. Incidence and severity of adverse events, laboratory and electrocardiogram (ECG) abnormalities
2. 2. Maximal plasma concentration (Cmax) of entrectinib (F1, F06 given intact, F06 administered via feeding tube, and minitablets)
3. 3. Time of maximal plasma concentration (Tmax) of entrectinib (F1, F06 given intact, F06 administered via feeding tube, and minitablets)
4. 4. Area under the plasma concentration vs. time curve (AUC) of entrectinib (F1, F06 given intact, F06 administered via feeding tube, and minitablets)
5. 5. ORR in the efficacy evaluable and safety evaluable populations
6. 6. DOR and TTR as assessed by BICR and the investigator in the efficacy evaluable and safety evaluable populations:
7. 7. ORR, TTR, DOR in the efficacy evaluable and safety evaluable populations as assessed by BICR and the investigator with use of RECIST v1.1, RANO, and the Curie scale, as applicable
8. 8. CBR and PFS in the efficacy evaluable and safety evaluable populations as assessed by BICR and investigator with use of RECIST v1.1, RANO, and the Curie scale, as applicable
9. 9. OS in the efficacy evaluable and safety evaluable populations
10. 10. Assessment of growth (weight, height), puberty (Tanner), neurological function and neurocognitive function of patients on treatment
11. 11. Acceptability and palatability assessment for F06 capsules and minitablets formulation

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

F. Hoffmann-La Roche AG

Sponsor organisation

F. Hoffmann-La Roche AG

Address

Grenzacherstrasse 124

City

Basel

Postcode

4058

Country

Switzerland

Scientific contact point

Organisation

F. Hoffmann-La Roche AG

Contact name

Trial Information System - TISL

Public contact point

Organisation

F. Hoffmann-La Roche AG

Contact name

Trial Information System - TISL

Third parties 11

Locations

4 EU/EEA countries · 6 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 46 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications