A study to test the safety and efficacy of the drug larotrectinib for the treatment of tumors with NTRK-fusion in children

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Bayer Consumer Care AG, Bayer AG

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

11 Apr 2017 → ongoing

Decision date (initial)

2023-11-30

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2022-502668-20-00

EudraCT number

2016-003498-16

ClinicalTrials.gov

NCT02637687

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Dose response, Safety, Efficacy

Phase 1: The primary objective of the study is to determine the safety of oral larotrectinib, including dose-limiting toxicity (DLT), in pediatric patients with advanced solid or primary central nervous system (CNS) tumors.
Phase 2: To determine the overall response rate (ORR) as determined by an independent radiology review committee and measured by the proportion of patients with best overall confirmed response of complete response (CR) or partial response (PR) according to the appropriate tumor response criteria following treatment with larotrectinib in pediatric patients with an advanced cancer harboring a fusion involving NTRK1, NTRK2, or NTRK3 (collectively referred to as NTRK fusions) fusions.

Secondary objectives 14

1. Phase 1: To characterize the PK properties of larotrectinib in pediatric patients with advanced solid or primary CNS tumors
2. Phase 1: To identify the maximum tolerated dose (MTD) and/or the recommended dose of larotrectinib for further clinical investigation in this patient population.
3. Phase 1: To describe the antitumor activity of larotrectinib in pediatric patients with advanced solid or primary CNS tumors.
4. Phase 1: To describe pain and health related quality of life (HRQoL) in pediatric patients with an advanced solid or primary central nervous system (CNS) tumor treated with larotrectinib.
5. Phase 2: To determine the ORR based on the treating Investigator’s response assessment using Response Assessment in Neuro-Oncology (RANO) for primary CNS tumor criteria, and International Neuroblastoma Response Criteria (INRC) for neuroblastoma and Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) (Eisenhauer et al. 2009) for all other solid tumors.
6. Phase 2: To evaluate the duration of response (DOR) in patients with best overall response of CR or PR as determined by 1) an independent radiology review committee and 2) the treating Investigator.
7. Phase 2: To estimate the proportion of patients that has any tumor regression as a best response.
8. Phase 2: To evaluate the duration of progression-free survival (PFS) following initiation of larotrectinib.
9. Phase 2: To evaluate the duration of overall survival (OS) following initiation of larotrectinib.
10. Phase 2: To assess the safety profile and tolerability of larotrectinib.
11. Phase 2: To evaluate the clinical benefit rate (CBR) based on the proportion of patients with best overall response of CR, PR, or stable disease lasting 16 or more weeks following initiation of larotrectinib as determined by 1) an independent radiology review committee and 2) the treating Investigator.
12. Phase 2: To evaluate the concordance of prior molecular profiling that detected an NTRK fusion within the patient’s tumor with diagnostic tests being evaluated by the Sponsor.
13. Phase 2: To characterize post-operative staging and surgical margin status in patients who have definitive surgery following treatment with larotrectinib.
14. Phase 2: To describe the putative pretreatment surgical plan and capture the post treatment actual approach with an emphasis on the functional and cosmetic outcome.

Conditions and MedDRA coding

Solid tumors harboring NTRK fusion

Study design 1 period

Regulatory references

Scientific advice from competent authorities

Medicines And Healthcare Products Regulatory Agency, Swedish Medical Products Agency, National Agency For The Safety Of Medicine And Health Products

EMA paediatric investigation plan (PIP)

EMEA-001971-PIP02-16, EMEA-001971-PIP03-18

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Phase 1 (Closed): Phase 1: Birth through 21 years of age at cycle 1 day 1 (C1D1) with a locally advanced or metastatic solid tumor or primary CNS tumor that has relapsed, progressed or was nonresponsive to available therapies and for which no standard or available systemic curative therapy exists, or: Infants from birth and older with a diagnosis of malignancy and with a documented neurotrophic tyrosine kinase receptor (NTRK) fusion that has progressed or was nonresponsive to available therapies, and for which no standard or available curative therapy exists. or: Patients with locally advanced infantile fibrosarcoma (IFS) who would require, in the opinion of the Investigator, disfiguring surgery or limb amputation to achieve a complete surgical resection. Phase 1 dose escalation cohorts are closed to enrollment. Phase 1 dose expansion: In addition to the above stated Inclusion Criteria, patients eligible for enrollment into this cohort must have a malignancy with a documented NTRK gene fusion with the exception of patients with IFS, congenital mesoblastic nephroma tumors (CMN) or secretory breast cancer (SBC). Patients with IFS, CMN or SBC may enroll into this cohort with documentation of an ETS variant gene 6 (ETV6) rearrangement by fluorescence in situ hybridization (FISH) or reverse transcription polymerase chain reaction (RT-PCR) or a documented NTRK fusion by next generation sequencing (NGS).
2. Phase 2: Infants from birth and older at C1D1 with a locally advanced or metastatic IFS, patients with locally advanced IFS who would require, in the opinion of the Investigator, disfiguring surgery or limb amputation to achieve a complete surgical resection withdocumented ETV6 rearrangement (or NTRK3 rearrangement after discussion with the Sponsor) by FISH or RT-PCR or a documented NTRK fusion by e.g., NGS. or: Birth through 21 years of age at C1D1 with a locally advanced or metastatic solid tumor or primary CNS tumor that has relapsed, progressed or was nonresponsive to available therapies and for which no standard or available systemic curative therapy exists, with a documented NTRK gene fusion e.g., by NGS, or in the case of IFS, CMN or SBC with documented ETV6 rearrangement (or NTRK3 rearrangement after discussion with the Sponsor) by FISH or RT-PCR. Documented NTRK fusion by NGS shall be identified through molecular assays as routinely performed at CLIA or other similarly-certified laboratories. If CLIA or similar certification of the laboratory performing the molecular assay is not confirmed at the time of consent patients may be included after discussion with the Sponsor. Patients with NTRK-fusion positive benign tumors are also eligible. or: (including Expansion Phase) Potential patients older than 21 years of age with a tumor diagnosis with histology typical of a pediatric patient and an NTRK fusion may be considered for enrollment following discussion between the local site Investigator and the Sponsor.
3. patients with primary CNS tumors or cerebral metastasis
4. Karnofsky (those 16 years and older) or Lansky (those younger than 16 years) performance score of at least 50.
5. Adequate hematologic function
6. Adequate hepatic and renal function

Exclusion criteria 7

1. Major surgery within 14 days (2 weeks) prior to C1D1.
2. Clinically significant active cardiovascular disease or history of myocardial infarction within 6 months prior to C1D1, ongoing cardiomyopathy; current prolonged QTc interval > 480 milliseconds.
3. Active uncontrolled systemic bacterial, viral, or fungal infection.
4. Malabsorption syndrome or other condition affecting oral absorption.
5. Current treatment with a strong CYP3A4 inhibitor or inducer. Enzyme-inducing anti-epileptic drugs (EIAEDs) and dexamethasone for CNS tumors or metastases, on a stable dose, are allowed.
6. Pregnancy or lactation.
7. Phase 2 Only: Prior progression while receiving approved or investigational tyrosine kinase inhibitors targeting TRK, including entrectinib, repotrectinib, crizotinib and lestaurtanib. Patients who received a TRK inhibitor for less than 28 days of treatment and discontinued because of intolerance remain eligible.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 4

1. Phase 1: Number of subjects in an assigned dose cohort with treatment emergent adverse events (TEAEs) by grade assessed by National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v 4.03 who experience a Dose-limiting toxicity (DLT).
2. Phase 1: Number of participants with TEAEs
3. Phase 1: Severity of TEAEs
4. Phase 2: Overall response rate (ORR) by IRRC

Secondary endpoints 22

1. Phase 1: Maximum concentration of larotrectinib in plasma (Cmax)
2. Phase 1: Area under the concentration versus time curve from time 0 to t (AUC0–t) of larotrectinib in plasma
3. Phase 1: Oral clearance (CL/F)
4. Phase 1: Cerebral spinal fluid/plasma ratio of larotrectinib
5. Phase 1: Maximum tolerated dose (MTD)
6. Phase 1: Recommended dose for Phase 2
7. Phase 1: Overall Response Rate (ORR)
8. Phase 1: Mean change from baseline in Pain scores as assessed by the Wong-Baker Faces scale
9. Phase 1: Mean change in Health-related quality of life scores by Pediatrics Quality of Life - Core Module (PedsQL-Core)
10. Phase 2: Best overall response (BOR)
11. Phase 2: Duration of response (DOR)
12. Phase 2: Proportion of patients with any tumor regression (i.e., any decrease from baseline of the longest diameters of target lesions) as a best response
13. Phase 2: Progression-free survival (PFS)
14. Phase 2: Overall survival (OS)
15. Phase 2: Number of participants with Treatment emergent adverse events (TEAEs)
16. Severity of adverse events as assessed by NCI-CTCAE grading V 4.03
17. Phase 2: Clinical Benefit Rate (CBR)
18. Phase 2: Concordance coefficient
19. Phase 2: Post-operative tumor staging
20. Phase 2: Post-operative surgical margin assessment
21. Phase 2: Pre-treatment surgical plan to preserve function and cosmetic outcome
22. Phase 2: Post-treatment plans to conserve function and cosmetic outcome

Investigational products

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

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Bayer Consumer Care AG

Sponsor organisation

Bayer Consumer Care AG

Address

Peter Merian-Strasse 84

City

Basel

Postcode

4052

Country

Switzerland

Scientific contact point

Organisation

Bayer AG

Contact name

Therapeutic Area Head

Public contact point

Organisation

Bayer AG

Contact name

Therapeutic Area Head

Third parties 16

Bayer AG

Sponsor organisation

Bayer AG

Address

-

City

Leverkusen

Postcode

51368

Country

Germany

Scientific contact point

Organisation

Bayer AG

Contact name

Therapeutic Area Head

Public contact point

Organisation

Bayer AG

Contact name

Therapeutic Area Head

Sponsor responsibilities

Article 77 compliance

Bayer Consumer Care AG

Article 77 implementation

Bayer Consumer Care AG

Locations

9 EU/EEA countries · 12 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 8 files

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

Application history

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