E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Solid tumors harboring NTRK fusion |
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E.1.1.1 | Medical condition in easily understood language |
Solid cancers harboring an NTRK gene fusion, rare cancers caused by specific changes in the genes |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10007959 |
E.1.2 | Term | Central nervous system neoplasm NOS |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10007958 |
E.1.2 | Term | Central nervous system neoplasm |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10007960 |
E.1.2 | Term | Central nervous system neoplasms malignant NEC |
E.1.2 | System Organ Class | 100000004852 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10065147 |
E.1.2 | Term | Malignant solid tumor |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 23.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10081769 |
E.1.2 | Term | NTRK gene fusion overexpression |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Phase 1: The primary objective of the study is to determine the safety of oral larotrectinib, including DLT, in pediatric patients with advanced solid or primary 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. |
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E.2.2 | Secondary objectives of the trial |
Phase 1: - To characterize the PK properties of larotrectinib, describe the antitumor activity of larotrectinib and describe pain and health
related quality of life (HRQoL) in pediatric patients with advanced solid or primary CNS tumors.
- To identify the MTD and/or the recommended dose of larotrectinib for further clinical investigation in this patient population.
Phase 2: - To determine the ORR.
- To evaluate the duration of response (DOR), duration of progression-free survival (PFS) and duration of OS.
- To estimate the proportion of patients that has any tumor regression as a best response.
- To assess the safety profile and tolerability of larotrectinib.
- To evaluate the clinical benefit rate (CBR) and the concordance of prior molecular profiling.
- To characterize post-operative staging and surgical margin status.
- To describe the putative pretreatment surgical plan and capture the post treatment actual approach with an emphasis on the functional and cosmetic outcome. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Phase 1 (Closed):
-- Dose escalation: 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; OR
Infants from birth and older with a diagnosis of malignancy and with a documented 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 who would require, in the opinion of the investigator, disfiguring surgery or limb amputation to achieve a complete surgical resection. Phase I dose escalation cohorts are closed to enrollment.
-- Dose expansion: In addition to the above stated inclusion criteria, patients must have a malignancy with a documented NTRK gene fusion with the exception of patients with infantile fibrosarcoma, congenital mesoblastic nephroma or secretory breast cancer. Patients with infantile fibrosarcoma, congenital mesoblastic nephroma or secretory breast cancer may enroll into this cohort with documentation of an ETV6 rearrangement by FISH or RT-PCR or a documented NTRK fusion by next generation sequencing.
- Phase 2:
-- Infants from birth and older at C1D1 with a locally advanced or metastatic infantile fibrosarcoma, patients with locally advanced infantile fibrosarcoma who would require, in the opinion of the investigator, disfiguring surgery or limb amputation to achieve a complete surgical resection; 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 (or in the case of infantile fibrosarcoma, congenital mesoblastic nephroma or secretory breast cancer with documented ETV6 rearrangement (or NTRK3 rearrangement after discussion with the sponsor) by FISH or RT-PCR or a documented NTRK fusion by next generation sequencing) (identified through molecular assays as routinely performed at CLIA or other
similarly certified laboratories). Patients with NTRK-fusion positive benign tumors are also eligible; OR 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.
- Patients with primary CNS tumors or cerebral metastasis
- Karnofsky (those 16 years and older) or Lansky (those younger than 16 years) performance score of at least 50.
- Adequate hematologic function
- Adequate hepatic and renal function |
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E.4 | Principal exclusion criteria |
Patients meeting any of the following criteria are to be excluded from study participation:
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; or 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 other than those allowed per Section 6.3.2 of the study protocol.
6. Pregnancy or lactation.
7. Phase 2 only: Prior progression while receiving approved or investigational tyrosine kinase inhibitors targeting TRK, including entrectinib, crizotinib and lestaurtanib. Patients who received a TRK inhibitor for less than 28 days of treatment and discontinued because of intolerance remain eligible. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Phase 1:
1. Number of participants 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. Number of participants with TEAEs
3. Severity of TEAEs
Phase 2:
4. Overall response rate (ORR) by independent radiology review committee (IRRC) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase 1:
1. From Day 1 to Day 28 of Cycle 1 (1 Cycle=28 days)
2. From first dose of larotrectinib up to 93 months
3. From first dose of larotrectinib up to 93 months
Phase 2:
4. From first dose of Larotrectinib to disease progression or subsequent therapy or surgical intervention or death, up to 76 months
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|
E.5.2 | Secondary end point(s) |
Phase 1:
1. Maximum concentration of larotrectinib in plasma (Cmax)
2. Area under the concentration versus time curve from time 0 to t(AUC0–t) of larotrectinib in plasma
3. Oral clearance (CL/F)
4. Cerebral spinal fluid/plasma ratio of Larotrectinib
5. Maximum tolerated dose (MTD)
6. Recommended dose for Phase 2
7. Overall Response Rate (ORR)
8. Mean change from baseline in Pain scores as assessed by the Wong-Baker Faces scale
9. Mean change in Health-related quality of life scores by PedsQL-Core
Phase 2:
10. Best overall response (BOR)
11. Duration of response (DOR)
12. Progression-free survival (PFS)
13. Overall survival (OS)
14. Number of participants with Treatment emergent adverse events (TEAEs)
15. Severity of adverse events as assessed by NCI-CTCAE grading V 4.03
16. Clinical Benefit Rate (CBR)
17. Concordance coefficient
18. Post-operative tumor staging
19. Post-operative surgical margin assessment
20. Pre-treatment surgical plan to preserve function and cosmetic outcome
21. Post-treatment plans to conserve function and cosmetic outcome |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase 1:
1-3. Cohort 1 and 2: Cycle 1 Day 1 (C1D1) at 1 and 4 hours post-dose and C2D1 at pre-dose, and at 1 and 4 hours post-dose; Cohort 3 and Dose Expansion Cohort: C1D1 at 1 and 4 hours post-dose and C4D1 at pre-dose, 1 and 4 hours post-dose
4. C1D1 in conjunction with the post-dose 1-hour PK sample
5. Up to 16 months
6. Up to 16 months
7. Up to 93 months
8. Up to 93 months
9. Up to 93 months
Phase 2:
10. Up to 76 months
11. Up to 76 months
12. Up to 76 months
13. Up to 112 months
14. Up to 112 months
15. Up to 112 months
16. Up to 112 months
17. Up to 76 months
18. Up to 112 months
19. Up to 112 months
20. Up to 112 months
21. Up to 112 months |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
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E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 15 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Switzerland |
Ukraine |
Australia |
Canada |
China |
Israel |
Japan |
Korea, Republic of |
Russian Federation |
Turkey |
United Kingdom |
United States |
Czechia |
Denmark |
France |
Germany |
Ireland |
Italy |
Netherlands |
Poland |
Spain |
Sweden |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 10 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 16 |
E.8.9.2 | In all countries concerned by the trial years | 10 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 22 |