| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Central Nervous System Neoplasms and advanced solid tumors
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| E.1.1.1 | Medical condition in easily understood language |
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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 | LLT |
| E.1.2 | Classification code | 10049516 |
| E.1.2 | Term | Malignant tumor |
| 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) |
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| 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.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Starting from Protocol V11.0 (10JUL2019), newly enrolled patients will only enter Phase II.
Phase I :Determine safety of oral larotrectinib , including Dose-Limiting Toxicity (DLT), in pediatric patients with advanced solid or primary Central Nervous System tumors.
Phase II: Determine 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 (collective referred to as NTRK fusions).
Solid tumors, except for primary CNS tumors and neuroblastomas, will be assessed by RECIST 1.1. Primary CNS tumors will be evaluated by the RANO criteria, and neuroblastoma assessments will utilize the INRC. |
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| E.2.2 | Secondary objectives of the trial |
Phase I
To characterize the pharmacokinetic properties of larotrectinib 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
To describe the antitumor activity of larotrectinib in pediatric patients with advanced solid or primary CNS tumors
To describe pain and health related quality of life in pediatric patients with advanced solid or primary CNS tumors treated with larotrectinib
Phase 2
To determine the ORR based on the treating investigator's response assessment using RANO for primary CNS tumor criteria, and INRC for neuroblastoma and RECIST1.1 for all other solid tumors
To evaluate the DOR in patients with best overall response of CR or PR
To estimate the proportion of patients that have any tumor regression as a best response
To evaluate the duration of PPFS following initiation of larotrectinib
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Phase 1: 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 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 for which no standard or systemic curative therapy exists or
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.
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 with documented 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.
2.Patients with primary CNS tumors or cerebral metastasis:
a) Must be neurologically stable based on stable neurologic exam for 7 days prior to enrollment
b) Must have not required increasing doses of steroids within the 7 days prior to study entry to manage CNS symptoms
c) Phase 2 Only: Imaging study performed within 28 days before C1D1 while on stable dose steroid medication for at least 7 days immediately before and during the imaging study.
3. Histologic verification of malignancy at original diagnosis or relapse, except in patients with intrinsic brain stem tumors, optic pathway gliomas, or patients with pineal tumors and elevations of CSF or serum tumor markers including alpha-fetoprotein or beta-human chorionic gonadotropin (HCG).
4. Evaluable and/or measurable disease
a) Phase 1: Patients must have evaluable and/or measurable disease as defined by RECIST, RANO, or INRC.
b) Phase 2: Patients with a solid or CNS tumor or neuroblastoma must have at least one measurable lesion as defined by RECIST 1.1, RANO, or INRC.
5. Karnofsky (those 16 years and older) or Lansky (those younger than 16 years) performance score of at least 50.
6. Patients must have fully recovered from the acute toxic effects of all prior anti-cancer chemotherapy
7. An archival tumor tissue sample must be available. If archival tumor tissue sample is not available, a fresh biopsy (at a primary or at one metastatic site) should be performed.
8. For patients without known BM involvement:
a) ANC) ≥ 1.0 *10^9/L and
b) Platelet count ≥ 100.0 *10^9/L
c) Hemoglobin ≥ 8.0 g/dL
9. Patients with BM involvement will not be evaluable for hematologic DLT and can enroll with:
a) ANC ≥ 0.75*10^9/L and
b) Platelet count ≥ 50.0*10^9/L
c) Hemoglobin ≥ 8.0 g/dL
10.Adequate hepatic and renal function, defined as:
a) Bilirubin ≤ 2.5 upper limit of normal (ULN) for age
b) Serum glutamic-pyruvic transaminase (SGPT)/alanine aminotransferase (ALT) ≤ 2.5 × ULN.
c) Estimated glomerular filtration rate ≥ 30 mL/minute/1.73m^2based on local institutional practice for determination
11. Ability to comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation.
12. Willingness of male and female patients with reproductive potential to observe conventional and highly effective birth control for the duration of treatment and for 1 month following study completion.
13. Ability to swallow capsules, liquid or gastric access via a naso- or gastric tube.
14. Parent/guardian of child or adolescent patient has the ability to understand, agree to, and sign the ICF and applicable Pediatric Assent Form before initiation of any protocol-related procedures; patient has the ability to give assent at the time of parental/guardian consent |
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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 and able to tolerate oral medications.
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 I: Safety of oral larotrectinib, including dose-limiting toxicity (DLT) until the Maximum Tolerated Dose or suitable dose based on PK exposure or unacceptable DLT are reached.
Pase II: 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) by the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1), or
Response Assessment in Neuro-Oncology (RANO) criteria for primary CNS tumors, and International Neuroblastoma Response Criteria (INRC) for neuroblastoma, as appropriate. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Every cohort from baseline until disease progression,unacceptable toxicity, patient’s withdrawal of consent, or death.
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| E.5.2 | Secondary end point(s) |
PK analysis: Plasm and CSF concentrations of larotrectinibwill be determined with a validtaed bioanalytical assay.
Pain and Health related QoL: in patients 3 years age or older pain will be assessed by the Wong-Baker Faces scale. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The PK parameters will be calculated from the C1D1 and C2D1 (cohorts 1&2)and C4D1 (Phase 1 Dose Escalation cohort 3, Phase 1 Dose Expansion cohorts and Phase 2 Efficacy cohorts).
Pain and Health related QoL: Mean changes over time will be analyzed descriptively by time-point. |
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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 | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 14 |
| 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 |
| Australia |
| Canada |
| China |
| Denmark |
| France |
| Germany |
| Ireland |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Netherlands |
| Poland |
| Spain |
| Sweden |
| Switzerland |
| United Kingdom |
| United States |
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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 | 8 |
| E.8.9.1 | In the Member State concerned days | 2 |
| E.8.9.2 | In all countries concerned by the trial years | 11 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 16 |
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