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 | 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 | 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) |
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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 V.11(10JUL2019), newly enrolled patients will only enter Phase II. Phase I: Determine safety of oral larotrectinib (LOXO-101), including Dose-Limiting Toxicity (DLT), in pediatric patients with advanced solid or primary CNS tumors.
Phase II: 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 (referred to as NTRK fusions). |
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E.2.2 | Secondary objectives of the trial |
To determine the ORR based on the treating investigator's response assessment using RANO for primary CNS tumor criteria, and INRC for
neuroblastoma and RECIST 1.1 for all other solid tumors.
To evaluate the durationcriteria
To evaluate the duration of response in subjects with best overall response of CR or PR as determined by 1) an independant radilogy review committee and 2) the treating investigator
To estimate the proportion of patients that are in tumor regression as a best response
To evaluate the duration of PPFS following initiation of larotrectinib
To evaluate the duration of OS following initiation of larotrectinib
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Starting from Protocol Version 11 (10 JUL 2019), newly enrolled patients will only enter Phase 2.
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
Phase 2: Patients with locally advanced or metastatic infantile fibrosarcoma 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 for whIch no standard or available systemic curative therapy exists, with a documented NTRK gene fusion e.g. by NGS or in case of IFS (Infantile FibroSarcoma), CMN (Congenital Mesoblastic Nephroma tumors) or SBC (Secretory Breast Cancer), they may enroll into this cohort with documentation of an ETV6 rearrangement (or NTRK3 rearrangement after discussion with the sponsor) by FISH or RT-PCR. Documented NTRK fusion by NGS shall 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.
Patients must have fully recovered from the acute toxic effects of all prior anti-cancer chemotherapy
Willingness of male and female patients with reproductive potential to utilize double effective birth control methods for the duration of treatment and for 1 month following study completion
Ability to swallow capsules, liquid or gastric access via a naso- or gastric tube |
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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) |
Germany will not enroll patients into the Phase 1 Dose Escalation cohorts, but will enroll into the Phase 1 Expansion and Phase 2 Efficacy cohorts.
Phase I: Safety of oral larotrectinib (LOXO-101), 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 subjects 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 larotrectinib (LOXO-101) will 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) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
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
| No |
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 | 3 |
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 | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | |
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 |