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 | 20.0 |
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 | 20.0 |
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 | 20.0 |
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 |
Phase I : To determine the safety of oral larotrectinib (LOXO-101), including Dose-Limiting Toxicity (DLT), in pediatric patients with advanced solid or primary Central Nervous System tumors. Phase II: To determine the 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, as appropriate, following treatment with larotrectinib (LOXO-101) in pediatric subjects with an advanced cancer harboring a fusion involving NTRK1, NTRK2, or NTRK3 (collective 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 RECIST 1.1 or RANO criteria 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 subjects that are in tumor regression as a best response To evaluate the duration of PPFS following initiation of larotrectinib (LOXO 101) To evaluate the duration of OS following initiation of larotrectinib (LOXO 101)
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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 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 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 with a documented NTRK gene fusion. 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 observe conventional and effective birth control for the duration of treatment and for 3 months 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) |
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, 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 validated 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 and every 4 cycles thereafter (cohortes 3 and higher) data. 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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 13 |
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 |
France |
Germany |
Italy |
Spain |
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 | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |