Oral TRK Inhibitor LOXO-101 (Larotrectinib) for Treatment of Advanced Pediatric Solid or Primary Central Nervous System Tumors (SCOUT)

Study ID: STU 012016-035

Summary

This is a multicenter, open-label, Phase 1 study in pediatric patients with advanced solid or primary CnS tumors. LoXo-101 will be administered in oral liquid or capsule form twice a day (BiD), with the dose escalation according to SimCyp[RegisteredTM] modeling for Cohorts 1 and 2 and with a BSa-based dose for Cohort 3 and subsequent cohorts. The starting dose level used is based on a dose that has been previously tested in adults which has not met dose limiting toxicity criteria. For Cohorts 1 and 2,PK modeling (SimCyp[RegisteredTM]) has been used to select a start dose for pediatric patients that's predicted to equal the exposure achieved in adult patients taking a dose of 100 mg BiD. The modeling takes into account body size differences and ontogeny of the enzymes that metabolize LoXo-101. interim analysis of PK data from Cohorts 1 and 2 indicated that a body-surface area based dose would provide more consistent PK. Doses for Cohort 3 and subsequent cohorts will be based on BSa without regard to the patient's age. Given this change in dosing strategy, the incremental increase in dose between Cohort 2 and Cohort 3 is more modest than typically used in early phase trials. The maximum dose administered will not exceed the recommended Phase 2 dose of 100mg BiD in the adult Phase 2 trial, regardless of the patient's BSa. escalation will proceed through the planned 5 dose levels, or until the MTD is reached, or until the Sponsor determines based on PK exposure that a suitable dose has been achieved. at dose level 4, at least 3 subjects less than 1 m2 will be enrolled before escalating dose further. escalation to dose level 5 will only proceed if [Less Than]2 of 6 participants at dose level 4 have first cycle DLT, including at least 3 participants less than 1 m2, anD if less than 66% of participants less than 1 m2 treated at dose level 4 have first dose exposure in the desired range. Cohorts 3 and higher will use a BSa-based dose. The maximum dose given will be no higher than the highest cleared cohort in the adult Phase 1 trial. This trial will use a Rolling 6 dose escalation scheme. a minimum of 3 patients and a maximum of 6 patients may be enrolled in an open cohort. all patients in a given cohort must have completed safety assessments through Cycle (C) 1, Day (D) 28, and received a minimum of 75% of the planned total dose in C1 (unless due to toxicity) to be eligible for the assessment of a dose limiting toxicity (DLT). a Safety Review Committee will be convened for each cohort dose escalation decision, but will only be required to convene prior to a cohort escalation if there is a DLT reported in a cohort. a minimum of 3 patients in a given cohort must have completed 28 days of safety assessment in C1 without DLT, and a maximum of 1 DLT may be seen in 6 patients who have completed the DLT window before the next cohort initiates accrual. escalation will proceed through all dose levels or until the Sponsor determines that a suitable dose has been achieved based on PK exposure or unacceptable DLT's as noted above. if [GreaterThanorequalTo] 2 ([Greater Than] 33%) of patients within a cohort experience a DLT, then further enrollment to that cohort will stop and the cohort data will be reviewed by the Safety Review Committee. in order for the MTD to be determined, the Safety Review Committee will evaluate whether the previous lower dose level will be considered the MTD, whether an intermediate dose level should be evaluated, and/or whether additional patients need to be evaluated at this dose level if the DLTs seen at this dose level are considered to be not serious or equivocal with regard to causal relationship to LoXo-101. Based on the interim evaluation of the safety and tolerability data of the previous cohort, it may be decided to enroll additional patients in a previously studied cohort, provided the DLT rate was [Less Than] 33% in that cohort, or that accrual will take place at an intermediate dose level in order to more closely characterize DLT(s) and accurately identify the MTD.

Participant Eligibility

Inclusion Criteria:

Pediatric patients ≥ 1 day old on Cycle 1 Day 1 (C1D1)
Phase 1 only: 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, 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. The Phase I dose escalation cohorts are closed to enrollment. 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.
Phase 2 only: 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 with a documented NTRK gene fusion (identified through molecular assays as routinely performed at CLIA or other similarly-certified laboratories) 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's Medical Monitor. Patients with NTRK-fusion positive benign tumors are also eligible.
Karnofsky (those 16 years old or older) or Lansky (those younger than 16 years) performance score of at least 50
Adequate hematologic function: Absolute neutrophil count (ANC) ≥ 1.0 109/L, platelet count ≥ 100.0 109/L and hemoglobin ≥ 8.0 g/dL (patients with bone marrow involvement will not be evaluable for hematologic DLT and can enroll with ANC ≥ 0.75 109/L, platelet count ≥ 50.0 109/L and hemoglobin ≥ 8.0 g/dL)
Adequate hepatic function: Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 upper limit of normal (ULN) for age (patients with documented Gilbert's Disease may be enrolled with Sponsor approval).
Adequate renal function: Estimated glomerular filtration rate ≥ 30 mL/minute using the Cockroft-Gault formula or: a serum creatinine based on age/gender as outlined in the protocol

Exclusion Criteria:

Investigational agent, anticancer therapy, or major surgery within 14 days (2 weeks) prior to C1D1
Clinically significant active cardiovascular disease or history of prolonged QT interval corrected for heart rate (QTc)
Current treatment with a strong cytochrome P450 (CYP) 3A4 inhibitor or inducer (EIAEDs and dexamethasone for CNS tumors or metastases, on a stable dose, are allowed)
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.

Cancer Related: Yes
Healthy Volunteers: No
UT Southwestern Principal Investigator: Theodore W Laetsch

Contact:

Scott Baier

scott.baier@childrens.com