ONC-403-001, A Two-Part Study of TB-403 in Pediatric Subjects with Relapsed or Refractory Medulloblastoma, Neuroblastoma, Ewing Sarcoma, or Alveolar Rhabdomyosarcoma

Study ID: STU 052016-012

Summary

This is a Phase 1 / 2a, 2-part, multicenter, single-arm, consecutive-cohort, open-label study with TB-403. a treatment cycle is defined as the period of time from administration of a single dose of TB-403 on Day 1 to next administration of study drug (typically 14 days from last dose if there is no delay due to drug-related toxicity). in the event of toxicity, a delay up to 28 days from last dose is allowed for resolution of the toxicity to Grade 1 or baseline. Therefore, the duration of a treatment cycle may range from 14 to 28 days, depending on toxicities. Subjects who require a [Greater Than] 28-day treatment interval for resolution of a drug-related toxicity to Grade 1 or baseline will be discontinued from study drug. Part a (Phase 1: Subjects with MB, nB, eS or aRMS) Part a of the study is a Phase 1, single-agent, single ascending dose study of TB-403 in pediatric subjects with relapsed or refractory MB, nB, eS, or aRMS. Part a will involve up to 4 dose cohorts using a 3 +3 escalation scheme for TB-403. For each dose cohort, the first 3 subjects must be at least 2 years of age. optional Continuation of Treatment (Cycles 2 through 12) at the end of the DLT assessment period (i.e., after 1 cycle of therapy), subjects will be given the option to continue with TB-403 at the same dose level they received during Cycle 1. Subjects may continue with TB-403 as a single agent or in combination with temozolomide or etoposide, based on the investigator's judgment. Part B (Phase 2a: Subjects with MB) after the MTD or SMD is determined in Part a, the TSG will confirm if the safety profile of TB-403 is adequate for initiating Part B. Part B will be a Phase 2a, multiple-dose study of TB-403 administered at the MTD / SMD identified in Part a. in Part B, 12 pediatric subjects with relapsed or refractory MB will be administered TB-403 as a single agent for 2 cycles (or 8 weeks, whichever occurs sooner). Thereafter, the subject may continue with TB-403 as a single agent or in combination with temozolomide or etoposide, based on the investigator's judgment. if possible, subjects with complete response (CR) should continue with single agent therapy; subjects with progressive disease (PD) can only continue with combination chemotherapy or be discontinued.

Participant Eligibility

A subject must meet all of the following inclusion criteria to be included in the study: 1. Provide written informed consent (Subject or legal representative) 2. Be > 6 months and < 18 years of age. For each dose cohort in Part A, the first 3 subjects must be at least 2 years of age. 3. Have a histologically-confirmed diagnosis of MB, NB, ES, or ARMS 4. Have documented relapse or refractoriness after standard-of-care therapy 5. Have undergone magnetic resonance imaging (MRI) for MB, a computerized tomography (CT) / metaiodobenzylguanidine (MIBG) scan (if MIBG avid) for NB, CT / MRI for ES or ARMS within 1 month prior to first dose of study treatment 6. Have a Lansky score >= 40 for subjects up to 16 years of age or a Karnofsky score >= 40 for subjects 16 years of age to < 18 years 7. Have adequate organ function, defined as: * Peripheral absolute neutrophil count >= 1.5 x 109/L * Platelet count >= 100 x 109/L (transfusion to reach this level is permitted) * Hemoglobin >= 8mg/dL (transfusion to reach this level is permitted) * International normalized ratio (INR) < 1.5; partial thromboplastin time (PTT) < 1.5 upper limit of normal (ULN) * Creatinine clearance > 50 mL/min/1.73m2 OR serum creatinine <= specified maximum values based on age as described below: * 6 months to 3 years of age: serum creatinine <= 0.4mg/dL * 3 to 13 years of age: serum creatinine <= 0.7mg/dL * > 13 years of age: serum creatinine <= 1mg/dL * Serum aspartate aminotransferase (AST) and serum alanine aminotransferase (ALT) < 2.5 x ULN; serum total bilirubin < 1.5 x ULN 8. Have no symptoms of cranial hypertension or convulsions within 14 days before Cycle 1 Day 1 (anti-epileptic drugs and corticoids are allowed to control any preexisting symptoms) 9. If female of child bearing potential, must not be lactating and must have a negative pregnancy test (blood or urine, at the discretion of the investigator) prior to enrollment and use effective contraception during study participation. Women should continue effective contraception for 3 months following last dose of TB-403. 10. If a sexually-active male, must agree to use a latex condom during any sexual contact with females of child bearing potential while participating in the study and for 3 months following last dose of TB-403. 11. For subjects on corticosteroids for endocrine deficiencies or tumor-associated symptoms, must be on a stable (or decreasing) dose for at least 7 days before first dose of study treatment. Additional Criteria for Sub-Studies: Subjects who are willing to participate in the CSF sub-study must sign additional informed consent. Subjects who are willing to participate in the correlative biologic sub-study must sign additional informed consent to provide tumor tissue for analysis of protein and gene expression.

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

Contact:

Caitlyn Ambrose

Caitlyn.Ambrose@childrens.com