Recruitment

Recruitment Status
Not yet recruiting
Estimated Enrollment
Same as current

Summary

Conditions
  • Rhabdomyosarcoma
  • Sarcoma, Ewing
Type
Interventional
Phase
Phase 1Phase 2
Design
Allocation: Non-RandomizedIntervention Model: Sequential AssignmentMasking: None (Open Label)Primary Purpose: Treatment

Participation Requirements

Age
Between 12 years and 39 years
Gender
Both males and females

Description

Background: Irinotecan is a prodrug of an inhibitor of topoisomerase 1 (active metabolite is SN-38) with known activity in sarcomas, however it has limitations including suboptimal bioavailability and systemic side effects including severe diarrhea and bone marrow suppression. Preclinical and clinic...

Background: Irinotecan is a prodrug of an inhibitor of topoisomerase 1 (active metabolite is SN-38) with known activity in sarcomas, however it has limitations including suboptimal bioavailability and systemic side effects including severe diarrhea and bone marrow suppression. Preclinical and clinical evidence has demonstrated that prolonged exposure to topoisomerase 1 inhibition produces superior responses in pediatric-type sarcomas, compared to shorter exposures of irinotecan. PEN-866 is a novel molecule consisting of SN-38 conjugated to a heat shock protein 90 (HSP90) inhibitor that has been shown to have a pharmacokinetic (PK) advantage over irinotecan in preclinical models. Preclinical and clinical data have shown that PEN-866 acts as a tumor delivery agent for SN-38, allowing SN-38 to remain in tumor cells substantially longer than it remains in normal cells. In preclinical models of Ewing sarcoma and rhabdomyosarcoma, PEN-866 has superior efficacy and pharmacodynamics compared to irinotecan. PEN-866 has completed phase 1 testing in adults as a single agent but has yet to be tested in any combinations. Vincristine/irinotecan/temozolomide (VIT) is a standard relapse regimen for several pediatric sarcomas, with objective responses reported in a subset of subjects with Ewing sarcoma and rhabdomyosarcoma. Objectives: Phase 1: Determine the maximum tolerated/recommended phase 2 dose (MTD/RP2D) of PEN-866 that can be combined with vincristine and temozolomide in adolescent and young adult (AYA) subjects (12-39 years) with relapsed or refractory solid tumors Phase 2: Determine the objective response rate (CR + PR by RECIST v1.1) of the combination of vincristine, temozolomide and PEN-866 at the RP2D in AYA subjects (12-39 years) with relapsed or refractory Ewing sarcoma and rhabdomyosarcoma after a maximum of 18 cycles of the combination Eligibility: Phase 1 Age >= 12 and < 39 years of age Diagnosis of a relapsed or refractory solid tumor and have archival tissue available. Adequate performance status and adequate major organ function and have recovered from acute toxicity of all prior therapies. Phase 2 Age >= 12 and < 39 years of age Diagnosis of relapsed or refractory Ewing sarcoma or rhabdomyosarcoma and have archival tissue available Subjects must not have received prior combination therapy with irinotecan and temozolomide Adequate performance status and adequate major organ function and have recovered from acute toxicity of all prior therapies. Design: Open label phase 1/2 study to evaluate the safety and preliminary efficacy of PEN-866 given in combination with vincristine and temozolomide in adolescents and young adults with relapsed or refractory solid tumors Phase 1 portion will use a standard 3 + 3 design with limited dose escalations to define the MTD or the highest safe dose tested of PEN-866 when given in combination with standard dosing of vincristine (1.5 mg/m2 IV on days 1 and 8) and temozolomide (100 mg/m2 orally on days 1-5) given in 21 day cycles Phase 2 component will use Simon minimax two-stage phase II trial design and will enroll two expansion cohorts of subjects (Ewing sarcoma and rhabdomyosarcoma) For the Ewing sarcoma cohort, up to a total of 25 evaluable subjects will be accrued. For the rhabdomyosarcoma cohort, up to a total of 17 evaluable subjects will be accrued. A potential additional phase 2 expansion cohort may open for enrollment with an amendment if there are subjects with diagnoses other than rhabdomyosarcoma or Ewing sarcoma who have demonstrated possible benefit from this combination by experiencing a response in the phase 1 portion of the trial. Maximum number of treatment cycles is 18. A maximum of 12 subjects will be required to determine the MTD during phase 1, and a maximum of 42 (25+17) evaluable subjects will be accrued for the phase 2 cohorts. To allow for a small number of inevaluable subjects and to accommodate screen failures, the accrual ceiling will be set at 64.

Tracking Information

NCT #
NCT04890093
Collaborators
Not Provided
Investigators
Principal Investigator: Christine M Heske, M.D. National Cancer Institute (NCI)