Vincristine and Temozolomide in Combination With PEN-866 for Adolescents and Young Adults With Relapsed or Refractory Solid Tumors

Rhabdomyosarcoma Clinical Trial

Official title: Phase 1/2 Study of Vincristine and Temozolomide in Combination With PEN-866 for Adolescents and Young Adults With Relapsed or Refractory Solid Tumors

Status Not yet recruiting

Clinical Trial Summary

Background:

The drug PEN-866 can remain in tumor cells longer than it does in normal cells. It also may be more effective than other drugs at treating Ewing sarcoma and rhabdomyosarcoma. Researchers want to learn if combining PEN-866 with other drugs can treat certain cancers in adolescents and young adults.

Objective:

To learn if the combination of PEN-866 with vincristine and temozolomide can be used to treat adolescents and young adults with solid tumors that have returned after or did not respond to standard treatments, or for which there are no standard treatments.

Eligibility:

People ages 12-39 years who have solid tumors, Ewing sarcoma, or rhabdomyosarcoma that returned after or did not respond to standard treatments.

Design:

Participants will be screened with a medical history, physical exam, and eye exam. They will have heart function tests. They may have imaging scans of the chest, abdomen, and pelvis. They will give blood and urine samples. They may have a tumor biopsy. Some samples will be used for genetic testing. Some screening tests will be repeated during the study.

Participants will get 3 drugs for up to 18 cycles. Each cycle lasts 21 days. They will get PEN-866 and vincristine by IV infusion (a tube in their vein) on Days 1 and 8 of each cycle. They will take temozolomide by mouth on Days 1-5 of each cycle.

Participants will complete questionnaires about their physical, mental, and social health.

Participants will have a follow-up visit 30 days after treatment ends. They may be contacted by phone or email for the rest of their life.

Clinical Trial 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 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 participants 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) participants (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 participants (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

Participants 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 participants (Ewing sarcoma and rhabdomyosarcoma)

For the Ewing sarcoma cohort, up to a total of 25 evaluable participants will be accrued.

For the rhabdomyosarcoma cohort, up to a total of 17 evaluable participants will be accrued.

A potential additional phase 2 expansion cohort may open for enrollment with an amendment if there are participants 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 participants will be required to determine the MTD during phase 1, and a maximum of 42 (25+17) evaluable participants will be accrued for the phase 2 cohorts. To allow for a small number of inevaluable participants and to accommodate screen failures, the accrual ceiling will be set at 64. ;

Related Conditions & MeSH terms

• Neuroectodermal Tumors, Primitive, Peripheral
• Rhabdomyosarcoma
• Sarcoma
• Sarcoma, Ewing

• NCT number: NCT04890093
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Contact: Anne Goodwin, R.N.
• Phone: (240) 760-6195
• Email: goodwina@mail.nih.gov
• Status: Not yet recruiting
• Phase: Phase 1/Phase 2
• Start date: June 26, 2024
• Completion date: December 31, 2026