Phase 1/2 Trial to Evaluate the Safety and Efficacy of PEEL-224 in Combination With Vincristine and Temozolomide in Adolescents and Young Adults With Relapsed or Refractory Sarcomas

NCT06709495 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: 24-591
• Study Type: interventional
• Target: 63
• Locations: 1 country
• Sites: 3

Brief Summary

This research is being done to test a new drug called PEEL-224 in combination with two commercially available drugs, Vincristine and Temozolomide, and to determine how effective this combination of drugs is at treating Ewing Sarcoma (EWS) and Desmoplastic Small Round Cell Tumor (DSRCT), as well as multiple other kinds of sarcomas. The names of the study drugs and biological agents involved in this study are:

• PEEL-224 (a type of Topoisomerase 1 inhibitor)
• Vincristine (A type of vinca alkaloid)
• Temozolomide (A type of alkylating agent)
• Pegfilgrastim or Filgrastim (types of Myeloid growth factors)

Conditions

Desmoplastic Small Round Cell Tumor; Refractory Sarcoma; Osteosarcoma; Rhabdomyosarcoma; Sarcoma; Sarcoma, Ewing

Keywords

Sarcoma; Sarcoma, Ewing; Desmoplastic Small Round Cell Tumor; Refractory Sarcoma; Relapsed Sarcoma; osteosarcoma; rhabdomyosarcoma

Outcome Measures

Primary Outcomes (5)

• Maximum Tolerated Dose (MTD) (Phase 1)

  The MTD is determined by a Continual Reassessment Method (CRM) design and defined as the dose level with the posterior probability of dose-limiting toxicity (DLT) closest to the target toxicity rate of 0.3 with a maximum sample size of 15. The DLT observation period is up to 35 days long, beginning at the first dose of any of the three drugs in cycle 1 and ending at the occurrence of a DLT.

  Up to 35 days

• Number of Participants with Dose-Limiting Toxicities (Phase 1)

  Any ≥ Grade 2 CTCAE v5 adverse events that are possibly, probably, or definitely attributable to the combination of Vincristine, PEEL-224, and Temozolomide and within the first 35 days, beginning at the first dose of any of the three drugs in cycle 1 and ending at the occurrence of DLT or at the start of treatment in cycle 2 (whichever occurs first). To be evaluable for dose-limiting toxicity, a participant must also receive at least 75% of prescribed agents in cycle 1 and be followed for at least 35 days during cycle 1 or to the start of cycle 2 (whichever occurs first).

  Up to 35 days

• Number of Participants with DLTs (Phase 2)

  A safety monitoring rule will be applied to Phase 2 of the study for the overall participant cohort. The DLT observation period is up to 35 days long, beginning at the first dose of any of the three drugs in cycle 1 and ending at the occurrence of DLT or at the start of treatment in cycle 2 (whichever occurs first).

  Up to 35 days

• Objective Response Rate EWS Cohort (Phase 2)

  ORR is defined as the percentage of participants achieving complete response (CR) or partial response (PR) on treatment based on RECIST 1.1 criteria. Evaluable participants must have measurable disease at screening, be treated at RP2D dose, have received at least one dose of study drug, and either have evidence of clinical progression or have had at least one follow-up disease evaluation of their RECIST measurable disease after initiation of protocol therapy. The proportion of responders is calculated as the (number of responders) / (number of evaluable participants).

  Up to 5 years (based on accrual duration of 2 years)

• Objective Response Rate DSRCT Cohort (Phase 2)

  ORR is defined as the percentage of participants achieving complete response (CR) or partial response (PR) on treatment based on RECIST 1.1 criteria. Evaluable participants must have measurable disease at screening, be treated at RP2D dose, have received at least one dose of study drug, and either have evidence of clinical progression or have had at least one follow-up disease evaluation of their RECIST measurable disease after initiation of protocol therapy. The proportion of responders is calculated as the (number of responders) / (number of evaluable participants).

  Up to 5 years (based on accrual duration of 2 years)

Secondary Outcomes (19)

• Objective Response Rate Other Sarcoma Cohort

  Up to 5 years (based on accrual duration of 2 years)

• Median Progression-Free Survival (PFS) Other Sarcoma Cohort

  Approximately 2 years

• Overall Survival (OS) Other Sarcoma Cohort

  Up to 5 years (based on accrual duration of 2 years)

• Median PFS EWS Cohort

  Approximately 2 years

• OS EWS Cohort

  Up to 5 years (based on accrual duration of 2 years)

Study Arms (9)

Phase 1: Dose Escalation PEEL-224 Dose Level 0

EXPERIMENTAL

Up to 15 participants will be enrolled using a Bayesian design, the Continual Reassessment Method (CRM), to determine the maximum tolerated dose of PEEL-224 and starting at Dose Level 0. Transition to a lower dose level will be determined by types of dose-limiting toxicities observed per the protocol. * Baseline visit with assessments and imaging * Cycle 1 (21 day cycle): * Days 1 through 5: Predetermined dose of Temozolomide 1x daily * Days 1 and 8: Predetermined dose of PEEL-224 1x daily and predetermined dose of Vincristine 1x daily * Day 10: Myeloid growth factor (Pegfilgrastim or Filgrastim) administration 1x daily * Cycle 2 through End of Treatment (21 day cycles): * Days 1 through 5: Predetermined dose of Temozolomide 1x daily * Days 1 and 8: Predetermined dose of PEEL-224 1x daily and predetermined dose of Vincristine 1x daily * Imaging every 2 cycles until Cycle 6 and then every 3 cycles * End of study visit

Drug: PEEL-224; Drug: Temozolomide; Drug: Vincristine; Biological: Pegfilgrastim; Biological: Filgrastim

Phase 1: Dose Escalation PEEL-224 Dose Level -1A

EXPERIMENTAL

Transition to a lower dose level will be determined by types of dose-limiting toxicities observed per the protocol, otherwise establishment of the MTD/RP2D will be according to the CRM model. * Baseline visit with assessments and imaging * Cycle 1 (21 day cycle): * Days 1 through 5: Predetermined dose of Temozolomide 1x daily * Days 1 and 8: Predetermined dose of PEEL-224 1x daily and predetermined dose of Vincristine 1x daily * Day 10: Myeloid growth factor (Pegfilgrastim or Filgrastim) administration 1x daily * Cycle 2 through End of Treatment (21 day cycles): * Days 1 through 5: Predetermined dose of Temozolomide 1x daily * Days 1 and 8: Predetermined dose of PEEL-224 1x daily and predetermined dose of Vincristine 1x daily * Imaging every 2 cycles until Cycle 6 and then every 3 cycles * End of study visit

Drug: PEEL-224; Drug: Temozolomide; Drug: Vincristine; Biological: Pegfilgrastim; Biological: Filgrastim

Phase 1: Dose Escalation PEEL-224 Dose Level -1B

EXPERIMENTAL

Transition to a lower dose level will be determined by types of dose-limiting toxicities observed per the protocol, otherwise establishment of the MTD/RP2D will be according to the CRM model. * Baseline visit with assessments and imaging * Cycle 1 (21 day cycle): * Days 1 through 5: Predetermined dose of Temozolomide 1x daily * Days 1 and 8: Predetermined dose of PEEL-224 1x daily and predetermined dose of Vincristine 1x daily * Day 10: Myeloid growth factor (Pegfilgrastim or Filgrastim) administration 1x daily * Cycle 2 through End of Treatment (21 day cycles): * Days 1 through 5: Predetermined dose of Temozolomide 1x daily * Days 1 and 8: Predetermined dose of PEEL-224 1x daily and predetermined dose of Vincristine 1x daily * Imaging every 2 cycles until Cycle 6 and then every 3 cycles * End of study visit

Drug: PEEL-224; Drug: Temozolomide; Drug: Vincristine; Biological: Pegfilgrastim; Biological: Filgrastim

Phase 1: Dose Escalation PEEL-224 Dose Level -2

EXPERIMENTAL

Establishment of the MTD/RP2D will be according to the CRM design. * Baseline visit with assessments and imaging * Cycle 1 (21 day cycle): * Days 1 through 5: Predetermined dose of Temozolomide 1x daily * Days 1 and 8: Predetermined dose of PEEL-224 1x daily and predetermined dose of Vincristine 1x daily * Day 10: Myeloid growth factor (Pegfilgrastim or Filgrastim) administration 1x daily * Cycle 2 through End of Treatment (21 day cycles): * Days 1 through 5: Predetermined dose of Temozolomide 1x daily * Days 1 and 8: Predetermined dose of PEEL-224 1x daily and predetermined dose of Vincristine 1x daily * Imaging every 2 cycles until Cycle 6 and then every 3 cycles * End of study visit

Drug: PEEL-224; Drug: Temozolomide; Drug: Vincristine; Biological: Pegfilgrastim; Biological: Filgrastim

Phase 1: Dose Escalation PEEL-224 Dose Level 1

EXPERIMENTAL

Escalation to Dose Level 2 or establishment of the MTD/RP2D will be determined by the CRM design. * Baseline visit with assessments and imaging * Cycle 1 (21 day cycle): * Days 1 through 5: Predetermined dose of Temozolomide 1x daily * Days 1 and 8: Predetermined dose of PEEL-224 1x daily and predetermined dose of Vincristine 1x daily * Day 10: Myeloid growth factor (Pegfilgrastim or Filgrastim) administration 1x daily * Cycle 2 through End of Treatment (21 day cycles): * Days 1 through 5: Predetermined dose of Temozolomide 1x daily * Days 1 and 8: Predetermined dose of PEEL-224 1x daily and predetermined dose of Vincristine 1x daily * Imaging every 2 cycles until Cycle 6 and then every 3 cycles * End of study visit

Drug: PEEL-224; Drug: Temozolomide; Drug: Vincristine; Biological: Pegfilgrastim; Biological: Filgrastim

Phase 1: Dose Escalation PEEL-224 Dose Level 2

EXPERIMENTAL

Establishment of the MTD/RP2D will be determined by the CRM design. * Baseline visit with assessments and imaging * Cycle 1 (21 day cycle): * Days 1 through 5: Predetermined dose of Temozolomide 1x daily * Days 1 and 8: Predetermined dose of PEEL-224 1x daily and predetermined dose of Vincristine 1x daily * Day 10: Myeloid growth factor (Pegfilgrastim or Filgrastim) administration 1x daily * Cycle 2 through End of Treatment (21 day cycles): * Days 1 through 5: Predetermined dose of Temozolomide 1x daily * Days 1 and 8: Predetermined dose of PEEL-224 1x daily and predetermined dose of Vincristine 1x daily * Imaging every 2 cycles until Cycle 6 and then every 3 cycles * End of study visit

Drug: PEEL-224; Drug: Temozolomide; Drug: Vincristine; Biological: Pegfilgrastim; Biological: Filgrastim

Phase 2: Dose Expansion Ewing Sarcoma

EXPERIMENTAL

Administration of PEEL-224 will be at the RP2D, and safety monitoring rules will be applied for the occurrence of dose-limiting toxicities. 15 participants will be enrolled and will complete: * Baseline visit with assessments and imaging * Cycle 1 (21 day cycle): * Days 1 through 5: Predetermined dose of Temozolomide 1x daily * Days 1 and 8: Predetermined dose of PEEL-224 1x daily and predetermined dose of Vincristine 1x daily * Day 10: Myeloid growth factor (Pegfilgrastim or Filgrastim) administration 1x daily * Cycle 2 through End of Treatment (21 day cycles): * Days 1 through 5: Predetermined dose of Temozolomide 1x daily * Days 1 and 8: Predetermined dose of PEEL-224 1x daily and predetermined dose of Vincristine 1x daily * Imaging every 2 cycles until Cycle 6 and then every 3 cycles * End of study visit

Drug: PEEL-224; Drug: Temozolomide; Drug: Vincristine; Biological: Pegfilgrastim; Biological: Filgrastim

Phase 2: Dose Expansion DSRCT

EXPERIMENTAL

Administration of PEEL-224 will be at the RP2D, and safety monitoring rules will be applied for the occurrence of dose-limiting toxicities. 15 participants will be enrolled and will complete: * Baseline visit with assessments and imaging * Cycle 1 (21 day cycle): * Days 1 through 5: Predetermined dose of Temozolomide 1x daily * Days 1 and 8: Predetermined dose of PEEL-224 1x daily and predetermined dose of Vincristine 1x daily * Day 10: Myeloid growth factor (Pegfilgrastim or Filgrastim) administration 1x daily * Cycle 2 through End of Treatment (21 day cycles): * Days 1 through 5: Predetermined dose of Temozolomide 1x daily * Days 1 and 8: Predetermined dose of PEEL-224 1x daily and predetermined dose of Vincristine 1x daily * Imaging every 2 cycles until Cycle 6 and then every 3 cycles * End of study visit

Drug: PEEL-224; Drug: Temozolomide; Drug: Vincristine; Biological: Pegfilgrastim; Biological: Filgrastim

Phase 2: Dose Expansion Other Sarcoma

EXPERIMENTAL

Administration of PEEL-224 will be at the RP2D, and safety monitoring rules will be applied for the occurrence of dose-limiting toxicities. 15 participants will be enrolled and will complete: * Baseline visit with assessments and imaging * Cycle 1 (21 day cycle): * Days 1 through 5: Predetermined dose of Temozolomide 1x daily * Days 1 and 8: Predetermined dose of PEEL-224 1x daily and predetermined dose of Vincristine 1x daily * Day 10: Myeloid growth factor (Pegfilgrastim or Filgrastim) administration 1x daily * Cycle 2 through End of Treatment (21 day cycles): * Days 1 through 5: Predetermined dose of Temozolomide 1x daily * Days 1 and 8: Predetermined dose of PEEL-224 1x daily and predetermined dose of Vincristine 1x daily * Imaging every 2 cycles until Cycle 6 and then every 3 cycles * End of study visit

Drug: PEEL-224; Drug: Temozolomide; Drug: Vincristine; Biological: Pegfilgrastim; Biological: Filgrastim

Interventions

Vincristine DRUG

Vinca alkaloid, 1 or 2mL vials, via intravenous (into the vein) infusion per institutional policy.

Phase 1: Dose Escalation PEEL-224 Dose Level -1A; Phase 1: Dose Escalation PEEL-224 Dose Level -1B; Phase 1: Dose Escalation PEEL-224 Dose Level -2; Phase 1: Dose Escalation PEEL-224 Dose Level 0; Phase 1: Dose Escalation PEEL-224 Dose Level 1; Phase 1: Dose Escalation PEEL-224 Dose Level 2; Phase 2: Dose Expansion DSRCT; Phase 2: Dose Expansion Ewing Sarcoma; Phase 2: Dose Expansion Other Sarcoma

Pegfilgrastim BIOLOGICAL

Myeloid growth factor administered per institutional standards.

Also known as: Neupogen

Phase 1: Dose Escalation PEEL-224 Dose Level -1A; Phase 1: Dose Escalation PEEL-224 Dose Level -1B; Phase 1: Dose Escalation PEEL-224 Dose Level -2; Phase 1: Dose Escalation PEEL-224 Dose Level 0; Phase 1: Dose Escalation PEEL-224 Dose Level 1; Phase 1: Dose Escalation PEEL-224 Dose Level 2; Phase 2: Dose Expansion DSRCT; Phase 2: Dose Expansion Ewing Sarcoma; Phase 2: Dose Expansion Other Sarcoma

PEEL-224 DRUG

Topoisomerase 1 inhibitor, 200mg amber vial, via intravenous (into the vein) infusion per protocol.

Phase 1: Dose Escalation PEEL-224 Dose Level -1A; Phase 1: Dose Escalation PEEL-224 Dose Level -1B; Phase 1: Dose Escalation PEEL-224 Dose Level -2; Phase 1: Dose Escalation PEEL-224 Dose Level 0; Phase 1: Dose Escalation PEEL-224 Dose Level 1; Phase 1: Dose Escalation PEEL-224 Dose Level 2; Phase 2: Dose Expansion DSRCT; Phase 2: Dose Expansion Ewing Sarcoma; Phase 2: Dose Expansion Other Sarcoma

Temozolomide DRUG

Alkylating agent, 5, 20, 100, 140, 180, or 250 mg capsule, taken orally per standard of care.

Also known as: Temodar, Temodal

Phase 1: Dose Escalation PEEL-224 Dose Level -1A; Phase 1: Dose Escalation PEEL-224 Dose Level -1B; Phase 1: Dose Escalation PEEL-224 Dose Level -2; Phase 1: Dose Escalation PEEL-224 Dose Level 0; Phase 1: Dose Escalation PEEL-224 Dose Level 1; Phase 1: Dose Escalation PEEL-224 Dose Level 2; Phase 2: Dose Expansion DSRCT; Phase 2: Dose Expansion Ewing Sarcoma; Phase 2: Dose Expansion Other Sarcoma

Filgrastim BIOLOGICAL

Myeloid growth factor administered per institutional standards.

Also known as: Nivestym, Granix, Zarxio, Filgrastim-Aafi, Filgrastim-Sndz, Tbo-Filgrastim,, RHG-CSF

Phase 1: Dose Escalation PEEL-224 Dose Level -1A; Phase 1: Dose Escalation PEEL-224 Dose Level -1B; Phase 1: Dose Escalation PEEL-224 Dose Level -2; Phase 1: Dose Escalation PEEL-224 Dose Level 0; Phase 1: Dose Escalation PEEL-224 Dose Level 1; Phase 1: Dose Escalation PEEL-224 Dose Level 2; Phase 2: Dose Expansion DSRCT; Phase 2: Dose Expansion Ewing Sarcoma; Phase 2: Dose Expansion Other Sarcoma

Eligibility Criteria

• Age: 12 Years - 49 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Patients in all cohorts must have relapsed or refractory disease after standard therapy.
• Patients must have:
• Evaluable or measurable disease; and
• Histologic diagnosis of sarcoma
• EWS cohort: Patients must have:
• RECIST measurable disease at study entry;
• Histologic diagnosis consistent with Ewing sarcoma; and
• Molecular evidence of a FET-ETS family translocation including but not limited to any of the following:
• EWSR1::FLI1, EWSR1::ERG, EWSR1::ETV1, EWSR1::ETV4, EWSR1::FEV, FUS::FLI1, FUS::ERG
• DSRCT cohort: Patients must have:
• RECIST measurable disease at study entry;
• Histologic diagnosis consistent with DSRCT; and
• Molecular evidence of an EWSR1::WT1 fusion
• Other sarcoma cohort: Patients must have:
• RECIST evaluable or measurable disease; and

You may not qualify if:

• Patients who have received prior treatment with PEEL-224.
• Patients who have had progressive disease while receiving irinotecan and temozolomide in combination will be excluded from the Phase 2 EWS and DSRCT cohorts only.
• Participants who are receiving any other anti-cancer agents for this condition.
• Patients receiving strong P450 CYP1A2 and CYP3A4 inhibitors and/or inducers with 14 days of the first planned dose of PEEL-224. NOTE: levofloxacin is permitted and preferred over ciprofloxacin for patients needing a fluoroquinolone.
• Patients who have received a solid organ or allogeneic stem cell transplant
• Pregnant participants, given that the effects of PEEL-224 on the developing human fetus are unknown.
• Breastfeeding mothers, because there is an unknown risk for adverse events in nursing infants secondary to treatment of the mother with PEEL-224.
• Patients with a history of allergic reactions attributed to PEGylated drugs, camptothecins, temozolomide or vincristine.
• Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

Sponsors & Collaborators

• Peel Therapeutics Inc: collaborator
• David S Shulman, MD: lead

Study Sites (3)

Boston Children's Hospital

Boston, Massachusetts, 02115, United States

NOT YET RECRUITING

Dana-Farber Cancer Institute

Boston, Massachusetts, 02115, United States

RECRUITING

Brigham and Women's Hospital

Boston, Massachusetts, 02215, United States

NOT YET RECRUITING

MeSH Terms

Conditions

Sarcoma; Sarcoma, Ewing; Desmoplastic Small Round Cell Tumor; Osteosarcoma; Rhabdomyosarcoma

Interventions

Temozolomide; Vincristine; pegfilgrastim; Filgrastim; Granulocyte Colony-Stimulating Factor; pegylated granulocyte colony-stimulating factor

Condition Hierarchy (Ancestors)

Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Myosarcoma; Neoplasms, Muscle Tissue

Intervention Hierarchy (Ancestors)

Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Study Officials

• David Shulman, MD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Central Study Contacts

David Shulman, MD

CONTACT

617-632-6670; david_shulman@dfci.harvard.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Sponsor Investigator

Study Record Dates

• First Submitted: November 17, 2024
• First Posted: November 29, 2024
• Study Start: January 27, 2025
• Primary Completion (Estimated): November 1, 2028
• Study Completion (Estimated): September 1, 2029
• Last Updated: February 19, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Data can be shared no earlier than 1 year following the date of publication
• Access Criteria: Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu

Locations

US (3)