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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

Study Purpose

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)

Recruitment Criteria

Accepts Healthy Volunteers

Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms

 No
Study Type

An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.


An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.


Searching Both is inclusive of interventional and observational studies.

 Interventional
Eligible Ages 12 Years - 49 Years
Gender All
More Inclusion & Exclusion Criteria

Inclusion Criteria:

-Patients in all cohorts must have relapsed or refractory disease after standard therapy. Inclusion Criteria Phase 1 (only) diagnosis requirements: -Patients must have:
  • - Evaluable or measurable disease; and.
  • - Histologic diagnosis of sarcoma.
Inclusion Criteria Phase 2 (only) diagnosis requirements.
  • - 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.
  • - Histologic diagnosis of sarcoma.
Patients with EWS or DSRCT with evaluable but not measurable disease may participate in this cohort.
  • - Slots in this cohort will include three dedicated slots for patients with rhabdomyosarcoma, three dedicated slots for patients with osteosarcoma and three dedicated slots for patients with other translocation-associated round cell sarcomas.
  • - Age: ≥ 12 years and ≤ 49 years.
  • - Weight: Patients must be ≥ 40 kg.
  • - Performance Status: Karnofsky ≥ 50% for patients >16 year of age and Lansky ≥ 50% for patients ≤ 16 years of age.
(see Appendix A for definitions of Lansky and Karnofsky Performance Status).
  • - Participants must meet the following organ and marrow function as defined below: Adequate Bone Marrow Function: - Hematologic Requirements for Subjects without Bone Marrow Involvement by.
Disease:
  • - Absolute neutrophil count (ANC) ≥ 1,000/uL.
  • - Platelet count ≥100,000/uL (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment) --Hematologic Requirements for Subjects with Bone Marrow Involvement by Disease: - ANC ≥750 /uL.
  • - Platelets ≥50,000 /uL (may receive platelet transfusions) Not known to be refractory to red cell and/or platelet transfusions.
--Adequate Renal Function: Creatinine clearance or radioisotope GFR ≥70ml/min/1.73 m2 or A serum creatinine based on age/sex as follows:
  • - Age: 12 to < 13 years, Maximum Serum Creatinine (mg/dL): Male 1.2, Female 1.2.
  • - Age 13 to < 16 years, Maximum Serum Creatinine (mg/dL): Male 1.5, Female 1.4.
---≥ 16 years, Maximum Serum Creatinine (mg/dL): Male 1.7, Female 1.4. --Adequate Liver Function:
  • - Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal (ULN) for age.
  • - SGPT (ALT) ≤110 U/L.
For the purpose of this study, the ULN for SGPT is 45 U/L.
  • - Adequate Cardiac Function: QTc < 480 msec.
-Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy except organ function as noted above. Patients must meet the following minimum washout periods prior to enrollment:
  • - Myelosuppressive chemotherapy: At least 14 days after the last dose of myelosuppressive chemotherapy.
  • - Radiotherapy: - At least 14 days after local XRT (small port, including cranial radiation); - At least 90 days must have elapsed after prior TBI, craniospinal XRT or if >50% radiation of pelvis; - At least 42 days must have elapsed if other substantial BM radiation.
  • - Small molecule biologic therapy: At least 7 days following the last dose of a biologic agent.
  • - Monoclonal antibody: At least 21 days must have elapsed after the last dose of antibody.
  • - Myeloid and platelet growth factors: At least 14 days following the last dose of long-acting myeloid growth factor (e.g. Neulasta) or 7 days following short-acting myeloid or platelet growth factor.
  • - Autologous hematopoietic stem cell transplant and stem cell boost: Patients must be at least 60 days from day 0 of an autologous stem cell transplant or stem cell boost.
  • - Cellular Therapies (e.g., CART, NK-cell based therapy): The patient must be and at least 42 days from cellular therapy administration.
  • - Major Surgery: At least 2 weeks from prior major surgical procedure.
Note: Biopsy, CNS shunt placement/revision, and central line placement/removal are not considered major.
  • - Irinotecan, liposomal irinotecan, and/or temozolomide: Patients may have received prior irinotecan, liposomal irinotecan, and/or temozolomide.
NOTE: 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. -For patients with metastatic disease to the CNS enrolling to the phase 1 portion of the trial or the "other sarcoma" cohort, any baseline neurologic deficits (including seizure) must be stable for at least one week prior to study enrollment. Patients with CNS metastatic disease receiving corticosteroids must be on a stable or decreasing dose at time of study entry.
  • - Patients with CNS metastatic disease will not be eligible for the phase 2 EWS and DSRCT cohorts.
  • - Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
  • - The effects of PEEL-224 in combination with temozolomide and vincristine on the developing human fetus are unknown.
For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of PEEL-224 administration.
  • - Ability to understand and/or the willingness of the patient (or parent or legally authorized representative, if minor) to provide informed consent, using an institutionally approved informed consent procedure.
  • - Any participant must obtain prior approval from insurance to reimburse oral temozolomide for the duration of the study or agree to self-pay for oral temozolomide.

Exclusion Criteria:

  • - 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.

Trial Details

Trial ID:

This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.

 NCT06709495
Phase

Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.

Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.

Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.

Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.

 Phase 1/Phase 2
Lead Sponsor

The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.

 David S Shulman, MD
Principal Investigator

The person who is responsible for the scientific and technical direction of the entire clinical study.

 David Shulman, MD
Principal Investigator Affiliation Dana-Farber Cancer Institute
Agency Class

Category of organization(s) involved as sponsor (and collaborator) supporting the trial.

 Other, Industry
Overall Status Recruiting
Countries United States
Conditions

The disease, disorder, syndrome, illness, or injury that is being studied.

 Sarcoma, Sarcoma, Ewing, Desmoplastic Small Round Cell Tumor, Refractory Sarcoma, Osteosarcoma, Rhabdomyosarcoma
Additional Details

This is an open-label, single-arm, non-randomized, phase I/II trial 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. This is the first time that PEEL-224 will be given in combination with Vincristine and Temozolomide to humans. In Phase 1, the safety and tolerability of PEEL-224 in combination with Vincristine and Temozolomide will be assessed by dose escalation and establishment of a Recommended Phase 2 Dose. In Phase 2 the efficacy of the drug combination will be assessed in three separate cohorts of participants. The U.S. Food and Drug Administration (FDA) has not approved PEEL-224 as a treatment for Relapsed or Refractory Sarcoma. The U.S. Food and Drug Administration (FDA) has not approved Vincristine and Temozolomide for Relapsed or Refractory Sarcoma, but it has been approved for other uses. The research study procedures include screening for eligibility, study treatment in-clinic visits, X-rays, Computerized Tomography (CT) scans, Magnetic Resonance Imaging (MRI) scans, or Positron Emission Tomography (PET) scans, blood tests, urine tests, and electrocardiograms (ECGs). Participants will receive study treatment for up to 34 cycles (approximately 2 years) and will be followed for up to 1 year after the last participant has received the last dose of treatment. It is expected that about 63 people will take part in this research study. PEEL Therapeutics is funding this research study by providing the study drug, PEEL-224.

Arms & Interventions

Arms

Experimental: Phase 1: Dose Escalation PEEL-224 Dose Level 0

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

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

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

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

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

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

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

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

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

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

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

Experimental: Phase 2: Dose Expansion Ewing Sarcoma

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

Experimental: Phase 2: Dose Expansion DSRCT

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

Experimental: Phase 2: Dose Expansion Other Sarcoma

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

Interventions

Drug: - PEEL-224

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

Drug: - Temozolomide

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

Drug: - Vincristine

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

Biological: - Pegfilgrastim

Myeloid growth factor administered per institutional standards.

Biological: - Filgrastim

Myeloid growth factor administered per institutional standards.

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

Boston Children's Hospital, Boston, Massachusetts

Status

Not yet recruiting

Address

Boston Children's Hospital

Boston, Massachusetts, 02115

Site Contact

David Shulman, MD

[email protected]

617-632-6670

Dana-Farber Cancer Institute, Boston, Massachusetts

Status

Recruiting

Address

Dana-Farber Cancer Institute

Boston, Massachusetts, 02115

Site Contact

David Shulman, MD

[email protected]

617-632-6670

Brigham and Women's Hospital, Boston, Massachusetts

Status

Not yet recruiting

Address

Brigham and Women's Hospital

Boston, Massachusetts, 02215

Site Contact

David Shulman, MD

[email protected]

617-632-6670

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