PEEL-224 + Vincristine + Temozolomide for Sarcoma

Recruiting at 2 trial locations

Overseen By David Shulman, MD

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: David S Shulman, MD

Must not be taking: CYP1A2/3A4 inhibitors/inducers

Disqualifiers: Pregnancy, Breastfeeding, Organ transplant, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

Duration: Up to 2 years

63 Participants Needed

Trial Summary

What is the purpose of this trial?

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)

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but you cannot be on other anti-cancer agents or certain strong enzyme inhibitors or inducers. It's best to discuss your current medications with the trial team to see if they are allowed.

What data supports the effectiveness of the drug combination PEEL-224, Vincristine, and Temozolomide for treating sarcoma?

Temozolomide has shown effectiveness in treating various types of brain tumors, such as gliomas and oligodendroglial tumors, and has been used in combination with other drugs like vincristine to enhance its effects. This suggests potential benefits when used in combination with other drugs for treating sarcoma. ^{1 2 3 4 5}

Is the combination of PEEL-224, Vincristine, and Temozolomide safe for humans?

Temozolomide has been studied in various trials and is generally well-tolerated, but it can cause side effects like fatigue, nausea, vomiting, and low blood cell counts. In some studies, serious side effects like thrombocytopenia (low platelet count) and confusion were observed. Vincristine is known to cause side effects such as nerve damage and constipation. There is no specific safety data available for PEEL-224 in humans. ^{1 2 6 7 8}

What makes the drug combination PEEL-224, Vincristine, and Temozolomide unique for treating sarcoma?

This drug combination is unique because it includes PEEL-224, which may offer a novel mechanism of action or synergy with Vincristine and Temozolomide, potentially providing a new option for sarcoma patients who have limited standard treatments available. ^{1 9 10 11 12}

Research Team

David S Shulman, MD

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

This trial is for adolescents and young adults with certain types of sarcomas that have come back or didn't respond to previous treatments. Participants should be diagnosed with conditions like Ewing Sarcoma or Desmoplastic Small Round Cell Tumor, among others.

Inclusion Criteria

I am between 12 and 49 years old.

My blood, kidney, liver, and heart are functioning well.

I have recovered from side effects of my previous cancer treatment.

Exclusion Criteria

Breastfeeding mothers

Pregnant participants

My cancer progressed despite treatment with irinotecan and temozolomide.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive PEEL-224 in combination with Vincristine and Temozolomide in 21-day cycles, with imaging every 2 cycles until Cycle 6 and then every 3 cycles

Up to 2 years

In-clinic visits for each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

Treatment Details

Interventions

• PEEL-224
• Temozolomide
• Vincristine

Trial Overview The study tests a new drug, PEEL-224, combined with Vincristine and Temozolomide. It aims to find out how effective this mix is against various sarcomas in those who've had relapses or refractory disease.

Participant Groups

Group I: Phase 2: Dose Expansion Other Sarcoma Experimental Treatment 5 Interventions

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

Group II: Phase 2: Dose Expansion Ewing Sarcoma Experimental Treatment 5 Interventions

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

Group III: Phase 2: Dose Expansion DSRCT Experimental Treatment 5 Interventions

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

Group IV: Phase 1: Dose Escalation PEEL-224 Dose Level 2 Experimental Treatment 5 Interventions

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

Group V: Phase 1: Dose Escalation PEEL-224 Dose Level 1 Experimental Treatment 5 Interventions

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

Group VI: Phase 1: Dose Escalation PEEL-224 Dose Level 0 Experimental Treatment 5 Interventions

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

Group VII: Phase 1: Dose Escalation PEEL-224 Dose Level -2 Experimental Treatment 5 Interventions

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

Group VIII: Phase 1: Dose Escalation PEEL-224 Dose Level -1B Experimental Treatment 5 Interventions

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

Group IX: Phase 1: Dose Escalation PEEL-224 Dose Level -1A Experimental Treatment 5 Interventions

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

Who Is Running the Clinical Trial?

David S Shulman, MD

Lead Sponsor

Trials

1

Recruited

60+

Peel Therapeutics Inc

Industry Sponsor

Trials

3

Recruited

160+

Findings from Research

The TMZ-resistant glioma cell line SF188/TR showed a 6-fold resistance to temozolomide and cross-resistance to various other anticancer agents, indicating a significant challenge in treating resistant tumors.

Increased activity of the enzyme alkylguanine alkyltransferase (AGT) was identified as a primary mechanism of resistance to TMZ, while changes in the balance of pro-apoptotic and anti-apoptotic proteins contributed to broader cross-resistance to other drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biochemical changes associated with a multidrug-resistant phenotype of a human glioma cell line with temozolomide-acquired resistance. Ma, J., Murphy, M., O'Dwyer, PJ., et al.[2022]

In a phase II trial involving 46 patients with progressive low-grade glioma, Temozolomide (Temodar) demonstrated a 61% objective response rate, with 24% achieving complete response and 37% achieving partial response.

The treatment showed promising safety, with limited toxicity observed; however, one patient experienced severe complications, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of temozolomide in patients with progressive low-grade glioma. Quinn, JA., Reardon, DA., Friedman, AH., et al.[2022]

Temozolomide is a promising drug for combination therapies due to its ability to cross the blood-brain barrier, good safety profile, and effectiveness against solid tumors like malignant glioma, especially when combined with carmustine or irinotecan.

Studies indicate that administering carmustine before temozolomide results in lower toxicity and a higher maximum tolerated dose, while the combination of temozolomide followed by irinotecan shows greater effectiveness than either drug alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide in combination with other cytotoxic agents. Prados, M.[2019]

In a phase II trial involving 38 patients with recurrent oligodendroglial tumors, temozolomide (TMZ) demonstrated a high response rate, with 52.6% of patients showing a complete or partial response, indicating its efficacy as a first-line chemotherapy.

TMZ was generally well tolerated, with hematologic side effects being the most common, and only one patient discontinuing treatment due to toxicity, suggesting a favorable safety profile for chemotherapy-naive patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of first-line chemotherapy with temozolomide in recurrent oligodendroglial tumors: the European Organization for Research and Treatment of Cancer Brain Tumor Group Study 26971. van den Bent, MJ., Taphoorn, MJ., Brandes, AA., et al.[2022]

In a phase II trial involving 26 patients with advanced mycosis fungoides/Sézary syndrome, temozolomide (TMZ) showed an overall response rate of 27%, with 8% achieving complete remission and 19% partial remission, indicating its potential efficacy in this patient population.

Despite the low levels of MGMT in malignant CD4(+) T cells, which suggested sensitivity to TMZ, the study found that pretreatment levels of MGMT and mismatch repair proteins did not predict treatment response, indicating that other resistance mechanisms may be at play.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter phase II trial of temozolomide in mycosis fungoides/sezary syndrome: correlation with O⁶-methylguanine-DNA methyltransferase and mismatch repair proteins. Querfeld, C., Rosen, ST., Guitart, J., et al.[2021]

In a phase I trial involving 38 patients with advanced solid tumors, the combination of intravenous methoxyamine (MX) and oral temozolomide (TMZ) was found to be safe, with no dose-limiting toxicities observed, allowing for a maximum tolerated dose of TMZ at 200 mg/m² daily for 5 days alongside MX at 150 mg/m² on day 1.

The trial showed that while there were some grade 3 and 4 adverse events, the combination therapy resulted in a partial response in one patient and prolonged stable disease in six others, suggesting potential efficacy in certain tumor types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I clinical trial of temozolomide and methoxyamine (TRC-102), an inhibitor of base excision repair, in patients with advanced solid tumors. Eads, JR., Krishnamurthi, SS., Saltzman, J., et al.[2022]

In a study involving 46 children with solid tumors resistant to conventional therapy, NSC-45388 was administered safely at doses of 200-450 mg/m2/day for 5 consecutive days, with major toxic effects including nausea and decreased blood cell counts.

Objective responses to NSC-45388 were observed in 3 children with neuroblastoma and 1 child with rhabdomyosarcoma, indicating that while the drug has minimal activity as a single agent, it shows potential for further evaluation in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

5-(3,3-Dimethyl-1-triazeno)imidazole-4-carboxamide (NSC-45388) in the treatment of solid tumors in children. Finklestein, JZ., Albo, V., Ertel, I., et al.[2016]

Temozolomide (TMZ) is well tolerated in patients with glioma and melanoma, with dose-limiting toxicity primarily being thrombocytopenia, observed at maximum tolerated doses of 150 mg/m2/day for patients with prior nitrosourea exposure and 250 mg/m2/day for those without.

The study showed promising antitumor activity, with two complete responses in patients without prior nitrosourea treatment, suggesting that TMZ could be an effective treatment option for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of temozolomide (NSC 362856) in patients with advanced cancer. Dhodapkar, M., Rubin, J., Reid, JM., et al.[2018]

The protracted d × 5×2 schedule of vincristine, irinotecan, and temozolomide (VIT) demonstrated a significantly higher objective response rate (54.5%) compared to the shorter d × 5 schedule (20.8%) in patients with relapsed or refractory Ewing sarcoma, based on a study of 46 patients.

Patients on the d × 5 schedule experienced more severe adverse events, indicating that the d × 5×2 schedule not only provided better efficacy but also had a more favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Longer versus Shorter Schedules of Vincristine, Irinotecan, and Temozolomide (VIT) for Relapsed or Refractory Ewing Sarcoma: A Randomized Controlled Phase 2 Trial. Xu, J., Xie, L., Sun, X., et al.[2023]

Ecteinascidin-743 (ET-743) demonstrated activity in advanced soft tissue sarcoma and osteosarcoma patients, with two partial responses and ten disease stabilizations observed among 29 patients treated in a phase I study and compassionate use program.

The treatment was generally well-tolerated, though some patients experienced significant side effects, including grade 3 to 4 neutropenia in 32% of treatment cycles, indicating that while ET-743 can be effective, monitoring for adverse effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ecteinascidin-743: a marine-derived compound in advanced, pretreated sarcoma patients--preliminary evidence of activity. Delaloge, S., Yovine, A., Taamma, A., et al.[2018]

A combination of temozolomide and irinotecan was found to be tolerable and active in treating advanced Ewing sarcoma, with 1 complete response and 3 partial responses observed among 14 evaluable patients.

The treatment regimen was manageable, with minimal myelosuppression and only 11% of courses experiencing grade 3-4 diarrhea, suggesting that home administration of irinotecan is safe and feasible for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide and intravenous irinotecan for treatment of advanced Ewing sarcoma. Wagner, LM., McAllister, N., Goldsby, RE., et al.[2018]

The VIT regimen, consisting of vincristine, irinotecan, and temozolomide, showed an overall control rate of 52% in treating relapsed or refractory sarcomas in a study of 26 patients, indicating its potential efficacy for this challenging condition.

The treatment was relatively safe, with no reported treatment-related mortality, and demonstrated promising survival rates of 79.3% at 1 year and 45.5% at 2 years, suggesting it could be a viable option for young patients with limited treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vincristine, Irinotecan, and Temozolomide as a Salvage Regimen for Relapsed or Refractory Sarcoma in Children and Young Adults. Ju, HY., Park, M., Lee, JA., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Biochemical changes associated with a multidrug-resistant phenotype of a human glioma cell line with temozolomide-acquired resistance. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Phase II trial of temozolomide in patients with progressive low-grade glioma. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Temozolomide in combination with other cytotoxic agents. [2019]

4. United States pubmed.ncbi.nlm.nih.gov

Phase II study of first-line chemotherapy with temozolomide in recurrent oligodendroglial tumors: the European Organization for Research and Treatment of Cancer Brain Tumor Group Study 26971. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Multicenter phase II trial of temozolomide in mycosis fungoides/sezary syndrome: correlation with O⁶-methylguanine-DNA methyltransferase and mismatch repair proteins. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Phase I clinical trial of temozolomide and methoxyamine (TRC-102), an inhibitor of base excision repair, in patients with advanced solid tumors. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

5-(3,3-Dimethyl-1-triazeno)imidazole-4-carboxamide (NSC-45388) in the treatment of solid tumors in children. [2016]

8. United States pubmed.ncbi.nlm.nih.gov

Phase I trial of temozolomide (NSC 362856) in patients with advanced cancer. [2018]

9. United States pubmed.ncbi.nlm.nih.gov

Longer versus Shorter Schedules of Vincristine, Irinotecan, and Temozolomide (VIT) for Relapsed or Refractory Ewing Sarcoma: A Randomized Controlled Phase 2 Trial. [2023]

10. United States pubmed.ncbi.nlm.nih.gov

Ecteinascidin-743: a marine-derived compound in advanced, pretreated sarcoma patients--preliminary evidence of activity. [2018]

11. United States pubmed.ncbi.nlm.nih.gov

Temozolomide and intravenous irinotecan for treatment of advanced Ewing sarcoma. [2018]

12. Korea (South) pubmed.ncbi.nlm.nih.gov

Vincristine, Irinotecan, and Temozolomide as a Salvage Regimen for Relapsed or Refractory Sarcoma in Children and Young Adults. [2022]