ADI-PEG 20 + Ifosfamide + Radiotherapy for Soft Tissue Sarcoma

Recruiting in Palo Alto (17 mi)

Overseen by Mia Weiss, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Washington University School of Medicine

Must not be taking: Herbal medicines, CYP2C8 substrates

Disqualifiers: Low grade STS, Metastatic disease, Allergic reactions, Prior chemotherapy, others

Stay on Your Current Meds

No Placebo Group

Trial Summary

What is the purpose of this trial?

In this study, patients with soft tissue sarcoma (STS) will receive ADI-PEG 20 and ifosfamide in combination with radiation as neoadjuvant therapy. In phase I of the study, up to 5 dose levels will be tested to find the recommended phase II dose (RP2D), after which patients enrolling to phase II will be treated at that dose level to assess efficacy.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop all current medications, but certain medications are restricted. You must stop taking herbal medicines, some supplements, and specific medications that affect heart rhythm or interact with the trial drugs within a certain period before starting the trial. Please discuss your current medications with the trial team to ensure they are safe to continue.

What data supports the effectiveness of the drug ADI-PEG 20 for treating soft tissue sarcoma?

Research shows that ADI-PEG 20, which depletes arginine (a building block for proteins), has been effective in treating certain cancers like melanoma and liver cancer by targeting cancer cells that can't make arginine on their own. This suggests it might also help in treating soft tissue sarcoma, especially when combined with other treatments. ^{1 2 3 4 5}

Is the combination of ADI-PEG 20, Ifosfamide, and Radiotherapy safe for humans?

ADI-PEG 20 has been tested in various clinical trials and is generally well-tolerated with manageable side effects in patients with different types of cancer, such as melanoma and hepatocellular carcinoma. However, specific safety data for the combination with Ifosfamide and Radiotherapy is not provided in the available research. ^{1 2 4 6 7}

What makes the ADI-PEG 20 drug unique for treating soft tissue sarcoma?

ADI-PEG 20 is unique because it depletes arginine, an amino acid that certain cancer cells need to grow, and targets tumors that lack the enzyme argininosuccinate synthetase (ASS1), making it effective against specific cancers that are sensitive to arginine depletion. ^{1 2 3 4 8}

Research Team

Mia Weiss, MD

Principal Investigator

Washington University School of Medicine

Eligibility Criteria

Adults with intermediate or high-grade soft tissue sarcoma of the trunk/extremities, size ≥5 cm, planning curative surgery. Must be 18+, have normal organ/bone marrow function, no distant metastasis, and agree to contraception. Excludes those with prior radiotherapy in the area, significant recent bleeding or heart issues, active infections needing IV antibiotics, pregnant/breastfeeding women, known Hepatitis B/C or HIV.

Inclusion Criteria

I have enough tumor tissue available for analysis, or I have received special permission to enroll without it.

I have a grade 2-3 soft tissue sarcoma larger than 5 cm and plan to treat it with the goal of curing it.

My cancer hasn't spread far and surgery is planned to remove the main tumor.

Exclusion Criteria

I have not had chemotherapy for my current sarcoma but may have had it for another cancer over three years ago.

My cancer is a specific type of sarcoma but not bone or cartilage sarcoma.

Currently receiving any other investigational agents

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Phase I

Patients receive ADI-PEG 20, ifosfamide, and radiotherapy in a dose-escalation study to determine the recommended Phase II dose

7 weeks

Multiple visits for dose administration and monitoring

Treatment Phase II

Patients receive ADI-PEG 20, ifosfamide, and radiotherapy at the recommended Phase II dose

9 weeks

Multiple visits for dose administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

16 weeks

Visits at time of surgical resection and periodic follow-ups

Long-term Follow-up

Participants are monitored for disease-free survival and overall survival

120 weeks

Treatment Details

Interventions

• ADI PEG20 (Enzyme Depletion)
• Ifosfamide (Alkylating Agent)
• Radiotherapy (Radiation Therapy)

Trial Overview The trial tests ADI-PEG 20 plus Ifosfamide combined with Radiotherapy as a pre-surgery treatment for soft tissue sarcoma. Phase I determines the safest dose level; Phase II assesses its effectiveness at that dose.

Participant Groups

Group I: Phase II: ADI-PEG 20 + ifosfamide + radiotherapy Experimental Treatment 4 Interventions

Patients will receive ADI-PEG 20 on Day -7 of Cycle 1 and Days 1, 8, and 15 of each of three 21-day cycles, and ifosfamide per the RP2D determined in Phase I of the study on days 1 through 5 of each cycle. Mesna will be given on days 1 through 5 with ifosfamide as supportive care. Patients will also receive radiotherapy (XRT) starting on Week 4.

Group II: Phase I: ADI-PEG 20 + ifosfamide + radiotherapy Experimental Treatment 4 Interventions

Patients will receive ADI-PEG 20 on Day -7 of Cycle 1 and Days 1, 8, and 15 of each of three 21-day cycles, and ifosfamide per dose escalation/de-escalation schedule on days 1 through 5 of each cycle. Mesna will be given on days 1 through 5 with ifosfamide as supportive care. Patients will also receive radiotherapy (XRT) starting on Week 4.

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

David H. Perlmutter

Washington University School of Medicine

Chief Executive Officer since 2015

MD from Washington University School of Medicine

Paul Scheel

Washington University School of Medicine

Chief Medical Officer since 2022

MD from Washington University School of Medicine

Polaris Group

Industry Sponsor

Trials

25

Recruited

3,400+

Headquarters

Cayman Islands

Known For

Anti-Cancer Therapies

Top Products

ADI-PEG 20

Findings from Research

ADI-PEG 20, a pegylated enzyme that depletes arginine, was found to be well tolerated when combined with standard chemotherapy (gemcitabine and nab-paclitaxel) in patients with metastatic pancreatic cancer, with a recommended phase 2 dose of 36 mg/m2 weekly.

The treatment showed promising efficacy, with an overall response rate of 45.5% and a median overall survival time of 11.3 months among patients receiving the recommended dose, indicating potential benefits for both previously treated and untreated patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1/1B trial of ADI-PEG 20 plus nab-paclitaxel and gemcitabine in patients with advanced pancreatic adenocarcinoma. Lowery, MA., Yu, KH., Kelsen, DP., et al.[2022]

In a phase I study involving 18 patients with advanced solid tumors, the combination of pegylated arginine deiminase (ADI-PEG 20) and docetaxel showed manageable toxicity, with only one instance of dose-limiting toxicity and common hematologic side effects like leukopenia.

The treatment demonstrated promising clinical activity, with four partial responses and seven patients achieving stable disease, leading to further studies planned for specific cancer types at a recommended phase II dose of 36 mg/m².

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Trial of Arginine Deprivation Therapy with ADI-PEG 20 Plus Docetaxel in Patients with Advanced Malignant Solid Tumors. Tomlinson, BK., Thomson, JA., Bomalaski, JS., et al.[2022]

In patients with ASS1-deficient malignant pleural mesothelioma (MPM) undergoing treatment with pegylated arginine deiminase (ADI-PEG20), increased macrophage infiltration was found to promote the survival of cancer cells, indicating a resistance mechanism against the therapy.

The study identified a CXCR2-dependent chemotactic signature and the role of IL-1α in macrophages, which contributes to the production of argininosuccinate that supports MPM cell viability, suggesting that targeting this macrophage-mediated resistance could enhance the effectiveness of arginine deprivation therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A role for macrophages under cytokine control in mediating resistance to ADI-PEG20 (pegargiminase) in ASS1-deficient mesothelioma. Phillips, MM., Pavlyk, I., Allen, M., et al.[2023]

ADI-PEG20 is an innovative anticancer enzyme that effectively depletes arginine, which is crucial for certain tumors like malignant melanoma and hepatocellular carcinoma that cannot produce it themselves.

Early Phase I - II trials have demonstrated that ADI-PEG20 has antitumor activity and manageable side effects, but further large-scale Phase II and randomized Phase III trials are necessary to fully assess its efficacy in treating these cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pegylated arginine deiminase: a novel anticancer enzyme agent. Feun, L., Savaraj, N.[2019]

In a phase 1b study involving 25 patients, the combination of pegylated arginine deiminase (ADI-PEG 20) and pembrolizumab was found to be safe, although there was a higher-than-expected incidence of Grade 3/4 neutropenia in 40% of patients.

Treatment with ADI-PEG 20 led to increased T cell infiltration in tumors, which may enhance the effectiveness of pembrolizumab, with partial responses observed in 24% of heavily pretreated patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1b study of pegylated arginine deiminase (ADI-PEG 20) plus Pembrolizumab in advanced solid cancers. Chang, KY., Chiang, NJ., Wu, SY., et al.[2021]

The new drug ADI PEG20,000 mw effectively reduced plasma arginine levels in a patient with unresectable hepatocellular cancer, leading to a decrease in tumor size and serum alpha-fetoprotein levels, indicating a positive clinical response.

The treatment was well-tolerated with no reported toxicities or side effects, suggesting that ADI PEG20,000 mw could be a promising low-toxicity option for patients with this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regression of hepatocellular cancer in a patient treated with arginine deiminase. Curley, SA., Bomalaski, JS., Ensor, CM., et al.[2018]

ADI-PEG 20, a PEGylated arginine deiminase, is well-tolerated in clinical studies and shows anti-tumor effects by inhibiting the growth of arginine auxotrophic cancers both in vitro and in vivo.

The treatment enhances T-cell infiltration in tumors and can improve anti-tumor responses when combined with immune checkpoint inhibitors like anti-PD-1 and anti-PD-L1, suggesting a potential role in modifying the tumor immune microenvironment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PEGylated arginine deiminase can modulate tumor immune microenvironment by affecting immune checkpoint expression, decreasing regulatory T cell accumulation and inducing tumor T cell infiltration. Brin, E., Wu, K., Lu, HT., et al.[2018]

Arginine deiminase (ADI) can be effectively formulated with polyethylene glycol (PEG) to enhance its pharmacokinetic and pharmacodynamic properties, particularly when using PEG of 20 kDa, which improves its stability and effectiveness as a cancer treatment.

The PEGylation of ADI significantly reduces the immune response against the enzyme, leading to lower antibody production in experimental animals compared to unmodified ADI, suggesting a safer and more effective therapeutic option for tumors that require arginine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Poly(ethylene glycol) (PEG) conjugated arginine deiminase: effects of PEG formulations on its pharmacological properties. Holtsberg, FW., Ensor, CM., Steiner, MR., et al.[2019]

References

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

A phase 1/1B trial of ADI-PEG 20 plus nab-paclitaxel and gemcitabine in patients with advanced pancreatic adenocarcinoma. [2022]

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

Phase I Trial of Arginine Deprivation Therapy with ADI-PEG 20 Plus Docetaxel in Patients with Advanced Malignant Solid Tumors. [2022]

3. Switzerland pubmed.ncbi.nlm.nih.gov

A role for macrophages under cytokine control in mediating resistance to ADI-PEG20 (pegargiminase) in ASS1-deficient mesothelioma. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Pegylated arginine deiminase: a novel anticancer enzyme agent. [2019]

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

Phase 1b study of pegylated arginine deiminase (ADI-PEG 20) plus Pembrolizumab in advanced solid cancers. [2021]

6. Greece pubmed.ncbi.nlm.nih.gov

Regression of hepatocellular cancer in a patient treated with arginine deiminase. [2018]

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

PEGylated arginine deiminase can modulate tumor immune microenvironment by affecting immune checkpoint expression, decreasing regulatory T cell accumulation and inducing tumor T cell infiltration. [2018]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Poly(ethylene glycol) (PEG) conjugated arginine deiminase: effects of PEG formulations on its pharmacological properties. [2019]