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

Recruiting at 2 trial locations

Overseen By Mia Weiss, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

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 You can continue your current medications while participating

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

Compensation: Varies

Number of Visits: Unknown

35 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment combination for people with soft tissue sarcoma, a cancer affecting the body's connective tissues. The goal is to determine the optimal dose of a new drug, ADI-PEG 20 (pegylated arginine deiminase), when combined with ifosfamide and radiotherapy, and then assess its effectiveness in shrinking tumors before surgery. People with soft tissue sarcoma in the trunk or limbs who are planning for surgery might be suitable candidates for this trial. As a Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this new drug combination.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that combining ADI-PEG 20 with ifosfamide and radiotherapy may enhance treatment for soft tissue sarcoma. One study found that most patients tolerated this combination well. Although some side effects occurred, they were usually mild to moderate. Ifosfamide, a drug already used in cancer treatment, can cause side effects like nausea and low blood cell counts. Radiotherapy might lead to skin irritation and fatigue. ADI-PEG 20 affects how cancer cells use energy, and previous patients have generally tolerated it well. Overall, this combination treatment has shown promise in managing side effects safely while targeting cancer cells. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of ADI-PEG 20 with ifosfamide and radiotherapy for soft tissue sarcoma because it offers a novel approach that targets cancer metabolism. Unlike most treatments that focus solely on killing cancer cells directly, ADI-PEG 20 works by starving cancer cells of arginine, an amino acid they need to grow. By combining this with ifosfamide and radiotherapy, the treatment not only attacks the cancer cells from multiple angles but also potentially enhances the effectiveness of existing therapies. This innovative strategy could lead to more effective and faster results compared to traditional options like surgery, chemotherapy, and standard radiotherapy.

What evidence suggests that this trial's treatments could be effective for soft tissue sarcoma?

This trial will evaluate the combination of ADI-PEG 20, ifosfamide, and radiotherapy for treating soft tissue sarcoma (STS). Research shows that combining ADI-PEG 20 with ifosfamide and radiotherapy might help treat STS. ADI-PEG 20 works by depriving certain cancer cells of a nutrient they need to grow. Ifosfamide is a chemotherapy drug that kills cancer cells, and radiotherapy uses high-energy rays to destroy them. Early studies have shown promising results with similar treatment combinations. Although more research is needed, this combination is believed to enhance the effectiveness of standard treatments. ^{2 5 6 7 8}

Who Is on the Research Team?

Mia Weiss, MD

Principal Investigator

Washington University School of Medicine

Are You a Good Fit for This Trial?

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

Currently receiving any other investigational agents

I have a serious heart condition.

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• ADI PEG20
• Ifosfamide
• Radiotherapy

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.

How Is the Trial Designed?

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+

Polaris Group

Industry Sponsor

Trials

25

Recruited

3,400+

Headquarters

Cayman Islands

Known For

Anti-Cancer Therapies

Top Products

ADI-PEG 20

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05813327

NCT05813327 | Neoadjuvant ADI-PEG 20 + Ifosfamide ... In this study, patients with soft tissue sarcoma (STS) will receive ADI-PEG 20 and ifosfamide in combination with radiation as neoadjuvant therapy.

2. withpower.com withpower.com/trial/phase-2-sarcoma-6-2023-e6d7f

ADI-PEG 20 + Ifosfamide + Radiotherapy for Soft Tissue ... In this study, patients with soft tissue sarcoma (STS) will receive ADI-PEG 20 and ifosfamide in combination with radiation as neoadjuvant therapy.

3. centerwatch.com centerwatch.com/clinical-trials/listings/NCT05813327/neoadjuvant-adi-peg-20-ifosfamide-radiotherapy-in-soft-tissue-sarcoma

Neoadjuvant ADI-PEG 20 + Ifosfamide + Radiotherapy in ... In this study, patients with soft tissue sarcoma (STS) will receive ADI-PEG 20 and ifosfamide in combination with radiation as neoadjuvant ...

4. siteman.wustl.edu siteman.wustl.edu/clinical-trial/202305073/

202305073 - Siteman Cancer Center 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 ...

5. med.stanford.edu med.stanford.edu/dirbas/clinical-trials/stanford-apbi-trial?start=2120

Stanford APBI Trial | Dirbas Clinical Research Group | Stanford ... 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 ...

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.TPS11591

A phase I/II trial of neoadjuvant pegylated arginine ... We hypothesize that the combination of ADI-PEG 20, ifosfamide, and radiation therapy can potentiate cellular death. ... treatment of soft tissue ...

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.2057

Phase IB trial of pegylated arginine deiminase (ADI-PEG ... ADI-PEG 20 exploits the different metabolic ability for synthesizing arginine (Arg) between normal and neoplastic cells to reduce tumor cell growth.

8. careacross.com careacross.com/clinical-trials/trial/NCT05813327

Neoadjuvant ADIPEG 20 Ifosfamide Radiotherapy in Soft ... Summary: In this study, patients with soft tissue sarcoma (STS) will receive ADI-PEG 20 and ifosfamide in combination with radiation as neoadjuvant therapy. In ...