ADI-PEG 20 + Chemotherapy for Leiomyosarcoma

Recruiting at 33 trial locations

Overseen By Stephanie V Rumund

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Polaris Group

Must not be taking: Antiretrovirals, Immunosuppressants

Disqualifiers: Brain metastases, Uncontrolled illness, HIV, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 104 weeks

300 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

The trial aims to test the effectiveness and safety of an experimental treatment called ADI-PEG 20 (pegylated arginine deiminase), combined with chemotherapy, for individuals with leiomyosarcoma (LMS). This cancer is a soft tissue sarcoma that can be difficult to treat, especially when advanced or metastasized. Participants will receive either the experimental treatment or a placebo alongside standard chemotherapy drugs to determine which is more effective. Candidates may qualify if they have advanced LMS previously treated with at least one chemotherapy regimen containing doxorubicin and can manage daily life despite the cancer. As a Phase 3 trial, this study represents the final step before FDA approval, offering a chance to contribute to potentially groundbreaking cancer treatment advancements.

Will I have to stop taking my current medications?

The trial requires a washout period (time without taking certain medications) for chemotherapy agents, which is 5 half-lives before joining the study. If you are currently receiving chemotherapy, immunotherapy, or radiation therapy, you will need to stop these treatments before participating.

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

Research shows that using ADI-PEG 20 with the chemotherapy drugs gemcitabine and docetaxel is generally safe for patients. Previous studies found that these drugs can be safely administered at specific doses: 600 mg/m² for gemcitabine and 60 mg/m² for docetaxel. Patients did not experience unexpected side effects at these doses.

Another study suggested that ADI-PEG 20 is well-tolerated when combined with other cancer treatments, meaning most people don't have severe side effects. Since this trial is in a later phase, it indicates that the treatment has already demonstrated a good safety record in earlier research.

Overall, current evidence supports that ADI-PEG 20, combined with these chemotherapy drugs, is safe for use in humans. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for leiomyosarcoma?

Researchers are excited about ADI-PEG 20 for treating leiomyosarcoma because it introduces a new mechanism of action by depleting arginine, an amino acid that some cancer cells depend on to grow. Unlike standard chemotherapy options like doxorubicin or ifosfamide, ADI-PEG 20 targets a metabolic vulnerability in the cancer cells, potentially enhancing the effectiveness of chemotherapy. This unique approach could offer a more targeted attack on cancer cells while sparing healthy ones, potentially leading to fewer side effects and improved outcomes for patients.

What evidence suggests that ADI-PEG 20 combined with chemotherapy could be effective for leiomyosarcoma?

Research shows that ADI-PEG 20, when combined with chemotherapy, can help treat soft tissue sarcoma, including leiomyosarcoma (LMS). In this trial, one group of participants will receive ADI-PEG 20 with the chemotherapy drugs gemcitabine and docetaxel. Previous studies have found this combination to be safe and effective. ADI-PEG 20 breaks down arginine, a nutrient cancer cells need to grow, which can slow or stop cancer cell growth. Early results suggest that this combination may reduce tumor size or slow the disease in LMS patients. ^{1 2 4 5 6}

Who Is on the Research Team?

John S Bomalaski

Principal Investigator

Polaris Group

Are You a Good Fit for This Trial?

This trial is for adults over 18 with advanced or metastatic Leiomyosarcoma (LMS), a type of soft tissue sarcoma, previously treated with an anthracycline. Participants must have measurable disease and good performance status, meaning they can carry out daily activities without significant limitations. They should not have had more than two systemic treatments but may have received Gemcitabine (Gem) or Docetaxel (Doc) over a year ago.

Inclusion Criteria

My cancer is identified as either uterine or non-uterine LMS.

My soft tissue sarcoma is confirmed to be grade 2 or 3 and treatable with specific chemotherapy.

I was treated with Gemcitabine or Docetaxel over a year ago.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ADI-PEG 20 or placebo plus Gemcitabine and Docetaxel in 21-day cycles

Up to 104 weeks

Weekly visits for drug administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• ADI PEG20
• Placebo

Trial Overview The study is testing the effectiveness and safety of ADI-PEG 20 combined with chemotherapy drugs Gemcitabine and Docetaxel versus placebo plus these chemotherapies in patients with LMS who've already undergone some treatment. The goal is to see if ADI-PEG 20 can improve outcomes for these patients.

How Is the Trial Designed?

Group I: ADIGemDoc Experimental Treatment 1 Intervention

ADI-PEG 20: 36 mg/m2 on Day -7 of Cycle 1, and Days 1, 8, and 15 of each 21-day cycle Gemcitabine: 600 mg/m2 on days 1 and 8 of each 21-day cycle Docetaxel: 60 mg/m2 on day 8 of each 21-day cycle

Group II: PBOGemDoc Placebo Group 1 Intervention

Placebo: matched PBO on Day -7 of Cycle 1, and Days 1, 8, and 15 of each 21-day cycle Gemcitabine: 900 mg/m2 on days 1 and 8 of each 21-day cycle Docetaxel: 75 mg/m2 on day 8 of each 21-day cycle

Who Is Running the Clinical Trial?

Polaris Group

Lead 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 patient-derived orthotopic xenograft (PDOX) mouse model was developed to test treatments for leiomyosarcoma, a rare and difficult-to-treat cancer, using a tumor from a patient's thigh.

In this study, the combination of gemcitabine and docetaxel, trabectedin, and temozolomide were found to be highly effective against leiomyosarcoma, while the commonly used first-line treatment, doxorubicin, was ineffective, highlighting the PDOX model's ability to identify effective therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A patient-derived orthotopic xenograft (PDOX) nude-mouse model precisely identifies effective and ineffective therapies for recurrent leiomyosarcoma. Zhang, Z., Hu, K., Kiyuna, T., et al.[2020]

Trabectedin, a new DNA-damaging agent, was well tolerated and led to 17 months of disease stability in a 76-year-old patient with progressive metastatic leiomyosarcoma, demonstrating its potential as a treatment option for advanced cases.

The treatment with trabectedin did not result in cumulative toxicity over 22 cycles, suggesting it may be a safer alternative compared to traditional chemotherapy regimens for patients who have limited options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prolonged disease stability with trabectedin in a heavily pretreated elderly patient with metastatic leiomyosarcoma of the thigh and renal failure: a case report and review of the literature. Galizia, D., Palesandro, E., Nuzzo, AM., et al.[2019]

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]

Adjuvant gemcitabine-docetaxel (GD) chemotherapy for Stage I uterine leiomyosarcoma has seen a significant increase in usage from 6.5% to 46.9% between 2006 and 2013, indicating a growing trend in treatment practices.

However, the study found no significant difference in disease-free or overall survival between women who received GD chemotherapy and those who did not, suggesting that the chemotherapy may not provide a clear benefit in improving survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant gemcitabine-docetaxel chemotherapy for stage I uterine leiomyosarcoma: Trends and survival outcomes. Littell, RD., Tucker, LY., Raine-Bennett, T., et al.[2022]

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 II study involving 34 patients with unresectable leiomyosarcoma (LMS), the combination of gemcitabine and docetaxel showed a high overall response rate of 53%, indicating significant efficacy in treating this challenging cancer, especially in patients who had previously received doxorubicin.

The treatment was generally well-tolerated, with manageable hematologic toxicities, such as neutropenia and thrombocytopenia, but rare instances of severe complications like neutropenic fever, suggesting a favorable safety profile for this chemotherapy regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: results of a phase II trial. Hensley, ML., Maki, R., Venkatraman, E., 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]

In a study of 42 women with advanced uterine leiomyosarcoma, the combination of fixed-dose rate gemcitabine and docetaxel as first-line treatment resulted in a 35.8% overall objective response rate, with a median response duration of 6 months.

The treatment was associated with significant myelosuppression, including grade 4 neutropenia in 12% of patients, but also demonstrated a median overall survival of over 16 months, indicating its potential effectiveness despite the risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fixed-dose rate gemcitabine plus docetaxel as first-line therapy for metastatic uterine leiomyosarcoma: a Gynecologic Oncology Group phase II trial. Hensley, ML., Blessing, JA., Mannel, R., et al.[2022]

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-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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05712694

NCT05712694 | Study of ADI-PEG 20 or Placebo Plus Gem ... Study Overview. Brief Summary. To compare the efficacy and safety in subjects with advanced or metastatic LMS previously treated with an anthracycline.

2. 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. The encouraging safety and ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3086545/

Pegylated arginine deiminase: a novel anticancer enzyme ... Furthermore, their data showed that native ADI reduced arginine levels in mice to 40 – 50% at 24 h after injection, whereas ADI-PEG20 reduced circulating ...

4. meetings.asco.org meetings.asco.org/abstracts-presentations/238342

Phase I/II study of pegylated arginine deiminase (ADI-PEG ... A phase II trial of ADI-PEG 20, G and D was shown to be a safe and efficacious combination in soft tissue sarcoma (STS). We are conducting a phase I/II trial ...

5. careacross.com careacross.com/clinical-trials/trial/NCT05712694

Study of ADI-PEG 20 or Placebo Plus Gem and Doc in ... Summary: To compare the efficacy and safety in subjects with advanced or metastatic LMS previously treated with an anthracycline. Detailed description: This is ...

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.2021.39.15_suppl.11508

Phase II trial of pegylated arginine deiminase in ... Conclusions: The combination of ADI-PEG20 with G+D can be safely and effectively given at a dose of 600mg/m2 G and 60mg/m2 D. Future randomized ...