ADI-PEG 20 + Chemotherapy for Prostate Cancer

Overseen By Ana Aparicio, MD

Age: 18+

Sex: Male

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Carboplatin, Cisplatin, Cabazitaxel

Disqualifiers: Uncontrolled infection, Viral hepatitis, Lung disease, others

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

Compensation: Varies

Number of Visits: Unknown

30 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 advanced prostate cancer that resists typical hormonal therapies. The researchers aim to determine the best dose of an experimental drug, ADI-PEG 20, when combined with two chemotherapy drugs, carboplatin and cabazitaxel. They seek men with prostate cancer that has spread and meets specific criteria, such as certain tumor types or disease progression after hormone therapy. This research could benefit those who have not succeeded with other treatments. As a Phase 1 trial, the focus is on understanding how the treatment works in people, offering participants the chance to be among the first to receive this new treatment.

Do I need to stop my current medications for this trial?

The trial protocol does not specify if you need to stop taking your current medications. However, it does exclude patients who have not recovered from adverse events of previous treatments to a certain level, and those with unresolved toxicity from previous therapies. It's best to discuss your specific medications with the trial investigators.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, it does mention that patients should not have unresolved side effects from previous treatments, except for certain prostate cancer therapies and bone-strengthening medications.

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

Research has shown that ADI-PEG 20 is generally safe and well-tolerated in people. In earlier studies, no serious side effects emerged that would prevent dose escalation when combined with other treatments like radiation or hormone therapy. This suggests it can likely be used safely alongside other treatments.

Amivantamab and tepotinib have already received FDA approval for other uses. This indicates they have been tested and found safe for people, although side effects can vary based on treatment combinations and individual patient factors. Participants in the trial should be aware of possible side effects and discuss them with their doctor. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about ADI-PEG 20 combined with chemotherapy for prostate cancer because it offers a unique approach compared to current treatments. Unlike standard options, which often include hormone therapy, surgery, or radiation, ADI-PEG 20 works by depleting a key nutrient that cancer cells need to grow, specifically targeting arginine. This mechanism of action is different from traditional treatments, potentially providing a new way to slow or stop cancer progression. Additionally, combining ADI-PEG 20 with chemotherapy might enhance the effectiveness of treatment, offering hope for improved outcomes in patients.

What evidence suggests that this trial's treatments could be effective for prostate cancer?

Research has shown that ADI-PEG 20 might help treat prostate cancer by reducing arginine, a nutrient cancer cells need. One study found that 85% of patients experienced stable disease without progression. Another study reported that 4.7% of patients saw their cancer completely disappear when using ADI-PEG 20 alone. In this trial, participants will join a study group and receive one of up to two dose levels of ADI-PEG 20. Some patients had stable disease, while others responded well when ADI-PEG 20 was combined with other drugs. Although concerns about side effects exist, the treatment appears promising and is undergoing further testing. ^{1 3 4 5 6}

Who Is on the Research Team?

Ana Aparicio

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for men over 18 with aggressive variant prostate cancer (AVPC) that has spread, as shown by scans. They must consent to tissue collection and agree to birth control if their partners can have children. Participants need good organ function, low testosterone levels on treatment, and a performance status score of ≤2. Men who've had more than one chemo or specific drugs for CRPC aren't eligible.

Inclusion Criteria

My prostate cancer has been confirmed by a lab test.

My organs and bone marrow are functioning well, as tested within the last week.

You have proof that your disease is getting worse based on specific measurements or tests.

Exclusion Criteria

I have been treated for prostate cancer with carboplatin, cisplatin, or cabazitaxel.

I have active hepatitis or chronic liver disease.

I have another cancer with a high chance of coming back within 2 years.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation and Monotherapy Maintenance

Participants receive ADI-PEG20 with carboplatin and cabazitaxel to determine the optimal dose and assess safety and tolerability

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Amivantamab
• Tepotinib

Trial Overview The study aims to find the safest dose of ADI-PEG20 when used with carboplatin and cabazitaxel in treating AVPC. It's a phase I/II trial which means they're looking at safety, side effects, and early signs of how well it works.

How Is the Trial Designed?

Group I: Dose Escalation and Monotherapy Maintenance Experimental Treatment 3 Interventions

Participants will be assigned to a study group and dose level of ADI-PEG20 based on when participant join this study. Up to 2 dose levels of ADI-PEG20 may be tested. Up to 15 participants will be enrolled per dose level.

Amivantamab is already approved in United States, European Union for the following indications:

Approved in United States as Rybrevant for:

• Locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations
• Locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations

Approved in European Union as Rybrevant for:

• Locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations
• Locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Published Research Related to This Trial

In a phase I trial involving 28 men with androgen-independent prostate cancer, the combination of imatinib and docetaxel showed a maximum-tolerated dose of docetaxel at 30 mg/m², with notable side effects including fatigue and nausea.

The treatment led to significant declines in prostate-specific antigen (PSA) levels, with 38% of patients experiencing a PSA decline greater than 50%, indicating potential long-term efficacy of the combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Platelet-derived growth factor receptor inhibitor imatinib mesylate and docetaxel: a modular phase I trial in androgen-independent prostate cancer. Mathew, P., Thall, PF., Jones, D., et al.[2018]

In a study of 32 men with bone-predominant metastatic castration-resistant prostate cancer, the combination of radium-223 and sipuleucel-T led to a significant increase in progression-free survival (39 weeks vs. 12 weeks) and overall survival (not reached vs. 2.6 years) compared to sipuleucel-T alone.

Despite the combination treatment showing lower immune responses (3.2-fold less T-cell response), it resulted in a higher rate of PSA decline (>50% in 31% of patients), suggesting that radium-223 may enhance the clinical effectiveness of sipuleucel-T.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized Phase II Trial of Sipuleucel-T with or without Radium-223 in Men with Bone-metastatic Castration-resistant Prostate Cancer. Marshall, CH., Fu, W., Wang, H., et al.[2022]

Amivantamab-vmjw has shown a 40% overall response rate in patients with metastatic non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations, based on a phase 1 trial involving 81 participants, indicating its efficacy after platinum-based chemotherapy.

The treatment resulted in a median progression-free survival of 8.3 months and an overall survival of 22.8 months, with an acceptable safety profile, marking it as a significant advancement for patients with limited treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Amivantamab-Vmjw: A Novel Treatment for Patients with NSCLC Harboring EGFR Exon 20 Insertion Mutation after Progression on Platinum-Based Chemotherapy. Shah, V., McNatty, A., Simpson, L., et al.[2023]

The combination of pegylated IFN-alpha-2b (PEG-IFN-alpha-2b) and docetaxel significantly inhibited prostate cancer growth in nude mice, reducing tumor weight by 83% compared to controls, highlighting the efficacy of this dual treatment approach.

PEG-IFN-alpha-2b not only targets tumor cells but also induces apoptosis in tumor-associated endothelial cells, leading to decreased microvessel density and reduced production of proangiogenic factors, which enhances the overall anti-tumor effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibition of growth and metastasis of orthotopic human prostate cancer in athymic mice by combination therapy with pegylated interferon-alpha-2b and docetaxel. Huang, SF., Kim, SJ., Lee, AT., et al.[2019]

In a phase 3 trial involving 308 patients with advanced non-small-cell lung cancer (NSCLC) and EGFR exon 20 insertions, the combination of amivantamab and chemotherapy significantly improved progression-free survival compared to chemotherapy alone, with a median of 11.4 months versus 6.7 months.

The combination therapy also showed a higher response rate, with 73% of patients achieving a complete or partial response compared to 47% in the chemotherapy-only group, indicating that amivantamab enhances the effectiveness of standard chemotherapy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Amivantamab plus Chemotherapy in NSCLC with EGFR Exon 20 Insertions. Zhou, C., Tang, KJ., Cho, BC., et al.[2023]

In a phase 1 dose-expansion study involving 32 patients with ASS1-deficient malignant pleural mesothelioma, the combination of pegargiminase, pemetrexed, and cisplatin showed a high disease control rate of 93.5% and a manageable safety profile, with most adverse events being mild.

Resistance to pegargiminase treatment was associated with significant macrophage recruitment and changes in the tumor immune microenvironment, suggesting that further research is needed to enhance the effectiveness of arginine deprivation therapies in mesothelioma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expansion Phase 1 Study of Pegargiminase Plus Pemetrexed and Cisplatin in Patients With Argininosuccinate Synthetase 1-Deficient Mesothelioma: Safety, Efficacy, and Resistance Mechanisms. Szlosarek, PW., Phillips, MM., Pavlyk, I., et al.[2022]

In a study of men with metastatic castration-resistant prostate cancer (mCRPC) treated with sipuleucel-T, a delayed PSA response was observed, with 19.9% of patients in the PROCEED registry showing a PSA50 response at a median of 5.5 months after treatment.

The median overall survival for patients in the PROCEED cohort was 49 months, suggesting that sipuleucel-T may provide a significant survival benefit despite low immediate response rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes in men with metastatic castration-resistant prostate cancer who received sipuleucel-T and no immediate subsequent therapy: experience at Dana Farber and in the PROCEED Registry. Wei, XX., Kwak, L., Hamid, A., et al.[2022]

In a phase I/II trial involving men with androgen-independent prostate cancer, the combination of thalidomide, paclitaxel, and estramustine showed promising efficacy, with 76% of patients experiencing a significant decrease in prostate-specific antigen levels.

The treatment was generally well-tolerated, with minimal dose-limiting toxicity at the lowest thalidomide dose (200 mg daily), and only 13% of patients experiencing significant adverse effects, suggesting a favorable safety profile for further studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thalidomide/estramustine/paclitaxel in metastatic androgen-independent prostate cancer. Mathew, P., Logothetis, CJ., Dieringer, PY., et al.[2016]

Amivantamab, approved for treating non-small cell lung cancer with specific genetic mutations, works by targeting two pathways: the epithelial growth factor receptor and mesenchymal epithelial transition factor, enhancing the immune response against cancer cells.

Preclinical studies indicate that Amivantamab effectively inhibits cancer cell growth in models with exon20 insertions of the epithelial growth factor receptor, suggesting its potential as a targeted therapy for this specific patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Amivantamab: A New Hope in Targeting Non-small Cell Lung Cancer. Billowria, K., Das Gupta, G., Chawla, PA.[2023]

Amivantamab is a bispecific monoclonal antibody that targets both EGFR and MET, specifically developed for treating non-small cell lung cancer (NSCLC) with EGFR Exon 20 insertion mutations.

It received its first approval in the USA on May 21, 2021, for adult patients with advanced NSCLC who have progressed after platinum-based chemotherapy, and is currently in preregistration in multiple countries including the EU and Japan.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Amivantamab: First Approval. Syed, YY.[2021]

In a study of 71,606 men with castration-resistant prostate cancer, 7% received emerging therapies like abiraterone and enzalutamide, indicating these treatments are becoming common in clinical practice.

Among those receiving emerging therapies, 61% also used denosumab or zoledronic acid, particularly in patients with bone metastases, highlighting a trend towards combined treatment approaches for better management of prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An Observational Study of Concomitant Use of Emerging Therapies and Denosumab or Zoledronic Acid in Prostate Cancer. Liede, A., Wade, S., Lethen, J., et al.[2019]

In a study of 250 patients with metastatic, chemotherapy-naive, androgen-independent prostate cancer, intermittent chemotherapy with docetaxel and calcitriol led to a significant treatment holiday, with a median duration of 18 weeks for the first holiday.

Upon resuming treatment, 45.5% of patients showed a significant reduction in PSA levels, indicating that many patients can effectively respond to retreatment after a break, suggesting a potential strategy for managing this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intermittent chemotherapy in patients with metastatic androgen-independent prostate cancer: results from ASCENT, a double-blinded, randomized comparison of high-dose calcitriol plus docetaxel with placebo plus docetaxel. Beer, TM., Ryan, CW., Venner, PM., et al.[2018]

Siltuximab, when combined with docetaxel, was found to be safe for patients with castration-resistant prostate cancer (CRPC), with only a few cases of dose-limiting toxicity reported among 39 patients in a phase 1 study.

The combination treatment showed promising efficacy, with 62% of patients achieving a significant decline in PSA levels, indicating a potential therapeutic benefit for CRPC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1 study of a chimeric monoclonal antibody against interleukin-6, siltuximab, combined with docetaxel in patients with metastatic castration-resistant prostate cancer. Hudes, G., Tagawa, ST., Whang, YE., et al.[2021]

Current treatments for androgen-independent prostate cancer have not significantly improved survival rates, highlighting the need for new therapeutic strategies.

The review discusses various novel drugs and treatment approaches, including targeting apoptosis, antiangiogenesis, and growth factor receptors, which are being tested in combination with traditional chemotherapy to enhance patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel clinical trials in androgen-independent prostate cancer. Gulley, J., Dahut, W.[2019]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4452427/

Phase I trial of arginine deprivation therapy with ADI-PEG ... ADI-PEG 20 demonstrated reasonable toxicity in combination with docetaxel. Promising clinical activity was noted and expansion cohorts are now accruing for both ...

2. ascopubs.org ascopubs.org/doi/10.1200/jco.2015.33.15_suppl.e16116

ADI-PEG 20 plus docetaxel (DOC) in men with castrate ... Two pts stopped treatment due to therapy related toxicity. Conclusions: Despite promising preclinical data, combination ADI PEG20 + DOC did not ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT06085729?term=AREA%5BBasicSearch%5D(AREA%5BConditionSearch%5D(ADI%20Peg20))&rank=6

Phase I/II Study of PEGylated Arginine Deiminase (ADI ... Patients must meet at least one of the following AVPC criteria: i. Histologically proven small cell (neuroendocrine) prostate carcinoma ii. Exclusive visceral ...

4. aacrjournals.org aacrjournals.org/clincancerres/article/21/11/2480/124605/Phase-I-Trial-of-Arginine-Deprivation-Therapy-with

Phase I Trial of Arginine Deprivation Therapy with ADI-PEG 20 ... The 2 patients with PSA response had stable disease on imaging. The overall disease control rate in evaluable disease was 85%, including 4 of 6 patients with ...

5. nature.com nature.com/articles/s41598-017-10542-4

A Phase II Study of Arginine Deiminase (ADI-PEG20) in ... In this study, we showed that single-agent ADI-PEG20 therapy resulted in a CR rate of 4.7% (95% CI, 0~11.2%) and a stable disease rate of 16.3% ...

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

Phase IB trial of pegylated arginine deiminase (ADI-PEG ... Conclusions: The addition of ADI-PEG 20 to RT + TMX was safe, and no DLT was observed. The RP2D of ADI-PEG 20 was determined to be 36mg/m2. AEs ...