Evofosfamide + Zalifrelimab + Balstilimab for Prostate Cancer

Overseen By Charles Schweizer, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: ImmunoGenesis

Must be taking: Anti-androgens

Must not be taking: Systemic steroids, QT-prolonging drugs

Disqualifiers: Autoimmune diseases, Uncontrolled infection, others

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

Compensation: Varies

Number of Visits: Unknown

71 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and effectiveness of a combination of three investigational drugs—evofosfamide, zalifrelimab, and balstilimab—for treating certain advanced cancers. The focus is on advanced or metastatic prostate cancer unresponsive to standard hormone treatment, pancreatic cancer, and a type of head and neck cancer not linked to HPV. It suits patients with these cancers who haven't found success with other treatments. As a Phase 1, Phase 2 trial, the research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group, offering patients a chance to explore new treatment avenues.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, if you are on certain medications like strong or moderate CYP3A4 inhibitors or inducers, you may need to switch to an alternative regimen at least 4 weeks before joining the study. Patients with prostate cancer can continue anti-androgen and bone-targeted therapies.

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

Research continues to assess the safety and effectiveness of combining evofosfamide, zalifrelimab, and balstilimab. Although complete data on their safety in humans is not yet available, similar studies have provided some insights.

Evofosfamide targets low-oxygen areas in tumors, potentially enhancing the effectiveness of other treatments. Zalifrelimab and balstilimab help the immune system combat cancer cells. These treatments have been used in other studies and are generally well-tolerated, though side effects can occur.

This is a Phase 1/2 study, where researchers determine the optimal dose and monitor for side effects. This phase often marks the first use of these drugs together in people, so safety information is still being gathered. If these treatments have approval for other uses, some safety information is already known, but this study will offer more specific details. Discuss potential risks and benefits with a doctor before deciding to join a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for castration-resistant prostate cancer, which often include hormonal therapies and chemotherapy, Evofosfamide + Zalifrelimab + Balstilimab offers a unique approach by combining an immunotherapy strategy with a prodrug activation mechanism. Evofosfamide is a prodrug that becomes active in low-oxygen environments, like those found in tumors, delivering a potent punch directly to cancer cells. Meanwhile, Zalifrelimab and Balstilimab are immune checkpoint inhibitors that help unleash the immune system against cancer. Researchers are excited about this combination because it targets the tumor environment directly while also empowering the body's own defenses, potentially leading to more effective and targeted treatment outcomes.

What evidence suggests that this trial's treatments could be effective for prostate cancer, pancreatic cancer, and HPV-negative squamous cell carcinoma of the head and neck?

Research has shown that evofosfamide targets low-oxygen areas in tumors, making them easier to treat. Early results suggest evofosfamide can help overcome resistance in solid tumors. Zalifrelimab and balstilimab enhance the immune system's ability to recognize and attack cancer cells. Studies with similar drugs have demonstrated they can boost the body's immune response to cancer. This trial will evaluate the combination of evofosfamide, zalifrelimab, and balstilimab for various cancers, including prostate cancer, pancreatic cancer, and certain head and neck cancers. Using these treatments together might be more effective by addressing both the tumor environment and the cancer's ability to evade the immune system. ^{1 2 3 4 6}

Are You a Good Fit for This Trial?

This trial is for adults with advanced prostate, pancreatic, or HPV-negative head and neck cancers without standard treatment options. Participants must have a life expectancy of at least 3 months, measurable disease, good organ function, and an ECOG status of 0-2. They should not be on certain drugs that affect the immune system or have uncontrolled diseases.

Inclusion Criteria

Minimum estimated life expectancy of at least 3 months

It's been over 3 weeks since my last chemo or radiation treatment.

My bone marrow and liver are working well.

Exclusion Criteria

I am not taking strong or moderate drugs that affect liver enzyme CYP3A4.

I am not using any other cancer treatments.

I have an active autoimmune disease that is not under control.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Dose Escalation

Determine the maximum tolerated dose of evofosfamide in combination with zalifrelimab and balstilimab

8-12 weeks

Phase 2 Dose Expansion

Evaluate the Phase 2 dose of the triplet combination in 3 cohorts: prostate cancer, pancreatic cancer, and HPV-negative SCCHN

16-24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Balstilimab
• Evofosfamide
• Zalifrelimab

Trial Overview The study tests the safety and effectiveness of combining evofosfamide with zalifrelimab and balstilimab in treating specific advanced cancers. It's a Phase 1/2 trial where patients receive all three investigational drugs to see how well they work together.

How Is the Trial Designed?

Group I: Pancreatic cancer Experimental Treatment 3 Interventions

Evofosfamide + zalifrelimab + balstilimab

Group II: Human papilloma virus-negative squamous cell carcinoma of the head and neck Experimental Treatment 3 Interventions

Evofosfamide + zalifrelimab + balstilimab

Group III: Castration-resistant prostate cancer Experimental Treatment 3 Interventions

Evofosfamide + zalifrelimab + balstilimab

Who Is Running the Clinical Trial?

ImmunoGenesis

Lead Sponsor

Trials

3

Recruited

210+

Agenus Inc.

Industry Sponsor

Trials

58

Recruited

4,900+

Published Research Related to This Trial

The IMbassador250 trial involving 759 men with metastatic castration-resistant prostate cancer found that adding atezolizumab to enzalutamide did not improve overall survival, although it had an acceptable safety profile.

However, patients with high levels of PD-L1 expression and certain immune gene signatures showed longer progression-free survival, suggesting that careful patient selection could enhance the effectiveness of immune checkpoint inhibitors in this cancer type.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab with enzalutamide versus enzalutamide alone in metastatic castration-resistant prostate cancer: a randomized phase 3 trial. Powles, T., Yuen, KC., Gillessen, S., et al.[2023]

In a study involving 132 patients with metastatic castration-resistant prostate cancer, the combination of cabozantinib and atezolizumab demonstrated an objective response rate of 23%, indicating promising antitumor activity after prior hormonal therapies.

While the treatment showed efficacy, 55% of patients experienced grade 3-4 treatment-related adverse events, with pulmonary embolism and diarrhea being the most common, suggesting that while the combination is effective, careful monitoring for side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib in combination with atezolizumab in patients with metastatic castration-resistant prostate cancer: results from an expansion cohort of a multicentre, open-label, phase 1b trial (COSMIC-021). Agarwal, N., McGregor, B., Maughan, BL., et al.[2022]

Combining atezolizumab, an anti-PD-L1 immunotherapy, with enzalutamide, an androgen receptor antagonist, did not improve survival rates in patients with metastatic prostate cancer.

Further research is needed to understand the mechanisms of resistance to immunotherapy in the prostate tumor microenvironment, which may help improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-PD-L1 plus enzalutamide does not improve overall survival in prostate cancer. Siddiqui, BA., Subudhi, SK., Sharma, P.[2023]

Recent advancements in prostate cancer treatment include new drugs like abiraterone acetate and enzalutamide, which effectively target androgen receptor signaling and have shown significant benefits when combined with androgen deprivation therapy (ADT) for advanced stages of the disease.

Ongoing clinical trials are exploring various innovative therapies, including second-generation AR antagonists and targeted treatments based on molecular profiling, which aim to personalize and improve treatment outcomes for prostate cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent Advances in Prostate Cancer Treatment and Drug Discovery. Nevedomskaya, E., Baumgart, SJ., Haendler, B.[2022]

In three cases of metastatic castration-resistant prostate cancer (mCRPC), patients showed significant responses to anti-PD-1 immunotherapy after being treated with bipolar androgen therapy (BAT) and enzalutamide, suggesting a potential strategy for enhancing immunotherapy effectiveness.

Two of the patients had inactivating mutations in HR DNA repair genes (BRCA2, ATM), indicating that specific genetic profiles may influence the success of immune checkpoint blockade in prostate cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Extreme responses to immune checkpoint blockade following bipolar androgen therapy and enzalutamide in patients with metastatic castration resistant prostate cancer. Markowski, MC., Shenderov, E., Eisenberger, MA., et al.[2021]

In a pilot phase II study involving eight Black men with metastatic castrate-resistant prostate cancer (mCRPC), the PD-L1 inhibitor avelumab did not achieve the primary endpoint of a 50% reduction in prostate-specific antigen (PSA) levels after 8 weeks, indicating a lack of clinical efficacy.

The study was halted early due to safety concerns, as patients experienced rapid clinical progression, with a median time to PSA progression of only 35 days, suggesting that avelumab may not be a suitable treatment option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Black Patients with Metastatic Castrate-Resistant Prostate Cancer Have a Shorter Time Interval Between PSA and Clinical Progression on Novel Hormonal Therapies plus Avelumab. Hawkins, CM., Barata, PC., Cotogno, P., et al.[2023]

In a study of 326 prostate adenocarcinoma patients from Spain and Norway, high expression of the immune checkpoint protein B7-H3 was linked to worse outcomes, including biochemical and clinical recurrence, indicating its potential as a target for immunotherapy.

Unlike B7-H3, PD-L1 expression did not show a correlation with clinical outcomes, suggesting that B7-H3 may be a more relevant biomarker for treatment strategies in prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune checkpoint B7-H3 protein expression is associated with poor outcome and androgen receptor status in prostate cancer. Nunes-Xavier, CE., Kildal, W., Kleppe, A., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06782555

NCT06782555 | A Study of Evofosfamide in Combination ... The purpose of this Phase 1/2 study is to test the overall safety, tolerability, and effectiveness of the combination investigational drugs evofosfamide, ...

2. trialx.com trialx.com/clinical-trials/listings/295030/a-study-of-evofosfamide-in-combination-with-zalifrelimab-and-balstilimab/?&radius=10&place=A&user_country=Concord%20N

A Study of Evofosfamide in Combination with Zalifrelimab ... The purpose of this Phase 1/2 study is to test the overall safety, tolerability, and effectiveness of the combination investigational drugs ...

3. withpower.com withpower.com/trial/evofosfamide-zalifrelimab-balstilimab-for-prostate-cancer-766cb

Evofosfamide + Zalifrelimab + Balstilimab for Prostate Cancer The purpose of this Phase 1/2 study is to test the overall safety, tolerability, and effectiveness of the combination investigational drugs evofosfamide, ...

4. targetedonc.com targetedonc.com/view/evofosfamide-trial-targets-hypoxia-in-resistant-solid-tumors

Evofosfamide Trial Targets Hypoxia in Resistant Solid ... The first patient was dosed in a phase 1/2 trial of evofosfamide with checkpoint inhibitors for hypoxia-reversal in resistant solid tumors.

5. app.trialscreen.org app.trialscreen.org/trials/phase-1-2-evofosfamide-combination-zalifrelimab-balstilimab-trial-nct06782555

A Study of Evofosfamide in Combination with Zalifrelimab ... This Interventional study is looking for people with Metastatic Prostate Cancer, Metastatic Head and Neck Squamous Cell Carcinoma in Houston ...

6. clin.larvol.com clin.larvol.com/trial-detail/NCT06782555

A Study of Evofosfamide in Combination with Zalifrelimab ... A Study of Evofosfamide in Combination with Zalifrelimab and Balstilimab. P1/2. ImmunoGenesis. N=71. Recruiting. NON_RANDOMIZED. Publications (1) Outcome