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

Trial Summary

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.

What data supports the effectiveness of the drug combination Evofosfamide, Zalifrelimab, and Balstilimab for prostate cancer?

The research indicates that immune checkpoint inhibitors, like Balstilimab and Zalifrelimab, have shown limited benefits in prostate cancer, but may be effective in certain patients with specific genetic mutations. Combination therapies, such as those involving immune checkpoint inhibitors, might improve response rates, suggesting potential for the drug combination to be effective in selected patients. ^{1 2 3 4 5}

What makes the drug combination of Evofosfamide, Zalifrelimab, and Balstilimab unique for prostate cancer?

This drug combination is unique because it combines Evofosfamide, which targets low-oxygen areas in tumors, with Zalifrelimab and Balstilimab, which are immune checkpoint inhibitors that help the immune system attack cancer cells. This approach is different from standard treatments that primarily focus on hormone therapy or chemotherapy. ^{1 3 4 6 7}

What is the purpose of this trial?

The purpose of this Phase 1/2 study is to test the overall safety, tolerability, and effectiveness of the combination investigational drugs evofosfamide, zalifrelimab, and balstilimab in treating advanced or metastatic castration-resistant prostate cancer, pancreatic cancer, and human papilloma virus (HPV)-negative squamous cell carcinoma of the head and neck (SCCHN).

Eligibility Criteria

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.

Measurable disease as defined by RECIST 1.1 or PCWG3 criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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 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]

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]

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]

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]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Recent Advances in Prostate Cancer Treatment and Drug Discovery. [2022]

2. England 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). [2022]

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

Atezolizumab with enzalutamide versus enzalutamide alone in metastatic castration-resistant prostate cancer: a randomized phase 3 trial. [2023]

4. United States 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. [2021]

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

Anti-PD-L1 plus enzalutamide does not improve overall survival in prostate cancer. [2023]

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

Immune checkpoint B7-H3 protein expression is associated with poor outcome and androgen receptor status in prostate cancer. [2022]

7. England 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. [2023]