Cell Therapy + Enzalutamide for Prostate Cancer

Overseen By Fred Hutch Intake

Age: 18+

Sex: Male

Trial Phase: Phase 1 & 2

Sponsor: Fred Hutchinson Cancer Center

Must be taking: Androgen inhibitors

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: Autoimmune disease, Uncontrolled infection, others

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

Compensation: Varies

Number of Visits: 6

Duration: Up to 1 year

48 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot use other investigational anti-cancer agents during the trial, except for androgen deprivation therapy.

What data supports the effectiveness of the treatment Cell Therapy + Enzalutamide for Prostate Cancer?

Research shows that targeting STEAP1 with CAR T cells can effectively attack prostate cancer cells, and enzalutamide has shown benefits in some prostate cancer patients. Combining these approaches may enhance the immune response against prostate cancer. ^{1 2 3 4 5}

Is the combination of cell therapy and Enzalutamide safe for prostate cancer treatment?

The combination of Enzalutamide with other treatments, like Entinostat, has shown a promising safety profile in early studies for prostate cancer. Additionally, STEAP1-targeted CAR T cell therapies have demonstrated safety in preclinical models, suggesting they may be safe for further development in humans. ^{1 2 5 6 7}

What makes the STEAP1 CART treatment for prostate cancer unique?

The STEAP1 CART treatment is unique because it involves using genetically modified immune cells (CAR T-cells) to specifically target and attack prostate cancer cells, which is different from traditional treatments like enzalutamide that focus on blocking androgen receptors to slow cancer growth. ^{7 8 9 10 11}

What is the purpose of this trial?

This phase I/II trial tests the safety and effectiveness of cell therapy (STEAP1 CART) with enzalutamide in treating patients with prostate cancer that continues to grow despite surgical or medical treatments to block androgen production (castration-resistant) and that has spread from where it first started (the prostate) to other places in the body (metastatic). Prostate cancer is the second leading cause of cancer deaths in men. Localized prostate cancer is often curable and even metastatic disease may respond to treatment for a few years. Despite multiple therapies, including hormone therapy and chemotherapy, metastatic castration-resistant prostate cancer (mCRPC) still remains an incurable disease. Recently, adoptive cellular immunotherapies have been developed to transfer immunogenic cells to the patient to produce an anti-tumor response. Chimeric antigen receptor T (CART)-cell therapy is a type of treatment in which a patient's T-cells (a type of immune cell) are changed in the laboratory so they will attack tumor cells. T cells are taken from a patient's blood. Then the gene for a special receptor that binds to a certain protein on the patient's tumor cells is added to the T cells in the laboratory. The special receptor is called a chimeric antigen receptor (CAR). Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of certain cancers. Prostate stem cell antigen and prostate specific membrane antigen CAR T cell therapies have been shown to be safe and effective, but objective tumor responses remain rare. STEAP1 is an antigen that promotes cancer growth and spread and is found to be broadly expressed in mCRPC tissues. STEAP1 CART is CAR T cells that have been engineered with a STEAP1 antigen to better target prostate tumor cells. Enzalutamide is in a class of medications called androgen receptor inhibitors. It works by blocking the effects of androgen (a male reproductive hormone) to stop the growth and spread of cancer cells. Giving STEAP1 CART with enzalutamide may kill more tumor cells in patients with mCRPC.

Research Team

Rosa Nadal Rios, MD, PhD

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Eligibility Criteria

This trial is for men with metastatic castration-resistant prostate cancer, which has spread beyond the prostate and resists treatment to lower male hormones. Participants must have tried hormone therapy and chemotherapy without success.

Inclusion Criteria

My cancer can be measured by scans or I have cancer in the bones with a PSA level over 1.

Fertile male participants and their female partners must be willing to use an effective contraceptive method before, during, and for at least 4 months after the STEAP1 CART cell infusion

My liver function tests, specifically AST and ALT, are within normal limits.

Exclusion Criteria

I am taking more than 15 mg of prednisone daily, but use it in short bursts for my condition.

I am not using any other experimental cancer treatments, except for hormone therapy to lower androgen levels.

My infections, including HIV or hepatitis, are well-controlled with medication.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Leukapheresis and Pre-treatment

Patients undergo leukapheresis and receive cyclophosphamide and fludarabine intravenously on days -5, -4, and -3

1 week

3 visits (in-person)

Treatment

Patients receive STEAP1 CART infusion on day 0 and may receive enzalutamide orally starting on day 0

Up to 1 year

Multiple visits (in-person and virtual)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 15 years

Regular visits at 2, 3, 4, 5, 6, 9, and 12 months, then every 6 months up to year 5, followed by yearly up to year 15

Treatment Details

Interventions

• Enzalutamide
• STEAP1 CART

Trial Overview The trial tests STEAP1 CART cell therapy combined with enzalutamide, a drug blocking male hormones. It's checking if this combo can better target and kill prostate cancer cells that have spread and don't respond to usual treatments.

Participant Groups

Group I: Treatment (STEAP1 CART, enzalutamide) Experimental Treatment 13 Interventions

Patients undergo leukapheresis then receive cyclophosphamide IV and fludarabine IV on days -5, -4 and -3 and STEAP1 CART IV on day 0. Patients may receive enzalutamide PO on day 0 then QD in the absence of disease progression or unacceptable toxicity. Patients also undergo a tumor biopsy at baseline, day 14 and optionally at progression. Patients additionally undergo blood sample collection, NM bone scan and CT scan, or MRI or PET scan throughout study. Additionally, patients may undergo ECHO or MUGA at screening.

Who Is Running the Clinical Trial?

Fred Hutchinson Cancer Center

Lead Sponsor

Trials

583

Recruited

1,341,000+

PromiCell Therapeutics, Inc.

Collaborator

Trials

1

Recruited

50+

Findings from Research

The study identified STEAP2 as a promising target for CAR-T therapy in prostate cancer due to its high expression on tumor cells and limited presence in normal tissues, reducing the risk of off-target effects.

The engineered CAR-T therapy, AZD0754, showed strong anti-tumor activity in both laboratory and mouse models, demonstrating its potential as a safe and effective treatment option for prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor activity of AZD0754, a dnTGFβRII-armored, STEAP2-targeted CAR-T cell therapy, in prostate cancer. Zanvit, P., van Dyk, D., Fazenbaker, C., et al.[2023]

STEAP1 is a promising target for CAR T cell therapy in metastatic prostate cancer, showing effectiveness even at low antigen levels and demonstrating safety in preclinical models.

Combining STEAP1 CAR T cell therapy with a localized IL-12 treatment enhances the immune response against tumors, improving antitumor efficacy and addressing issues of treatment resistance due to STEAP1 antigen escape.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell and tumor-localized IL-12 immunotherapy. Bhatia, V., Kamat, NV., Pariva, TE., et al.[2023]

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 the SPARTAN study involving 1207 patients with nonmetastatic castration-resistant prostate cancer, apalutamide significantly improved health-related quality of life (HRQoL) compared to placebo, with patients maintaining better scores over time.

Patients receiving apalutamide experienced minimal side effects and reported no worsening of fatigue, while those on placebo showed a decline in quality of life after about one year, highlighting the efficacy and tolerability of apalutamide in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health-related Quality of Life at the SPARTAN Final Analysis of Apalutamide for Nonmetastatic Castration-resistant Prostate Cancer Patients Receiving Androgen Deprivation Therapy. Oudard, S., Hadaschik, B., Saad, F., et al.[2022]

The development of a CAR targeting STEAP1, which is found in about 90% of prostate cancers, shows promise as it effectively directs T cells to attack cancer cells while sparing normal tissues.

In mouse models, STEAP1 CAR T cells not only infiltrated tumors but also significantly inhibited tumor growth and improved survival, indicating strong potential for clinical application in treating prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of STEAP1 targeting chimeric antigen receptor for adoptive cell therapy against cancer. Jin, Y., Lorvik, KB., Jin, Y., et al.[2022]

In a small phase I study involving 6 patients with metastatic castration-resistant prostate cancer (CRPC), the combination of entinostat and enzalutamide demonstrated a promising safety profile, with manageable side effects and no significant increase in fatigue.

Entinostat did not alter the plasma concentration of enzalutamide and showed biological activity by increasing histone H3 acetylation in peripheral blood mononuclear cells, suggesting potential mechanisms for its efficacy in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Study of Entinostat in Combination with Enzalutamide for Treatment of Patients with Metastatic Castration-Resistant Prostate Cancer. Lin, J., Elkon, J., Ricart, B., et al.[2021]

Enzalutamide, when combined with a Twist-targeting immunotherapy, significantly improved overall survival in a mouse model of castration-resistant prostate cancer (CRPC), extending survival from 10.3 weeks to 27.5 weeks.

The study found that enzalutamide did not impair the immune response generated by the Twist vaccine, suggesting that this combination therapy could be a safe and effective strategy for treating advanced-stage prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination therapy with a second-generation androgen receptor antagonist and a metastasis vaccine improves survival in a spontaneous prostate cancer model. Ardiani, A., Farsaci, B., Rogers, CJ., et al.[2021]

Enzalutamide (XTANDI) is an FDA-approved treatment for castration-resistant prostate cancer (CRPC) that effectively targets androgen receptor signaling, which is crucial for cancer progression.

In a Phase III clinical trial involving men with CRPC after chemotherapy, enzalutamide was well tolerated and significantly improved overall survival by 4.8 months, as indicated by reduced serum prostate-specific antigen (PSA) levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzalutamide: a novel anti-androgen with prolonged survival rate in CRPC patients. Dhingra, R., Sharma, T., Singh, S., et al.[2021]

In a phase 3 trial involving 1401 men with nonmetastatic, castration-resistant prostate cancer, enzalutamide significantly improved median overall survival to 67.0 months compared to 56.3 months for placebo, indicating a 27% lower risk of death.

The safety profile of enzalutamide was consistent with previous studies, with a similar rate of serious adverse events compared to placebo, primarily involving fatigue and musculoskeletal issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzalutamide and Survival in Nonmetastatic, Castration-Resistant Prostate Cancer. Sternberg, CN., Fizazi, K., Saad, F., et al.[2021]

The PREVAIL Phase 3 trial demonstrated that enzalutamide significantly improves radiographic-progression free survival in men with castration-resistant prostate cancer (CRPC), with 65% of patients showing no progression compared to those on placebo.

Enzalutamide also provided a median overall survival benefit of 32.4 months versus 30.2 months for the placebo group, indicating its efficacy as a treatment option before chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzalutamide for treatment of CRPC: rationale for sequencing and potential clinical biomarker for resistance. Lochrin, SE., Figg, WD., Finn, SP.[2020]

In a long-term study of 67 patients with hormone-naïve prostate cancer, enzalutamide monotherapy resulted in a 100% prostate-specific antigen (PSA) response rate at 97 weeks for those who remained on treatment, indicating its strong efficacy.

The treatment was well-tolerated with minimal negative effects on total-body bone mineral density, although common side effects included gynecomastia and fatigue.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term Efficacy and Safety of Enzalutamide Monotherapy in Hormone-naïve Prostate Cancer: 1- and 2-Year Open-label Follow-up Results. Tombal, B., Borre, M., Rathenborg, P., et al.[2021]

References

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

Antitumor activity of AZD0754, a dnTGFβRII-armored, STEAP2-targeted CAR-T cell therapy, in prostate cancer. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell and tumor-localized IL-12 immunotherapy. [2023]

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. Netherlands pubmed.ncbi.nlm.nih.gov

Health-related Quality of Life at the SPARTAN Final Analysis of Apalutamide for Nonmetastatic Castration-resistant Prostate Cancer Patients Receiving Androgen Deprivation Therapy. [2022]

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

Development of STEAP1 targeting chimeric antigen receptor for adoptive cell therapy against cancer. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Phase I Study of Entinostat in Combination with Enzalutamide for Treatment of Patients with Metastatic Castration-Resistant Prostate Cancer. [2021]

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

Combination therapy with a second-generation androgen receptor antagonist and a metastasis vaccine improves survival in a spontaneous prostate cancer model. [2021]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Enzalutamide: a novel anti-androgen with prolonged survival rate in CRPC patients. [2021]

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

Enzalutamide and Survival in Nonmetastatic, Castration-Resistant Prostate Cancer. [2021]

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

Enzalutamide for treatment of CRPC: rationale for sequencing and potential clinical biomarker for resistance. [2020]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Long-term Efficacy and Safety of Enzalutamide Monotherapy in Hormone-naïve Prostate Cancer: 1- and 2-Year Open-label Follow-up Results. [2021]