Targeted Drugs + Radiation Therapy for Prostate Cancer

(SBRT-AMICO Trial)

Overseen By Research Nurse Navigator

Age: 18+

Sex: Male

Trial Phase: Phase 2

Sponsor: Catherine Spina

Must not be taking: Antibiotics, Immunosuppressants, CYP3A4 inducers

Disqualifiers: Brain metastases, Severe infection, Autoimmune, others

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

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

Compensation: Varies

Number of Visits: Unknown

Duration: 6 months

23 Participants Needed

Trial Summary

What is the purpose of this trial?

This study will evaluate the safety and effectiveness of a combination of study drugs including zimberelimab, etrumadenant, and quemliclustat in combination with metastasis-directed irradiation in men with hormone sensitive oligometastatic prostate cancer. The study aims to test the hypothesis that targeted inhibition of the adenosine signaling axis (quemliclustat (CD73 antagonist) + etrumadenant (A2AR/A2BR antagonist)) and immune checkpoint inhibition (zimberelimab, α-PD-1) in combination with metastasis-directed stereotactic body radiation therapy (SBRT) will improve local control, progression-free survival (PFS), and hormone therapy-free survival and mitigate immunosuppressive changes to the tumor microenvironment (TME), compared to SBRT alone.

Will I have to stop taking my current medications?

The trial requires participants to stop taking certain medications that could interact with the study drugs. Specifically, you must not have taken certain strong inhibitors or inducers of specific enzymes and proteins within 4 weeks or 5 drug-elimination half-lives before starting the study treatment. It's best to discuss your current medications with the study team to determine if any need to be stopped.

What data supports the effectiveness of the treatment Stereotactic Body Radiation Therapy (SBRT) for prostate cancer?

Research involving 344 patients treated with SBRT for high-risk prostate cancer showed that this treatment can be effective, as it was explored for its efficacy and safety in multiple trials. ^{1 2 3 4 5}

Is the combination of targeted drugs and radiation therapy generally safe for prostate cancer treatment?

Early clinical trials suggest that combining immunotherapy drugs with radiation therapy can be safe for treating prostate cancer, but some patients may experience immune-related side effects like muscle inflammation and thyroid issues. ^{6 7 8 9 10}

What makes the drug Zimberelimab combined with radiation therapy unique for prostate cancer treatment?

Zimberelimab is an immune checkpoint inhibitor that, when combined with radiation therapy, may enhance the immune system's ability to fight prostate cancer, offering a novel approach compared to traditional treatments that primarily target androgen receptors or use chemotherapy. ^{1 11 12 13 14}

Research Team

Catherine S. Spina, MD, PhD

Principal Investigator

Columbia University

Eligibility Criteria

Men with hormone-sensitive oligometastatic prostate cancer, confirmed by biopsy, who have a life expectancy over 12 months and are in relatively good health (ECOG 0-2). They must have had primary treatment for prostate cancer and now present with limited metastases. Participants need normal organ/marrow function, PSA levels between 1-50 ng/mL, testosterone above 125 ng/mL, and agree to effective contraception if their partners can bear children.

Inclusion Criteria

I have undergone a procedure to prevent pregnancy permanently.

I will not donate sperm for 6 months after my last dose of the study drugs.

Intrauterine device

Exclusion Criteria

I have had lung conditions like pulmonary fibrosis or pneumonia, or my CT scan shows active lung inflammation.

I haven't taken any OCT2 sensitive drugs in the last 4 weeks or 5 half-lives of the drug.

I haven't taken strong antibiotics in the last 2 weeks, except for prevention.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-Treatment

Participants receive quemliclustat and etrumadenant for 4 weeks prior to metastasis-directed SBRT

4 weeks

Radiation

Participants undergo metastasis-directed stereotactic body radiation therapy (SBRT)

1 week

Treatment

Participants start zimberelimab within one week of completing SBRT

6 months

Follow-up

Participants are monitored for safety, effectiveness, and biochemical recurrence-free survival

12 months

Treatment Details

Interventions

• Etrumadenant
• Quemliclustat
• Stereotactic Body Radiation Therapy
• Zimberelimab

Trial Overview The trial is testing the combination of zimberelimab (an immune checkpoint inhibitor), etrumadenant and quemliclustat (both targeting adenosine signaling) along with targeted radiation therapy. The goal is to see if this combo improves survival without hormones, controls local tumor growth better than radiation alone, and positively affects the tumor environment.

Participant Groups

Group I: Treatment with quemliclustatm, etrumadenant, zimberelimab and SBRT Experimental Treatment 4 Interventions

Subjects with metastatic prostate cancer will receive quemliclustat and etrumadenant for 4 weeks prior to metastasis-directed SBRT (Stereotactic Body Radiation Therapy). Within one week of completing SBRT, subjects will also start zimberelimab.

Who Is Running the Clinical Trial?

Catherine Spina

Lead Sponsor

Trials

1

Recruited

20+

Arcus Biosciences, Inc.

Industry Sponsor

Trials

44

Recruited

7,500+

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]

New treatments for metastatic castrate-resistant prostate cancer (CRPC) are being developed, including drugs targeting the androgen receptor like abiraterone and MDV3100, which show promise in improving patient outcomes.

Cytotoxic chemotherapy with docetaxel has shown benefits for overall survival, but ongoing research is focused on enhancing these effects with new therapies, including bone-targeted treatments and immunotherapies, such as autologous vaccines and anti-CTLA4 antibodies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[New drugs in metastatic castration-resistant prostate cancer]. Albiges, L., Loriot, Y., Gross-Goupil, M., et al.[2018]

In a study of 14 men with high-risk localized prostate cancer, Sonidegib treatment led to a significant reduction in GLI1 mRNA expression (over 60-fold), indicating effective suppression of the Hedgehog signaling pathway, which is involved in cancer progression.

Sonidegib was well tolerated with no severe adverse events reported, but the overall impact on disease-free survival was similar to the observation group, suggesting that while the drug effectively targets the Hedgehog pathway, its clinical benefits in terms of cancer progression remain uncertain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacodynamic and pharmacokinetic neoadjuvant study of hedgehog pathway inhibitor Sonidegib (LDE-225) in men with high-risk localized prostate cancer undergoing prostatectomy. Ross, AE., Hughes, RM., Glavaris, S., et al.[2022]

In a study involving 17 men with high-risk localized prostate cancer, sunitinib was found to be well tolerated at doses of 12.5 mg and 25 mg, establishing a recommended phase 2 dose of 25 mg daily for further testing.

The combination of sunitinib with androgen deprivation therapy and radiation therapy showed feasibility, but higher doses (37.5 mg) led to significant dose-limiting toxicities, indicating the importance of careful dose management in this treatment regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sunitinib plus androgen deprivation and radiation therapy for patients with localized high-risk prostate cancer: results from a multi-institutional phase 1 study. Corn, PG., Song, DY., Heath, E., et al.[2021]

In a study involving 344 high-risk prostate cancer patients with a median follow-up of 49.5 months, stereotactic body radiation therapy (SBRT) demonstrated a high 4-year biochemical recurrence-free survival rate of 81.7% and distant metastasis-free survival rate of 89.1%.

The treatment showed a favorable safety profile, with low incidences of late grade ≥3 genitourinary (2.3%) and gastrointestinal (0.9%) toxicities, indicating that SBRT is both effective and safe for high-risk prostate cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stereotactic Body Radiotherapy for High-Risk Localized Carcinoma of the Prostate (SHARP) Consortium: Analysis of 344 Prospectively Treated Patients. van Dams, R., Jiang, NY., Fuller, DB., et al.[2022]

Ipilimumab, an anti-CTLA-4 antibody, shows promise in enhancing immune response against prostate cancer when combined with a GM-CSF-secreting vaccine (GVAX), particularly when administered after vaccination, leading to increased CD8 T cell activity in the prostate.

Incorporating low-dose cyclophosphamide into the treatment regimen further improves the efficacy of the combined anti-CTLA-4 and GVAX therapy, suggesting a potential new approach for clinical trials in advanced prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sequencing CTLA-4 blockade with cell-based immunotherapy for prostate cancer. Wada, S., Jackson, CM., Yoshimura, K., et al.[2021]

In a phase II trial involving men with metastatic castration-resistant prostate cancer (mCRPC) who were progressing on enzalutamide, the anti-PD-1 antibody pembrolizumab showed unexpected antitumor activity, with three out of ten patients achieving significant reductions in prostate-specific antigen (PSA) levels.

The presence of immune cell infiltrates and PD-L1 expression in tumor biopsies from responders suggests that certain biological markers may predict the effectiveness of PD-1 inhibitors in prostate cancer, warranting further investigation into this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer. Graff, JN., Alumkal, JJ., Drake, CG., et al.[2022]

In a case study of a patient with heavily treated metastatic castration-resistant prostate cancer (mCRPC), combining the immune checkpoint inhibitor pembrolizumab with radiation therapy resulted in a significant tumor response, suggesting a potential new treatment strategy.

The findings support the idea that combining immune checkpoint inhibitors with pro-immune agents like radiation may enhance treatment efficacy in mCRPC, warranting further investigation into this approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dramatic response to combination pembrolizumab and radiation in metastatic castration resistant prostate cancer. Han, HJ., Li, YR., Roach, M., et al.[2020]

Immunotherapy drugs have been recently approved for treating genitourinary cancers like bladder, renal, and prostate cancer, showing promise in enhancing treatment outcomes.

Combining immunotherapy with radiation therapy may improve tumor cell killing both at the targeted site and potentially at distant sites, known as the abscopal effect, making this combination a focus of ongoing clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunotherapy Combined With Radiation Therapy for Genitourinary Malignancies. Ukleja, J., Kusaka, E., Miyamoto, DT.[2021]

A meta-analysis of 12 clinical trials involving patients with metastatic castration-resistant prostate cancer showed that immune checkpoint inhibitors have a 10% objective response rate and a 55% one-year overall survival rate, indicating potential efficacy in this patient population.

The treatment was well tolerated, with all-grade adverse events occurring in 82% of patients and severe adverse events (grade ≥ 3) in 42%, suggesting that while side effects are common, they are manageable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and safety of immune checkpoint inhibitors in metastatic castration-resistant prostate cancer: A systematic review and meta-analysis. Wang, XH., Wang, ZQ., Mu, ZY., et al.[2023]

A case study of a patient with castration-resistant prostate cancer showed that combining ablative stereotactic body radiation therapy with ongoing enzalutamide treatment resulted in a durable complete remission, despite prior progression on the medication.

This finding highlights the potential for innovative treatment strategies in advanced prostate cancer and suggests the need for further clinical trials to explore this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stereotactic body radiation therapy for the treatment of oligoprogression on androgen receptor targeted therapy in castration-resistant prostate cancer. Nguyen, TC., Bajwa, R., Bari, S., et al.[2020]

Sunitinib, a multi-tyrosine kinase inhibitor, effectively radiosensitized human prostate cancer cells (DU145 and PC3) in vitro, reducing their survival after radiation treatment, but did not enhance tumor growth delay when given concurrently with radiation in vivo.

The enhanced tumor growth delay observed when sunitinib was administered after radiation suggests it may target the tumor stroma, helping to prevent regrowth of irradiated tumors, indicating a potential new strategy for prostate cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical evaluation of sunitinib, a multi-tyrosine kinase inhibitor, as a radiosensitizer for human prostate cancer. Brooks, C., Sheu, T., Bridges, K., et al.[2023]

Stereotactic body radiotherapy (SBRT) is effective for treating localized and metastatic prostate cancer, as prostate cancer shows increased sensitivity to higher radiation doses due to its low α/β ratio.

There is potential for combining SBRT with systemic therapies like androgen deprivation therapy (ADT) and immunotherapy, as SBRT may enhance immune responses, making it a promising area for ongoing research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Translating the Immunobiology of SBRT to Novel Therapeutic Combinations for Advanced Prostate Cancer. Adorno Febles, VR., Blacksburg, S., Haas, JA., et al.[2020]

In a study involving 31 men with metastatic castration-resistant prostate cancer (mCRPC), the combination of the PD-L1 inhibitor avelumab and stereotactic ablative body radiotherapy (SABR) resulted in a disease control rate of 48%, indicating that nearly half of the patients experienced cancer control for at least 6 months.

The treatment was found to be safe, with only 16% of patients experiencing severe treatment-related adverse events, suggesting that this combination therapy could be a promising option for patients who have not responded to previous treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avelumab Combined with Stereotactic Ablative Body Radiotherapy in Metastatic Castration-resistant Prostate Cancer: The Phase 2 ICE-PAC Clinical Trial. Kwan, EM., Spain, L., Anton, A., et al.[2022]

References

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

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

2. France pubmed.ncbi.nlm.nih.gov

[New drugs in metastatic castration-resistant prostate cancer]. [2018]

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

Pharmacodynamic and pharmacokinetic neoadjuvant study of hedgehog pathway inhibitor Sonidegib (LDE-225) in men with high-risk localized prostate cancer undergoing prostatectomy. [2022]

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

Sunitinib plus androgen deprivation and radiation therapy for patients with localized high-risk prostate cancer: results from a multi-institutional phase 1 study. [2021]

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

Stereotactic Body Radiotherapy for High-Risk Localized Carcinoma of the Prostate (SHARP) Consortium: Analysis of 344 Prospectively Treated Patients. [2022]

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

Sequencing CTLA-4 blockade with cell-based immunotherapy for prostate cancer. [2021]

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

Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Dramatic response to combination pembrolizumab and radiation in metastatic castration resistant prostate cancer. [2020]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Immunotherapy Combined With Radiation Therapy for Genitourinary Malignancies. [2021]

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

The efficacy and safety of immune checkpoint inhibitors in metastatic castration-resistant prostate cancer: A systematic review and meta-analysis. [2023]

11. England pubmed.ncbi.nlm.nih.gov

Stereotactic body radiation therapy for the treatment of oligoprogression on androgen receptor targeted therapy in castration-resistant prostate cancer. [2020]

12. England pubmed.ncbi.nlm.nih.gov

Preclinical evaluation of sunitinib, a multi-tyrosine kinase inhibitor, as a radiosensitizer for human prostate cancer. [2023]

13. Switzerland pubmed.ncbi.nlm.nih.gov

Translating the Immunobiology of SBRT to Novel Therapeutic Combinations for Advanced Prostate Cancer. [2020]

14. Switzerland pubmed.ncbi.nlm.nih.gov

Avelumab Combined with Stereotactic Ablative Body Radiotherapy in Metastatic Castration-resistant Prostate Cancer: The Phase 2 ICE-PAC Clinical Trial. [2022]