Targeted Drugs + Radiation Therapy for Prostate Cancer
(SBRT-AMICO Trial)
Recruiting in Palo Alto (17 mi)
Overseen byCatherine S. Spina, MD, PhD
Age: 18+
Sex: Male
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Catherine Spina
Must not be taking: Antibiotics, Immunosuppressants, CYP3A4 inducers
Disqualifiers: Brain metastases, Severe infection, Autoimmune, others
No Placebo Group
Prior Safety Data
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.
12345Is 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.
678910What 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.
111121314Eligibility 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
+26 more
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.
+25 more
Trial 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
Participant Groups
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.
1Treatment groups
Experimental Treatment
Group I: Treatment with quemliclustatm, etrumadenant, zimberelimab and SBRTExperimental Treatment4 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.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Columbia University Irving Medical Center / NewYork-Presbyterian HospitalNew York, NY
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Who Is Running the Clinical Trial?
Catherine SpinaLead Sponsor
Arcus Biosciences, Inc.Industry Sponsor
References
Recent Advances in Prostate Cancer Treatment and Drug Discovery. [2022]Novel drugs, drug sequences and combinations have improved the outcome of prostate cancer in recent years. The latest approvals include abiraterone acetate, enzalutamide and apalutamide which target androgen receptor (AR) signaling, radium-223 dichloride for reduction of bone metastases, sipuleucel-T immunotherapy and taxane-based chemotherapy. Adding abiraterone acetate to androgen deprivation therapy (ADT) in order to achieve complete androgen blockade has proven highly beneficial for treatment of locally advanced prostate cancer and metastatic hormone-sensitive prostate cancer (mHSPC). Also, ADT together with docetaxel treatment showed significant benefit in mHSPC. Ongoing clinical trials for different subgroups of prostate cancer patients include the evaluation of the second-generation AR antagonists enzalutamide, apalutamide and darolutamide, of inhibitors of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway, of inhibitors of DNA damage response, of targeted alpha therapy and of prostate-specific membrane antigen (PSMA) targeting approaches. Advanced clinical studies with immune checkpoint inhibitors have shown limited benefits in prostate cancer and more trials are needed to demonstrate efficacy. The identification of improved, personalized treatments will be much supported by the major progress recently made in the molecular characterization of early- and late-stage prostate cancer using “omics” technologies. This has already led to novel classifications of prostate tumors based on gene expression profiles and mutation status, and should greatly help in the choice of novel targeted therapies best tailored to the needs of patients.
[New drugs in metastatic castration-resistant prostate cancer]. [2018]Despite that greater knowledge of prostate cancer biology has led to the isolation of many new and promising targets, treatment of metastatic prostate cancer is still challenging. New agents targeting these molecules are currently under development in large randomized phase III trials, to improve overall survival and the quality of life of patients with metastatic castrate-resistant prostatic cancer (CRPC). Cytotoxic chemotherapy (docetaxel-based chemotherapy) demonstrated clinical benefit on overall survival, but could be improved. Drugs targeting directly or not the androgen receptor such as abiraterone or new specific peripheral anti-androgens (MDV3100) are very promising. Bone targeted therapies (endothelin1 receptor A inhibitor, RANK ligant, metabolic irradiation) are also very promising and are in development in large phase III trials. Antiangiogenic therapies could also be effective in CRPC. Autologous vaccin against prostatic acid phosphatase seems to prolong overall survival and other vaccin and immunotherapy strategies are in development (anti-CTLA4 antibody). A recent analogue of thalidomide, probably more efficient, lenalidomide is also in development.
Pharmacodynamic and pharmacokinetic neoadjuvant study of hedgehog pathway inhibitor Sonidegib (LDE-225) in men with high-risk localized prostate cancer undergoing prostatectomy. [2022]To determine the pharmacodynamic effects of Sonidegib (LDE-225) in prostate tumor tissue from men with high-risk localized prostate cancer, by comparing pre-surgical core-biopsy specimens to tumor tissue harvested post-treatment at prostatectomy.
Sunitinib plus androgen deprivation and radiation therapy for patients with localized high-risk prostate cancer: results from a multi-institutional phase 1 study. [2021]To evaluate the feasibility of administering sunitinib in combination with androgen deprivation therapy and external-beam intensity modulated radiation therapy (XRT) in patients with localized high-risk prostate cancer.
Stereotactic Body Radiotherapy for High-Risk Localized Carcinoma of the Prostate (SHARP) Consortium: Analysis of 344 Prospectively Treated Patients. [2022]To explore the efficacy and toxicity of stereotactic body radiation therapy (SBRT) in high-risk prostate cancer (HRPCa) in a consortium of 7 institutional phase 2 trials and prospective registries.
Sequencing CTLA-4 blockade with cell-based immunotherapy for prostate cancer. [2021]The FDA recently approved an anti-CTLA-4 antibody (Iplimumab) for the treatment of metastatic melanoma. This decision was based on Phase III results, which demonstrate that blocking this immune checkpoint provides a survival advantage in patients with advanced disease. As a single agent, ipilimumab is also being clinically evaluated in advanced (metastatic, castrate-resistant) prostate cancer and two randomized, placebo-controlled Phase III studies have recently completed accrual.
Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer. [2022]While programmed cell death 1 (PD-1) inhibitors have shown clear anti-tumor efficacy in several solid tumors, prior results in men with metastatic castration resistant prostate cancer (mCRPC) showed no evidence of activity. Here we report unexpected antitumor activity seen in mCRPC patients treated with the anti-PD-1 antibody pembrolizumab. Patients with evidence of progression on enzalutamide were treated with pembrolizumab 200 mg IV every 3 weeks for 4 doses; pembrolizumab was added to standard dose enzalutamide. Three of the first ten patients enrolled in this ongoing phase II trial experienced rapid prostate specific antigen (PSA) reductions to ≤ 0.2 ng/ml. Two of these three patients had measurable disease upon study entry; both achieved a partial response. There were three patients with significant immune-related adverse events. One had grade 2 myositis, one had grade 3 hypothyroidism, and one had grade 2 hypothyroidism. None of these patients had a response. Two of the three responders had a baseline tumor biopsy. Immunohistochemistry from those biopsies showed the presence of CD3+, CD8+, and CD163+ leukocyte infiltrates and PD-L1 expression. Genetic analysis of the two responders revealed markers of microsatellite instability in one. The surprising and robust responses seen in this study should lead to re-examination of PD-1 inhibition in prostate cancer.
Dramatic response to combination pembrolizumab and radiation in metastatic castration resistant prostate cancer. [2020]Immune checkpoint inhibitors targeting PD-1 and PD-L1 have demonstrated anti-tumor activity in several advanced solid malignancies. In previously treated metastatic castration resistant prostate cancer (mCRPC), a small subset of patients have a therapeutic response to checkpoint inhibition. Those who do respond to anti-PD-1/PD-L1 therapy have a marked, durable response to treatment, suggesting some derive long-term benefit from immune checkpoint blockade. In other cancers, one strategy to increase the efficacy of immune checkpoint blockade is to combine it with a pro-immune stimulatory agent, such as radiation. Here we present a case of a patient with heavily treated mCRPC who had a significant tumor response to concurrent pembrolizumab and radiation therapy to the primary prostatic mass. We review the growing evidence supporting the use of this combination therapy in other cancers and its potential benefit and safety in mCRPC. Our report highlights a potential therapeutic approach that should be further investigated in previously treated mCRPC.
Immunotherapy Combined With Radiation Therapy for Genitourinary Malignancies. [2021]Immunotherapy drugs have recently been approved by the Food and Drug Administration for the treatment of several genitourinary malignancies, including bladder cancer, renal cancer, and prostate cancer. Preclinical data and early clinical trial results suggest that immune checkpoint inhibitors can act synergistically with radiation therapy to enhance tumor cell killing at local irradiated sites and in some cases at distant sites through an abscopal effect. Because radiation therapy is commonly used in the treatment of genitourinary malignancies, there is great interest in testing the combination of immunotherapy with radiation therapy in these cancers to further improve treatment efficacy. In this review, we discuss the current evidence and biological rationale for combining immunotherapy with radiation therapy, as well as emerging data from ongoing and planned clinical trials testing the efficacy and tolerability of this combination in the treatment of genitourinary malignancies. We also outline outstanding questions regarding sequencing, dose fractionation, and biomarkers that remain to be addressed for the optimal delivery of this promising treatment approach.
The efficacy and safety of immune checkpoint inhibitors in metastatic castration-resistant prostate cancer: A systematic review and meta-analysis. [2023]We aim to assess the efficacy and safety profiles of immune checkpoint inhibitors in patients with metastatic castration-resistant prostate cancer using a meta-analysis.
Stereotactic body radiation therapy for the treatment of oligoprogression on androgen receptor targeted therapy in castration-resistant prostate cancer. [2020]Castration-resistant prostate cancer is an incurable disease. To date, six agents-abiraterone, enzalutamide, docetaxel, cabazitaxel, radium-223 and sipuleucel-T- have shown clinical efficacy in phase III clinical trials, leading to their FDA approval. Patients are typically sequenced through most or all of these agents, and then eventually succumb to their disease. Development of new treatments remains an unmet need. We report a case of a patient who progressed on enzalutamide with a single enlarging metastatic lesion, was treated with ablative stereotactic body radiation therapy while maintaining the same systemic treatment, who then had durable complete remission. Our findings have important clinical implications and suggest novel clinical trials for this difficult to treat disease.
Preclinical evaluation of sunitinib, a multi-tyrosine kinase inhibitor, as a radiosensitizer for human prostate cancer. [2023]Many prostate cancers demonstrate an increased expression of growth factor receptors such as vascular endothelial growth factor receptor (VEGFR) and platelet derived growth factor receptor (PDGFR) which have been correlated with increased resistance to radiotherapy and poor prognosis in other tumors. Therefore, response to radiation could potentially be improved by using inhibitors of these abnormally activated pathways. We have investigated the radiosensitizing effects of sunitinib, a potent, multi-tyrosine kinase inhibitor of the VEGFR and PDGFR receptors, on human prostate cancer cells.
Translating the Immunobiology of SBRT to Novel Therapeutic Combinations for Advanced Prostate Cancer. [2020]Stereotactic body radiotherapy (SBRT) is an increasingly used radiation modality for the treatment of both localized and metastatic prostate cancer. Substantial data suggests that prostate cancer may be more sensitive to higher doses of radiation per fraction due to its low α/β ratio. This increased sensitivity raises important questions as to how SBRT should be combined with systemic therapy for clinically significant prostate cancer, including whether androgen deprivation therapy retains its beneficial effects when combined with SBRT. Furthermore, pre-clinical and clinical data suggest pronounced immunomodulatory effects of SBRT, including observed improvements in T cell priming and trafficking. These data support investigational strategies combining SBRT with immunotherapy. Here we aim to review the data for the use of SBRT in both the local and metastatic disease settings as well as ongoing translational and clinical research examining combinations with ADT, immunotherapy and other targeted agents.
Avelumab Combined with Stereotactic Ablative Body Radiotherapy in Metastatic Castration-resistant Prostate Cancer: The Phase 2 ICE-PAC Clinical Trial. [2022]Immune checkpoint inhibitor monotherapy in metastatic castration-resistant prostate cancer (mCRPC) has produced modest results. High-dose radiotherapy may be synergistic with checkpoint inhibitors.