Pembrolizumab + AR Inhibitors for Prostate Cancer
Recruiting in Palo Alto (17 mi)
+3 other locations
Overseen ByScott Tagawa, MD, MS
Age: 18+
Sex: Male
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Weill Medical College of Cornell University
No Placebo Group
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?This is a phase I/II study investigating the combination of 225Ac-J591 (a drug that can deliver radiation to prostate cancer cells) with pembrolizumab (immunotherapy, a drug that increases the immune system's ability to destroy cancer cells). This study will assess whether 225Ac-J591 + pembrolizumab + androgen receptor pathway inhibitor (ARPI) is more effective against prostate cancer than pembrolizumab + ARPI alone.
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 must continue primary androgen deprivation therapy if you haven't had an orchiectomy, and you can stay on bisphosphonates or denosumab if you've been on a stable dose for at least 4 weeks before starting the trial.
What data supports the effectiveness of the treatment Pembrolizumab + AR Inhibitors for Prostate Cancer?
Research shows that PSMA-targeted therapies, like 225Ac-J591, have been effective in treating prostate cancer by targeting a specific protein highly expressed in these cancer cells. Additionally, androgen receptor inhibitors, such as darolutamide, have shown success in treating prostate cancer by blocking hormones that fuel cancer growth.
12345Is the combination of Pembrolizumab and AR inhibitors safe for prostate cancer treatment?
The safety of 225Ac-J591, a component of the treatment, was evaluated in a study for prostate cancer, showing it was generally well-tolerated with a defined maximum tolerated dose. Another study on 225Ac-L1, a similar compound, showed some off-target effects mainly in the kidneys and liver, but it was considered promising for further evaluation. These findings suggest that while there are some risks, the treatment has been generally safe in studies.
12678How is the treatment with Pembrolizumab and AR Inhibitors for prostate cancer different from other treatments?
This treatment is unique because it combines Pembrolizumab, an immune therapy, with androgen receptor inhibitors and a targeted alpha therapy using 225Ac-J591, which delivers radiation directly to prostate cancer cells. This approach targets prostate-specific membrane antigen (PSMA) on cancer cells, potentially offering a more effective treatment for patients who have developed resistance to standard therapies.
124910Eligibility Criteria
Men over 18 with advanced prostate cancer that's resistant to hormone therapy and has progressed after certain treatments. They must have a good performance status, normal organ function, and agree to contraception during the trial plus 4 months after. Exclusions include other cancers within 2 years, active infections like HIV or hepatitis, recent blood clots or radiotherapy, autoimmune diseases requiring treatment in the last 2 years, current participation in another study drug trial.Inclusion Criteria
My testosterone levels are below 50 ng/dL, and I am on hormone therapy or have had an orchiectomy.
My blood counts and kidney, liver, and clotting functions are within normal ranges.
My prostate cancer is worsening, shown by rising PSA levels, new bone lesions, or growth in scans.
I am older than 18 years.
I am fully active or can carry out light work.
I am a man over 18 with a confirmed prostate cancer diagnosis.
I agree to use contraception and not donate sperm for 4 months after my last treatment dose.
Exclusion Criteria
I have an immune system disorder or have been on high-dose steroids or other immune-weakening medicines recently.
I am currently being treated for an infection.
I have not received a live vaccine in the last 30 days.
I have been treated with specific immune therapy for cancer.
I had another cancer but was treated successfully and have been cancer-free for 2 years.
I have a history of myelodysplastic syndrome.
I have been diagnosed with HIV.
I have a history of Hepatitis B or active Hepatitis C.
I haven't had cancer treatment or experimental drugs in the last 4 weeks.
I have had or currently have lung inflammation treated with steroids.
I have an active tuberculosis infection.
I haven't had certain bone-targeted radioisotope treatments recently, but radium-223 over 12 weeks ago is okay.
I have received an organ or tissue transplant from another person.
Participant Groups
The trial is testing if adding a radioactive drug called 225Ac-J591 to pembrolizumab (an immunotherapy) and an ARPI (androgen receptor pathway inhibitor) can better fight prostate cancer than just pembrolizumab + ARPI. It's a phase I/II study which means they're looking at safety and effectiveness.
2Treatment groups
Experimental Treatment
Group I: Pembrolizumab + ARPIExperimental Treatment3 Interventions
Patients will receive pembrolizumab (400mg every 6 weeks) and ARPI (standard dose schedule) without 225Ac-J591.
Group II: Pembrolizumab + 225Ac-J591 + ARPIExperimental Treatment4 Interventions
Patients will receive one dose of 225Ac-J591 (single dose, either 65 or 90 Kbq/kg) in combination with pembrolizumab (400mg every 6 weeks) and ARPI (standard dose schedule, examples of ARPI include enzalutamide and apalutamide).
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
Columbia University Irving Cancer CenterNew York, NY
New York Presbyterian/Brooklyn Methodist HospitalBrooklyn, NY
Dana-Farber Cancer InstituteBoston, MA
New York Presbyterian/Weill Cornell Medical CenterNew York, NY
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Who is running the clinical trial?
Weill Medical College of Cornell UniversityLead Sponsor
Merck Sharp & Dohme LLCIndustry Sponsor
United States Department of DefenseCollaborator
References
Darolutamide Potentiates the Antitumor Efficacy of a PSMA-targeted Thorium-227 Conjugate by a Dual Mode of Action in Prostate Cancer Models. [2023]Androgen receptor (AR) inhibitors are well established in the treatment of castration-resistant prostate cancer and have recently shown efficacy also in castration-sensitive prostate cancer. Although most patients respond well to initial therapy, resistance eventually develops, and thus, more effective therapeutic approaches are needed. Prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancer and presents an attractive target for radionuclide therapy. Here, we evaluated the efficacy and explored the mode of action of the PSMA-targeted thorium-227 conjugate (PSMA-TTC) BAY 2315497, an antibody-based targeted alpha-therapy, in combination with the AR inhibitor darolutamide.
Prostate-Specific Membrane Antigen-Targeting Alpha Emitter via Antibody Delivery for Metastatic Castration-Resistant Prostate Cancer: A Phase I Dose-Escalation Study of 225Ac-J591. [2023]Label="PURPOSE" NlmCategory="OBJECTIVE">Novel therapies are needed to extend survival in metastatic castration-resistant prostate cancer (mCRPC). Prostate-specific membrane antigen (PSMA), a cell surface antigen overexpressed in PC, provides a validated target. This dose-escalation study investigated the safety, efficacy, maximum tolerated dose (MTD), and recommended phase II dose (RP2D) for 225Ac-J591, anti-PSMA monoclonal antibody J591 radiolabeled with the alpha emitter actinium-225.
Health-related quality of life and pain outcomes with [177Lu]Lu-PSMA-617 plus standard of care versus standard of care in patients with metastatic castration-resistant prostate cancer (VISION): a multicentre, open-label, randomised, phase 3 trial. [2023]Label="BACKGROUND">In VISION, the prostate-specific membrane antigen (PSMA)-targeted radioligand therapy lutetium-177 [177Lu]Lu-PSMA-617 (vipivotide tetraxetan) improved radiographic progression-free survival and overall survival when added to protocol-permitted standard of care in patients with metastatic castration-resistant prostate cancer. Here, we report additional health-related quality of life (HRQOL), pain, and symptomatic skeletal event results.
An Overview of Targeted Alpha Therapy with 225Actinium and 213Bismuth. [2019]Recent reports of the remarkable therapeutic efficacy of 225Ac-labeled PSMA- 617 for therapy of metastatic castration-resistant prostate cancer have underlined the clinical potential of targeted alpha therapy.
Radionuclide Treatment Yields Responses in mCRPC. [2020]In a phase II, single-arm prospective trial, a novel, targeted radionuclide called Lutetium-177 PSMA-617 extended survival and improved quality of life in men with metastatic, castration-resistant prostate cancer whose disease advanced despite standard therapy.
Efficacy and Safety of 225Ac-PSMA-617-Targeted Alpha Therapy in Metastatic Castration-Resistant Prostate Cancer: A Systematic Review and Meta-Analysis. [2022]Label="OBJECTIVE" NlmCategory="OBJECTIVE">To conduct a meta-analysis of the efficacy and safety of 225Ac-PSMA-617 in the treatment of metastatic castration-resistant prostate cancer based on existing clinical evidence.
Preclinical Evaluation of 213Bi- and 225Ac-Labeled Low-Molecular-Weight Compounds for Radiopharmaceutical Therapy of Prostate Cancer. [2022]Prostate-specific membrane antigen (PSMA)-targeted radiopharmaceutical therapy is a new option for patients with advanced prostate cancer refractory to other treatments. Previously, we synthesized a β-particle-emitting low-molecular-weight compound, 177Lu-L1 which demonstrated reduced off-target effects in a xenograft model of prostate cancer. Here, we leveraged that scaffold to synthesize α-particle-emitting analogs of L1, 213Bi-L1 and 225Ac-L1, to evaluate their safety and cell kill effect in PSMA-positive (+) xenograft models. Methods: The radiochemical synthesis, cell uptake, cell kill, and biodistribution of 213Bi-L1 and 225Ac-L1 were evaluated. The efficacy of 225Ac-L1 was determined in human PSMA+ subcutaneous and micrometastatic models. Subacute toxicity at 8 wk and chronic toxicity at 1 y after administration were evaluated for 225Ac-L1. The absorbed radiation dose of 225Ac-L1 was determined using the biodistribution data and α-camera imaging. Results:213Bi- and 225Ac-L1 demonstrated specific cell uptake and cell kill in PSMA+ cells. The biodistribution of 213Bi-L1 and 225Ac-L1 revealed specific uptake of radioactivity within PSMA+ lesions. Treatment studies of 225Ac-L1 demonstrated activity-dependent, specific inhibition of tumor growth in the PSMA+ flank tumor model. 225Ac-L1 also showed an increased survival benefit in the micrometastatic model compared with 177Lu-L1. Activity-escalated acute and chronic toxicity studies of 225Ac-L1 revealed off-target radiotoxicity, mainly in kidneys and liver. The estimated maximum tolerated activity was about 1 MBq/kg. α-Camera imaging of 225Ac-L1 revealed high renal cortical accumulation at 2 h followed by fast clearance at 24 h. Conclusion:225Ac-L1 demonstrated activity-dependent efficacy with minimal treatment-related organ radiotoxicity. 225Ac-L1 is a promising therapeutic for further clinical evaluation.
Three-year Safety of Radium-223 Dichloride in Patients with Castration-resistant Prostate Cancer and Symptomatic Bone Metastases from Phase 3 Randomized Alpharadin in Symptomatic Prostate Cancer Trial. [2022]In Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial, radium-223 versus placebo prolonged overall survival with favorable safety in castration-resistant prostate cancer patients with symptomatic bone metastases. Long-term radium-223 monitoring underlies a comprehensive safety and risk/benefit assessment.
68Ga-PSMA-11 PET Imaging of Response to Androgen Receptor Inhibition: First Human Experience. [2021]The purpose of this work was to evaluate the effect of androgen receptor (AR) inhibition on prostate-specific membrane antigen (PSMA) uptake imaged using 68Ga-PSMA-11 PET in a mouse xenograft model and in a patient with castration-sensitive prostate cancer.
Long-term survival outcomes of salvage [225Ac]Ac-PSMA-617 targeted alpha therapy in patients with PSMA-expressing end-stage metastatic castration-resistant prostate cancer: a real-world study. [2023]Label="PURPOSE">Despite the existence of various treatment options, the prognosis for patients with metastatic castration-resistant prostate cancer (mCRPC) remains unfavorable. One potential therapeutic approach is the use of [225Ac]Ac-PSMA-617, a targeted alpha therapy (TAT) that administers alpha-particle radiation specifically to prostate cancer cells expressing PSMA. In this study, we report the long-term survival outcomes of this novel therapy in a series of patients with mCRPC who have exhausted all standard treatment options.