Phase Ib/II Study of Radionuclide 177Lutetium-PSMA-617 Therapy in Combination With Pembrolizumab for Treatment of Metastatic Castration Resistant Prostate Cancer (mCRPC)
Overview
- Phase
- Phase 1
- Intervention
- Pembrolizumab
- Conditions
- Metastatic Castration Resistant Prostate Cancer
- Sponsor
- Peter MacCallum Cancer Centre, Australia
- Enrollment
- 37
- Locations
- 4
- Primary Endpoint
- Prostate Specific Antigen (PSA) response
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief Summary
This investigator driven study will examine the safety, tolerability and efficacy of the combination of 177Lutetium-PSMA (177Lu-PSMA) and pembrolizumab in patients with metastatic Castration Resistant Prostate Cancer (mCRPC). 177Lu-PSMA is a compound that binds to the extra-cellular domain of the prostate-specific membrane antigen. Pembrolizumab is an antibody targeted against anti-programmed cell death 1 (PD-1).This is a single arm study where all patients will be treated with 177Lu-PSMA for upto 6 doses and pembrolizumab for upto 35 cycles.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients must meet the following criteria for study entry:
- •Patient who are at least 18 years of age who have provided written informed consent.
- •Histologically confirmed adenocarcinoma of the prostate without neuroendocrine or small cell differentiation.
- •Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1 (see Appendix 1).
- •Patients must have progressed on prior enzalutamide, abiraterone and/or apalutamide for treatment of prostate cancer.
- •Determination of disease progression on second generation androgen receptor targeted agent determined by the local investigator. Progressive disease is defined by PCWG3 as any one of the following:
- •PSA progression: minimum of two rising PSA values from a baseline measurement with an interval of ≥ 1 week between each measurement. The PSA value at screening should be ≥ 1ng/ml.
- •Soft tissue or visceral disease progression as per modified RECIST 1.1 criteria (see Appendix 2)
- •Bone progression: ≥ 2 new lesions on bone scan (Appendix 2)
- •At least 2 weeks since the completion of surgery or radiotherapy prior to registration. Any clinically relevant sequelae from the surgery or radiotherapy must have improved to grade 1 prior to registration.
Exclusion Criteria
- •Site(s) of disease that are FDG positive with low PSMA expression defined by PSMA SUVmax \<
- •Previous history or presence of brain metastases or leptomeningeal metastases.
- •Any prior exposure to anti-PD-1, anti-PD-L1/L2, anti-CTLA-4 antibody or any other antibody or drug specifically targeting T cell co-stimulation or checkpoint pathway.
- •Any prior treatment with cabazitaxel.
- •Any prior exposure to 177Lu-PSMA.
- •Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
- •Patients with active, known or suspected autoimmune disease including Sjogren's syndrome. Patients with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are eligible.
- •Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
- •Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. Participants with ≤ Grade 2 neuropathy may be eligible.
- •Patients with a condition requiring systemic treatment with either corticosteroids (\> 10mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of registration. Inhaled or topical steroids, and adrenal replacement doses ≤ 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
Arms & Interventions
177Lu-PSMA + Pembrolizumab
200mg pembrolizumab given 3 weekly for upto 35 cycles and 6-weekly 177Lu-PSMA treatments for upto 6 cycles starting at 8.5GBq with administered radioactivity reduced by 0.5GBq for each cycle.
Intervention: Pembrolizumab
177Lu-PSMA + Pembrolizumab
200mg pembrolizumab given 3 weekly for upto 35 cycles and 6-weekly 177Lu-PSMA treatments for upto 6 cycles starting at 8.5GBq with administered radioactivity reduced by 0.5GBq for each cycle.
Intervention: 177Lu-PSMA
Outcomes
Primary Outcomes
Prostate Specific Antigen (PSA) response
Time Frame: Through study completion, up until 24 months after the last patient commences treatment.
PSA response will be defined as a 50% or greater decrease in PSA from baseline to the lowest post-baseline PSA result. A second consecutive value obtained 3 or more weeks later is required to confirm the PSA response.
Incidence of Treatment-Emergent Adverse Events [Safety]
Time Frame: Through treatment completion, maximum of 24 months
Safety will be measured by serious adverse events (SAEs) and AEs assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0.
Tolerability
Time Frame: Through treatment completion, maximum of 24 months
Tolerability is defined as the time from treatment commencement until treatment discontinuation due to toxicity. Participants who ceased treatment due to reasons other than toxicity will be censored at the time of ceasing protocol treatment and participants who died while on treatment from reasons unrelated to the treatment will be censored at the date of death.
Secondary Outcomes
- Radiographic progression free survival(Through study completion, up until 24 months after the last patient commences treatment.)
- PSA-progression free survival(Through study completion, up until 24 months after the last patient commences treatment.)
- Overall survival(Through study completion, up until 24 months after the last patient commences treatment)
- Overall Response Rate by modified RECIST1.1(Through study completion, up until 24 months after the last patient commences treatment)
- Duration of objective tumour response as assessed by modified RECIST 1.1 for soft tissue and PCWG3 for bone lesions(Through study completion, up until 24 months after the last patient commences treatment)
- Time to treatment (TTR) response(Through study completion, up until 24 months after the last patient commences treatment)
- Change in pain(Through treatment completion, maximum of 24 months)
- Change in Health Related Quality of Life (HRQoL)(Through treatment completion, maximum of 24 months)