A Phase 2 Study of Pembrolizumab Plus 177Lu-PSMA-617 in Patients With Metastatic Castration Resistant Prostate Cancer
概览
- 阶段
- 2 期
- 干预措施
- Pembrolizumab
- 疾病 / 适应症
- Castrate Resistant Prostate Cancer
- 发起方
- University of California, San Francisco
- 入组人数
- 48
- 试验地点
- 1
- 主要终点
- Median radiographic progression-free survival (rPFS) at 12 months
- 状态
- 招募中
- 最后更新
- 15天前
概览
简要总结
This is a single-center, open-label, study of Prostate-Specific Membrane Antigen (PSMA)-targeted radionuclide therapy with 177Lu-PSMA-617 in combination with pembrolizumab in participants with metastatic castrate-resistant prostate cancer (mCRPC) who have previously progressed on at least one prior androgen pathway inhibitor (e.g., abiraterone, enzalutamide, apalutamide).
详细描述
PRIMARY OBJECTIVE: I. To determine the 12-month radiographic progression-free survival rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria in patients with mCRPC treated with pembrolizumab and 177Lu-PSMA-617. SECONDARY OBJECTIVES: I. To determine the median radiographic progression-free survival per RECIST v. 1.1 and PCWG3 criteria in patients with mCRPC treated with pembrolizumab and 177Lu-PSMA-617. II. To determine the objective response rate per RECIST v. 1.1 and PCWG3 criteria in patients with mCRPC treated with pembrolizumab and 177Lu-PSMA-617. III. To determine the median duration of objective response per RECIST v. 1.1 and PCWG3 criteria in patients with mCRPC treated with pembrolizumab and 177Lu-PSMA-617. IV. To determine the greater than 50% decline from baseline PSA (PSA50) and greater than 90% decline from baseline PSA (PSA90) response rate by PCWG3 criteria at any time point on study, as well as individually following each dose of 177Lu-PSMA-617. V. To determine the median time to PSA progression (TTPP) following each dose of 177Lu-PSMA-617 (e.g., TTPP-1, TTPP-2, etc.), as measured by PCWG3 criteria. VI. To determine the median overall survival in patients with mCRPC treated with pembrolizumab and 177Lu-PSMA-617. VII. To characterize the safety profile of the combination of pembrolizumab and 177Lu-PSMA-617 in patients with mCRPC. EXPLORATORY OBJECTIVES: I. To determine the lesion-specific response by baseline uptake on PSMA PET. II. To determine the patterns of PSMA expression at the time of each TTPP event and at radiographic progression. III. To further characterize the tumor microenvironment using Single-cell RNA sequencing (scRNA-seq) of paired metastatic tumor biopsies (a biopsy is required if there is an accessible lesion). IV. To develop a biomarker predictive of durable response based on Cytometry by time of flight (CyTOF) profiling of whole blood samples collected at baseline and early time points on treatment. V. To determine whether successive doses of 177Lu-PSMA-617 leads to ablation of effector T cells and up- regulation of myeloid cell states in the periphery and tumor microenvironment. VI. To characterize participant reported outcomes using the Brief Pain Inventory and The Functional Assessment of Cancer Therapy - Prostate (FACT-P) instruments. VII. To correlate the number of 177Lu-PSMA-617 re-priming doses and PSA progression events with radiographic rPFS. VIII. To evaluate and compare the efficacy of 177Lu-PSMA-617 between the subgroup of participants who received a single dose of 177Lu-PSMA-617 followed by adaptive dosing, and the subgroup of participants who received two doses of 177Lu-PSMA-617 followed by adaptive dosing. IX. To evaluate and compare efficacy between the subgroup of participants who received Schedule 1 versus Schedule 2 dosing. X. To evaluate and compare efficacy between the subgroup of participants who have received prior taxane chemotherapy versus participants who were taxane-naïve at the time of study entry. OUTLINE: Participants will receive two doses of 177Lu-PSMA-617 and may continue treatment for up to a total of six total doses in the absence of unequivocal clinical progression, or unacceptable toxicity, with minimum interval of 6 weeks between doses. Participants will also receive pembrolizumab and may continue study treatment until unequivocal evidence of clinical progression or at physician's discretion based on clinical evaluation. Participants will undergo safety follow-up visits approximately 30 days and 90 days following the end of treatment visit. Participants will then be seen in clinic or contacted by telephone every 3 months to assess survival/disease/anti-cancer therapy status until death, withdrawal of consent, or the end of the study, whichever occurs first until study closure.
研究者
入排标准
入选标准
- •Histologically confirmed prostate adenocarcinoma that is progressive metastatic castration-resistant prostate cancer by Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria at the time of study entry.
- •Male participants who are at least 18 years of age on the day of signing informed consent.
- •Castrate level of serum testosterone at study entry (\< 50 ng/dL). Note: Participants without prior bilateral orchiectomy are required to remain on Luteinizing hormone-releasing hormone (LHRH) analogue treatment for duration of study.
- •Prior progression on at least one second generation androgen signaling inhibitor including abiraterone, apalutamide, darolutamide, and/or enzalutamide.
- •Adverse events related to prior anti-cancer treatment (excluding LHRH analogs) must have recovered to Grade \<= 1 (except for any grade alopecia and grade \<= 2 neuropathy).
- •Prior radiotherapy is allowed if the last radiotherapy treatment was greater than 2 weeks from start of study treatment on cycle 1, day 1 (C1D1). Note- Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (\<=2 weeks of radiotherapy) to non-central nervous system (CNS) disease.
- •At least one Prostate-Specific Membrane Antigen (PSMA) Positron Emission Tomography (PET) (PSMA PET) avid lesion on screening PSMA PET. A positive lesion is defined as uptake above background liver.
- •Eastern Cooperative Oncology Group (ECOG) performance status \<= 1 (Karnofsky \>= 70%).
- •Demonstrates adequate organ function as defined below:
- •Adequate bone marrow function:
排除标准
- •De novo small cell neuroendocrine prostate cancer will not be allowed due to putative lower PSMA expression in this tumor subtype. Note-Treatment-emergent small cell neuroendocrine prostate cancer detected in metastatic tumor biopsy is not excluded.
- •Soft tissue lesions (lymph nodes \> 1.5 centimeter (cm) in short axis, visceral/soft tissue lesions \> 1 cm) on screening Computerized tomography (CT) that are negative on PSMA PET. Note: Negative lesions on PSMA PET are defined as those with uptake below the background liver.
- •Has received other systemic anti-cancer therapies administered within 14 days, or 5 half-lives, whichever is shorter, prior to initiation of study treatment. Note: LHRH analogues are the exception.
- •Untreated brain metastases at study entry.
- •Receipt of prior PSMA-directed treatment (e.g., radiotherapy, immunotherapy, or antibody-drug conjugate).
- •Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-Programmed cell death-ligand 2 (PD-L2) agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), OX 40, CD137).
- •Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment on C1D
- •Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.
- •Receipt of \> 2 lines of prior taxane-based chemotherapy.
- •Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
研究组 & 干预措施
Pembrolizumab, 177Lu-PSMA-617
Participants will receive 400 mg of Pembrolizumab every 6 weeks and an infusion of 7.4 gigabequerel (GBq) (+/- 10%) of 177Lu-PSMA-617 on Cycle 1 Day 1 (of a 28 day cycle), and 6 weeks later, then at the first subsequent rise in PSA for up to six total doses, in the absence of unequivocal clinical progression, radiographic progression, or unacceptable toxicity, with a minimum interval of 6 weeks between doses.
干预措施: Pembrolizumab
Pembrolizumab, 177Lu-PSMA-617
Participants will receive 400 mg of Pembrolizumab every 6 weeks and an infusion of 7.4 gigabequerel (GBq) (+/- 10%) of 177Lu-PSMA-617 on Cycle 1 Day 1 (of a 28 day cycle), and 6 weeks later, then at the first subsequent rise in PSA for up to six total doses, in the absence of unequivocal clinical progression, radiographic progression, or unacceptable toxicity, with a minimum interval of 6 weeks between doses.
干预措施: 177Lu-PSMA-617
结局指标
主要结局
Median radiographic progression-free survival (rPFS) at 12 months
时间窗: 12 months
rPFS is defined as the amount of time from the initiation of study therapy and the day of first documented radiographic disease progression per RECIST version 1.1 and PCWG3 criteria. The proportion of patients without radiographic progression at 12 months from initiation of trial therapy will be reported along with the 95% confidence interval.
次要结局
- Overall median radiographic rPFS(Up to 5 years)
- Median duration of objective response (DOR)(Up to 10 months)
- Proportion of participants with 50% decline in PSA (PSA50)(Up to 10 months)
- Proportion of participants with 90% decline in PSA (PSA90)(Up to 10 months)
- Median time to PSA progression (TTPP1) following the first dose of 177Lu-PSMA-617(Up to 10 months)
- Proportion of participants with PSA50 following the first dose of 177Lu-PSMA-617(Up to 10 months)
- Objective response rate (ORR)(Up to 10 months)
- Proportion of participants with PSA90 following the first dose of 177Lu-PSMA-617(Up to 10 months)
- Median time to PSA progression (TTPP2) following the second dose of 177Lu-PSMA-617(Up to 10 months)
- Proportion of participants with PSA50 following the second dose of 177Lu-PSMA-617(Up to 10 months)
- Proportion of participants with PSA90 following the second dose of 177Lu-PSMA-617(Up to 10 months)
- Median time to PSA progression (TTPP3) following the third dose of 177Lu-PSMA-617(Up to 10 months)
- Proportion of participants with PSA50 following the third dose of 177Lu-PSMA-617(Up to 10 months)
- Proportion of participants with PSA90 following the third dose of 177Lu-PSMA-617(Up to 10 months)
- Median time to PSA progression (TTPP4) following the fourth dose of 177Lu-PSMA-617(Up to 10 months)
- Proportion of participants with PSA50 following the fourth dose of 177Lu-PSMA-617(Up to 10 months)
- Proportion of participants with PSA90 following the fourth dose of 177Lu-PSMA-617(Up to 10 months)
- Median time to PSA progression (TTPP5) following the fifth dose of 177Lu-PSMA-617(Up to 10 months)
- Proportion of participants with PSA50 following the fifth dose of 177Lu-PSMA-617(Up to 10 months)
- Proportion of participants with PSA90 following the fifth dose of 177Lu-PSMA-617(Up to 10 months)
- Median time to PSA progression (TTPP6) following the sixth dose of 177Lu-PSMA-617(Up to 10 months)
- Proportion of participants with PSA50 following the sixth dose of 177Lu-PSMA-617(Up to 10 months)
- Proportion of participants with PSA90 following the sixth dose of 177Lu-PSMA-617(Up to 10 months)
- Median overall survival (OS)(Up to 5 years)
- Percentage of participants with reported treatment-emergent adverse events(Up to 10 months)