Phase I/II Dose-escalation Study of Fractionated and Multiple Dose 225Ac-J591 for Progressive Metastatic Castration Resistant Prostate Cancer
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 60
- 试验地点
- 2
- 主要终点
- Number of Participants With Dose Limiting Toxicity (DLT)
研究概览
简要总结
The purpose of the initial (phase I) portion of this study is to find a dose level and administration schedule of the study drug, 225Ac-J591, that can be given without severe side effects. The purpose of the second (phase II) portion of the study is to determine the proportion of those with PSMA-positive tumors with >50% PSA decline following 225Ac-J591 treatment in two regimens.
详细描述
This clinical trial is for men with progressive metastatic castration resistant prostate cancer. The purpose of this study is to find the highest dose level of the study drug, 225Ac-J591, that can be given without severe side effects. The research study is being done because the standard treatments for prostate cancer that has spread beyond the prostate gland are intended to minimize the adverse effects of the disease. These treatments, however, are not curative.
Patients who choose to participate in this study will have a screening visit to determine whether or not they are eligible to participate in the study. There are two different regimens for men with progressive mCRPC with and without prior 177Lu-PSMA-RL treatment.
The fractionated dose regimen is a single cycle of study drug administered on Day 1 and Day 15. The dose-limiting toxicity assessment period is 8 weeks for the fractionated dose regimen (starting from Cycle 1 Day 1).
The multiple dose regimen is a single dose of 225Ac-J591 per cycle, with each cycle administered every 6 weeks up to 4 cycles. The dose-limiting toxicity assessment period is up to 9 weeks past the 2nd dose of 225Ac-J591. Following treatment, short-term follow up is planned until radiographic progression, expected to be 6 months.
The study medication is called 225Ac-J591, and is administered as a single fractionated cycle day 1 and day 15 in the fractionated dose regimen and as a single dose per cycle repeated every 6 weeks in the multiple dose regimen. Upon completion of investigational treatment with 225Ac-J591, participants will undergo 68Ga-PSMA-HBED-CC injection and same day PET/CT to document treatment response. 68Ga-PSMA-HBED-CC is comprised of gallium-68, which is a positron-emitting radionuclide linked to PSMA-HBED-CC (aka PSMA11), which is a small molecule targeting PSMA. 68Ga-PSMA-HBED-CC will be administered intravenously prior to PET/CT at screening and at follow up imaging x2. Subsequent survival data and additional treatment(s) information will be captured from their routine standard of care (SOC) visits. During the other study visits, participants will undergo routine tests and procedures, such as physical examinations, and blood tests. Some blood tests will be done for research purposes only. After completion of therapy, participants may be contacted on a periodic basis to see how they are doing.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 99 Years（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Histologically or cytologically confirmed adenocarcinoma of prostate
- •Documented progressive metastatic CRPC based on Prostate Cancer Working
- •Group 3 (PCWG3) criteria, which includes at least one of the following criteria:
- •PSA progression
- •Objective radiographic progression in soft tissue
- •New bone lesions
- •Have serum testosterone < 50 ng/dL. Subjects must continue primary androgen deprivation with an LHRH/GnRH analogue (agonist/antagonist) if they have not undergone orchiectomy
- •Have previously been treated with at least one of the following in any disease state:
- •Androgen receptor signaling inhibitor (such as enzalutamide)
- •CYP 17 inhibitor (such as abiraterone acetate)
- •Have previously received taxane chemotherapy (in any disease state), been determined to be ineligible for taxane chemotherapy by their physician, or refused taxane chemotherapy.
- •Age > 18 years
- •Patients must have normal organ and marrow function as defined below:
- •Absolute neutrophil count >2,000 cells/mm3
- •Hemoglobin ≥9 g/dL
- •Platelet count >150,000 x 109/uL
- •Serum creatinine <1.5 x upper limit of normal (ULN) or calculated creatinine clearance ≥ 60 mL/min/1.73 m2 by Cockcroft-Gault
- •Serum total bilirubin <1.5 x ULN (unless due to Gilbert's Syndrome in which case direct bilirubin must be normal)
- •Serum AST and ALT <3 x ULN in absence of liver metastases; < 5x ULN if due to liver metastases (in both circumstances bilirubin must meet entry criteria)
- •ECOG performance status of 0-2
- •Ability to understand and the willingness to sign a written informed consent document
- •For patients enrolled in the post-177Lu-PSMA-RL cohorts, must have previously received either 177Lu-PSMA-617 or 177Lu-PSMA-I&T
排除标准
- •Implantation of investigational medical device ≤4 weeks of Treatment Visit 1 (Day 1) or current enrollment in oncologic investigational drug or device study
- •Use of investigational drugs ≤4 weeks or <5 half-lives of Cycle 1, Day 1 or current enrollment in investigational oncology drug or device study
- •Prior systemic beta-emitting bone-seeking radioisotopes (e.g. samarium-153, strontium-89)
- •For patients enrolled in the post-177Lu-PSMA-RL cohorts: prior radium-223
- •Untreated hydronephrosis
- •Known active brain metastases or leptomeningeal disease
- •History of deep vein thrombosis and/or pulmonary embolus within 1 month of C1D1
- •Other serious illness(es) involving the cardiac, respiratory, CNS, renal, hepatic or hematological organ systems which might preclude completion of this study or interfere with determination of causality of any adverse effects experienced in this study
- •Radiation therapy for treatment of PC ≤4 weeks of Day 1 Cycle 1
- •Chemotherapy for treatment of PC ≤4 weeks of Day 1 Cycle 1
- •Patients on stable dose of bisphosphonates or denosumab, which have been started no less than 4 weeks prior to treatment start, may continue on this medication, however patients are not allowed to initiate bisphosphonate/Denosumab therapy during the DLT-assessment period of the study
- •Having partners of childbearing potential and not willing to use a method of birth control deemed acceptable by the principle investigator and chairperson during the study and for 1 month after last study drug administration
- •Currently active other malignancy other than non-melanoma skin cancer. Patients are considered not to have "currently active" malignancy if they have completed any necessary therapy and are considered by their physician to be at less than 30% risk of relapse
- •Known history of myelodysplastic syndrome
- •Bone scan with confluent lesions and lack of urinary tracer consistent with a "superscan" as determined by the investigator
研究组 & 干预措施
Multiple Dose 45 KBq/kg
Participants in this multiple dose cohort received 45 KBq/Kg of 225Ac-J591 every 6 weeks, up to 4 cycles.
干预措施: 68Ga-PSMA-HBED-CC injection (Diagnostic Test)
Multiple Dose 45 KBq/kg
Participants in this multiple dose cohort received 45 KBq/Kg of 225Ac-J591 every 6 weeks, up to 4 cycles.
干预措施: Multiple Dose of 225Ac-J591 at 45 KBq/kg (Drug)
Multiple Dose 55 KBq/kg
Participants in this multiple dose cohort received 55 KBq/Kg of 225Ac-J591 every 6 weeks, up to 4 cycles.
干预措施: Multiple Dose of 225Ac-J591 at 55 KBq/kg (Drug)
Multiple Dose 65 KBq/kg
Participants in this multiple dose cohort received 65 KBq/Kg of 225Ac-J591 every 6 weeks, up to 4 cycles.
干预措施: Multiple Dose of 225Ac-J591 at 65 KBq/kg (Drug)
Fractionated Dose 45 KBq/kg
Participants in this cohort received a single cycle of 45 KBq/kg of 225Ac-J591, administered as a fractionated dose on days 1 and 15.
干预措施: Fractionated Dose of 225Ac-J591 at 45 KBq/kg (Drug)
Fractionated Dose 55 KBq/kg
Participants in this cohort received a single cycle of 55 KBq/kg of 225Ac-J591, administered as a fractionated dose on days 1 and 15.
干预措施: Fractionated Dose of 225Ac-J591 at 55 KBq/kg (Drug)
Fractionated Dose 60 KBq/kg
Participants in this cohort receive a single cycle of 60 KBq/kg of 225Ac-J591, administered as a fractionated dose on days 1 and 15.
This was also the dose level for the expansion cohort of fractionated dose regimen.
干预措施: Fractionated Dose of 225Ac-J591 at 60 KBq/kg (Drug)
Fractionated Dose 65 KBq/kg
Participant in this cohort receive a single cycle of 65 KBq/kg of 225Ac-J591, administered as a fractionated dose on days 1 and 15.
干预措施: Fractionated Dose of 225Ac-J591 at 65 KBq/kg (Drug)
Fractionated Dose (prior 177Lu-PSMA-RL) 45 KBq/kg
Participants in this cohort, who were previously treated with 177Lu-PSMA-RL, received a single cycle of 45 KBq/kg of 225Ac-J591, administered as a fractionated dose on days 1 and 15.
干预措施: Fractionated Dose of 225Ac-J591 at 45 KBq/kg (Prior 177Lu-PSMA-RL) (Drug)
Fractionated Dose (prior 177Lu-PSMA-RL) 50 KBq/kg
Participants in this cohort, who were previously treated with 177Lu-PSMA-RL, received a single cycle of 50 KBq/kg of 225Ac-J591, administered as a fractionated dose on days 1 and 15.
干预措施: Fractionated Dose of 225Ac-J591 at 50 KBq/kg (Prior 177Lu-PSMA-RL) (Drug)
Fractionated Dose (prior 177Lu-PSMA-RL) 50 KBq/kg
Participants in this cohort, who were previously treated with 177Lu-PSMA-RL, received a single cycle of 50 KBq/kg of 225Ac-J591, administered as a fractionated dose on days 1 and 15.
干预措施: 68Ga-PSMA-HBED-CC injection (Diagnostic Test)
Multiple Dose 55 KBq/kg
Participants in this multiple dose cohort received 55 KBq/Kg of 225Ac-J591 every 6 weeks, up to 4 cycles.
干预措施: 68Ga-PSMA-HBED-CC injection (Diagnostic Test)
Multiple Dose 65 KBq/kg
Participants in this multiple dose cohort received 65 KBq/Kg of 225Ac-J591 every 6 weeks, up to 4 cycles.
干预措施: 68Ga-PSMA-HBED-CC injection (Diagnostic Test)
Fractionated Dose 45 KBq/kg
Participants in this cohort received a single cycle of 45 KBq/kg of 225Ac-J591, administered as a fractionated dose on days 1 and 15.
干预措施: 68Ga-PSMA-HBED-CC injection (Diagnostic Test)
Fractionated Dose 55 KBq/kg
Participants in this cohort received a single cycle of 55 KBq/kg of 225Ac-J591, administered as a fractionated dose on days 1 and 15.
干预措施: 68Ga-PSMA-HBED-CC injection (Diagnostic Test)
Fractionated Dose 60 KBq/kg
Participants in this cohort receive a single cycle of 60 KBq/kg of 225Ac-J591, administered as a fractionated dose on days 1 and 15.
This was also the dose level for the expansion cohort of fractionated dose regimen.
干预措施: 68Ga-PSMA-HBED-CC injection (Diagnostic Test)
Fractionated Dose 65 KBq/kg
Participant in this cohort receive a single cycle of 65 KBq/kg of 225Ac-J591, administered as a fractionated dose on days 1 and 15.
干预措施: 68Ga-PSMA-HBED-CC injection (Diagnostic Test)
Fractionated Dose (prior 177Lu-PSMA-RL) 45 KBq/kg
Participants in this cohort, who were previously treated with 177Lu-PSMA-RL, received a single cycle of 45 KBq/kg of 225Ac-J591, administered as a fractionated dose on days 1 and 15.
干预措施: 68Ga-PSMA-HBED-CC injection (Diagnostic Test)
结局指标
主要结局
Number of Participants With Dose Limiting Toxicity (DLT)
时间窗: Collected from Day 1 through 6 months
DLTs will be measured by utilizing the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Maximum Tolerated Dose (MTD)
时间窗: Collected from Day 1 through 6 months
The dose that produces an "acceptable" level of toxicity or that, if exceeded, would put subjects at "unacceptable" risk for toxicity. MTD is defined as the dose level at which no more than two patients out of six experienced dose-limiting toxicity (DLT).
Recommended Phase II Dose (RP2D) of 225Ac-J591 in Fractionated Dose and Multiple Dose Regimens Both Pre- and Post-treatment With 177Lu-PSMA-RL
时间窗: Collected from Day 1 through 6 months
Number of Participants With PSMA-positive Tumors With >50% PSA Decline Following 225Ac-J591 in Each Cohort Regimen
时间窗: Collected from Day 1 through 6 months
Number of participants achieving greater than 50% PSA decline (relative to baseline/pre-treatment PSA). Response may occur at any time following treatment initiation and prior to going off study or initiation of new therapy
Number of participants with dose limiting toxicity (DLT)
时间窗: Collected from Day 1 through 6 months
DLTs will be measured by utilizing the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Cumulative maximum tolerated dose (MTD)
时间窗: Collected from Day 1 through 6 months
The dose that produces an "acceptable" level of toxicity or that, if exceeded, would put subjects at "unacceptable" risk for toxicity. MTD is defined as the dose level at which no more than two patients out of six experienced dose-limiting toxicity (DLT).
Recommended phase II dose (RP2D) of 225Ac-J591 in fractionated dose and multiple dose regimens both pre- and post-treatment with 177Lu-PSMA-RL
时间窗: Collected from Day 1 through 6 months
Proportion of participants with PSMA-positive tumors with >50% PSA decline following 225Ac-J591 in two regimens both pre- and post- treatment with 177Lu-PSMA-RL
时间窗: Collected from Day 1 through 6 months
Proportion of participants achieving greater than 50% PSA decline (relative to baseline/pre-treatment PSA). Response may occur at any time following treatment initiation and prior to going off study or initiation of new therapy.
次要结局
- Number of Participants With Radiographic Response(Imaging performed at timepoints from Day 1 through study completion, approximately 3 years.)
- Overall Survival Following 225Ac-J591 Treatment(Collected from Day 1 through study completion, approximately 3 years.)
- Change in Disease Assessment With 68Ga-PSMA-11 PET/CT Prior to and Following Investigational Treatment(Scans performed during screening period (within 30 days of Cycle 1 Day 1) and at Day 85 from Cycle 1 Day 1.)
- Number of Participants With Change in Circulating Tumor Cells (CTC) Count at 12 Weeks Following 225Ac-J591(Samples will be collected at Screening and Day 85)
- Number of Participants With Adverse Events(Collected from Day 1 through study completion, approximately 3 years)
- Assess Biochemical Progression-free Survival(Collected from Day 1 through study completion, approximately 3 years)
- Assess the Proportion With Different Levels of PSA Decline Following 225Ac-J591(Collected from Day 1 through study completion, approximately 3 years)
- Change in disease assessment with 68Ga-PSMA-11 PET/CT prior to and following investigational treatment(Scans will be performed at screening, day 85 and day 168)
- Change in circulating tumor cells (CTC) and the rate of favorable and undetectable CTC count at 12 weeks following 225Ac-J591(Samples will be collected at screening, day 1, day 85 and at disease progression)
- Safety of treatment and adverse event rate(Will be collected from Day 1 through study completion up to 3 years)
- Assess biochemical progression-free survival(Will be collected from Day 1 through study completion up to 3 years)
- Assess the proportion with different levels of PSA decline following 225Ac-J591(Will be collected from Day 1 through study completion up to 3 years)
- Number of participants with radiographic response(Imaging performed at timepoints from Day 1 through study completion up to 3 years)
- Overall survival following 225Ac-J591 treatment(Collected from Day 1 through study completion up to 3 years)