A Phase 2, Open-label Study Evaluating Dosimetry, Randomized Dose Optimization, Dose Escalation and Efficacy of Ac-225 Rosopatamab Tetraxetan in Participants With PSMA PET-Positive Castration-Resistant Prostate Cancer
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 93
- 试验地点
- 17
- 主要终点
- Part 4: Incidence of AEs and SAEs overall, by severity, by relationship to study drug, and leading to discontinuation of study intervention
研究概览
简要总结
This is a four-part study evaluating the safety and efficacy of a PSMA-directed radioantibody (rosopatamab tetraxetan, conjugated to either In-111 or Ac-225). Part 1 will consist of one administration of In-111-rosopatamab tetraxetan to characterize the biodistribution of the radioantibody to target organs and prostate cancer lesions. Participants then will be enrolled into either Part 2 (Dose Optimization) or Part 3 (Dose Escalation and Expansion) depending on their prior treatment history. Part 4 will be an extended regimen in dose escalation and expansion. Participants qualifying for Part 2 will be randomized to receive Ac-225 rosopatamab tetraxetan in a single fractionated cycle (dose administration on Day 1 and Day 15) at either 45 or 60 kBq/Kg. Participants qualifying for Part 3 must have received prior Lu-177-PSMA-radioligand therapy and will receive Ac-225 rosopatamab tetraxetan in a single fractionated cycle at 45, 55, or 60 kBq/Kg. Dose limiting toxicities (DLTs) will be monitored in Part 3 to determine the recommended phase 2 dose (RP2D), and the study may enroll additional participants to be treated with the RP2D dose level. Participants qualifying for Part 4 will initially receive two doses (dose administration on Day 1 and Day 15) at the dose level selected in Part 2, followed by a single third dose of Ac-225 rosopatamab tetraxetan administered approximately 12 weeks after completion of the Part 2 fractionated dosing regimen. The starting dose level for Part 4 will be 22 kBq/kg (or fixed activity equivalent). Dose limiting toxicities (DLTs) will be monitored following administration of the third dose in Part 4 to determine the recommended phase 2 dose (RP2D) of a third dose of Ac-225 rosopatamab tetraxetan. Participants enrolled into any part will attend study visits which will include blood samples, electrocardiogram (ECG), radiographic imaging, and physical examinations along with other assessments.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Progressive CRPC defined as castrate levels of testosterone and progressing by at least one of the following criteria:
- •Serum PSA progression as defined by PCWG3 (rising PSA consisting of two consecutive increases measured at least 3 weeks apart, of a rise of >25%, and with an absolute rise of 2.0 ng/mL.
- •Soft tissue progression defined as a ≥20% increase in the sum of the diameter (short axis for nodal lesions and long axis for non-nodal lesions) of all target lesions based on the smallest sum of the diameter since the previous treatment was started or the appearance of one or more new lesions by CT/magnetic resonance imaging (MRI)
- •Progression of bone disease defined by PCWG3 as evaluable disease or new bone lesions by bone scan
- •Identification of new soft tissue or bone lesions on PSMA PET imaging
- •Metastatic disease defined as either or both of the following:
- •Parts 1, 2, 3, and 4: Documented M1 disease on conventional imaging (CT/MRI of the chest/abdomen/pelvis and/or Technetium 99m [99mTc] whole-body bone scan)
- •Parts 1, 2, and 4 only: Identification of bone lesion(s), extra-pelvic soft tissue lesion(s), or visceral metastases on PSMA PET imaging with an FDA-approved imaging agent
- •PSMA PET-positive disease, defined as at least one PSMA-positive metastatic lesion and no PSMA-negative lesions
- •Progression following treatment with ADT and at least one ARSI (e.g., enzalutamide, apalutamide, darolutamide, and/or abiraterone acetate)
- •The standard of care use (in the setting of metastatic CRPC with significant burden of active bone metastases) of antiresorptive bone-targeted agents (e.g., zoledronic acid, denosumab) is required for all participants without a contraindication, for at least 4 weeks prior to administration of Ac-225 rosopatamab tetraxetan.
- •Participants with HIV are eligible if they are well-controlled (i.e, an undetectable HIV viral load (<50 copies/mL) within 6 months of enrollment and a stable ART regimen for at least 6 months prior to enrollment) and at low risk for HIV-related illness
- •Part 3 Only:
- •Prior treatment with Lu-177-PSMA-radioligand therapy
- •Prior treatment with up to only one taxane-based chemotherapy regimen is allowed
排除标准
- •Superscans by nuclear medicine/99mTc bone scan
- •A known malignancy that is progressing or has required active treatment within the past 3 years other than CRPC, which is expected to alter life expectancy or may interfere with CRPC disease assessment
- •Prior platinum-based chemotherapy
- •Prior PARP inhibitors (e.g., olaparib or rucaparib)
- •Prior treatment with Radium-223, Actinium-225, Strontium-89, Samarium-153, Rheunium-186, or Rhenium-188
- •Participants receiving anti-coagulants or anti-platelet drugs (e.g., aspirin or nonsteroidal anti-inflammatory drugs [NSAIDs]) who cannot discontinue use if platelet count decreases to <50,000
- •Part 2 and 4 Only:
- •Prior chemotherapy for CRPC. Prior taxane chemotherapy for HSPC is allowed if discontinued ≥1 year prior to randomization
- •Prior radiopharmaceutical therapy (e.g., Ra-223, Lu-177-PSMA-617, or Lu-177-PSMA-I&T)
- •Prior PSMA-targeted therapy, except for bispecific or CAR-T therapies
- •Part 3 Only:
- •Prior PSMA-targeted therapy (e.g., antibody-drug conjugates or CAR-T therapy), except for Lu-177-PSMA-radioligand therapy and bispecific or CAR-T therapies
研究组 & 干预措施
Part 1: 148 ± 37 MBq In-111 rosopatamab tetraxetan
干预措施: In-111 rosopatamab tetraxetan (Biological)
Part 2: 45 kBq/kg Ac-225 rosopatamab tetraxetan
干预措施: 45 kBq/kg Ac-225 rosopatamab tetraxetan (Biological)
Part 2: 60 kBq/kg Ac-225 rosopatamab tetraxetan
干预措施: 60 kBq/kg Ac-225 rosopatamab tetraxetan (Biological)
Part 3: Dose Escalation and Expansion
Participants previously treated with Lu-177-PSMA-radioligand therapy will be assigned to receive one of the three dose levels (45 kBq/kg, 55 kBq/kg, or 60 kBq/kg, or equivalent fixed dose activity) depending on the dose limiting toxicities (DLTs) observed.
干预措施: 45 kBq/kg or equivalent fixed dose activity Ac-225 rosopatamab tetraxetan (Biological)
Part 3: Dose Escalation and Expansion
Participants previously treated with Lu-177-PSMA-radioligand therapy will be assigned to receive one of the three dose levels (45 kBq/kg, 55 kBq/kg, or 60 kBq/kg, or equivalent fixed dose activity) depending on the dose limiting toxicities (DLTs) observed.
干预措施: 55 kBq/kg or equivalent fixed dose activity Ac-225 rosopatamab tetraxetan (Biological)
Part 3: Dose Escalation and Expansion
Participants previously treated with Lu-177-PSMA-radioligand therapy will be assigned to receive one of the three dose levels (45 kBq/kg, 55 kBq/kg, or 60 kBq/kg, or equivalent fixed dose activity) depending on the dose limiting toxicities (DLTs) observed.
干预措施: 60 kBq/kg or equivalent fixed dose activity Ac-225 rosopatamab tetraxetan (Biological)
Part 4: Dose Escalation and Expansion
Participants will initially receive two doses of the Part 2 selected dose level, followed by a single third dose of Ac-225 rosopatamab tetraxetan approximately 12 weeks after the completion of the Part 2 fractionated dosing regimen. Participants will be assigned to receive one of the three dose levels (22 kBq/kg, 34 kBq/kg, or 45 kBq/kg, or equivalent fixed dose activity) depending on the dose limiting toxicities (DLTs) observed.
干预措施: Single dose 22 kBq/kg or equivalent fixed dose activity Ac-225 rosopatamab tetraxetan (Biological)
Part 4: Dose Escalation and Expansion
Participants will initially receive two doses of the Part 2 selected dose level, followed by a single third dose of Ac-225 rosopatamab tetraxetan approximately 12 weeks after the completion of the Part 2 fractionated dosing regimen. Participants will be assigned to receive one of the three dose levels (22 kBq/kg, 34 kBq/kg, or 45 kBq/kg, or equivalent fixed dose activity) depending on the dose limiting toxicities (DLTs) observed.
干预措施: Single dose 34 kBq/kg or equivalent fixed dose activity Ac-225 rosopatamab tetraxetan (Biological)
Part 4: Dose Escalation and Expansion
Participants will initially receive two doses of the Part 2 selected dose level, followed by a single third dose of Ac-225 rosopatamab tetraxetan approximately 12 weeks after the completion of the Part 2 fractionated dosing regimen. Participants will be assigned to receive one of the three dose levels (22 kBq/kg, 34 kBq/kg, or 45 kBq/kg, or equivalent fixed dose activity) depending on the dose limiting toxicities (DLTs) observed.
干预措施: Single dose 45 kBq/kg or equivalent fixed dose activity Ac-225 rosopatamab tetraxetan (Biological)
结局指标
主要结局
Part 4: Incidence of AEs and SAEs overall, by severity, by relationship to study drug, and leading to discontinuation of study intervention
时间窗: Screening through Week 12
Part 4: Determine the recommended Phase 2 dose (RP2D) of Ac-225 rosopatamab tetraxetan
时间窗: Through end of study (approximately 3 years)
Part 1: Visual evaluation on whole body planar scans (days 1 and 4) with comparison to reference scans for the presence of radiolabeled rosopatamab textraxetan in organs of interest (e.g., liver, circulation, spleen) to determine biodistribution
时间窗: Day 1 and Day 4
Part 2: Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) overall, by severity, and leading to discontinuation of study intervention
时间窗: Screening through Week 12
Part 2: Proportion of participants who achieve a greater than or equal to 50% decline in prostate-specific antigen (PSA50)
时间窗: Through end of study (approximately 3 years) or until PSA progression as defined by PCWG3 criteria
Part 3: Determine the recommended Phase 2 dose (RP2D) of Ac-225 rosopatamab tetraxetan
时间窗: Day 1 through 6 weeks
Part 3 (Participants treated at RP2D): Proportion of participants who achieve a greater than or equal to 50% decline in prostate-specific antigen (PSA50)
时间窗: Through end of study (approximately 3 years) or until PSA progression as defined by PCWG3 criteria
Part 3: Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) overall, by severity, and leading to discontinuation of study intervention
时间窗: Screening through Week 12
次要结局
- Part 4: Proportion of participants who achieve PSA50(Through end of study (approximately 3 years))
- Part 4: Biochemical progression-free survival (bPFS) as assessed by the Prostate Cancer Working Group 3 (PCWG3)(Through end of study (approximately 3 years) or until disease progression)
- Part 2: Determine the clearance of rosopatamab tetraxetan and Ac-225 rosopatamab tetraxetan via measurement of whole blood and serum levels at specified serial timepoints(Through Week 8)
- Part 2: Radioactivity levels of Ac-225 rosopatamab tetraxetan(Through Day 21)
- Part 2: Radiation dosimetry of Ac-225 rosopatamab tetraxetan: Absorbed radiation dose (expressed as Gy/MBq) in normal organs(Day 1 through Day 15)
- Part 2: Biochemical progression-free survival (bPFS) as assessed by the Prostate Cancer Working Group 3 (PCWG3)(Through end of study (approximately 3 years) or until disease progression)
- Part 3: Proportion of participants who achieve PSA50(Through end of study (approximately 3 years))
- Part 3: Determine the clearance of rosopatamab tetraxetan and Ac-225 rosopatamab tetraxetan from the circulation via measurement in the serum at specified serial timepoints(Through Week 8)
- Part 3: Radioactivity levels of Ac-225 rosopatamab tetraxetan(Through Week 8)