A Phase Ib/II Open-label, Multi-center Study of AMO959 With Lutetium (177Lu) Vipivotide Tetraxetan (AAA617) in Combination With an Androgen Receptor Pathway Inhibitor (ARPI) in Adult Participants With PSMA-positive Metastatic Castration Resistant Prostate Cancer (mCRPC)
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 123
- 试验地点
- 23
- 主要终点
- Phase Ib: Incidence rate of Dose-limiting toxicities (DLTs)
研究概览
简要总结
The purpose of this phase Ib/II study is to (a) in Phase Ib evaluate the safety, tolerability, and pharmacokinetics (PK) of AMO959 when given in combination with lutetium (177Lu) vipivotide tetraxetan (also known as [177Lu]Lu-PSMA-617 or 177Lu-PSMA-617 and hereafter referred to as AAA617) with an androgen receptor pathway inhibitor (ARPI) in participants with metastatic castration resistant prostate cancer (mCRPC) who have failed one prior ARPI and with or without prior taxane exposure, and (b) in Phase II evaluate the preliminary efficacy of AMO959 in combination with AAA617 and ARPI in participants with mCRPC who have failed one prior ARPI, but who have not yet been exposed to taxane treatment.
详细描述
This study will consist of two phases:
- The escalation phase (Ib) will consist of provisionally three dose level cohorts of 3-6 participants investigating the safety, tolerability, and to determine the recommended dose for expansion (RDE) of AMO959 with standard dose of AAA617 +/- ARPI (abiraterone or enzalutamide). Initially AMO959 monotherapy will be administered, and then AMO959 will be given along with AAA617 in the same participants. Dose escalation meetings (DEMs) will occur when all participants in a dose level cohort have completed the DLT evaluation period or have experienced a DLT prior to the end of the evaluation period.
- The Phase II will follow with 25 participants per arm randomized in a 1:1:1 ratio treated at the RDE(s) of AMO959 along with AAA617 and ARPI (abiraterone or enzalutamide) and AAA617 and ARPI (abiraterone or enzalutamide).
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
- •Signed informed consent must be obtained prior to participation in the study.
- •Participants must be adults ≥ 18 years of age.
- •Participants must have an ECOG performance status of 0 to
- •Participants must have histologically confirmed adenocarcinoma of the prostate. Participants with other histology (e.g. neuroendocrine, intraductal subtype) are not eligible.
- •Phase Ib: Prior exposure of up to 1 line of taxane-based chemotherapy is permissible. Phase II: Participants must not have received taxane-based chemotherapy in mCRPC setting (allowed in mHSPC setting).
- •Participants must have PSMA-PET positive disease assessed by using a PSMA imaging agent that is approved as per protocol and are eligible as determined by the sponsor's central reading rules.
- •Castration level of testosterone (< 50 ng/dL), and/or use of concomitant ADT
- •Participant must have been diagnosed with mCRPC with documented progressive disease while on treatment with ARPI in mHSPC or earlier setting as their last treatment (and did not progress on more than one ARPI), based on at least 1 of the following criteria:
- •Serum/plasma PSA progression is defined as 2 increases in PSA measured at least 1 week apart. The minimal start value is 2.0 ng/mL; 1.0 ng/mL is the minimal starting value if confirmed rise in PSA is the only indication of progression as per PCWG3 guidelines.
- •Soft-tissue progression defined PCWG3-modified RECIST v1.1 (Eisenhauer et al 2009, Scher et al 2016).
- •Progression of bone disease: 2 new lesions; only positivity on the bone scan defines metastatic disease to bone (PCWG3 criteria Scher et al 2016).
排除标准
- •Concurrent local (radiation therapy to the prostate with curative intent or other prostate antineoplastic ablative procedures) or systemic (hormonal ablation, chemotherapy, immunotherapy, , RLTs) antineoplastic treatments, or within 28 days of enrollment (Phase Ib) or randomization (Phase II)
- •Prior treatment with any RLT or PSMA-targeted agents (approved or investigational)
- •Any other investigational agents within 28 days prior to first dose of any study treatment
- •Concurrent serious medical conditions that may interfere with study procedures or followup
- •Participants with a history of CNS metastases must have received therapy (surgery, whole brain radiation therapy, stereotactic radiosurgery) and be neurologically stable, asymptomatic, and not taking corticosteroids for the purpose of maintaining neurologic integrity.
- •Other protocol-defined inclusion/exclusion criteria may apply.
研究组 & 干预措施
Phase 1b: Doublet
Participants will receive AMO959 BID for first 14 days followed by AAA617+AMO959 every 6 weeks for a maximum of 6 cycles.
干预措施: AMO959 (Drug)
Phase 1b: Triplet
Participants will receive AAA617 on day 1 followed by AMO959 BID (days 2-15), repeated every 6 weeks, for a maximum of 6 cycles with an ARPI (abiraterone or enzalutamide) administered continuously starting on day 1.
干预措施: AMO959 (Drug)
Phase 1b: Food Effect
Participants will receive a single dose of AMO959 on Day 1 (fed), followed by 2-day washout, then AMO959 BID (fasted) for 14 days followed by 2-day washout and AAA617+AMO959 (fasted) every 6 weeks for a maximum of 6 cycles.
干预措施: AMO959 (Drug)
Phase II: Arm 1
Participants will receive AAA617 on day 1 followed by AMO959 BID (days 2-15), repeated every 6 weeks, for a maximum of 6 cycles with an ARPI (abiraterone or enzalutamide administered continuously starting on day 1.
干预措施: AAA617 (Radiation)
Phase II: Arm 1
Participants will receive AAA617 on day 1 followed by AMO959 BID (days 2-15), repeated every 6 weeks, for a maximum of 6 cycles with an ARPI (abiraterone or enzalutamide administered continuously starting on day 1.
干预措施: Enzalutamide (Drug)
Phase II: Arm 1
Participants will receive AAA617 on day 1 followed by AMO959 BID (days 2-15), repeated every 6 weeks, for a maximum of 6 cycles with an ARPI (abiraterone or enzalutamide administered continuously starting on day 1.
干预措施: Abiraterone (Drug)
Phase II: Arm 2
Participants will receive AAA617 on day 1 followed by AMO959 BID (days 2-15), repeated every 6 weeks, for a maximum of 6 cycles with an ARPI (abiraterone or enzalutamide) administered continuously starting on day 1.
干预措施: AMO959 (Drug)
Phase II: Arm 2
Participants will receive AAA617 on day 1 followed by AMO959 BID (days 2-15), repeated every 6 weeks, for a maximum of 6 cycles with an ARPI (abiraterone or enzalutamide) administered continuously starting on day 1.
干预措施: AAA617 (Radiation)
Phase II: Arm 1
Participants will receive AAA617 on day 1 followed by AMO959 BID (days 2-15), repeated every 6 weeks, for a maximum of 6 cycles with an ARPI (abiraterone or enzalutamide administered continuously starting on day 1.
干预措施: AMO959 (Drug)
Phase II: Arm 3
Participants will receive AAA617 every 6 weeks for a maximum of 6 cycles, with ARPI (abiraterone or enzalutamide) administered continuously starting on day 1.
干预措施: Abiraterone (Drug)
Phase 1b: Doublet
Participants will receive AMO959 BID for first 14 days followed by AAA617+AMO959 every 6 weeks for a maximum of 6 cycles.
干预措施: AAA617 (Radiation)
Phase 1b: Triplet
Participants will receive AAA617 on day 1 followed by AMO959 BID (days 2-15), repeated every 6 weeks, for a maximum of 6 cycles with an ARPI (abiraterone or enzalutamide) administered continuously starting on day 1.
干预措施: AAA617 (Radiation)
Phase II: Arm 2
Participants will receive AAA617 on day 1 followed by AMO959 BID (days 2-15), repeated every 6 weeks, for a maximum of 6 cycles with an ARPI (abiraterone or enzalutamide) administered continuously starting on day 1.
干预措施: Abiraterone (Drug)
Phase II: Arm 3
Participants will receive AAA617 every 6 weeks for a maximum of 6 cycles, with ARPI (abiraterone or enzalutamide) administered continuously starting on day 1.
干预措施: AAA617 (Radiation)
Phase 1b: Triplet
Participants will receive AAA617 on day 1 followed by AMO959 BID (days 2-15), repeated every 6 weeks, for a maximum of 6 cycles with an ARPI (abiraterone or enzalutamide) administered continuously starting on day 1.
干预措施: Abiraterone (Drug)
Phase II: Arm 3
Participants will receive AAA617 every 6 weeks for a maximum of 6 cycles, with ARPI (abiraterone or enzalutamide) administered continuously starting on day 1.
干预措施: Enzalutamide (Drug)
Phase 1b: Triplet
Participants will receive AAA617 on day 1 followed by AMO959 BID (days 2-15), repeated every 6 weeks, for a maximum of 6 cycles with an ARPI (abiraterone or enzalutamide) administered continuously starting on day 1.
干预措施: Enzalutamide (Drug)
Phase II: Arm 2
Participants will receive AAA617 on day 1 followed by AMO959 BID (days 2-15), repeated every 6 weeks, for a maximum of 6 cycles with an ARPI (abiraterone or enzalutamide) administered continuously starting on day 1.
干预措施: Enzalutamide (Drug)
Phase 1b: Food Effect
Participants will receive a single dose of AMO959 on Day 1 (fed), followed by 2-day washout, then AMO959 BID (fasted) for 14 days followed by 2-day washout and AAA617+AMO959 (fasted) every 6 weeks for a maximum of 6 cycles.
干预措施: AAA617 (Radiation)
结局指标
主要结局
Phase Ib: Incidence rate of Dose-limiting toxicities (DLTs)
时间窗: Up to 42 days after the first AAA617 dose administration
Incidence of dose limiting toxicities (DLTs) with AMO959 in combination with AAA617 +/- ARPI A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness/injury, or concomitant medications that occurs within the evaluation period and meets any of the criteria specified in the protocol. The National Cancer Institute Common Terminology Criteria for Adverse events (NCI CTCAE) version 5.0 will be used for all grading.
Phase Ib: Incidence rate of Adverse Events (AEs) and Serious Adverse Events (SAEs)
时间窗: From date of start of study treatment, assessed up to approximately 45 months
Incidence of adverse events by type, frequency, and severity, as graded by the NCI CTCAE version 5.0.
Phase Ib: Number of Participants with dose adjustments
时间窗: From date of start of study treatment, assessed up to approximately 24 months
The number of participants with dose adjustments (reductions, interruption, or permanent discontinuation).
Phase Ib: Dose Intensity
时间窗: From date of start of study treatment, assessed up to approximately 24 months
Dose intensity (computed as the ratio of actual cumulative dose received and actual duration of exposure) and the relative dose intensity (computed as the ratio of dose intensity and planned dose intensity).
Phase Ib: Duration of exposure to each study drug
时间窗: From date of start of study treatment, assessed up to approximately 24 months
Duration of exposure (in months) to each study drug.
Phase II: Biochemical Response (PSA50)
时间窗: From date of start of study treatment, assessed up to approximately 24 months
Biochemical response (PSA50), defined as the proportion of participants who achieved a ≥ 50% decrease in PSA from baseline at any time during the treatment period prior to start of new anti-cancer therapy that is confirmed by a second PSA measurement ≥ 4 weeks later.
次要结局
- Prostate Specific Antigen 90 (PSA90) response(From date of start of study treatment, assessed up to approximately 24 months)
- Phase Ib: Prostate Specific Antigen 50 (PSA50) response(From date of start of study treatment, assessed up to approximately 24 months)
- Phase Ib and Phase II: Radiographic progression-free survival (rPFS)(From date of start of study treatment (Phase Ib) / randomization (Phase II), assessed up to approximately 24 months)
- Phase Ib and Phase II: Overall Response Rate (ORR)(From date of start of study treatment (Phase Ib) / randomization (Phase II), assessed up to approximately 24 months)
- Phase Ib and Phase II: Disease control rate (DCR)(From date of start of study treatment (Phase Ib) / randomization (Phase II), assessed up to approximately 24 months)
- Phase Ib and Phase II: Duration of Response (DoR)(From date of start of study treatment (Phase Ib) / randomization (Phase II), assessed up to approximately 24 months)
- Overall Survival (OS)(From date of start of study, assessed up to approximately 45 months)
- Phase II: Time to soft tissue progression (TTSTP)(From date of start of study randomization, assessed up to approximately 24 months)
- Phase Ib: Plasma concentrations of AMO959(Throughout run-in periods and first cycle with AAA617, assessed up to 6 months)
- Phase Ib: Plasma concentrations of AAA617(Throughout treatment periods with AAA617, assessed up to 6 months)
- Phase Ib: Time activity curves (TACs) for AAA617(Throughout treatment periods with AAA617, assessed up to 6 months)
- Phase Ib: Absorbed radiation doses in selected organs and tumor lesions for AAA617(Throughout treatment periods with AAA617, assessed up to 6 months)
- Phase II: Incidence rate of Adverse Events (AEs) and Serious Adverse Events (SAEs)(From date of start of study treatment, assessed up to approximately 45 months)
- Phase II: Number of Participants with dose adjustments(From date of start of study treatment, assessed up to approximately 24 months)
- Phase II: Dose Intensity(From date of start of study treatment, assessed up to approximately 24 months)
- Phase II: Duration of exposure to each study drug(From date of start of study treatment, assessed up to approximately 24 months)
- Phase II: Radiographic Progression Free Survival (rPFS) by Positron Emission Tomography (PET) (rPFS-PET)(From date of start of study randomization, assessed up to approximately 24 months)
- Phase II: Change from baseline in FACT-P Prostate Cancer Subscale (PCS)(From date of start of study, assessed up to approximately 45 months.)
- Phase II: Time to worsening on the Brief Pain Inventory - Short Form (BPI-SF)(From date of start of study, assessed up to approximately 45 months.)
- Phase II: Time to first symptomatic skeletal event (TTSSE)(From date of start of study randomization, assessed up to approximately 24 months.)