NeoPSMA: A Phase I/II, Open-label, Multi-center Study of Neoadjuvant Treatment With [177Lu]Lu-PSMA-R2 (AAA602) and [225Ac]Ac-PSMA-R2 (AAA802) in Adults With Prostate-specific Membrane Antigen (PSMA) Positive High-risk Localized Prostate Cancer (HRLPC) Prior to Radical Prostatectomy and Pelvic Lymph Node Dissection
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 入组人数
- 228
- 主要终点
- Number of participants with dose-limiting toxicities (DLTs) (Phase l)
研究概览
简要总结
The purpose of this trial is to learn more about the effects of AAA602 and AAA802 in men with prostate-specific membrane antigen (PSMA) positive high-risk localized prostate cancer (HRLPC) before surgery to remove the prostate and lymph nodes present in the pelvis area. Lymph nodes are small structures near the prostate that help fight infections. These lymph nodes are removed during surgery because they are a site the disease can spread to.
详细描述
This Phase I/II study is intended to determine the safety, tolerability, anti-tumor activity, pharmacokinetics, and dosimetry of neoadjuvant treatment with the radioligand therapies (RLT) [177Lu]Lu-PSMA-R2 (AAA602) and [225Ac]Ac-PSMA-R2 (AAA802) before surgery, i.e., radical prostatectomy (RP) and pelvic lymph node dissection (PLND), in participants with Prostate-Specific Membrane Antigen (PSMA)-positive high-risk localized prostate cancer (HRLPC).
Study CAAA802B12101 is a Phase I/II open-label, multi-center study investigating AAA602 and AAA802 as neoadjuvant RLTs before surgery in participants with PSMA-positive HRLPC. In Phase I, participants will be assigned to AAA602 or AAA802 dose escalation cohorts to determine the respective maximum tolerated dose (MTD) and/or the recommended dose for Phase II (RP2D). In Phase II, participants will be randomized to one or two investigational arms, i.e., the RP2D of AAA602 or AAA802, or to the control arm. Therefore, Phase II will have two or three treatment arms. In the control arm, participants will be treated with the standard of care (SoC), i.e., they will not receive any neoadjuvant treatment. Supportive care will be allowed.
Following the last dose of completed RLT, participants will complete a post-treatment imaging/Safety follow-up visit. Upon discontinuation of RLT, participants will complete an end of treatment (EOT) visit prior to the post-treatment imaging/Safety follow-up visit.
If participants undergo surgery, the post-treatment imaging/Safety follow-up visit will be performed before undergoing surgery.
After surgery, participants will complete a post-surgery visit and enter the LTFU. No adjuvant treatment is allowed between surgery and biochemical recurrence (BCR).
研究设计
- 研究类型
- Interventional
- 分配方式
- 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 100 Years（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Adults ≥ 18 years of age.
- •Participants must have PSMA-positive disease as assessed by PSMA PET/CT scan using a PSMA imaging agent as protocol instructed, with eligibility being determined by the sponsor's central reading rules.
- •Histologically confirmed high-risk adenocarcinoma of an intact prostate, and (a) 1 of the following at diagnosis: Gleason score ≥ 8 and/or PSA ≥ 20 nanogram per milliliters (ng/mL), and/or ≥ cT3a or (b) Gleason score 4+3 and PSA ≥ 20 nanogram per milliliters (ng/mL).
- •Adequate organ function:
- •Bone marrow reserve:
- •White blood cell (WBC) count ≥ 3.0 x 109/L and absolute neutrophil count (ANC) ≥ 1.5 x 109/L.
- •Platelets ≥ 75 x 109/L.
- •Hemoglobin ≥ 8 g/dL
- •Hepatic function:
- •Total bilirubin ≤ 1.5 x the institutional upper limit of normal (ULN). For participants with known Gilbert's Syndrome ≤ 3 x ULN is permitted.
- •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 x ULN
- •Albumin > 3.0 g/dL
- •Renal function:
- •Creatinine clearance ≥ 60 mL/min. Note that participants with findings indicating blockage of urinary outflow are not eligible. No evidence of congenital renal abnormalities with known effect on renal function or voiding abnormalities that may interfere, in the opinion of the principal investigator, with the safe administration of the study treatment.
- •An Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or
- •Indicated to receive radical prostatectomy (RP) and pelvic lymph node dissection (PLND).
- •Sexually active participants with female partners of childbearing potential are eligible to participate if they agree to follow one of the following methods of contraception consistently, starting from screening, during the study and for at least 6 months after the last dose of study treatment:
- •Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent.
- •Are sterilized (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate);
- •Agree to use a male condom and have their partner use a highly effective method of contraception (failure rate < 1% per year) as described in Section 8.4.6 when having penile-vaginal intercourse with a woman of childbearing potential who is not currently pregnant, and who agrees to the use of a condom by her partner.
- •In addition, participants must refrain from donating sperm starting from Screening, during the study and for at least 6 months after the last dose of the study medication.
- •Sexually active participants with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse; or use a male condom during each episode of penile penetration during the study.
排除标准
- •Subjects taking prohibited therapies as described in the protocol
- •Any approved or investigational systemic anti-cancer therapy (e.g. chemotherapy, investigational therapy, immunotherapy or biological therapy including monoclonal antibodies) administered for the treatment of HRLPC within 28 days (or 5 times the half-life of that therapy whichever is longer) of the anticipated day C1D
- •Previous treatment with any approved or investigational radioligand therapy, approved or investigational radioisotopes.
- •Prior or concurrent radiation therapy of the prostate, other prostate antineoplastic ablative procedures, or hormonal ablation for prostate cancer.
- •Diagnosed with other active malignancies that are expected to alter life expectancy or may interfere with disease assessment. Participants with a prior history of malignancy that has been adequately treated and who have been disease free and treatment free for more than 3 years prior to randomization are eligible, as are participants with adequately treated non-melanoma skin cancer and superficial bladder cancer.
- •Other protocol-defined Inclusion/exclusion may apply.
研究组 & 干预措施
AAA602
AAA602 will be administered as a single intravenous dose. Dose escalation and de-escalation steps will be performed in accordance with the BOIN design.
干预措施: AAA602 (Drug)
AAA602
AAA602 will be administered as a single intravenous dose. Dose escalation and de-escalation steps will be performed in accordance with the BOIN design.
干预措施: Gallium (68Ga) gozetotide (Drug)
AAA602
AAA602 will be administered as a single intravenous dose. Dose escalation and de-escalation steps will be performed in accordance with the BOIN design.
干预措施: Piflufolastat (18F) (Drug)
AAA602
AAA602 will be administered as a single intravenous dose. Dose escalation and de-escalation steps will be performed in accordance with the BOIN design.
干预措施: Flotufolastat F 18 (Drug)
AAA602
AAA602 will be administered as a single intravenous dose. Dose escalation and de-escalation steps will be performed in accordance with the BOIN design.
干预措施: 18F-PSMA-1007 (Drug)
AAA802
AAA802 will be administered as a single intravenous dose Dose escalation/de-escalation steps will be performed in accordance with the BOIN design.
干预措施: AAA802 (Drug)
AAA802
AAA802 will be administered as a single intravenous dose Dose escalation/de-escalation steps will be performed in accordance with the BOIN design.
干预措施: Gallium (68Ga) gozetotide (Drug)
AAA802
AAA802 will be administered as a single intravenous dose Dose escalation/de-escalation steps will be performed in accordance with the BOIN design.
干预措施: Piflufolastat (18F) (Drug)
AAA802
AAA802 will be administered as a single intravenous dose Dose escalation/de-escalation steps will be performed in accordance with the BOIN design.
干预措施: Flotufolastat F 18 (Drug)
AAA802
AAA802 will be administered as a single intravenous dose Dose escalation/de-escalation steps will be performed in accordance with the BOIN design.
干预措施: 18F-PSMA-1007 (Drug)
结局指标
主要结局
Number of participants with dose-limiting toxicities (DLTs) (Phase l)
时间窗: At the end of cycle 1 (each cycle is maximum 6 weeks)
Incidence and severity of dose-limiting toxicities.
Biochemical recurrence free survival (BFS) (Phase ll)
时间窗: From the date of surgery until the date of confirmed biochemical recurrence or death due to any cause, whichever occurs first assessed to approximately 60 months
BFS is defined as the time from the date of surgery until the date of confirmed biochemical recurrence (PSA \> 0.2 ng/mL on two readings separated by at least 4 weeks measured at least 8 weeks after surgery).
次要结局
- Biochemical response as measured as Prostate Specific Antigen (PSA)50 (Phase ll)(From screening until the end of neoadjuvant treatment assessed to approximately 6 months)
- Overall Response Rate (ORR) at 12 months after surgery (Phase ll)(at 12 months after surgery)
- Change from baseline in domain scores of the EPIC-26 (Phase ll)(From screening to end of long term follow up assessed up to approximately 66 months)
- Change from baseline on FACT-GP5 item (Phase ll)(From screening to end of long term follow up assessed up to approximately 66 months)
- Overall Response Rate (ORR) (Phase l & ll)(Month 12, Month 15, Month 18)
- Percentage of participants with surgical complications graded according to the Clavien-Dindo classification (Phase l & ll)To evaluate surgical safety (phase l & ll)(From screening until post-surgery follow up assessed at approximately 7.5 months)
- Percentage of participants achieving a complete response to therapy (Phase l & ll)(From screening until end cycle 2 assessed up to 20 weeks (cycle is maximum 6 weeks))
- Percentage of participants achieving PSA < 0.2 (Phase l & ll)(From cycle 1 day 1 of post progression treatment to approximately 60 months after surgery)
- Percentage of participants with a functional response on PSMA PET/CT(From screening until the end of neoadjuvant treatment assessed to approximately 6 months)
- Percentage of participants achieving pathological complete response (absence of disease) or minimal residual disease (Phase l & ll)(From screening until post-surgery follow up assessed at approximately 7.5 months)
- Concordance in the evaluation of pathological response between local review and independent central review (Phase l & ll)(From screening until post-surgery follow up assessed at approximately 7.5 months)
- Radiation absorbed doses in organs and tumors of AAA602 (Phase l & ll)(From cycle 1 day 1 until until approximately cycle 2 day 3 (cycle is maximum 6 weeks))
- Time concentration profiles and Pharmacokinetics parameters of AAA802 and AAA602(From cycle 1 day 1 until until approximately cycle 1 day 3 (cycle is maximum 6 weeks))