A Randomized Phase I/II Study of Neoadjuvant Treatment With 177-Lutetium- PSMA-617 With or Without Ipilimumab in Subjects With Very High-risk Prostate Cancer Who Are Candidates for Radical Prostatectomy (NEPI Trial)
概览
- 阶段
- 1 期
- 干预措施
- [177Lu]Lu-PSMA-617
- 疾病 / 适应症
- Very High Risk Prostate Carcinoma
- 发起方
- University Hospital, Essen
- 入组人数
- 1
- 试验地点
- 1
- 主要终点
- Feasibility to perform prostatectomy on time
- 状态
- 终止
- 最后更新
- 上个月
概览
简要总结
A randomized, open-label Phase I/II study of neoadjuvant treatment with [177Lu]Lu-PSMA-617 radioligandtherapy (LuPSMA) with or without Ipilimumab in participants with very high-risk prostate cancer who are candidates for Radical Prostatectomy.
详细描述
A randomized, open-label Phase I/II study of neoadjuvant treatment with \[177Lu\]Lu-PSMA-617 radioligandtherapy (LuPSMA) with or without Ipilimumab in participants with very high-risk prostate cancer who are candidates for Radical Prostatectomy. The study will be initiated by a safety cohort regarding the \[177Lu\]Lu- PSMA-617 dose including 6 to 12 patients, who will receive combination therapy with \[177Lu\]Lu-PSMA-617 and Ipilimumab. The Safety-Run-In-Phase follows a "none of three or one of six patients experienced intolerable events" approach per dose level. That is: The first 3 patients will receive 4 courses of ipilimumab (3 mg/kg) and 2 courses of 3.7 GBq \[177Lu\]Lu-PSMA-617. If no more than one of these patients develop grade 4 adverse reactions (ARs) without recovery within 3 weeks, another 3 patients will receive the same dosage. If no grade 4 AEs are observed in this second set of patients, we will enroll an additional 3 patients to increase the \[177Lu\]LuPSMA 617 dose to 7.4 GBq. If no more than one of those patients develop grade 4 ARs without recovery within 3 weeks back to grade ≤1 or to baseline values, another 3 patients will receive the same increased dosage. Provided that these patients do not develop grade 4 ARs, randomization of patients will be started. If the "none of three or one of six patients experienced intolerable events" approach per dose level is not passed the study will be terminated at this point. 46 patients with newly diagnosed very high-risk prostate cancer will be randomly assigned in a 1:1 ratio (Ipilimumab + \[177Lu\]Lu-PSMA- 617 vs. \[177Lu\]Lu-PSMA-617 alone) to receive 2 cycles of 7,4 GBq \[177Lu\]Lu-PSMA-617 with or without 4 cycles of concomitant Ipilimumab 3mg/kg prior to prostatectomy. Radioligandtherapy will be given at 6 weeks intervals while ipilimumab will be given every 3 weeks. For application of ipilimumab and \[177Lu\]Lu-PSMA-617 within one cycle (week 1 and 7), \[177Lu\]Lu-PSMA-617 is administered on day 1 and ipilimumab on day 3. ADT will be applied to all patients during the neoadjuvant treatment phase.
研究者
入排标准
入选标准
- •Must be ≥18 years of age
- •Signed an informed consent form (ICF) indicating that the participant understands the purpose of and procedures required for the study and is willing to participate in the study; participants must be willing and able to adhere to the prohibitions and restrictions specified in this protocol
- •Histologically confirmed adenocarcinoma of the prostate including following criteria: Very High-risk defined by a total Gleason-Score ≥4+4 (ISUP-GG 4+5) and clinical stage cT3 (digital rectal examination or imaging based) plus clinical nodal status cN+ or Serum-PSA level \>20ng/ml
- •Exclusion of metastases (M0) on conventional imaging and maximum oligometastatic status on PSMA PET imaging
- •Treatment naïve patients
- •Eastern Cooperative Oncology Group ECOG 0-1
- •Candidate for radical prostatectomy with pelvic lymph node dissection as per the investigator
- •Patients must be PSMA Positron Emission Tomography (PET) scan positive with a prostatic SUVmax \> 12 (PRIMARY Score: 5) .
- •Following laboratory criteria must be obtained within 14 days prior to randomization:
- •Bone marrow reserve
排除标准
- •Distant metastasis (clinical stage M1) on conventional imaging. Oligometastatic patients on exclusively PSMA PET imaging will not be excluded. Patients with PSA values below 20ng/ml and no evidence of nodal disease are excluded.
- •Prior treatment with androgen receptor antagonists. Treatment with GnRH analogs prior to ICF signature
- •Bilateral orchiectomy
- •History of prior systemic or local therapy for prostate cancer, including pelvic radiation for prostate cancer
- •Use of any investigational agent ≤4 weeks prior to randomization or any therapeutic procedure for prostate cancer at any time
- •Major surgery ≤4 weeks prior to randomization
- •Prior therapy with CTLA4 antibodies
- •Previous treatment with any of the following within 6 months of randomization:
- •Strontium-89, Samarium-153, Rhenium-186, Rhenium- 188, Radium-223,
- •Previous PSMA-targeted radioligand therapy
研究组 & 干预措施
Neoadjuvant Combination Therapy
4 cycles of Ipilimumab 3mg/kg + 2 cycles of 7,4 GBq \[177Lu\]Lu-PSMA-617
干预措施: [177Lu]Lu-PSMA-617
Neoadjuvant Combination Therapy
4 cycles of Ipilimumab 3mg/kg + 2 cycles of 7,4 GBq \[177Lu\]Lu-PSMA-617
干预措施: Ipilimumab
Neoadjuvant Mono Therapy
2 cycles of 7,4 GBq \[177Lu\]Lu-PSMA-617
干预措施: [177Lu]Lu-PSMA-617
结局指标
主要结局
Feasibility to perform prostatectomy on time
时间窗: During the intervention/procedure
Feasibility will be defined as the ability to perform prostatectomy in at least 75% of the Analysis population 85 days after start of neoadjuvant treatment with a maximum delay by 3 weeks. A treatment arm will be deemed not feasible in the actual study if \>25% of patients of that arm required a delay of surgery \>3 weeks.
Clinical activity: Proportion of participants in the full analysis set who achieve a pCR
时间窗: After surgery
The proportion of participants in the full analysis set who achieve a pathological complete response (pCR). The assessment of pCR will be reviewed by the central pathologist for all randomized patients with Radical Prostatectomy with pelvic lymphadenectomy conducted. The proportion of participants in the full analysis set who achieve a MRD. The assessment of MRD will be reviewed by the central pathologist for all randomized patients with Radical Prostatectomy with pelvic lymphadenectomy conducted.
次要结局
- Safety Profile of neoadjuvant treatment before radical prostatectomy(Start of neoadjuvant treatment up to 1 year after surgery)