Batra Jaspreet S, Niaz Muhammad Junaid, Whang Young E, Sheikh Arif, Thomas Charlene, Christos Paul, Vallabhajosula Shankar, Jhanwar Yuliya S, Molina Ana M, Nanus David M, Osborne Joseph R, Bander Neil H, Tagawa Scott T
Department of Urology, Weill Cornell Medicine, New York, NY.
Department of Medicine, Division of Hematology/Oncology, University of North Carolina School of Medicine, Chapel Hill, NC.
Urol Oncol. 2020 Nov;38(11):848.e9-848.e16. doi: 10.1016/j.urolonc.2020.05.028. Epub 2020 Jun 27.
Docetaxel remains a standard of care for metatsatic castration resistant porstate cancer (mCRPC) and has radiosensitizing properties. The dose limiting toxicity (DLT) of radioimmunotherapy is myelosuppression; dose fractionation of Lu-J591 allows similar administered doses with less toxicity. This study (NCT00916123) was designed to determine the safety, DLT, and maximum tolerated dose of fractionated Lu-J591 administered concurrently with standard docetaxel.
Men with progressive mCRPC received docetaxel 75 mg/m every 3 weeks with escalating 2 fractionated doses of Lu-J591 (1.48 GBq/m up to max of 2.96 GBq/m) with cycle 3. Cycle 4 of docetaxel was planned 6 weeks after cycle 3 to allow for recovery from Lu-J591-associated hematologic toxicity. DLT was defined as delay in docetaxel >3 weeks, prolonged myelosuppression or need for >2 platelet transfusions, febrile neutropenia, or grade ≥3 nonhematological toxicity following Lu-J591. PSA was assessed prior to each cycle and serial computed tomography (CT) and bone scan were performed.
Fifteen men with progressive mCRPC received dose-escalated targeted radionuclide therapy in 4 cohorts up to the highest planned dose (2.96 GBq/m). No DLT was seen at any dose level. Grade 4 neutropenia without fever occurred in 8 (53.5%) and thromboytopenia in 2 (13.3%), with 2 receiving prophylactic platelet transfusion. No grade ≥3 nonhematological toxicity was observed. 11 (73.3%) had >50% PSA decline, with 78.6% having favorable circulating tumor cell counts after Lu-J591. All patients had targeting of known sites of disease by planar Lu-J591 imaging.
The combination of Lu-J591 delivered as a single fractionated cycle with docetaxel/prednisone is feasible in patients with mCRPC. Without preselection for prostate-specific membrane antigen, accurate targeting of known sites of disease and a strong preliminary efficacy signal was observed.
多西他赛仍是转移性去势抵抗性前列腺癌（mCRPC）的标准治疗药物，且具有放射增敏特性。放射免疫疗法的剂量限制性毒性（DLT）是骨髓抑制；Lu-J591的剂量分割允许使用相似的给药剂量但毒性更低。本研究（NCT00916123）旨在确定与标准多西他赛同时给予的分割剂量Lu-J591的安全性、DLT和最大耐受剂量。
患有进展性mCRPC的男性每3周接受75mg/m²的多西他赛治疗，在第3周期时给予递增的2个分割剂量的Lu-J591（1.48GBq/m²，最高可达2.96GBq/m²）。多西他赛的第4周期计划在第3周期后6周进行，以便从与Lu-J591相关的血液学毒性中恢复。DLT定义为多西他赛延迟>3周、长期骨髓抑制或需要>2次血小板输注、发热性中性粒细胞减少或Lu-J591后≥3级非血液学毒性。在每个周期前评估前列腺特异性抗原（PSA），并进行系列计算机断层扫描（CT）和骨扫描。
15名患有进展性mCRPC的男性在4个队列中接受了剂量递增的靶向放射性核素治疗，直至最高计划剂量（2.96GBq/m²）。在任何剂量水平均未观察到DLT。8名（53.5%）出现无发热的4级中性粒细胞减少，2名（13.3%）出现血小板减少，其中2名接受了预防性血小板输注。未观察到≥3级非血液学毒性。11名（73.3%）的PSA下降>50%，78.6%在Lu-J591后循环肿瘤细胞计数良好。所有患者通过平面Lu-J59成像均显示已知疾病部位有靶向性。
对于mCRPC患者，将Lu-J591作为单个分割周期与多西他赛/泼尼松联合使用是可行的。在未对前列腺特异性膜抗原进行预选的情况下，观察到已知疾病部位的准确靶向性和强烈的初步疗效信号。
