PMID- 30402678 OWN - NLM STAT- MEDLINE DCOM- 20200205 LR - 20211204 IS - 1573-0646 (Electronic) IS - 0167-6997 (Linking) VI - 37 IP - 2 DP - 2019 Apr TI - Phase I/II study evaluating the safety and clinical efficacy of temsirolimus and bevacizumab in patients with chemotherapy refractory metastatic castration-resistant prostate cancer. PG - 331-337 LID - 10.1007/s10637-018-0687-5 [doi] AB - Background Mammalian target of rapamycin (mTOR) pathway and angiogenesis through vascular endothelial growth factor (VEGF) have been shown to play important roles in prostate cancer progression. Preclinical data in prostate cancer has suggested the potential additive effect dual inhibition of VEGF and mTOR pathways. In this phase I/II trial we assessed the safety and efficacy of bevacizumab in combination with temsirolimus for the treatment of men with metastatic castration-resistant prostate cancer (mCRPC). Methods In the phase I portion, eligible patients received temsirolimus (20 mg or 25 mg IV weekly) in combination with a fixed dose of IV bevacizumab (10 mg/kg every 2 weeks). The primary endpoint for the phase II portion was objective response measured by either PSA or RECIST criteria. Exploratory endpoints included changes in circulating tumor cells (CTC) and their correlation with PSA response to treatment. Results Twenty-one patients, median age 64 (53-82), with pre-treatment PSA of 205.3 (11.1-1801.0), previously treated with a median of 2 (0-5) lines of therapy for mCRPC received the combination of temsirolimus weekly at 20 mg (n = 4) or 25 mg (n = 17) with bevacizumab 10 mg/kg every 2 weeks (n = 21). Median time to progression was 2.6 months (95% CI, 1.2-3.9) and the median best PSA change from baseline to 12 weeks was a 32% increase (-40-632%) which met the predefined futility rule and led to early termination of the study. Nine patients (43%) had >/= grade 3 toxicity that included fatigue (24%), anorexia (10%), nausea/vomiting (5%) and lymphopenia (5%). In exploratory analysis, a decrease in CTC levels was observed in 9 out of 11 patients. No association between PSA levels and CTC levels was detected. Conclusions The combination of temsirolimus and bevacizumab showed limited clinical activity in mCRPC patients previously treated with chemotherapy and was associated with significant adverse events (AEs). Transient decrease in CTC levels was independent from PSA response. NCT01083368. FAU - Barata, Pedro C AU - Barata PC AD - Tulane University, New Orleans, LA, USA. FAU - Cooney, Matthew AU - Cooney M AD - Seidman Cancer Center, Case Comprehensive Cancer Center, University Hospitals, Cleveland, OH, USA. FAU - Mendiratta, Prateek AU - Mendiratta P AD - Seidman Cancer Center, Case Comprehensive Cancer Center, University Hospitals, Cleveland, OH, USA. FAU - Gupta, Ruby AU - Gupta R AD - Cleveland Clinic Taussig Cancer Institute, 9500 Euclid Ave/CA60, Cleveland, OH, 44195, USA. FAU - Dreicer, Robert AU - Dreicer R AD - Division of Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, VA, USA. FAU - Garcia, Jorge A AU - Garcia JA AD - Cleveland Clinic Taussig Cancer Institute, 9500 Euclid Ave/CA60, Cleveland, OH, 44195, USA. garciaj4@ccf.org. LA - eng SI - ClinicalTrials.gov/NCT01083368 PT - Clinical Trial, Phase I PT - Clinical Trial, Phase II PT - Journal Article PT - Multicenter Study DEP - 20181107 PL - United States TA - Invest New Drugs JT - Investigational new drugs JID - 8309330 RN - 0 (Biomarkers, Tumor) RN - 0 (Pyrroles) RN - 0 (VEGFA protein, human) RN - 0 (Vascular Endothelial Growth Factor A) RN - 0 (pyrrolo(2,1-c)(1,4)benzodiazepine) RN - 12794-10-4 (Benzodiazepines) RN - 2S9ZZM9Q9V (Bevacizumab) RN - 624KN6GM2T (temsirolimus) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Aged MH - Aged, 80 and over MH - Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics/*therapeutic use MH - Benzodiazepines/chemistry MH - Bevacizumab/administration & dosage MH - Biomarkers, Tumor/metabolism MH - Disease Progression MH - Drug Resistance, Neoplasm/drug effects MH - Follow-Up Studies MH - Gene Expression Regulation, Neoplastic/*drug effects MH - Humans MH - Male MH - Maximum Tolerated Dose MH - Middle Aged MH - Neoplasm Recurrence, Local/*drug therapy/metabolism/pathology MH - Prognosis MH - Prostatic Neoplasms, Castration-Resistant/*drug therapy/metabolism/pathology MH - Pyrroles/chemistry MH - *Salvage Therapy MH - Sirolimus/administration & dosage/analogs & derivatives MH - TOR Serine-Threonine Kinases/*antagonists & inhibitors MH - Tissue Distribution MH - Vascular Endothelial Growth Factor A/*antagonists & inhibitors OTO - NOTNLM OT - Bevacizumab OT - Castration-resistant prostate cancer OT - Phase I/II OT - Temsirolimus EDAT- 2018/11/08 06:00 MHDA- 2020/02/06 06:00 CRDT- 2018/11/08 06:00 PHST- 2018/09/25 00:00 [received] PHST- 2018/10/16 00:00 [accepted] PHST- 2018/11/08 06:00 [pubmed] PHST- 2020/02/06 06:00 [medline] PHST- 2018/11/08 06:00 [entrez] AID - 10.1007/s10637-018-0687-5 [pii] AID - 10.1007/s10637-018-0687-5 [doi] PST - ppublish SO - Invest New Drugs. 2019 Apr;37(2):331-337. doi: 10.1007/s10637-018-0687-5. Epub 2018 Nov 7.