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Phase I/II Study Evaluating the Safety and Clinical Efficacy of Temsirolimus and Bevacizumab in Patients with Chemotherapy Refra

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Phase I/II Study Evaluating the Safety and Clinical Efficacy of Temsirolimus and Bevacizumab in Patients with Chemotherapy Refra Investigational New Drugs (2019) 37:331–337 https://doi.org/10.1007/s10637-018-0687-5 PHASE II STUDIES Phase I/II study evaluating the safety and clinical efficacy of temsirolimus and bevacizumab in patients with chemotherapy refractory metastatic castration-resistant prostate cancer Pedro C. Barata1 & Matthew Cooney2 & Prateek Mendiratta 2 & Ruby Gupta3 & Robert Dreicer4 & Jorge A. Garcia3 Received: 25 September 2018 /Accepted: 16 October 2018 /Published online: 7 November 2018 # Springer Science+Business Media, LLC, part of Springer Nature 2018 Summary 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)or25mg(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. Keywords Phase I/II . Castration-resistant prostate cancer . Temsirolimus . Bevacizumab Introduction with an estimated 29,430 deaths in the year 2018 [1]. While most men with advanced disease respond to androgen depra- Prostate cancer is the most common cancer among men in the vation therapy (ADT), over time it becomes resistant to cas- United States and the second highest leading cause of death tration which is evidenced by a rising PSA, clinical and radio- logical evidence of disease progression, ultimately leading to mortality [2]. * Jorge A. Garcia [email protected] The treatment of metastatic castration resistant prostate cancer (mCRPC) has evolved significantly in the last decade. 1 Tulane University, New Orleans, LA, USA Prior to the regulatory approval of docetaxel in 2004 for 2 Seidman Cancer Center, Case Comprehensive Cancer Center, mCRPC [3, 4], the most commonly used cytotoxic agent University Hospitals, Cleveland, OH, USA was mitoxantrone and prednisone, providing palliation but 3 Cleveland Clinic Taussig Cancer Institute, 9500 Euclid Ave/CA60, no survival benefit [5, 6]. In addition, limited data existed Cleveland, OH 44195, USA for those with disease progression after docetaxel-based che- 4 Division of Hematology/Oncology, University of Virginia School of motherapy. Over the past several years a number of new Medicine, Charlottesville, VA, USA agents (novel hormonal therapies, chemotherapy, 332 Invest New Drugs (2019) 37:331–337 immunotherapy) have shown significant survival advantage adenocarcinoma of the prostate, with mCRPC and progressed and revolutionized the treatment landscape of mCRPC [7–10]. after either one or two prior chemotherapy regimens (docetax- Angiogenesis, through vascular endothelial growth factor el based or mitoxantrone based regimens). All patients were (VEGF) has shown to play an important role in prostate cancer required to have a castrated testosterone level of ≤50 ng/dL progression. VEGF is one of the most potent and specific and to remain on testosterone suppression therapy for the du- proangiogenic factors and its biological effects include endo- ration of the study. Prior chemotherapy had to be completed at thelial cell mitogenesis and migration, increased vascular per- least 4 weeks prior to study entry. Similarly, the use of a prior meability and suppression of dendritic cell maturation. In radiopharmaceutical agent (strontium, samarium) was permit- prostate cancer, several studies demonstrated an association ted provided it was completed at least 8 weeks prior to screen- of elevated levels of VEGF and higher Gleason scores, PSA ing with no residual adverse events (AEs) > grade (G)1 at the levels, clinical progression and inferior survival [11–14]. time of screening. Other inclusion criteria included adequate Bevacizumab is a humanized immunoglobulin G1 monoclo- bone marrow, kidney and hepatic function. Patients were nal antibody that binds and inhibits the biologically active excluded if they had significant cardiovascular disease isoforms of human VEGF. This agent has shown to be effec- and had received prior treatment with a VEGF or tive in several malignancies such as colorectal, breast, non- mTOR inhibitor. The use of strong CYP450 inducers small cell lung and kidney cancer [15–19]. or inhibitors was also not allowed. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway This phase I/II study was conducted at the Cleveland Clinic plays a key role in oncogenesis and deregulation of this path- and University Hospitals. The protocol (CASE7808 / way through phosphatase and tensin homolog (PTEN) sup- NCI2010–00308) was reviewed and approved by the Case pression was observed in aggressive prostate cancers [20, 21]. Comprehensive Cancer Center Institutional Review Board Mammalian target of rapamycin (mTOR) is a downstream and was conducted in accordance with the Declaration of signaling kinase of this pathway, regulating cell growth and Helsinki for human subject protection. All patients provided proliferation [22]. The inhibition of mTOR pathway have written informed consent prior to study entry. ClinicalTrials. shown clinical efficacy in other malignancies such as renal gov Identifier: NCT01083368. cell [23], breast [24] and neuroendocrine tumors [25]. Nonetheless, the complex regulatory process of the PI3K/ Akt pathway makes this pathway a challenging therapeutic Study design and treatment target with a number of clinical studies exploring its inhibition with modest efficacy in prostate cancer. Temsirolimus, an Eligible patients received weekly intravenous infusions of mTOR inhibitor, targets essential regulatory functions in the temsirolimus 20 mg (dose level 1) or 25 mg (dose level 2) in tumor as well as the tumor microenvironment with anti- combination with intravenous infusions of bevacizumab angiogenic properties via interfering with hypoxia inducible 10 mg/kg every 2 weeks. This study featured a staged- factor HIF1-alpha and VEGF production [26, 27]. cohort design to study primarily safety of the combination of While both temsirolimus and bevacizumab have modest temsirolimus and bevacizumab (phase I) and a main study clinical activity when used as monotherapy in prostate cancer cohort of up to 28 patients to evaluate the safety and efficacy [28, 29], both preclinical and clinical data suggested that this of the combination (phase II). combination is least additive in a variety of tumors [30–32]. The phase I portion of the study intended to establish a Of note, a phase I/II study investigating a fixed dose of maximum tolerated dose (MTD) of temsirolimus in com- temsirolimus with escalating doses of bevacizumab was safe bination with bevacizumab and employed a B3+3^ statis- and showed clinical antitumor activity in metastatic renal cell tical design model. In this portion of the study, three pa- cancer [33]. tients were initially treated at dose level 1 (temsirolimus To assess the potential synergistic activity of the dual inhi- 20 mg weekly plus bevacizumab 10 mg/kg every bition of mTOR and VEGF pathways, we conducted a phase 2 weeks). If no unacceptable toxicities were observed, a I/II trial of temsirolimus in combination with bevacizumab in new cohort of 3 patients would be treated at dose level 2 men with chemotherapy refractory mCRPC. (temsirolimus 25 mg weekly plus bevacizumab 10 mg/kg every 2 weeks), which was the expected recommended dose for the phase II portion of the study. Two other Materials and methods levels (dose 0 and − 1 were planned in the event of a dose-limiting toxicity - DLT). The phase II portion Eligibility consisted of treatment for up to 6 cycles of combination therapy. Each cycle consisted of temsirolimus dosed Eligible patients were > 18 years old, Eastern Cooperative weekly and bevacizumab every 2 weeks (1 cycle = Oncology Group (ECOG) 0–2 with histological confirmed 4weeks). Invest New Drugs (2019) 37:331–337 333 Efficacy and safety assessment evaluations were performed without knowledge of the clinical
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