ModraDoc006, an oral docetaxel formulation in combination with ritonavir (ModraDoc006/r), in metastasized castration-resistant prostate cancer (mCRPC): A multicenter phase I study.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 79-79
Author(s):  
Marit Vermunt ◽  
Debbie Robbrecht ◽  
Lot Devriese ◽  
Julie Janssen ◽  
Marianne Keessen ◽  
...  
Keyword(s):  
Adverse Events ◽  
Specific Antigen ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Treatment Naïve ◽  
Previously Treated ◽  
Grade 3 ◽  
Weekly Cycles ◽  
Dose Levels ◽  
Anti Tumor Activity

79 Background: ModraDoc006 is a novel formulation of docetaxel and to enhance bioavailability, this tablet is co-administered with ritonavir (r), an inhibitor of cytochrome p450 3A4 and P-glycoprotein. The safety, anti-tumor activity and pharmacokinetics (PK) of ModraDoc006/r were investigated by dose-escalation in patients with mCRPC, to propose a recommended phase 2 dose (RP2D). Methods: Progressive mCRPC patients, who were treatment naïve or previously treated with either abiraterone or enzalutamide, received a maximum of 30 weekly cycles of ModraDoc006/r in a bi-daily once weekly (BIDW) schedule. Plasma docetaxel concentrations were determined at the first 2 cycles up to 48h after intake of ModraDoc006/r. Adverse events were evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Serum Prostate Specific Antigen (PSA) levels were assessed every 6 weeks. Results: 23 patients were included, of whom 20 were evaluable for safety and PK. In 5 patients, the initial 30-20/100-100 dose was explored, with observation of one dose limiting toxicity (DLT) (grade 3 alanine aminotransferase increase). The next dose level of 30-20/200-200 resulted in 2 DLTs in 6 patients (grade 3 diarrhea and mucositis). Subsequently, two intermediate dose levels: 30-20/200-100 and 20-20/200-100 were explored in 6 and 3 patients. At the 30-20/200-100 dose, an adequate docetaxel exposure was achieved and 1 DLT (grade 3 diarrhea) was observed, with no DLTs at the 20-20/200-100 dose. Common treatment-related AEs (occurring in > 30% of all patients) were diarrhea, nausea, vomiting, anorexia and fatigue. Five patients completed the maximum of 30 weekly treatments. In 10 patients, evaluable for anti-tumor activity after treatment with ≥9 cycles, 4 confirmed and 2 non-confirmed PSA responses ( > 50% decrease) were observed. Conclusions: The RP2D of BIDW ModraDoc006/r in mCRPC was established as 30-20/200-100 mg. These results are encouraging for further development of ModraDoc006/r as a convenient, safe and effective alternative to IV docetaxel for mCRPC patients. A phase 2b study is currently being conducted. Clinical trial information: NCT03136640.

scholarly journals Phase III Study of Cabozantinib in Previously Treated Metastatic Castration-Resistant Prostate Cancer: COMET-1

2016 ◽  
Vol 34 (25) ◽  
pp. 3005-3013 ◽  
Author(s):  
Matthew Smith ◽  
Johann De Bono ◽  
Cora Sternberg ◽  
Sylvestre Le Moulec ◽  
Stéphane Oudard ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Adverse Events ◽  
Specific Antigen ◽  
Hazard Ratio ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Bone Biomarkers ◽  
End Point ◽  
Castration Resistant ◽  
Previously Treated

Purpose Cabozantinib is an inhibitor of kinases, including MET and vascular endothelial growth factor receptors, and has shown activity in men with previously treated metastatic castration-resistant prostate cancer (mCRPC). This blinded phase III trial compared cabozantinib with prednisone in patients with mCRPC. Patients and Methods Men with progressive mCRPC after docetaxel and abiraterone and/or enzalutamide were randomly assigned at a two-to-one ratio to cabozantinib 60 mg once per day or prednisone 5 mg twice per day. The primary end point was overall survival (OS). Bone scan response (BSR) at week 12 as assessed by independent review committee was the secondary end point; radiographic progression-free survival (rPFS) and effects on circulating tumor cells (CTCs), bone biomarkers, serum prostate-specific antigen (PSA), and symptomatic skeletal events (SSEs) were exploratory assessments. Results A total of 1,028 patients were randomly assigned to cabozantinib (n = 682) or prednisone (n = 346). Median OS was 11.0 months with cabozantinib and 9.8 months with prednisone (hazard ratio, 0.90; 95% CI, 0.76 to 1.06; stratified log-rank P = .213). BSR at week 12 favored cabozantinib (42% v 3%; stratified Cochran-Mantel-Haenszel P < .001). rPFS was improved in the cabozantinib group (median, 5.6 v 2.8 months; hazard ratio, 0.48; 95% CI, 0.40 to 0.57; stratified log-rank P < .001). Cabozantinib was associated with improvements in CTC conversion, bone biomarkers, and post–random assignment incidence of SSEs but not PSA outcomes. Grade 3 to 4 adverse events and discontinuations because of adverse events were higher with cabozantinib than with prednisone (71% v 56% and 33% v 12%, respectively). Conclusion Cabozantinib did not significantly improve OS compared with prednisone in heavily treated patients with mCRPC and progressive disease after docetaxel and abiraterone and/or enzalutamide. Cabozantinib had some activity in improving BSR, rPFS, SSEs, CTC conversions, and bone biomarkers but not PSA outcomes.

Efficacy, safety, tolerability, and pharmacokinetics of EPI-506 (ralaniten acetate), a novel androgen receptor (AR) N-terminal domain (NTD) inhibitor, in men with metastatic castration-resistant prostate cancer (mCRPC) progressing after enzalutamide and/or abiraterone.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 5032-5032
Author(s):  
Kim N. Chi ◽  
Ulka N. Vaishampayan ◽  
Michael S. Gordon ◽  
David C. Smith ◽  
Erin Rudsinski ◽  
...  
Keyword(s):  
Phase 1 ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Once Daily ◽  
Castration Resistant ◽  
Transcription Inhibitor ◽  
Grade 3 ◽  
Favorable Safety ◽  
Dose Levels ◽  
Anti Tumor Activity

5032 Background: EPI-506 (ralaniten acetate) is a first-in-class small molecule transcription inhibitor of the AR NTD. Nonclinical studies demonstrated activity against both full length and resistance-related AR species, including AR-v7. Methods: Open-label, single-arm, Phase 1/2 study evaluating EPI-506 administered orally once-daily. The Phase 1 is a 3+3 design to establish the safety, pharmacokinetic (PK) profile, and recommended phase 2 dose of EPI-506. Anti-tumor activity is also evaluated. Inclusion criteria included: mCRPC with progression after ≥1 line of hormonal therapy or chemotherapy, and progression on enzalutamide and/or abiraterone. Results: Eighteen patients (pts) have been enrolled in the dose escalation phase over 5 dose levels (80, 160, 320, 640, 1280 mg). Median age was 71 (range 58-87). Prior treatments included enzalutamide only (N = 7), abiraterone only (N = 2) or both (N = 9). Six pts have had prior chemotherapy. Seven pts have discontinued due to disease progression and 2 pts due to adverse events (AEs): Grade 4 elevated amylase (related) and Grade 4 gastrointestinal bleeding (unrelated). Median exposure was 98.5 days (range 26-338). Most frequently reported treatment emergent AEs were diarrhea (N = 7), nausea (N = 5) and fatigue (N = 3). One Grade 3 AE (AST elevation) at 1280 mg and one Grade 4 AE (increased amylase) at 640 mg were reported. PK data demonstrate a dose-proportional profile for Cmax and AUC coupled with an initial negative food effect up to 640 mg. At week 4 of continuous dosing, 3 of 18 evaluable pts demonstrated PSA declines ranging from 9 to 18% receiving doses ≥640 mg. Conclusions: EPI-506 is well-tolerated with a favorable safety profile. PK indicates dose-proportionality. PSA declines have been observed at doses associated with sub-therapeutic exposure in preclinical studies. This study is the first to evaluate targeting the AR NTD, a region critical for transcriptional function of all known AR species. Clinical trial information: NCT02606123.

scholarly journals Abiraterone in chemotherapy-naive patients with metastatic castration-resistant prostate cancer: a systematic review of ‘real-life’ studies

2018 ◽  
Vol 10 (10) ◽  
pp. 305-315 ◽  
Author(s):  
Michele Marchioni ◽  
Petros Sountoulides ◽  
Maida Bada ◽  
Sebastiano Rapisarda ◽  
Cosimo De Nunzio ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Adverse Events ◽  
Meta Analysis ◽  
Real Life ◽  
Castration Resistant Prostate Cancer ◽  
The Real ◽  
Castration Resistant ◽  
Real Life Setting ◽  
Grade 3 ◽  
Baseline Psa

Background: To assess the efficacy and safety of treatment with abiraterone acetate (AA) in chemotherapy-naïve men with metastatic castration-resistant prostate cancer (mCRPC) in the ‘real-life’ setting. Methods: Data acquisition on the outcomes of the use of AA in chemotherapy-naive patients with mCRPC was performed by a MEDLINE comprehensive systematic literature search using combinations of the following key words: ‘prostate cancer’, ‘metastatic’, ‘castration resistant’, ‘abiraterone’, ‘real life’, and excluding controlled clinical trials (phase II and III studies). Identification and selection of the studies was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) criteria. Outcomes of interest were overall survival (OS), progression-free survival (PFS), 12-week 50% reduction in prostate-specific antigen (PSA), and grade 3 and higher adverse events. Data were narratively synthesized in light of methodological and clinical heterogeneity. Results: Within the eight identified studies that fulfilled the criteria, a total of 801 patients were included in the meta-analysis. Baseline PSA ranged between 9.5 and 212.0 ng/ml. Most of the patients had bone metastases. Duration of treatment with AA was longer in the studies with lower baseline PSA levels. The median OS ranged between 14 and 36.4 months. The PFS, assessed according to different definitions, ranged from 3.9 to 18.5 months. A 50% PSA reduction at 12 weeks was reached by a variable percentage of patients ranging from 36.0% to 62.1%. Finally, the rate of grade 3 and higher adverse events was reported in three studies and ranged from 4.4% to 15.5%. Conclusions: Despite the high grade of heterogeneity among studies, treatment with AA seems to ensure good survival outcomes in the ‘real-life’ setting. However, prospective studies based on patients’ characteristics being more similar to ‘real-life’ patients are necessary.

scholarly journals Combined CTLA-4 and PD-L1 blockade in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer is associated with increased myeloid and neutrophil immune subsets in the bone microenvironment

2021 ◽  
Vol 9 (10) ◽  
pp. e002919
Author(s):  
Sumit K Subudhi ◽  
Bilal A Siddiqui ◽  
Ana M Aparicio ◽  
Shalini S Yadav ◽  
Sreyashi Basu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Adverse Events ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Immune Checkpoints ◽  
Castration Resistant Prostate Cancer ◽  
Bone Microenvironment ◽  
Castration Resistant ◽  
Number Of Patients ◽  
Measurable Disease

BackgroundImmune checkpoint therapy (ICT) has low response rates in patients with metastatic castration-resistant prostate cancer (mCRPC), in part due to few T cells in the tumor microenvironment (TME). Anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) promotes intratumoral T cell infiltration but induces upregulation of PD-1 and programmed death ligand-1 (PD-L1) within the prostate TME. Combined anti-CTLA-4 plus anti-PD-1 can partly overcome this adaptive resistance and was recently shown to augment responses in patients with mCRPC with measurable disease. Although bone is the most common site of metastasis in prostate cancer, patients with bone-predominant disease are frequently excluded from trials because they lack measurable disease, which limits assessment of disease progression and tissue sampling. We therefore designed this study to investigate combined ICT in mCRPC to bone.HypothesisCombined anti-CTLA-4 (tremelimumab) plus anti-PD-L1 (durvalumab) is safe and well tolerated in patients with chemotherapy-naïve mCRPC to bone.Patients and methodsIn this single-arm pilot study, men with chemotherapy-naïve mCRPC to bone received tremelimumab (75 mg intravenous) plus durvalumab (1500 mg intravenous) every 4 weeks (up to four doses), followed by durvalumab (1500 mg intravenous) maintenance every 4 weeks (up to nine doses). The primary endpoint was incidence of adverse events. Secondary endpoints included serum prostate-specific antigen (PSA), progression-free survival (PFS), radiographic PFS (rPFS), and maximal PSA decline.ResultsTwenty-six patients were treated between August 8, 2017 and March 28, 2019. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 11 patients (42%), with no grade 4 or 5 events. TRAEs leading to discontinuation occurred in three patients (12%). PSA decline ≥50% occurred in three patients (12%). Six patients (24%) achieved stable disease for >6 months. At a median follow-up of 43.6 months, median rPFS was 3.7 months (95% CI: 1.9 to 5.7), and median overall survival was 28.1 months (95% CI: 14.5 to 37.3). Post-treatment evaluation of the bone microenvironment revealed transcriptional upregulation in myeloid and neutrophil immune subset signatures and increased expression of inhibitory immune checkpoints.ConclusionsTremelimumab plus durvalumab was safe and well tolerated in patients with chemotherapy-naïve mCRPC to bone, with potential activity in a small number of patients as measured by rPFS. Combination of CTLA-4 and PD-L1 blockade with therapies targeting the myeloid compartment or other inhibitory immune receptors may be necessary to overcome mechanisms of resistance within prostate bone microenvironment.Trial registration numberNCT03204812.

scholarly journals Cabazitaxel for Metastatic Castration-Resistant Prostate Cancer: Retrospective Data Analysis from an Indian Centre

2016 ◽  
Vol 9 (2) ◽  
pp. 506-515
Author(s):  
Vanita Noronha ◽  
Amit Joshi ◽  
Vamshi Krishna Muddu ◽  
Vijay Maruti Patil ◽  
Kumar Prabhash
Keyword(s):  
Prostate Cancer ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Castration Resistant Prostate Cancer ◽  
Free Survival ◽  
Castration Resistant ◽  
Retrospective Data Analysis ◽  
Grade 3 ◽  
Named Patient Programme

Objective: To determine the efficacy and safety of cabazitaxel in metastatic castration-resistant prostate cancer (mCRPC) patients from the named patient programme (NPP) at our centre. Methods: mCRPC patients who progressed on docetaxel were given cabazitaxel intravenously every 3 weeks until disease progression or unacceptable toxicity occurred. Overall survival, progression-free survival, prostate-specific antigen response, quality of life (QOL) changes, and safety were reported. Results: Nine men received cabazitaxel (median: 7 cycles; range: 1–27) under the NPP and were followed until death. Median survival was 14.07 months (1.07–23.80) and progression-free survival was 2.67 months (1.07–20.27). QOL was stable for most patients. Common adverse events (grade ≥3) were neutropenia (n = 8), anaemia (n = 4), and leucopenia (n = 4). Conclusion: These data from 9 patients are consistent with the results reported in the TROPIC study with a manageable safety profile.

Low-Dose Docetaxel Combined with Dexamethasone Is Feasible for Patients with Castration-Resistant Prostate Cancer

Chemotherapy ◽  
2015 ◽  
Vol 61 (1) ◽  
pp. 23-31 ◽  
Author(s):  
Noriyoshi Miura ◽  
Nozomu Tanji ◽  
Yutaka Yanagihara ◽  
Terutaka Noda ◽  
Seiji Asai ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Low Dose ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Hematological Toxicity ◽  
Castration Resistant Prostate Cancer ◽  
Gastric Bleeding ◽  
Castration Resistant ◽  
Analgesic Agents ◽  
Grade 3

Aim: Docetaxel-based chemotherapy against castration-resistant prostate cancer (CRPC) has recently been shown to be effective and tolerable. The objective of this study was to retrospectively evaluate the efficacy and toxicity of low-dose docetaxel in combination with dexamethasone. Methods: Thirty-seven CRPC patients were administered a treatment regimen consisting of 50 mg/m2 docetaxel once every 3-4 weeks and 1 mg dexamethasone daily at our institution, between November 2004 and April 2014. Results: Twenty-four patients (65%) had a decrease in serum prostate-specific antigen (PSA) >50%. The median overall survival (OS) and PSA progression-free survival were 26.2 and 10.0 months, respectively. Ten of 12 patients (83%) taking analgesic agents reduced their intake because of decreased pain levels. Grade 3 febrile neutropenia occurred in 2 patients (5%). Nonhematological toxicities were less frequent but sometimes severe. Treatment-related death occurred in 2 octogenarian patients, 1 due to gastric bleeding and the other due to infective endocarditis. Conclusion: Low-dose docetaxel in combination with dexamethasone is feasible in Japanese CRPC patients. Hematological toxicity is less than that seen with standard docetaxel therapy, but it is necessary to monitor patients for severe nonhematological toxicities, particularly very elderly patients.

Phase II trial of bevacizumab and lenalidomide with docetaxel and prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC).

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 207-207 ◽  
Author(s):  
Bamidele Adesunloye ◽  
Xuan Huang ◽  
Yangmin M. Ning ◽  
Ravi A. Madan ◽  
James L. Gulley ◽  
...  
Keyword(s):  
Phase Ii Trial ◽  
Antiangiogenic Therapy ◽  
Perianal Fistula ◽  
Osteonecrosis Of The Jaw ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
High Incidence ◽  
Radiographic Disease ◽  
Grade 3 ◽  
Anti Tumor Activity

207 Background: Angiogenesis may be vital to mCRPC. Previously, we had shown the potent anti−tumor activity of dual antiangiogenic therapy by combining thalidomide (T) and bevacizumab (B) with docetaxel (D) and prednisone (P) in mCRPC (Ning JCO 2010). We hypothesized that combining lenalidomide (L), an analogue of T, with B, D, and P would have a more favorable efficacy/toxicity profile. Methods: All patients (pts) had chemotherapy−naïve mCRPC. 3 pts received R 15 mg daily, 3 pts had 20 mg daily, and the rest had 25 mg daily for 14 days of every 21−day cycle (C). All pts received D 75 mg/m2 and B 15 mg/kg on day 1 with P 10 mg and enoxaparin daily throughout each C. Pegfilgrastim was given on day 2. PSA was assayed each C with imaging after C2 and then after every 3C. Results: 47 of the planned 51 pts have been enrolled. Median age was 66 (51−82), Gleason score 8 (5−10), on−study PSA 91.6 ng/ml (0.15−3520), pre−study PSA doubling time 1.43 months (0.52−6.73), number of Cs 14 (1−31), and PFS was 19.3 months as of this analysis. Among 45 pts who have completed ≥2 cycles, 39 (86.7%) and 30 (66.7%) had PSA declines of ≥50% and ≥75%, respectively. Of 29 pts with measurable disease there were 2 CR, 21 PR, and 6 SD (79.3% overall RR). 10/47 pts were taken off study for radiographic disease progression and 5/47 for other reasons. Grade ≥3 toxicities included neutropenia (24/47), anemia (9/47), thrombocytopenia (5/47), weight loss (1/47), hypertension (3/47), and febrile neutropenia (4/47). Other toxicities included perianal fistula (3/47), rectal fissure (1/47), myocardial infarction (1/47), and osteonecrosis of the jaw (ONJ) (16/47, 34.0%). At the time of diagnosis of ONJ, 9/16 pts were on bisphosphonates and 3/16 had used bisphosphonates previously. Although the incidence of ONJ was higher than the 18.3% reported by Ning, a recent study of carboplatin plus weekly docetaxel reported an incidence of 29.3%. Conclusions: Dual antiangiogenic therapy with, B and L, plus D and P was associated with high PSA (86.7%) and tumor (79.3%) responses with manageable toxicities. Further studies are underway to explore the high incidence of ONJ.

Update on KEYNOTE-199, cohorts 1-3: Pembrolizumab (pembro) for docetaxel-pretreated metastatic castration-resistant prostate cancer (mCRPC).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 104-104 ◽  
Author(s):  
Emmanuel S. Antonarakis ◽  
Josep M. Piulats ◽  
Marine Gross-Goupil ◽  
Jeffrey C. Goh ◽  
Ulka N. Vaishampayan ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Response Rate ◽  
Phase 2 ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Phase 2 Study ◽  
Previously Treated ◽  
Grade 3 ◽  
Clinical Trial Information

104 Background: The KEYNOTE-199 multicohort phase 2 study (NCT02787005) showed that pembro monotherapy has antitumor activity and acceptable safety in patients (pts) with mCRPC previously treated with a next-generation hormonal agent (NHA) and docetaxel in cohort 1 (C1) (RECIST-measurable, PD-L1+ disease), C2 (RECIST-measurable, PD-L1− disease), and C3 (bone-predominant disease, irrespective of PD-L1). Updated results with additional follow-up for C1-3 are presented. Methods: Pts previously received ≥1 NHAs and 1 or 2 chemotherapies, including docetaxel. Pts received pembro 200 mg Q3W for 35 cycles or until progression or intolerable toxicity. Primary end point was ORR. Key secondary end points were DCR, DOR, PSA (≥50%) response rate, rPFS, OS, and safety. Results: Of 258 pts enrolled (C1=133; C2=67; C3=58), 6 completed (C1=4; C3=2) and 252 discontinued (C1=129; C2=67; C3=56) therapy, primarily due to progression (C1=106; C2=61; C3=45). Median follow-up was 9.6 mo (C1, 9.5; C2, 7.9; C3, 14.2). ORR (95% CI) for pts with measurable disease was 6% (2.6-11.5) in C1 and 3% (0.4-10.4) in C2 (Table; includes other efficacy results). Treatment-related AEs of any grade/grade 3-5 occurred in 57%/16% in C1, 60%/15% in C2, and 71%/17% in C3. 1 pt in each cohort died of a treatment-related AE (C1, sepsis; C2, unknown; C3, immune-related pneumonitis). Conclusions: With additional follow-up, pembro monotherapy continued to show antitumor activity and disease control in pts with RECIST-measurable and bone-predominant mCRPC previously treated with both NHA and docetaxel. Pts experienced durable responses. Safety was consistent with the known safety profile of pembro. Clinical trial information: NCT02787005. [Table: see text]

Overcoming docetaxel resistance in advanced castration-resistant prostate cancer (CRPC): A phase I/II trial of the combination of temsirolimus and docetaxel.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 250-250 ◽  
Author(s):  
Ignacio Duran ◽  
Clara Montagut ◽  
Emiliano Calvo ◽  
Susana Galtes ◽  
Alicia Navarrete ◽  
...  
Keyword(s):  
Advanced Solid Tumors ◽  
Castration Resistant Prostate Cancer ◽  
Mechanisms Of Resistance ◽  
Docetaxel Resistance ◽  
Castration Resistant ◽  
Common Grade ◽  
Grade 3 ◽  
Recommended Phase Ii Dose ◽  
Dose Levels ◽  
Preclinical Work

250 Background: Mechanisms of resistance to docetaxel (D) are not fully understood. Preclinical work showed that administration of temsirolimus (T) between courses of D delays the growth of PTEN deficient tumors in xenografts. (Wu et al. Cancer Res 2005) The current study aims to determine the recommended phase II dose (RPTD), toxicity, pharmacokinetics (PK) and preliminary activity of D in combination with T in CRPC patients (pts). Methods: Pts aged ≥ 18 with advanced solid tumors refractory to standard therapy, ECOG ≤2, adequate bone marrow and renal function were eligible. D was given once q. 3 weeks along with T on days 2, 9 &16. The protocol was later amended and day 9 of T omitted due to excessive myelotoxicity. A 3+3 rule dose escalation was used with the next dose levels (DL) planned: DL1: D 50mg/m2, T 15 mg; DL2: D 65mg/m2, T 15 mg; DL3: D 75mg/m2, T 15 mg; DL4: D 75mg/m2, T 25 mg. An expanded cohort for pts with CRPC who have progressed to D will enroll pts once the RPTD has been defined. Results: To date 13 pts have been enrolled, median age = 65 (range 35–76), 9 male and 8 ECOG 0, Forty-seven cycles (median: 2; range: 1–9) were administered. The most frequent related adverse events (AEs) of all grades expressed as % of cycles were: leucopenia (80.8%), hyperglycemia (70.2%), anemia (68.1%) and hypercholesterolemia (65.9%). The most common Grade 3–4 AEs as % of cycles were: leucopenia (27.6%), neutropenia (29.7%), and hypophosphatemia (23%). Two pts in DL2 experienced dose limiting toxicities (DLT) consisting of intolerable grade 2 mucositis and febrile neutropenia respectively. DL1 was expanded and 3 additional pts treated with no DLTs. No drug-drug PK interactions were observed. Among 13 pts evaluable for response, 6 (2 pancreas, 2 CRPC, 1 rectal and 1 sarcoma) achieved stable disease. One pt with CRPC who had previously progressed on docetaxel received 9 cycles of treatment with sustained clinical benefit. The expanded cohort for CRPC patients is opened and recruiting. Conclusions: T and D can be safely combined at reduced doses of both agents with no PK interaction. Preliminary antitumor activity has been observed in CRPC patients. Data on the expanded cohort will be presented.

Results of a phase II trial of abiraterone acetate (AA) combined with dutasteride (DUT) for men with metastatic castration resistant prostate cancer (mCRPC).

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 126-126
Author(s):  
Rana R. McKay ◽  
Lillian Werner ◽  
Katherine A. Zukotynski ◽  
Liran Domachevsky ◽  
Aymen Elfiky ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Scan ◽  
Specific Antigen ◽  
Abiraterone Acetate ◽  
Type I ◽  
Castration Resistant Prostate Cancer ◽  
Prior Therapy ◽  
Castration Resistant ◽  
Psa Nadir ◽  
Grade 3

126 Background: Although abiraterone acetate (AA), a CYP17 inhibitor, increases survival in men with metastatic castration resistant prostate cancer (mCRPC), tumors eventually progress on therapy. The primary purpose of this study was to identify mechanisms of resistance to AA via analysis of the androgen receptor signaling pathway in serial tumor biopsies of men receiving AA and dutasteride (DUT), a type I and II 5-α reductase inhibitor. In this analysis, we report secondary endpoints including prostate specific antigen (PSA) response, toxicity, and incidence of flare. Methods: We enrolled 40 men with mCRPC. Patients initially received AA (1,000 mg daily) and prednisone (5 mg daily). After two months (mos), DUT (3.5 mg daily) was added. Therapy was continued until radiographic progression. A flare was recorded on bone scan, CT, or both if there were worsening lesions from baseline to 3 mos, decreasing PSA more than 50% from baseline at 3 mos, and stabilization or reduction of lesions at 6 mos. Results: Median follow-up was 13 mos. At the time of analysis, nine men remain on treatment. Twenty five percent and 18% of men received prior therapy with ketoconazole and/or chemotherapy, respectively. The median PSA at baseline was 28.8 ng/mL. After 2 mos of AA, median PSA declined by 54% to 10.9 ng/mL. Median PSA nadir was 6.3 ng/mL, reached at a median of 3.2 mos from baseline. 34 men (85%) experienced some degree of PSA decline. Twenty four men (60%) had a greater than or equal to 50% PSA decline and 12 (30%) had a greater than or equal to 90% PSA decline, reached at a median of 1.4 and 2.4 mos from baseline, respectively. There were 73% grade 1, 23% grade 2, 4% grade 3, and no grade 4 adverse events (AEs).AEs of interest included fatigue (45%), hypertension (38%, n=2 grade 3), hypokalemia (15%, n=0 grade 3), liver function test increases (15%), and edema (2%, n=0 grade 3). Seventeen men had imaging available for analysis, of whom four (23%) had flare on both 3 mos CT and bone scan and four (23%) had flare on only 3 mos CT scan. Conclusions: Given time of median PSA nadir, DUT may enhance efficacy of AA, though this warrants further investigation. Therapy with AA, prednisone (5 mg daily), and DUT is well tolerated with low rates of severe mineralocorticoid toxicity. Flare is seen on imaging in 47% of patients receiving AA. Biopsy data evaluating mechanisms for resistance to AA are not yet available. Clinical trial information: NCT01393730.

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