Progressive Metastatic Castration-resistant Prostate Cancer Research Articles

A phase II study of once-daily dasatinib for patients with castration-resistant prostate cancer (CRPC) (CA180085)

5147 Background: Dasatinib is a potent oral SRC family kinase inhibitor that also inhibits c-KIT and PDGFR in vitro. The anti-proliferative/anti-metastatic activity as well as osteoclast inhibitory function of dasatinib in pre-clinical models supports its potential as a targeted therapy for prostate cancer. Previously we presented results on BID dosing of dasatinib in the treatment of CRPC (ASCO. 2008 Abstract 5156). A second group of patients (pts) was enrolled to investigate the activity, safety and bone effects of 100 mg once daily dosing. Methods: Male pts with progressive metastatic CRPC, rising PSA, castrate levels of testosterone (< 50 ng/dL) and no prior chemotherapy were enrolled. Dasatinib dose was 100 mg QD. Continuation of bisphosphonates was permitted. Primary endpoint was a composite of: PSA responses, bone scans and disease control by RECIST. Urinary N-telopeptide (uNTX) and bone alkaline phosphatase (BAP) were determined Q 4-weeks as indicators of bone metabolism. Results: 47 pts were treated (median treatment duration was 2.3 months). 11 patients were evaluable by RECIST; of these 64% achieved SD. The composite response rate was (8/47) 17%. Of 22 pts with bone scans, 50% were stable at 12 weeks and 3/9 (33%) were stable at 24 weeks. A prolonged PSA doubling time was observed in 32 of 39 pts (82%), including one pt with a PSA response. Of the pts with evaluable bone markers, including those who continued on bisphosphonate therapy, 20/41 (49%) had a ≥ 35% decrease in uNTX and 21/42 (50%) had a decrease from baseline in BAP. Grade 3/4 adverse events (AEs) were experienced by 13% of pts (diarrhea, asthenia, and pleural effusion [n=1]). Grade 1/2 AEs (≥ 15% of pts) were diarrhea, nausea, headache, fatigue, asthenia, anorexia and dyspnea. Conclusions: Fewer and less severe AEs were observed in all categories for the QD dosing group compared to the previously reported BID dosing cohort. In addition, preliminary clinical activity (tumor and PSA response; decreasing bone turnover [uNTX, BAP]), is now confirmed to be similar in pts treated with 100mg QD and BID dosing. These data support the relevance of further studies of dasatinib in metastatic CRPC. [Table: see text]

Circulating tumour cells as prognostic markers in progressive, castration-resistant prostate cancer: a reanalysis of IMMC38 trial data

Intermediate or surrogate endpoints for survival can shorten time lines for drug approval. We aimed to assess circulating tumour cell (CTC) count as a prognostic factor for survival in patients with progressive, metastatic, castration-resistant prostate cancer receiving first-line chemotherapy. We identified patients with progressive metastatic castration-resistant prostate cancer starting first-line chemotherapy in the IMMC38 trial. CTCs were isolated by immunomagnetic capture from blood samples at baseline and after treatment. Baseline variables, including CTC count, titre of prostate-specific antigen (PSA), and concentration of lactate dehydrogenase (LDH), and post-treatment variables (change in CTCs and PSA) were tested for association with survival with Cox proportional hazards models. Concordance probability estimates were used to gauge discriminatory strength of the informative factors in identifying patients at low-risk and high-risk of survival. Variables associated with high risk of death were high LDH concentration (hazard ratio 6.44, 95% CI 4.24-9.79), high CTC count (1.58, 1.41-1.77), and high PSA titre (1.26, 1.10-1.45), low albumin (0.10, 0.03-0.39), and low haemoglobin (0.72, 0.64-0.81) at baseline. At 4 weeks, 8 weeks, and 12 weeks after treatment, changes in CTC number were strongly associated with risk, whereas changes in PSA titre were weakly or not associated (p>0.04). The most predictive factors for survival were LDH concentration and CTC counts (concordance probability estimate 0.72-0.75). CTC number, analysed as a continuous variable, can be used to monitor disease status and might be useful as an intermediate endpoint of survival in clinical trials. Prospective recording of CTC number as an intermediate endpoint of survival in randomised clinical trials is warranted.

Phase I Trial of the Prostate-Specific Membrane Antigen–Directed Immunoconjugate MLN2704 in Patients With Progressive Metastatic Castration-Resistant Prostate Cancer

MLN2704 is an immunoconjugate designed to deliver the maytansinoid antimicrotubule agent drug maytansinoid-1 directly to prostate-specific membrane antigen (PSMA)-expressing cells via the PSMA-targeted monoclonal antibody MLN591. This novel immunoconjugate has shown cytotoxic anti-prostate cancer activity. This study investigated the safety profile, pharmacokinetics, immunogenicity, and preliminary antitumor activity of MLN2704. Patients with progressive, metastatic, castration-resistant prostate cancer received MLN2704 intravenously over 2.5 hours. Dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), pharmacokinetics, immunogenicity, and antitumor activity were assessed. Twenty-three patients received MLN2704 at doses of 18 to 343 mg/m(2). Eighteen of these patients received >or= three doses at 4-week intervals. Pharmacokinetics of conjugate levels were dose proportional. There was no correlation between clearance and body-surface area. MLN2704 was nonimmunogenic. Study drug-related grade 3 toxicities occurred in three (13%) of 23 patients, including uncomplicated febrile neutropenia (the only DLT) in one patient, reversible elevations in hepatic transaminases, leukopenia, and lymphopenia. No grade 4 toxicities were observed. The most frequent grade 1 or 2 toxicities included fatigue, nausea, and diarrhea. Neuropathy occurred in eight (35%) of 23 patients, including five of six patients treated at 343 mg/m(2). Two (22%) of the nine patients treated at 264 or 343 mg/m(2) had sustained a more than 50% decrease in prostate-specific antigen versus baseline, accompanied by measurable tumor regression in the patient treated at 264 mg/m(2). Therapeutic doses of MLN2704 can be administered safely on a repetitive basis. An MTD was not defined. MLN2704 is being administered at more frequent intervals in ongoing trials to determine an optimal dosing schedule.

Phase I/II trial of the prostate-specific membrane antigen (PSMA)-targeted immunoconjugate MLN2704 in patients (pts) with progressive metastatic castration resistant prostate cancer (CRPC)

4500 Background: MLN2704 is an immunoconjugate that utilizes the PSMA-targeted monoclonal antibody MLN591 to deliver the maytansinoid antimicrotubule agent DM1 directly to prostate cancer cells. This multicenter trial was designed to determine the tolerability, optimal dosing schedule and efficacy of MLN2704 in pts with progressive metastatic CRPC. Methods: Pts aged ≥18 yrs with progressive metastatic CRPC received MLN2704 i.v. over 2.5 hr q1wk, q2wks or q3wks for 12 wks, with additional doses permitted in responders. Doses within a given schedule were escalated in 40% increments in the absence of excessive dose-limiting toxicity (DLT). Results: 61 pts have been treated. The most common adverse events (AEs) were nausea, fatigue, and schedule-dependent neurotoxicity. The only DLT was gr 3 hepatic transaminitis in 1/6 pts at 330 mg/m2 q2wks; the only gr 4 AE was transient neutropenia, in 2 pts (330 mg/m2 q2wks and q3wks). Declines in PSA were most frequent at 330 mg/m2 q2wks ( table ), including 49–88% PSA declines in 4/6 pts. However, given the frequency of grade 2–3 peripheral neuropathy an additional cohort is being treated with 330mg/m2 on days 1 and 15 of a 6-wk cycle. Initial results with this 6-wk schedule indicate PSA declines with a lower incidence of gr 2–3 toxicities, particularly neuropathy. Conclusions: Accrual to the dose-escalation phase is complete. Dose-dependent antitumor effects were seen. Peripheral neuropathy has limited continuous dosing at higher dose levels prompting a schedule change. Accrual to the 6-wk schedule is continuing. [Table: see text] [Table: see text]

Phase 1/2 dose escalation trial of the prostate-specific membrane antigen (PSMA)-targeted immunoconjugate MLN2704 in patients with progressive metastatic castration-resistant prostate cancer (CRPC)

4615 Background: MLN2704 is an immunoconjugate that delivers the maytansinoid antimicrotubule agent DM1 directly to prostate cancer cells via the PSMA-targeted monoclonal antibody (Ab) MLN591. A ph...