Cancer Therapy: Clinical Whole Blood Stem Cell Reinfusion and Escalated Dose Melphalan in Castration-Resistant Prostate Cancer: A Phase 1 Study Jonathan Shamash 1 , Jimmy Jacob 2 , Samir Agrawal 1 , Thomas Powles 1 , Katherine Mutsvangwa 1 , Peter Wilson 1 , and Justin Stebbing 1 Abstract Purpose: Nontaxane-based chemotherapeutic options in castrate-resistant prostate cancer (CRPC) are limited despite the long natural history of the disease. We carried out a phase 1 dose-escalation study of the alkylating agent melphalan with autologous stem cell transplantation, comparing rapid changes in circulating tumor cells (CTC) and prostate-specific antigen (PSA) as a measure of response. Experimental Design: Cohorts of individuals with advanced CRPC received high-dose intravenous melphalan, and autologous blood was returned to patients during treatment. The efficacy endpoints were the PSA reduction rate, CTC response, survival parameters, toxicity and whether reinduction of endocrine sensitivity occurred. Results: Twenty-four patients were recruited. Dose escalation was feasible with the highest dose cohort being reached. Of 23 individuals evaluable for response, 16 had a PSA response of more than 30%; of 11 patients with soft tissue disease, 4 achieved a partial response and 7 had stable disease. Patients with CTC counts that decreased to less than 5 within 2 weeks from the start of therapy had a longer overall survival (30.6 months vs. 15.3 months, P ¼ 0.03) Treatment was associated with myelosuppression and frequent hospitalizations. In 20 patients after the study, hormone therapy was reintroduced when PSA increased again; response rates were high. Conclusions: Autologous transplantation following high-dose alkylating agent chemotherapy induces responses but proved toxic, although dose escalation proved possible. The possibility of using CTCs to identify responders at two weeks may be used to justify such an intensive approach. Many individuals went on to further respond to both docetaxel and hormonal therapy. Clin Cancer Res; 18(8); 2352–9. Ó2012 AACR. Introduction The management of prostate cancer is changing rapidly (1), and new agents such as abiraterone and MDV3100 are likely to alter the landscape, especially for those individuals with resistant prostate cancer (CRPC) who have already received chemotherapy (2–5). Although locally advanced and metastatic cases are managed by androgen deprivation in the first instance, once this treatment fails the use of chemotherapy is usually con- sidered. The most established therapy is with single-agent docetaxel, following the demonstration that it was able to modestly prolong survival in 2 randomized phase 3 studies (6, 7). A number of other agents have been shown to be efficacious, in keeping with the long natural history of CRPC. Cabazitaxel has now been approved by the U.S. Food and Drug Administration though many consider the toxicities unacceptable (8, 9); alkylating agents have also been used in the management of prostate cancer for many years although no effects on survival have been observed (10, 11). In one phase 2 study of intravenous melphalan using 30 mg/m 2 every 4 weeks in 27 patients, there were no objective responses although one quarter received more than 4 months of therapy due to overall disease stabilization (12). We have used chlorambucil-based therapy in a large number of CRPC cases and have shown disease stabilization and importantly reinduction of hormone sensitivity, that is, endocrine treatment (GnRH analogues, peripheral antiandrogens, corticosteroids, and estrogens) failing before chemotherapy subsequently Authors' Affiliations: 1 Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom and 2 Departments of Surgery and Cancer, Imperial College, Hammersmith Camus, London, United Kingdom Clinical trials number: (EUDRACT) 2006-002210-36. Corresponding Author: Justin Stebbing, Imperial College/Imperial Health- care NHS Trust, Charing Cross Hospital, 1st Floor, E Wing, Fulham Palace Road, London, W6 8RF United Kingdom. Phone: 44-203-311-8295; Fax: 44-203-311-1433; E-mail: j.stebbing@imperial.ac.uk doi: 10.1158/1078-0432.CCR-11-3293 Ó2012 American Association for Cancer Research. Clinical Cancer Research Clin Cancer Res; 18(8) April 15, 2012 2352 on May 26, 2020. © 2012 American Association for Cancer Research. clincancerres.aacrjournals.org Downloaded from Published OnlineFirst March 5, 2012; DOI: 10.1158/1078-0432.CCR-11-3293