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Prostate cancer is the leading cause of cancer-related death in men in the United States. A major cause of drug resistance in prostate and other epithelial tumors may be due to the presence of a fraction of tumor cells that retain the ability to initiate tumors and hence are termed tumor-initiating cells (TIC) or cancer stem cells. Here, we report that darinaparsin, an organic derivative of arsenic trioxide, is cytotoxic to prostate cancer cell lines as well as fresh prostate cancer cells from patients at low micromolar concentrations, and importantly inhibits the TIC subpopulations. It also inhibits growth of the castrate-resistant Du145 prostate tumor propagated as xenograft in mice and inhibits the tumor-initiating potential of prostate cancer cells. Although the mechanism by which darinaparsin acts is not completely known, we show that it kills prostate cancer cells by blocking cells in the G2–M phase of the cell cycle and inhibits Hedgehog signaling by downregulating Gli-2 transcriptional activity. These data provide a rationale for evaluating darinaparsin in patients with castrate-resistant prostate cancer. Mol Cancer Ther; 14(1); 23–30. ©2014 AACR.

Background: BIND-014 is a novel, prostate-specific membrane antigen (PSMA) targeted Accurin™ (polymeric nanoparticle) that contains docetaxel. PSMA is expressed on prostate cancer cells and on vasculature of many solid tumors types. In a phase 1 study in patients with solid tumors and two phase 2 studies, one study in patients with metastatic castration-resistant prostate cancer (mCRPC) and one study in non-small cell lung cancer (NSCLC), BIND-014 was generally well-tolerated and displayed anti-tumor activity across a range of tumor types. Because docetaxel-induced microtubule stabilization has the potential to cause contractile dysfunction in cardiac hypertrophy, the effects of BIND-014 on the cardiovascular system (CV) were examined. Material and Methods: Data from phase 1 and 2 studies were analyzed to determine the cardiovascular effects of BIND-014 administered by a 60-minute intravenous infusion at doses ranging from 3.5-75 mg/m2 on Day 1 of a 21-day cycle (Q3W). Electrocardiogram (ECG) measurements pre- and post-infusion were taken to determine the PR interval, QTc interval, RR interval and QRS complex. In addition, vital signs were collected for heart rate, respiratory rate, and pulse ox (phase 2 only) prior to infusion. Additional treatment-related adverse events (AEs) classified as cardiac disorders were collected throughout the patients' treatment. Results: For all 110 patients tested, the ECG data collected (PR, QTc, and QRS) remained in normal or clinically insignificant abnormal limits. Vitals signs for heart rate, respiratory rate, and pulse ox were also within normal or clinically insignificant abnormal limits. Seven patients experienced drug-related AEs ranging from grade (gr) 1-3; all 7 patients were dosed at 60 mg/m2. These included sinus tachycardia (3 pts, gr 1-2), angina pectoris (2 pts, gr 1&3), atrial fibrillation (1 pt, gr 1), bundle branch block right (1 pt, gr 1), supraventricular extrasystoles (1 pt, gr 1), supraventricular tachycardia (1 pt, gr 1), and tachycardia (1 pt, gr 1). Patients dosed below 60 mg/m2 did not experience any drug-related cardiovascular AEs. Conclusions: BIND-014 administered on a Q3W schedule in the phase 1 and 2 studies appeared well-tolerated at all dose levels studied. For all ECG and pulmonary evaluations, there were no indications of clinically significant cardiac abnormalities, and the incidence and severity of AEs was low. The results provide a basis for concluding that BIND-014 is a safe antitumor agent without the cardiovascular effects typically associated docetaxel. Citation Format: Jason Summa, Jean Kung, Lisa K. Adams, Stephen E. Zale, Hagop Youssoufian. Cardiovascular safety profile of BIND-014 (docetaxel nanoparticles for injectable suspension) evaluated in phase 1 and 2 studies. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A161.

Background: BIND-014 is a novel, prostate-specific membrane antigen (PSMA) targeted AccurinTM (polymeric nanoparticle) containing docetaxel. PSMA is expressed on prostate cancer cells and on vasculature of many solid tumors. In a phase 1 study in patients with solid tumors BIND-014 was generally well-tolerated and displayed anti-tumor activity across a range of tumor types. Evaluation of total drug pharmacokinetics (PK) for BIND-014 in this study demonstrated differentiated plasma profiles compared to docetaxel, which is likely attributable to the vascular retention of the nanoparticle. Total docetaxel quantitation does not distinguish between docetaxel that remains encapsulated or that is released from the nanoparticle. Here we describe a method for separation of encapsulated docetaxel and characterization of the PK of total and encapsulated BIND-014 docetaxel in the phase 1 study. Material and Methods: PK evaluation of BIND-014 was performed in 28 patients on Day 1 of a 21-day cycle (Q3W) over a dose range of 3.5 to 75 mg/m2. On Cycle 1, Day 1, blood was collected at pre-dose and at 30 minutes, 1, 2, 4, 6, 8, 24, 36, and 48 hours post-dose. A solid phase separation method in which released docetaxel binds to the matrix was developed for quantitation of encapsulated docetaxel. Encapsulated and total docetaxel were measured by LCMS. Peak concentration (Cmax), percent encapsulated, minimum concentration (Cmin), time to peak concentration (Tmax), area under the concentration-time curve (AUC), half-life (t1/2), clearance (CL) and volume of distribution (Vd) were determined for each patient using encapsulated and total plasma concentration data. Results: Plasma concentrations of BIND-014 persisted for at least 48 hours at the higher dose levels. Clearance was independent of the administered dose, indicating a linear dose-concentration relationship following a single intravenous administration. Evaluation of encapsulated docetaxel plasma concentrations at all dose levels and all timepoints studied demonstrated mean values between 91% and 98% of total docetaxel, indicating that most circulating docetaxel was encapsulated in nanoparticles. Conclusions: The total concentration of BIND-014 found in circulation compared to the concentration of encapsulated docetaxel was similar, indicating that the majority of docetaxel likely remains contained within the polymeric particle over the time course evaluated, and that the differentiated PK properties of BIND-014 compared to docetaxel, including greater Cmax and AUC and lower Vd and CL, are likely due largely to retention of encapsulated docetaxel within the vascular compartment. These results are consistent with the favorable tolerability profile of BIND-014 despite the markedly higher plasma concentrations for total BIND-014 compared to docetaxel at similar doses. Citation Format: Jason M. Summa, Daniel D. Von Hoff, Jasgit C. Sachdev, Monica M. Mita, Patricia M. LoRusso, Peter D. Eisenberg, Howard A. Burris, Lowell L. Hart, Hagop Youssoufian, Donald M. Parsons, Susan C. Low. Evaluation of total and encapsulated drug pharmacokinetics for BIND-014 (docetaxel nanoparticles for injectable suspension) in a phase 1 study. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B144.

Palifosfamide (Pa) is a novel DNA cross linker molecule that consists of the active anti-tumor metabolite of ifosfamide (I). Potential advantages over I include the abrogation of I-metabolite related toxicities, increased activity by virtue of increased dose delivery over time, and overcoming resistance mediated by aldehyde dehydrogenase (ALDH) overexpression. ALDH overexpression is associated with cancer cell stem-like potential in several tumor types. Pa has broad activity in vitro and in vivo preclinical models and has shown early activity in humans. A previous randomized study evaluating the addition of I to cisplatin and etoposide (E) in small cell lung cancer (SCLC) demonstrated improved survival, but with disabling increase in toxicity with the three-drug combination. We hypothesized that the substitution of Pa for I could increase the therapeutic advantage of a similar three-drug regimen. We initiated a multicenter phase I, open-label, dose-escalation study assessing the safety and efficacy of Pa in combination with carboplatin and E (PaCE regimen) in SCLC and in other cancers in which C+E is considered an appropriate therapeutic option. Tumor responses were assessed by RECIST 1.1 and relevant tumor markers. A total of 15 patients (8 females and 7 males) have been treated to date: 5 with SCLC, 2 with NSCLC, 2 with ovarian, 1 with testicular and 5 with other cancers. Serious adverse events have been reported in six patients, including, thrombocytopenia (4), leukopenia (2), and neutropenia (2). The maximum tolerated dose of Pa was determined to be 130 mg/m2 when administered in combination with E 90 mg/m2 and C AUC4. The dose limiting toxicity was neutropenic fever. To date, two radiological partial responses in five patients with SCLC and one complete response assessed by tumor markers in a patient with testicular cancer have been noted. Conclusion: This study is ongoing, and an additional cohort evaluating Pa 130 mg/m2 in combination with E 100 mg/m2 and C AUC 4 is being evaluated. Further clinical data will be presented. The PaCE combination appears to be tolerable and has demonstrated clinical activity. Based on these data, a confirmatory study in SCLC is planned. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B53.

An orally available form of Darinasparsin (D) an organic arsenical, is currently in Phase I trials. The parenteral form of D has shown antitumor activity in Phase II studies, in particular in patients with T-Cell Lymphoma. We tested D in four prostate cancer cell lines and after a 72h exposure, IC50's ranged from 2.5 to 12 micromolar, Du 145 cells being the most sensitive. Given the reports that arsenic trioxide inhibited Hedgehog signaling (Kim et al, PNAS 107:13432,2110), we tested the effect of D on Hedgehog signaling in prostate stem cells, isolated by adherence to collagen I, expression of CD 44, and lack of expression of CD24. D showed potent inhibition of DU 145 prostate cells adhering to collagen, inhibited prostate spheroid growth (IC50:2uM) and prostate stem cell colony formation. Western analysis showed that D decreased levels of the transcription factor Gli2, a downstream effector of Hedgehog signaling. Combination studies with taxotere, a FDA approved drug for the treatment of patients with advanced prostate cancer, showed synergistic cell kill at high fixed doses of the drugs. In contrast the combination of D with cabazitaxel showed less than additive effects. These studies encourage additional preclinical studies and a clinical trial of D in patients with advanced prostate cancer, alone and in combination with taxotere. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A61.