Drug Development for Prostate Cancer and other Metastatic Processes

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Our understanding of the biology of CRPC progression has led to the discovery of more effective targeted approaches that involve modulation of the androgen-AR system. We are interested in the preclinical and clinical development of CYP17A1 inhibitors and androgen receptor antagonists, with efforts on developing novel agents and characterizing the clinical pharmacology and/or treatment response of marketed agents. In collaboration with Dr. Ravi Madan (GMB, CCR, NCI), we recently completed an open-label phase II clinical trial evaluating the tolerability and efficacy of seviteronel in patients with mCRPC previously treated with enzalutamide. Seviteronel is a selective cytochrome P450c17a (CYP17) 17,20-lyase (lyase) inhibitor and androgen receptor antagonist with activity against prostate cancer cells in vitro and in vivo. Patients with mCRPC whose disease previously progressed while receiving enzalutamide therapy were divided into 2 cohorts on the basis of prior exposure to docetaxel. Seviteronel was administered without routine oral steroids either twice daily with dose titration (450 mg) or once daily without dose titration (600 or 750 mg). The primary objective was to determine the rate of significant prostate-specific antigen response (ie, decline of 50%) after 12 weeks of seviteronel therapy. Seventeen patients, with a median (range) age of 71 (60-92) years, were enrolled, with 8 patients having received prior docetaxel. Patients received a median of 2 cycles of treatment, with most patients discontinuing treatment because of toxicity related to the study drug. The most common adverse events included concentration impairment, fatigue, tremor, and nausea. Despite changes in dosing, the study was closed prematurely because of the high magnitude of toxicity. One (6%) of 17 patients experienced a significant decline in prostate-specific antigen. Seviteronel was not generally well tolerated nor associated with significant clinical responses in patients with mCRPC who had previously received enzalutamide. Further investigation of single-agent seviteronel in this patient population is not warranted; however, studies investigating seviteronel with low-dose dexamethasone are ongoing in patients with androgen receptor-positive tumors. We also conducted a population pharmacokinetic analysis of seviteronel in patients with advanced/metastatic CRPC or breast cancer. This study describes the PK of seviteronel (50-750 mg, QD or BID) using noncompartmental and population approaches from 243 patients with advanced breast or prostate cancer pooled across 4 clinical studies. First dose and steady-state PK were examined, as well as covariates including prandial status, sex and concomitant dexamethasone. Seviteronel PK can be characterized by transit absorption and a bi-phasic first-order elimination while accounting for covariance between random effects. Prandial status did not significantly affect any parameters to a clinically-relevant extent. Both sex and body weight were significant covariates on clearance, explaining 37% of the interindividual variability on that parameter. There were no significant effects from the race or the presence of a corticosteroid (either dexamethasone or prednisone). Seviteronel demonstrates linear PK over the dose range of 50-750 mg given either BID or QD in men with advanced CRPC or men and women with breast cancer. The disposition of seviteronel following oral administration is well described by this population PK model and can be used for accurate simulations for future studies with body weight and sex affecting clearance, but not to a clinically-meaningful degree requiring a change in the current dosing scheme. We are interested in understanding the mechanisms of resistance of prostate cancer regimens. Intratumoral hypoxia is also associated with CRPC progression and treatment resistance. Upregulation of hypoxia inducible factor-1alpha (HIF-1a) in hypoxic tumor cells provides a mechanism of acquired resistance to current hormonal therapies and chemotherapies by increasing angiogenesis and metastasis. Given that both AR and HIF-1a are key regulators of these processes, dual targeting of both signaling axes represents an attractive therapeutic approach. Enzalutamide is a potent second-generation androgen receptor (AR) antagonist with activity in CRPC. Although enzalutamide is initially effective, disease progression inevitably ensues with the emergence of resistance. Effective treatments for patients with mCRPC following disease progression on enzalutamide is currently an unmet clinical need. Our laboratory has previously shown that simultaneous inhibition of HIF-1a and AR pathways in vitro resulted in synergistic inhibition of AR-and HIF-dependent expression and prostate cancer cell growth, suggesting a possible mechanism for overcoming enzalutamide resistance and potentiating anti-AR therapy. NLG207 (formerly CRLX101) is a nanoparticle drug conjugate composed of 20(S)-camptothecin (a potent and highly selective topoisomerase I inhibitor) and a HIF1a inhibitor. Combination treatment with NLG207 and enzalutamide was evaluated in preclinical prostate cancer models of enzalutamide resistance. The effect of NLG207 and enzalutamide on average tumor volume and tumor re-growth after 3 weeks of treatment were evaluated in vivo using the subcutaneous 22Rv1 xenograft and castrated subcutaneous VCaP xenograft models. NLG207 in combination with enzalutamide reduced average tumor volume by 93% after 3 weeks of treatment (p0.05) and reduced the median rate of tumor growth by 54% (p0.0001) in comparison to vehicle control in the subcutaneous 22Rv1 xenograft model. The addition of NLG207 also enhanced the efficacy of enzalutamide alone in the castrated subcutaneous VCaP xenograft model, decreasing the median rate of tumor growth by 51% (p=0.0001). In vitro assessments of cell proliferation and gene expression further demonstrated anti-tumor activity via AR-HIF-1a crosstalk inhibition. Combination treatment with NLG207 and enzalutamide was shown to be effective in preclinical prostate cancer models of enzalutamide resistance. In collaboration with Dr. Madan (NCI), we are currently enrolling patients on a single arm pilot study to evaluate the safety and activity of combining CRLX101 with enzalutamide in patients with progressive mCRPC following prior enzalutamide treatment (NCT03531827). Moreover, we conducted a population pharmacokinetic analysis of NLG207 in adults with advanced solid tumors to characterize the complex PK of NLG207 and better describe CPT release from nanoparticles using a semi-mechanistic population PK (popPK) model. From 27 patients enrolled on two phase II clinical trials (NCT02769962 and NCT03531827), dense sampling was performed up to 48 hours post-administration of NLG207 during cycle one or six of treatment; samples were also collected at 360 hours post-dose. Bound and free CPT concentrations were quantified from each sample, resulting in 477 observations to build a popPK model using non-linear mixed-effects modelling. The PK of NLG207 was characterized by combining two linear two-compartment models with first-order kinetics each to describe bound and free CPT. Allometric scaling based on body weight provided the best body-size descriptor for all PK parameters. The semi-mechanistic popPK model confirmed nanoparticle behavior of bound CPT and mechanistically characterized CPT release from NLG207. The current analysis provides a strong foundation for future study as a potential predictive tool in ongoing NLG207 clinical trials.