A phase I open-label study of escalating-dose oral cyclophosphamide (CTX), docetaxel (D), zoledronic acid (ZA), and high-dose calcitriol (HDC) for castration-resistant prostate cancer (CRPC).

Abstract

e15079 Background: HDC is a biological agent with activity either alone or in combination in CRPC. Preclinical studies have demonstrated that HDC is synergistic with other cytototoxic agents such as D and oral CTX. Methods: Eligible patients (pts) had progressive, metastatic, chemo-naive CRPC with ECOG 0 or 1. Three pts were treated in each cohort, expanded by 3 pts if a dose-limiting toxicity (DLT) was observed in one pt. If no DLT occurred after all pts completed 1 cycle in a cohort, pts were enrolled at the next dose level. If a DLT was seen in 2 pts, the dose level was closed. D was given I.V. on day 1 with ZA 4mg I.V. at the dose of 60 mg/m2 in the first cycle and escalated to 70 mg/m2 for the next cycles if no DLT occurred. HDC was given P.O. at a fixed dose of 50mcg divided in 4 doses on day 0. Oral CTX was given on days D1-10 and dose levels were: cohort 1 50mg/d; cohort 2 100mg/d and cohort 3 150mg/d. Cycles were given every three weeks. Efficacy was explored as: maximal confirmed PSA decline; partial or complete response (PR+CR) by RECIST criteria and/or changes in bone scan. Results: Fourteen pts were enrolled to complete the dose-finding phase. Characteristics included median age of 68 yrs (range 55-81) and median baseline PSA of 74.6 ng/mL (range 11-571). DLTs by dose level are summarized as: cohort 1, DLT in 1 of 6 pts (febrile neutropenia (Gr) 4); cohort 2, DLT in 1 of 4 pts (neutropenia (Gr) 4); and no DLT in cohort 3. A pt in cohort 3 had acute myocardial infarction probably not related to therapy. Preliminary measures of efficacy by method of assessment and cohort assignment are summarized (Table). Conclusions: We conclude that the D 70 mg/m2, HDC 50 mcg, ZA 4mg every three weeks in combination with oral CTX 50mg (cohort 1) and 100mg (cohort 2) on days1-10 is safe and demonstrates anticancer efficacy. Cohort 1 Cohort 2 Cohort 3 Median # cycles (range) 5.5 (2-10) 5.5 (1-8) 4 (2-7) PSA decline > 30% 3/6 3/4 3/4 > 50% 3/6 2/4 3/4 RECIST PR+CR 2/4 2/4 2/4 Bone Stable 6/6 4/4 4/4 No significant financial relationships to disclose.