Phase 2 trial of weekly intravenous 1,25 dihydroxy cholecalciferol (Calcitriol) in combination with dexamethasone for castration‐resistant prostate cancer

Abstract

BACKGROUND: Preclinical data indicate that there is substantial antitumor activity and synergy between calcitriol and dexamethasone. On the basis of these data, the authors conducted a phase 2 trial of intravenous (iv) calcitriol at a dose of 74 lg weekly (based on a recent phase 1 trial) and dexamethasone in patients with castration-resistant prostate cancer (CRPC). METHODS: A 2-stage Kepner-Chang design was used. Oral dexamethasone at a dose of 4 mg was given weekly on Days 1 and 2, and iv calcitriol (74 lg over 1 hour) was administered weekly on Day 2 from 4 to 8 hours after the dexamethasone dose in patients with CRPC. Laboratory data were monitored weekly, and renal sonograms, computed tomography scans, and bone scans were obtained every 3 months. Disease response was assessed by using the Response Evaluation Criteria in Solid Tumors (RECIST) and standard criteria for prostate-specific antigen (PSA) response. The calcitriol dose was delineated by from the authors' recent phase 1 trial. RESULTS: Of 18 evaluable patients, 15 patients were Caucasian (83%). No patients had a complete or partial response by either RECIST or PSA response criteria. Fourteen patients had progressive disease, 2 patients refused to continue treatment (after 64 days and 266 days), and 2 patients remain on the trial (for 306 days and 412 days).The median time to disease progression was 106 days (95% confidence interval, 80-182 days). Fourteen episodes of grade 3 or 4 toxicity were noted in 7 patients (hyperglycemia, hypocalemia, chest pain, dyspnea, hypercalcemia, hypophosphatemia, cardiac arrhythmia, and pain). Only 1 episode of grade 3/ 4 toxicity was related definitely to calcitriol (hypercalcemia). No treatment-related deaths were noted. CONCLUSIONS: High-dose, iv calcitriol at a dose of 74 lg weekly in combination with dexamethasone was well tolerated but failed to produce a clinical or PSA response in men with CRPC.

Randomized, Open-Label Phase III Trial of Docetaxel Plus High-Dose Calcitriol Versus Docetaxel Plus Prednisone for Patients With Castration-Resistant Prostate Cancer

“…Also at issue was whether the dose of DN-101 was optimal, given recent data showing that intravenous formulations of DN-101 produce calcitriol concentrations in the 7 to 11 nmol/L range, and that an additional 25% to 30% more can be given safely if dexamethasone is added. [26][27][28] These data suggest that substantially higher doses could have been used, but whether the overall outcome would have been different is unknown.…”

Current progress in using vitamin D and its analogs for cancer prevention and treatment

“…on day 2, weekly II; CRPC Treatment well tolerated, did not produce a clinical or PSA response [114] Clinical studies of vitamin D analogs 3.5% responded with tumor volume reduction, inactive in treatment [115] Schwartz et al…”

“…An extension to this Phase I trial to investigate whether the addition of dexamethasone would allow further dose escalation of calcitriol with gefitinib weekly showed this combination yielded a calcitriol MTD of 125 µg [113]. The Phase II trial was set at the more conservative MTD of weekly 75 µg; intravenous calcitrol in combination with dexamethasone was well tolerated but produced no clinical or PSA response [114]. It was suspected that the reason for this negative finding may be due to the use of a MTD determined from the previous Phase I study, which was complicated by the administration of gefitinib.…”

Vitamin D and Prostate Cancer

“…Another phase II trial tested the combination of calcitriol, dexamethasone, and carboplatin in patients with CRPC and found a PSA response in 13 out of 34 patients [388]. Calcitriol administered intravenously at a high dose of 74 mg weekly in combination with dexamethasone (4 mg twice weekly) was well tolerated but failed to produce a clinical or PSA response in patients with CRPC [389].…”