Phase I, pharmacokinetic (PK), pharmacodynamic study of paricalcitol [19-nor-1 alpha, 25-(OH)2 D2] in combination with gemcitabine [2’,2’ difluorodeoxycytidine] in patients with advanced malignancies

Abstract

12010 Background: Calcitriol+ gemcitabine (gem) combination results in synergistic anti-tumor effect in preclinical models. Cytidine deaminase (CDD) inactivates gem into 2’,2’-difluorodeoxyuridine (dFdU) and its overexpression may lead to gem resistance. Calcitriol decreases CDD activity in peripheral blood mononuclear cells (PBM). Paricalcitol is cytotoxic in vitro and synergistic with several chemotherapeutic agents, including gem. We are conducting a phase I study of paricalcitol + fixed-dose gem. Objectives: The primary aim is to determine maximum tolerated dose (MTD) of the combination in patients (pts) with advanced cancer. Secondary aims are to evaluate toxicity, the effect of paricalcitol on gem PK, CDD activity in PBM and clinical outcome. Methods: Each cycle is 4 weeks: Gem 800 mg/m2 (over 80 min) weekly × 3, starting day 1; paricalcitol weekly, 24 h prior to gem, starting day 7. Standard 3+3 dose-escalation schema is used. Planned paricalcitol doses are 0.24, 0.72, 1.20, 1.8, 2.4 μg/kg, and 25% increments till MTD. Gem PK and CDD activity (PBM) are studied on days 1 and 8. Paricalcitol PK studies are obtained on day 7. Results: Fourteen pts with the following cancers: pancreatic (n=3), colon (n=3), lung (n=5), esophageal (n=1), bladder (n=1) and unknown primary (n=1) have been enrolled. No dose limiting toxicities have occurred. Median of 2 cycles were delivered (range 1–9). Grade 3 toxicities: anemia (n=3 pts), neutropenia (n=5), thrombocytopenia (n=3), thrombosis (n=2), anorexia (n=1), hypophosphatemia (n=1), dehydration (n=1), syncope (n=1), pneumonia (n=1) and chills (n=1). Grade 4 toxicities: anemia (n=1) and neutropenia (n=1). Hypercalcemia (> grade 1) did not occur. Stable disease occurred in 2 and progressive disease in 3. Conclusions: MTD was not reached at 1.8 μg/kg of paricalcitol with gem 800 mg/m2/week. Dose escalation is ongoing. PK data will be presented at meeting. Supported by NIH grants CA67267 and CA85142. [Table: see text]