A phase I study of high-dose calcitriol in combination with temozolomide for patients (Pts) with metastatic melanoma (MM).

9087 Background: Temozolomide (Tem) has demonstrated efficacy as an oral alternative for pts with MM on traditional and extended dosing schedules. Calcitriol has known antiproliferative properties in vitro, and has shown synergistic effects with chemotherapy. Additionally, vitamin D receptor (VDR) polymorphisms are associated with alterations in melanoma susceptibility and disease progression. Specifically, the VDR genotype tt/ff (Taq1 and Fok1 polymorphisms) has been associated with tumors >3.5mm, though no studies have focused on survival. Methods: Tem 150mg/m2was administered on days 2-8 and 16-22 every 28 days until progression or significant toxicity. Calcitriol was given on days 1 and 15 every 28 days with 3 pts at a dose of 0.2mcg/kg, 3 pts at 0.3mcg/kg, 3 pts at 0.5mcg/kg, and an additional 11 pts at a maximum dose of 0.5mcg/kg. VDR gene analysis was completed on 17/20 pts using PCR-RFLP based assays. Tolerability was the primary objective with secondary objectives of time to progression (PFS) and overall survival (OS), both as a whole and by VDR genotype. Results: Twenty pts (males=15) with MM treated with at least one prior systemic therapy or who were not candidates for interleukin-2 (conducted pre BRAF and anti CTLA agents), were accrued. Median age was 58. The regimen was well-tolerated with leukopenia, lymphopenia, thrombocytopenia, anemia, and thrombosis as the most common grade 3 or 4 toxicities at 10% incidence each, less than observed in prior studies (Patel et al Eur J Ca 2011). Obj RR was 10%. Median PFS was 1.8 mo with a mean of 2.7 cycles given. Pts with low-risk VDR genotype non-tt or ff (n= 11) had a median OS of 7.4 mo compared to 3.8 mo for tt or ff or both (n=6)(median ratio=1.95) from time of enrollment, although not statistically significant given small sample sizes. Conclusions: The extended dosing of Tem with calcitriol is a well-tolerated oral regimen in MM. The trend toward improved OS in non-tt/ff VDR genotypes is consistent with prior studies associating the tt/ff genotype with biologic aggressiveness. Whether this represents a benefit of the inclusion of calcitriol should be studied further. Clinical trial information: NCT00301067.