Background: Clinical studies of a combination of a potent proteasome inhibitor bortezomib (B) and oxaliplatin (Ox) are of interest because of potentially additive anti-tumor activity, but bortezomib and oxaliplatin both cause sensory neuropathy. This phase I dose-escalation study (with alternate dose levels escalating B and then Ox) focusing on neurotoxicity (NT) sought to establish a safe regimen. Methods: Patient entry criteria: metastatic solid tumors, PS 0-2, sensory neuropathy < grade 1, adequate organ function. Dose levels planned: B on D1, 4, 15, 18 (1.0, 1.3, 1.5 mg/m2) and Ox D1, 15 (60, 75, 85 mg/m2) every 28 days. Baseline and monthly NT assessments were performed by an independent neurologist (AB). Results: Of 30 entered, 24 completed cycle 1 NT assessment: 10 M/14 W; median age 56 years (range 35-74 years); diagnoses: stomach/GE junction (6); pancreas (3); liver/biliary (4); ovarian (3); melanoma (3); colon, appendix, urachus, oropharynx, Hodgkin’s (1 each), median number of cycles 2 (range 1-10). NT was not dose-limiting in cycle 1 but grade 3 and 4 NT were observed in 6 patients after median of 3.5 cycles (range 2-9 cycles) in dose levels 2 to 5. Among those 6 patients one had grade 3 sensory neuropathy and grade 4 ataxia after 4 cycles, one had grade 3 ataxia and neurogenic hypotension after 5 cycles, one had grade 3 ataxia after 2 cycles, and 3 had grade 3 sensory neuropathy after 3-9 cycles. Consequently, a 6th dose level (B 1.0 mg/m2 and Ox 85 mg/m2) opened: NT grade 3 or 4 did not occur in 6 patients receiving a median of 2 cycles (1-6). Evidence of activity was seen with 4 partial responses (1 biliary, 1 ampulla of Vater, 1 gastric, 1 ovarian). One gastric cancer patient treated at dose level 5 (had received 2 prior regimens) and continues in complete remission after dramatic response followed by gastric resection of residual tumor . The ovarian cancer patient treated at dose level 6 (had received 3 platinum-based out of 4 prior regimens) and sustained near total reduction of liver lesions and peritoneal disease. 6 other patients had stable disease. Conclusions: In the schedule used, B 1.0 mg/m2 and Ox 85 mg/m2 are a safe combination. Bortezomib may be the main contributor to neurotoxicity in this regimen at doses of 1.3 mg/m2 or higher.

(Supported by N01-CM-07003-74 and GCRC-M01-RR-00096)

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA