A phase I and pharmacokinetic study of oxaliplatin and bortezomib: activity, but dose-limiting neurotoxicity

Purpose

The potential synergy of modulating platinum-induced DNA damage by combining the proteasome inhibitor bortezomib with oxaliplatin was studied in patients with solid tumors, with special attention to avoidance of cumulative neurotoxicity (NT).

Patients and methods

In a 3 + 3 dose escalation design, patients received bortezomib at 1.0–1.5 mg/m² on days 1 and 4 and oxaliplatin at 60–85 mg/m² on day 1 of a 14-day cycle. NT assessments were performed at the start of every two cycles. Oxaliplatin pharmacokinetics (PK) were determined pre- and post-bortezomib.

Results

Thirty patients were enrolled with 25 (11 men, 14 women) fully evaluable for NT assessments at cycle 2. The median age was 56 years (range 35–74 years); median number of cycles received 2 (range 1–10). At dose levels 2–5 (B 1.3 mg/m²), patients manifested NT grades 3 and 4 at a median 3.4 cycles (range 2–9 cycles): 3 had ataxia (one also with sensory neuropathy or neurogenic hypotension, respectively) and 3 had just sensory neuropathy. A 6th dose-level reducing bortezomib to 1.0 mg/m² with oxaliplatin 85 mg/m²) was explored and no NT or dose limiting toxicities were noted among 7 evaluable patients (5 receiving two or more cycles). Four patients experienced a partial response—one with platinum-resistant ovarian cancer, another with gastroesophageal cancer, another with ampulla of Vater carcinoma, and a patient with cholangiocarcinoma. PK studies at dose levels 1 and 2 showed greater mean ultrafiltrable platinum when oxaliplatin was dosed after bortezomib.

Conclusions

Bortezomib 1.0 mg/m² × 2 every 14 days combines safely with oxaliplatin. At higher doses, cumulative NT (i.e., cerebellar signs and sensory neuropathy) occurs at an accelerated pace perhaps from a PK interaction.