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


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.
Division of Hematology and Oncology, NYU School of Medicine, 550 First Avenue, OBV C&D Bldg Rm 556, New York, NY, 10016, USA.
B
B
Kobrinsky
S O
SO
Joseph
F
F
Muggia
L
L
Liebes
A
A
Beric
A
A
Malankar
P
P
Ivy
H
H
Hochster
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000069286:Bortezomib; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000097:blood / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020258:Neurotoxicity Syndromes / Q000503:physiopathology / Q000517:prevention & control*; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010051:Ovarian Neoplasms / Q000097:blood / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000077150:Oxaliplatin; D061988:Proteasome Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D012720:Severity of Illness Index; D047368:Tumor Burden / Q000187:drug effects
D000970:Antineoplastic Agents; D001897:Boronic Acids; D009944:Organoplatinum Compounds; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000077150:Oxaliplatin; D000069286:Bortezomib