A phase I and pharmacologic study of sequences of the proteasome inhibitor, bortezomib (PS-341, Velcade), in combination with paclitaxel and carboplatin in patients with advanced malignancies.
OBJECTIVE
Bortezomib, a selective inhibitor of the 20S proteasome with activity in a variety of cancers, exhibits sequence-dependent synergistic cytotoxicity with taxanes and platinum agents. Two different treatment schedules of bortezomib in combination with paclitaxel and carboplatin were tested in this phase I study to evaluate the effects of scheduling on toxicities, pharmacodynamics and clinical activity.


METHODS
Patients with advanced malignancies were alternately assigned to receive (schedule A) paclitaxel and carboplatin (IV d1) followed by bortezomib (IV d2, d5, d8) or (schedule B) bortezomib (IV d1, d4, d8) followed by paclitaxel and carboplatin (IV d2) on a 21-day cycle.


RESULTS
Fifty-three patients (A 25, B 28) were treated with a median of 3 cycles (range 1-8) for schedule A and 3.5 cycles (range 1-10) for schedule B. Grade 3 or higher treatment related hematologic adverse events in all cycles of treatment included neutropenia (A 52%, B 50%), anemia (A 12%, B 7.1%) and thrombocytopenia (A 16%, B 17.9%). Non-hematologic treatment related adverse events were fairly mild (primarily grades 1 and 2). The maximum tolerated dose and the recommended doses for future phase II trials are bortezomib 1.2 mg/m2, paclitaxel 135 mg/m2 and carboplatin AUC = 6 for schedule A and bortezomib 1.2 mg/m2, paclitaxel 175 mg/m2 and carboplatin AUC = 6 for schedule B. Six (21.4%) partial responses (PR) were seen with schedule B. In contrast, only 1 (4%) PR was achieved with schedule A. Similar proteasome inhibition was achieved at MTD for both schedules.


CONCLUSIONS
Administration of sequential bortezomib followed by chemotherapy (schedule B) was well tolerated and associated with an encouraging number of objective responses in this small group of patients. Further studies with this administration schedule are warranted.
Ma
Cynthia
C
Division of Medical Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
Mandrekar
Sumithra J
SJ
Alberts
Steven R
SR
Croghan
Gary A
GA
Jatoi
Aminah
A
Reid
Joel M
JM
Hanson
Lorelei J
LJ
Bruzek
Laura
L
Tan
Angelina D
AD
Pitot
Henry C
HC
Erlichman
Charles
C
Wright
John J
JJ
Adjei
Alex A
AA
D000328:Adult; D000368:Aged; D000505:Alopecia / Q000139:chemically induced; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects; D000069286:Bortezomib; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D018450:Disease Progression; D005260:Female; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects; D012720:Severity of Illness Index; D016896:Treatment Outcome
D001897:Boronic Acids; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D016190:Carboplatin; D017239:Paclitaxel