Age-stratified phase I trial of a combination of bortezomib, gemcitabine, and liposomal doxorubicin in patients with advanced malignancies.
BACKGROUND
Preclinical data suggest synergistic activity of bortezomib, gemcitabine, and liposomal doxorubicin. Because tolerance to therapy may be attenuated in elderly patients, we performed an age-stratified phase I trial of this combination.


METHODS
Two parallel age-stratified arms (< 65 and ≥ 65 years old) were accrued (3 + 3 design). Starting doses included bortezomib 0.7 mg/m(2) (days 1 and 8), gemcitabine 500 mg/m(2) (days 1 and 8), and liposomal doxorubicin 20 mg/m(2) (day 1).


RESULTS
In the < 65-year-old group, 65 patients were treated; the maximum-tolerated dose was bortezomib 1.3 mg/m(2), gemcitabine 800 mg/m(2), and liposomal doxorubicin 35 mg/m(2). In the ≥ 65-year-old group, 28 patients were treated; the recommended phase II dose was bortezomib 1.0 mg/m(2), gemcitabine 800 mg/m(2), and liposomal doxorubicin 20 mg/m(2). Dose-limiting toxicities included thrombocytopenia and neutropenia. The most common toxicities were mild cytopenias, fatigue, and neuropathy. Ten patients achieved partial responses (6 of 7 patients with cutaneous T-cell lymphoma; 4 of 16 patients with small cell carcinomas, including lung, prostate, ovarian, and nasopharyngeal).


CONCLUSIONS
Combination of bortezomib, gemcitabine, and liposomal doxorubicin is well tolerated, but with a lower recommended phase II dose in elderly patients, and demonstrated antitumor activity, especially in T-cell and small cell histology malignancies.
Division of Cancer Medicine, Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program)-Unit 455, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. gfalchoo@mdanderson.org
G S
GS
Falchook
M
M
Duvic
D S
DS
Hong
J
J
Wheler
A
A
Naing
J
J
Lim
R
R
Kurzrock
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D002648:Child; D002675:Child, Preschool; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011719:Pyrazines / Q000008:administration & dosage; D016896:Treatment Outcome; D055815:Young Adult; D000093542:Gemcitabine
D001897:Boronic Acids; D011719:Pyrazines; D003841:Deoxycytidine; D000069286:Bortezomib; D004317:Doxorubicin; D000093542:Gemcitabine