Phase I study of Doxil and vinorelbine in patients with advanced malignancies.
BACKGROUND
This study was designed to define the maximum tolerated dose of pegylated liposomal doxorubicin (Doxil) and multiday vinorelbine (VNB), without and with prophylactic filgrastim, and to identify antineoplastic effect.


METHODS
Patients with resistant cancers were treated with Doxil 50 mg/m2 every four weeks, and with VNB 15 mg/m2 on the same day. The VNB dose escalations were accomplished in subsequent patient cohorts by adding VNB doses on consecutive days. When the maximum tolerated dose (MTD) of VNB with Doxil was defined, prophylactic filgrastim was added to define a second MTD.


RESULTS
Of 29 patients entered, two had early adverse events, and 27 received at least one full cycle with at least one month follow-up. The MTD of VNB, combined with Doxil 50 mg/m2, was 15 mg/m2 on day 1, with neutropenia as the dose-limiting toxicity. With prophylactic filgrastim, the MTD was 15 mg/m2 daily for two days, with neutropenia and stomatitis as dose-limiting toxicities. Palmar plantar erythrodysesthesia occurred frequently, usually after the third cycle. Objective responses were documented in six patients, all of whom received multiday VNB.


CONCLUSIONS
Doxil 50 mg/m2 on day 1 of a 28-day cycle can be safely combined with VNB 15 mg/m2 day 1, or with VNB 15 mg/m2 days 1 and 2 with filgrastim prophylaxis. Antineoplastic activity was observed in this heavily pretreated population. Future studies of Doxil 35-40 mg/m2 with multiday VNB may be worthwhile, especially in metastatic breast cancer.
Laufman
Leslie R
LR
Hematology Oncology Consultants, Inc., Columbus, Ohio 43235, USA. llaufman@columbus.rr.com
Spiridonidis
C Harris
CH
Jones
Jacqueline J
JJ
Rhodes
Virginia
V
Rossi
Karen
K
Wallace
Kelly
K
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D015331:Cohort Studies; D003131:Combined Modality Therapy; D003873:Dermatitis, Exfoliative / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects; D004334:Drug Administration Schedule; D004417:Dyspnea / Q000139:chemically induced; D005221:Fatigue / Q000139:chemically induced; D000069585:Filgrastim; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D008081:Liposomes; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009503:Neutropenia / Q000139:chemically induced / Q000517:prevention & control; D010292:Paresthesia / Q000139:chemically induced; D011994:Recombinant Proteins; D016879:Salvage Therapy; D014747:Vinblastine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D000077235:Vinorelbine
D008081:Liposomes; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D014747:Vinblastine; D004317:Doxorubicin; D000069585:Filgrastim; D000077235:Vinorelbine