Phase II evaluation of thalidomide in patients with metastatic breast cancer.
OBJECTIVE
To determine the efficacy, safety, pharmacokinetics, and effect on serum angiogenic growth factors of two dose levels of thalidomide in patients with metastatic breast cancer.


METHODS
Twenty-eight patients with progressive metastatic breast cancer were randomized to receive either daily 200 mg of thalidomide or 800 mg to be escalated to 1,200 mg. Fourteen heavily pretreated patients were assigned to each dose level. Each cycle consisted of 8 weeks of treatment. Pharmacokinetics and growth factor serum levels were evaluated.


RESULTS
No patient had a true partial or complete response. On the 800-mg arm, 13 patients had progressive disease at or before 8 weeks of treatment and one refused to continue treatment. The dose was reduced because of somnolence to 600 mg for five patients and to 400 mg for two and was increased for one to 1,000 mg and for four to 1,200 mg. On the 200-mg arm, 12 patients had progressive disease at or before 8 weeks and two had stable disease at 8 weeks, of whom one was removed from study at week 11 because of grade 3 neuropathy and the other had progressive disease at week 16. Dose-limiting toxicities included somnolence and neuropathy. Adverse events that did not require dose or schedule modifications included constipation, fatigue, dry mouth, dizziness, nausea, anorexia, arrhythmia, headaches, skin rash, hypotension, and neutropenia. Evaluation of circulating angiogenic factors and pharmacokinetic studies failed to provide insight into the reason for the lack of efficacy.


CONCLUSIONS
Single-agent thalidomide has little or no activity in patients with heavily pretreated breast cancer. Further studies that include different patient populations and/or combinations with other agents might be performed at the lower dose levels.
Baidas
S M
SM
Breast Cancer and Development Therapeutic Programs, Lombardi Cancer Center, Georgetown University Medical Center, Georgetown University, Washington, DC, USA. Baidass@gunet.georgetown.edu
Winer
E P
EP
Fleming
G F
GF
Harris
L
L
Pluda
J M
JM
Crawford
J G
JG
Yamauchi
H
H
Isaacs
C
C
Hanfelt
J
J
Tefft
M
M
Flockhart
D
D
Johnson
M D
MD
Hawkins
M J
MJ
Lippman
M E
ME
Hayes
D F
DF
D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004334:Drug Administration Schedule; D016228:Endothelial Growth Factors / Q000378:metabolism; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006133:Growth Substances / Q000378:metabolism; D006801:Humans; D008222:Lymphokines / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011446:Prospective Studies; D013792:Thalidomide / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D020533:Angiogenesis Inhibitors; D016228:Endothelial Growth Factors; D006133:Growth Substances; D008222:Lymphokines; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; D013792:Thalidomide; D020782:Matrix Metalloproteinases