Phase I trial of zoledronic acid + imatinib mesylate (Gleevec) in patients with bone metastases.
OBJECTIVE
Patients with bone metastases suffer from long-term skeletal morbidity and a reduction in quality of life. Treatment consists of radiation or surgery to prevent or repair fractures and bisphosphonates to delay skeletal-related events (SRE). Platelet-derived growth factor released from metastatic cancer cells may influence the development and progression of bone metastases. Imatinib mesylate (Gleevec) inhibits platelet-derived growth factor-receptor tyrosine kinase signaling, increases apoptosis, reduces proliferation, and lowers microvessel density in human tumors. This phase I study assessed the effects of the combination of zoledronic acid (a bisphosphonate used to delay SRE) and Gleevec on 15 evaluable patients with osteolytic or osteoblastic bone metastases.


RESULTS
Although 6 of 9 patients noted an improvement in pain and 1 patient was stable, the quality of life improved in only 3 patients. Dose limiting toxicity was observed in 0 of 5 (400 mg Gleevec), 2 of 5 (600 mg), and 4 of 5 (800 mg) patients. Although no patient required radiation and only 2 SRE occurred during the study, disease progression in bone and/or extraskeletal sites occurred in most patients.


CONCLUSIONS
The combination of zoledronic acid + Gleevec is not recommended in patients with bone metastases because of toxicity and limited clinical efficacy.
Lipton
Allan
A
Department of Medicine, The Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033, USA. alipton@psu.edu
Campbell-Baird
Cynthia
C
Harvey
Harold
H
Kim
Christian
C
Demers
Laurence
L
Costa
Luis
L
D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001549:Benzamides; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004164:Diphosphonates / Q000008:administration & dosage; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D007093:Imidazoles / Q000008:administration & dosage; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D009367:Neoplasm Staging; D010879:Piperazines / Q000008:administration & dosage; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011743:Pyrimidines / Q000008:administration & dosage; D012509:Sarcoma / Q000188:drug therapy* / Q000556:secondary; D015996:Survival Rate; D016896:Treatment Outcome; D000077211:Zoledronic Acid
D001549:Benzamides; D004164:Diphosphonates; D007093:Imidazoles; D010879:Piperazines; D011743:Pyrimidines; D000077211:Zoledronic Acid; D000068877:Imatinib Mesylate