Modulation of chemotherapy resistance with low dose suramin in refractory non-small cell lung cancer (NSCLC) patients: A phase I study of sequential non-cross resistant chemotherapy.

2104 Background: Primary and acquired chemotherapy resistance have been primary determinants of poor outcome in pts with metastatic NSCLC. Over expression of mdr-1 glycoprotein and glutathione and its transferase do not account for the ineffectiveness of chemotherapy. Basic fibroblast growth factor (bFGF) in the tumor milieu induces resistance which is enhanced by acidic fibroblast growth factor (aFGF). Our group has shown that low dose suramin (S) (10-15 μM) inhibits b/a FGF receptor binding and reverses chemotherapy resistance in vivo.,Pts with platinum refractory stage IIIB/IV NSCLC (no prior docetaxel or gemcitabine but prior S permitted) were randomized to receive 3 cycles of docetaxel (75 mg/m IV over 1 h q 3 wks)/S (Arm A) or gemcitabine (1250 mg/m IV over 30 min d 1 and 8 q 3 wks)/S (Arm B). S was infused over 30 min, 2.5 hrs prior to the chemotherapy. S dose was per nomogram derived from previous studies as follows: Dose in mg = FACTOR x (actual body surface area). First dose Factor was 125, whereas on subsequent doses, it depended on the time since prior dose. After radiologic evaluation at 9 weeks (3 cycles), pts with response (CR/PR) were continued on treatment until progressive disease (PD) at which time pts could cross over to the other regimen. Those pts with stable or PD at the initial 9 week evaluation crossed over to the other regimen to receive 3 cycles and re-evaluation.,12 pts were randomized - 6 each to Arm A and Arm B. Toxicity was mild to moderate. In Arm A 3 pts had neutropenic fevers, therefore 6 additional pts were treated at Docetaxel 57 mg/m. No severe toxicity was seen in the later 6 pts, or in Arm B. Response after 3 cycles was as follows: Arm A - 1 PR, 6 SD; Arm B -3 SD; after cross over 1 PR, 3 SD. Median TTP was 118 d for the entire group, which includes 3 PD free at 6 mos. Pharmacokinetics revealed targeted S concentrations of ≥ 10 μM maintained in 87% and ≤ 50 μM maintained in all of the treatments. 8 pts (including 1 PR and 6 SD) had prior S.,Low dose S with Docetaxel 57 mg/mor Gemcitabine 1250 mg/m is well tolerated and has activity as second line therapy. Phase II testing is planned. Supported in part by NCI UO1CA76576 [Table: see text].