Phase II trial of fenretinide in advanced renal carcinoma

Purpose : Fenretinide, a synthetic form of retinoid, induced apoptosis even in chemotherapy resistant cell lines. A phase II study was hence conducted to evaluate toxicity and efficacy of fenretinide in metastatic renal cancer. Methods : Eligibility included unresectable or metastatic renal cell carcinoma (RCC), adequate organ function and Zubrod performance status ≦2. Prior immunotherapy and a maximum of one prior chemotherapy regimen were allowed. Fenretinide was administered at a dose of 900 mg/m 2 twice daily orally for 7 days in a 21-day cycle. Toxicity was assessed at the start of each cycle, and response every 2 cycles. Results : Nineteen eligible patients enrolled of which fifteen had visceral/bone metastases. Seventeen patients had prior nephrectomy and 11 had prior immunotherapy. 76 cycles of therapy were delivered. Therapy was very well tolerated with few severe toxicities consisting of thrombosis in 1 individual and grade 3 fatigue, nausea and diarrhea in 1 patient. 5 patients had grade 2 nyctalopia and 3 patients had transient grade 2 visual toxicity. No objective responses were noted. Stable disease was seen in seven of nineteen cases (37%, 90% C.I. 0.21–0.59). Median time to progression was 1.5 months and median duration of stable disease was 5.8 months (90% C.I. 3.0–8.4). Median survival was 10 months. Tumor fenretinide levels were obtained in three patients and were in the lower end of the therapeutic range. Conclusion : Fenretinide was well tolerated but demonstrated minimal activity that was consistent with results of intratumoral drug measurements. Strategies are needed that will increase systemic and tumor levels of fenretinide.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45264/1/10637_2005_Article_5864.pd

A Phase I Clinical Trial of Spicamycin Derivative KRN5500 (NSC 650426) Using a Phase I Accelerated Titration “2B” Design

The spicamycin derivative KRN5500 was considered as a potential anti-cancer agent based on in vitro and preclinical studies. A Phase I study involving 24 cancer patients in whom tumors were refractory to all other conventional therapies was conducted to determine the dose limiting toxicity, maximum tolerated dose, effectiveness, and pharmacokinetic parameters of this drug administered by 1-h IV infusion daily for five consecutive days every 3 weeks. Using an accelerated dose titration strategy, 8.4 mg/m 2 /d × 5 days was the maximum administered dose. Severe gastrointestinal and hepatic toxicities were observed at doses at or above 4.3 mg/m 2 /d × 5. The recommended Phase II dose is 4.3 mg/m 2 /d × 5. The distribution of KRN5500 followed a two-compartment model, and clearance did not decrease significantly over the dose range 0.8–8.4 mg/m 2 /d × 5. No significant correlation was observed between plasma levels and toxicity. No tumor responses were observed among the 14 patients evaluable for response.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45232/1/10637_2004_Article_5109792.pd