Browsing by Author "Wade, James"

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    Clinical Assessment of 5-Fluorouracil/Leucovorin, Nab-Paclitaxel, and Irinotecan (FOLFIRABRAX) in Untreated Patients with Gastrointestinal Cancer Using UGT1A1 Genotype–Guided Dosing
    (American Association for Cancer Research, 2020-01-01) Joshi, Smita S.; Catenacci, Daniel V. T.; Karrison, Theodore G.; Peterson, Jaclyn D.; Zalupski, Mark M.; Sehdev, Amikar; Wade, James; Sadiq, Ahad; Picozzi, Vincent J.; Amico, Andrea; Marsh, Robert; Kozloff, Mark F.; Polite, Blase N.; Kindler, Hedy L.; Sharma, Manish R.; Medicine, School of Medicine
    Purpose: 5-fluorouracil/leucovorin, irinotecan, and nab-paclitaxel are all active agents in gastrointestinal cancers; the combination, FOLFIRABRAX, has not been previously evaluated. UDP Glucuronosyltransferase 1A1 (UGT1A1) clears SN-38, the active metabolite of irinotecan. UGT1A1*28 polymorphism reduces UGT1A1 enzymatic activity and predisposes to toxicity. We performed a trial to assess the safety and tolerability of FOLFIRABRAX with UGT1A1 genotype-guided dosing of irinotecan. Experimental Design: Patients with previously untreated, advanced gastrointestinal cancers received FOLFIRABRAX with prophylactic pegfilgrastim every 14 days. UGT1A1 *1/*1, *1/*28, and *28/*28 patients received initial irinotecan doses of 180, 135, and 90 mg/m2, respectively. 5-FU 2400 mg/m2 over 46 hours, leucovorin 400 mg/m2, and nab-paclitaxel 125 mg/m2 were administered. Doses were deemed tolerable if the dose limiting toxicity (DLT) rate during cycle 1 was ≤35% in each genotype group. DLTs were monitored using a sequential procedure. Results: Fifty patients enrolled: 30 pancreatic, 9 biliary tract, 6 gastroesophageal, and 5 others. DLTs occurred in 5/23 (22%) *1/*1 patients, 1/19 (5%) *1/*28 patients, and 0/7 *28/*28 patients. DLTs were all grade 3: diarrhea (3 patients), nausea (2 patients), and febrile neutropenia (1 patient). The overall response rate was 31%. Response rates in pancreatic, gastroesophageal, and biliary tract cancers were 34%, 50%, and 11%, respectively. Eighteen patients (36%) received therapy for at least 24 weeks. Conclusion: FOLFIRABRAX with genotype-guided dosing of irinotecan is tolerable in patients with advanced gastrointestinal cancer and UGT1A1*1*1 or UGT1A1*1*28 genotypes. Too few *28/*28 patients were enrolled to provide conclusive results. Responses occurred across multiple tumor types.
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    Phase II randomized, double-blind, placebo-controlled study of tivantinib in men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC)
    (Springer Nature, 2018-10) Monk, Paul; Liu, Glenn; Stadler, Walter M.; Geyer, Susan; Huang, Ying; Wright, John; Villalona-Calero, Miguel; Wade, James; Szmulewitz, Russell; Gupta, Shilpa; Mortazavi, Amir; Dreicer, Robert; Pili, Roberto; Dawson, Nancy; George, Saby; Garcia, Jorge A.; Medicine, School of Medicine
    Background Tivantinib is a non-ATP competitive inhibitor of c-MET receptor tyrosine kinase that may have additional cytotoxic mechanisms including tubulin inhibition. Prostate cancer demonstrates higher c-MET expression as the disease progresses to more advanced stages and to a castration resistant state. Methods 80 patients (pts) with asymptomatic or minimally symptomatic mCRPC were assigned (2:1) to either tivantinib 360 mg PO BID or placebo (P). The primary endpoint was progression free survival (PFS). Results Of the 80 pts. enrolled, 78 (52 tivantinib, 26 P) received treatment and were evaluable. Median follow up is 8.9 months (range: 2.3 to 19.6 months). Patients treated with tivantinib had significantly better PFS vs. those treated with placebo (medians: 5.5 mo vs 3.7 mo, respectively; HR = 0.55, 95% CI: 0.33 to 0.90; p = 0.02). Grade 3 febrile neutropenia was seen in 1 patient on tivantinib while grade 3 and 4 neutropenia was recorded in 1 patient each on tivantinib and placebo. Grade 3 sinus bradycardia was recorded in two men on the tivantinib arm. Conclusions Tivantinib has mild toxicity and improved PFS in men with asymptomatic or minimally symptomatic mCRPC.