Overall Major Response Rate Research Articles

Phase II trial of tesetaxel, an oral taxane, as second-line therapy for patients with advanced gastroesophageal cancer.

4077 Background: Tesetaxel is a novel, orally administered taxane. It is not a substrate for P-glycoprotein, and preclinical data suggest tesetaxel has potent antitumor activity that exceeds standard taxanes in human tumor xenografts while causing substantially less neuropathy. Tesetaxel is not associated with hypersensitivity, thus eliminating the need for premedication and extended observation. A prior study showed an overall major response rate (ORR) of 20% with tesetaxel used as 2nd-line therapy in patients (pts) with advanced gastric cancer. We previously showed that “flat” (i.e., non weight-based) dosing with tesetaxel was associated with excessive variability; therefore, we amended the final trial design to evaluate whether we could extend the prior observations in a confirmatory Phase 2 trial using the MTD. Methods: Eligibility included: adenocarcinoma of stomach/GE junction; 1 prior fluoropyrimidine-platinum regimen; ECOG PS 0-1; and adequate organ function. Tesetaxel was administered orally once every 3 weeks starting at 27 mg/m2 escalated to 35 mg mg/m2 pending tolerance. ORR was the primary endpoint; estimated overall survival (OS) was secondary. Results: To date, 24 pts -- from a final target of 27 – have been enrolled (10 men, 14 women; median age, 58 yrs [range, 26-81]). Preliminary ORR in 15 evaluable cases to date are shown in the table below. At this time, only 4 pts have died and median survival is too early to estimate. Grade 3-4 adverse events have included neutropenia (27%), anemia, fatigue (13% each), and anorexia (7%). One pt (7%) experienced Grade 3 peripheral neuropathy. There have been no episodes of febrile neutropenia. Conclusions: Oral tesetaxel administered once every 3 weeks is active against gastric cancer in the 2nd-line setting. The observed 20% ORR confirms earlier data and appears at least equivalent to docetaxel (ORR= 5%-19%), as reported in 4 prior studies in this population. Tesetaxel was well tolerated and was not been associated with hypersensitivity. We expect to present final ORR and estimated OS from this trial. [Table: see text]

Tesetaxel, a novel oral taxane, as second-line therapy for advanced gastroesophageal cancer: Activity in a dose-ranging study.

47 Background: Standard taxanes require extended IV infusion and are associated with potentially severe hypersensitivity and cumulative neuropathy. Tesetaxel is a structurally novel orally active taxane with potent and superior antitumor activity relative to standard taxanes in human tumor xenografts that overexpress P-glycoprotein. Tesetaxel is not associated with hypersensitivity, thus eliminating the need for both premedication and extended medical/nursing observation. A prior study showed an overall major response rate (ORR) of 20% as 2nd-line therapy in pts with advanced gastric cancer. Since pharmacokinetic and safety data suggested that flat dosing of tesetaxel might be feasible, we evaluated both flat and weight-based dosing in a new dose-ranging study. Methods: Eligibility: adenocarcinoma (stomach or GE junction); treatment with 1 fluoropyrimidine/platinum analog regimen; ECOG PS 0-1; and adequate organ function. Tesetaxel was administered Q3 weeks at flat starting doses (40 mg and 50 mg) in Cohorts 1 and 2, respectively. When flat dosing proved impractical, a weight-based dose was used for Cohort 3 (27 mg/m2 with escalation to 35 mg mg/m2 pending tolerability). ORR was the primary endpoint. Results: To date, 36 pts (29 men, 7 women; median age, 58 years [range: 25-81]) have been enrolled in this ongoing study, with results as shown below. Median survival is 7.8 and 7.5 months in Cohorts 1 and 2, respectively, and is too early to estimate in Cohort 3. Uncomplicated neutropenia was the most common ≥ 3 event (13%). Conclusions: Extreme body weight differences resulted in marked underdosing and precluded flat dosing. Our data confirm that tesetaxel is active against gastroesophageal cancers in the 2nd-line setting using the weight-based Q3 week regimen. [Table: see text]