Group sequential design (GSD) is widely used in clinical trials in which correlated tests of multiple hypotheses are used. Multiple primary objectives resulting in tests with known correlations include evaluating 1) multiple experimental treatment arms, 2) multiple populations, 3) the combination of multiple arms and multiple populations, or 4) any asymptotically multivariate normal tests. In this paper, we focus on the first 3 of these and extend the framework of the weighted parametric multiple test procedure from fixed designs with a single analysis per objective to a GSD setting where different objectives may be assessed at the same or different times, each in a group sequential fashion. Pragmatic methods for design and analysis of weighted parametric group sequential design(WPGSD) under closed testing procedures are proposed to maintain the strong control of familywise Type I error rate (FWER) when correlations between tests are incorporated. This results in the ability to relax testing bounds compared to designs not fully adjusting for known correlations, increasing power or allowing decreased sample size. We illustrate the proposed methods using clinical trial examples and conduct a simulation study to evaluate the operating characteristics.
A stable-label i.v./oral study design was conducted to investigate the pharmacokinetics (PK) of odanacatib. Healthy, postmenopausal women received oral doses of unlabeled odanacatib administered simultaneously with a reference of 1 mg i.v. stable 13C-labeled odanacatib. The absolute bioavailability of odanacatib was 30% at 50 mg (the phase 3 dose) and 70% at 10 mg, which is consistent with solubility-limited absorption. Odanacatib exposure (area under the curve from zero to infinity) increased by 15% and 63% when 50 mg was administered with low-fat and high-fat meals, respectively. This magnitude of the food effect is unlikely to be clinically important. The volume of distribution was ∼100 liters. The clearance was ∼0.8 l/h (13 ml/min), supporting that odanacatib is a low–extraction ratio drug. Population PK modeling indicated that 88% of individuals had completed absorption of >80% bioavailable drug within 24 hours, with modest additional absorption after 24 hours and periodic fluctuations in plasma concentrations contributing to late values for time to Cmax in some subjects.
Abstract Purpose: This phase I study, conducted in advanced-stage cancer patients, assessed the safety and tolerability of oral vorinostat (suberoylanilide hydroxamic acid), single-dose and multiple-dose pharmacokinetics of vorinostat, and the effect of a high-fat meal on vorinostat pharmacokinetics. Experimental Design: Patients (n = 23) received single doses of 400 mg vorinostat on day 1 (fasted) and day 5 (fed) with 48 hours of pharmacokinetic sampling on both days. Patients received 400 mg vorinostat once daily on days 7 to 28. On day 28, vorinostat was given (fed) with pharmacokinetic sampling for 24 hours after dose. Results: The apparent t1/2 of vorinostat was short (∼1.5 hours). A high-fat meal was associated with a small increase in the extent of absorption and a modest decrease in the rate of absorption. A short lag time was observed before detectable levels of vorinostat were observed in the fed state, and Tmax was delayed. Vorinostat concentrations were qualitatively similar following single-dose and multiple-dose administration; the accumulation ratio based on area under the curve was 1.21. The elimination of vorinostat occurred primarily through metabolism, with <1% of the given dose recovered intact in urine. The most common vorinostat-related adverse experiences were mild to moderate nausea, anorexia, fatigue, increased blood creatinine, and vomiting. Conclusions: Vorinostat concentrations were qualitatively similar after single and multiple doses. A high-fat meal increased the extent and modestly decreased the rate of absorption of vorinostat; this effect is not anticipated to be clinically meaningful. Continued investigation of 400 mg vorinostat given once daily in phase II and III efficacy studies is warranted.
BackgroundIn KEYNOTE-012 (NCT01848834) and KEYNOTE-059 (NCT02335411), pembrolizumab demonstrated manageable safety and promising antitumor activity alone or in combination with chemotherapy in patients with advanced G/GEJ cancer.Compared with chemotherapy alone, chemotherapy combined with pembrolizumab in the neoadjuvant/adjuvant setting can provide additional benefit to patients with locally advanced, resectable G/GEJ cancer.KEYNOTE-585 is a phase 3, randomized, double-blind study of chemotherapy combined with pembrolizumab versus chemotherapy combined with placebo as neoadjuvant/adjuvant treatment for locally advanced resectable G/GEJ cancer.Methods Key eligibility criteria in KEYNOTE-585 (NCT03221426) include age ≥18 years; previously untreated G/GEJ adenocarcinoma (Siewert type 2 or 3 tumors; Siewert type 1 tumor eligibility limited to those for whom planned treatment is perioperative chemotherapy and resection), with no evidence of metastatic disease; planning to undergo surgery after preoperative chemotherapy; Eastern Cooperative Oncology Group performance status 0-1; adequate organ function; no active autoimmune disease.Patients will be randomly assigned 1:1 to receive chemotherapy + pembrolizumab (arm 1) or chemotherapy + placebo (arm 2).Stratification factors are geographic region (Asia vs Non-Asia), primary tumor location (stomach vs GEJ), and tumor stage (II/III vs IVa).All patients will receive neoadjuvant (preoperative) chemotherapy + pembrolizumab every 3 weeks (Q3W) for 3 cycles or chemotherapy + placebo Q3W for 3 cycles followed by surgery and then adjuvant chemotherapy + pembrolizumab Q3W for 3 cycles or chemotherapy + placebo Q3W for 3 cycles followed by monotherapy with pembrolizumab or placebo Q3W for 11 cycles; treatment will continue for up to 17 cycles overall.Chemotherapy consists of cisplatin 80 mg/m 2 intravenously + either capecitabine 1000 mg/m 2 twice daily orally or 5fluorouracil 800 mg/m 2 intravenously (investigator's choice).Pembrolizumab 200 mg was administered intravenously.Adjuvant monotherapy consists of pembrolizumab (arm 1) or placebo (arm 2).Primary end points are overall survival (OS), event-free survival, and rate of pathologic complete response (defined as no invasive disease and histologically negative nodes) per central review.Adverse events (AEs) are graded per National Cancer Institute Common Terminology Criteria for Adverse Events v4.0 and will be monitored for 30 days after treatment end (90 days for serious AEs).Patients are followed up for survival every 12 weeks until death, withdrawal from study, or study termination.Planned enrolment is approximately 800 patients.
Adjustment of statistical significance levels for repeated analysis in group sequential trials has been understood for some time. Similarly, methods for adjustment accounting for testing multiple hypotheses are common. There is limited research on simultaneously adjusting for both multiple hypothesis testing and multiple analyses of one or more hypotheses. We address this gap by proposing adjusted-sequential p-values that reject an elementary hypothesis when its adjusted-sequential p-values are less than or equal to the family-wise Type I error rate (FWER) in a group sequential design. We also propose sequential p-values for intersection hypotheses as a tool to compute adjusted sequential p-values for elementary hypotheses. We demonstrate the application using weighted Bonferroni tests and weighted parametric tests, comparing adjusted sequential p-values to a desired FWER for inference on each elementary hypothesis tested.
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