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Design and rationale of the QUAZAR Lower-Risk MDS (AZA-MDS-003) trial: a randomized phase 3 study of CC-486 (oral azacitidine) plus best supportive care vs placebo plus best supportive care in patients with IPSS lower-risk myelodysplastic syndromes and poor prognosis due to red blood cell transfusion-dependent anemia and thrombocytopenia.

ABSTRACT: BACKGROUND:CC-486 is an oral formulation of the epigenetic modifier azacitidine. In an expanded phase 1 trial, CC-486 demonstrated clinical and biological activity in patients with International Prognostic Scoring System (IPSS) lower-risk (low- and intermediate-1-risk) myelodysplastic syndromes (MDS) with poor prognostic features including anemia and/or thrombocytopenia who may have required red blood cell or platelet transfusions. The overall response rate was 40 %, including hematologic improvement in 28 % of patients and RBC transfusion independence sustained for 56 days in 47 % of patients with baseline transfusion dependence. Based on the results of this study, the randomized, placebo-controlled phase 3 QUAZAR Lower-Risk MDS trial (AZA-MDS-003) was initiated. The design and rationale for this trial comparing CC-486 with placebo for the treatment of patients with IPSS lower-risk MDS with poor prognostic features are described. METHODS:Patients must have IPSS lower-risk MDS with red blood cell (RBC) transfusion-dependent anemia and thrombocytopenia. Eligible patients are randomized 1:1 to receive 300 mg of CC-486 or placebo once daily for the first 21 days of 28-day treatment cycles. Disease status assessments occur at the end of cycle 6 and patients may continue to receive treatment unless there is evidence of progressive disease, lack of efficacy, or unacceptable toxicity. The primary endpoint is RBC transfusion independence for???84 days, assessed according to International Working Group 2006 criteria. Secondary endpoints include overall survival, hematologic response including platelet response and erythroid response, RBC transfusion independence for???56 days, duration of RBC transfusion independence, time to RBC transfusion independence, rate of acute myeloid leukemia (AML) progression, time to AML progression, clinically significant bleeding events, safety, health-related quality of life, and healthcare resource utilization. CONCLUSIONS:This study will provide data on the efficacy and safety of CC-486 in the treatment of IPSS lower-risk MDS with poor prognosis due to the presence of both RBC transfusion-dependent anemia and thrombocytopenia. Positive results of the AZA-MDS-003 study may expand treatment options for patients with IPSS lower-risk MDS. TRIAL REGISTRATION:ClinicalTrials.gov NCT01566695, registered March 27, 2012.

SUBMITTER: Garcia-Manero G

PROVIDER: S-EPMC4855808 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Design and rationale of the QUAZAR Lower-Risk MDS (AZA-MDS-003) trial: a randomized phase 3 study of CC-486 (oral azacitidine) plus best supportive care vs placebo plus best supportive care in patients with IPSS lower-risk myelodysplastic syndromes and poor prognosis due to red blood cell transfusion-dependent anemia and thrombocytopenia.

Garcia-Manero Guillermo G Almeida Antonio A Giagounidis Aristoteles A Platzbecker Uwe U Garcia Regina R Voso Maria Teresa MT Larsen Stephen R SR Valcarcel David D Silverman Lewis R LR Skikne Barry B Santini Valeria V

BMC hematology 20160503

<h4>Background</h4>CC-486 is an oral formulation of the epigenetic modifier azacitidine. In an expanded phase 1 trial, CC-486 demonstrated clinical and biological activity in patients with International Prognostic Scoring System (IPSS) lower-risk (low- and intermediate-1-risk) myelodysplastic syndromes (MDS) with poor prognostic features including anemia and/or thrombocytopenia who may have required red blood cell or platelet transfusions. The overall response rate was 40 %, including hematologi ...[more]

PMID: 27148452

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Project description:ObjectivesSpasticity is an incurable chronic condition, and patients with spasticity frequently experience symptoms such as muscle stiffness, restricted mobility, fatigue, spasms, and pain. The study objective was to assess the cost-effectiveness of abobotulinumtoxinA plus best supportive care compared with best supportive care alone for the early treatment of adult lower limb spasticity following an acute event (e.g. stroke or traumatic brain injury), from an Australian payer perspective.MethodsUsing clinical data from published pivotal trials, an economic model based on a Markov model was developed to capture changes in treatment costs, healthcare resource use costs, functional outcomes, and health-related quality of life over a lifetime horizon. Scenario analyses and a probabilistic sensitivity analysis were conducted to explore the uncertainty in the model parameters and assumptions used in the base case.ResultsAbobotulinumtoxinA plus best supportive care was cost-effective versus best supportive care, yielding an incremental cost-effectiveness ratio of $35,721 per quality-adjusted life year gained. Sensitivity analyses confirm the robustness of the base case, with most results remaining below the commonly acceptable cost-effectiveness willingness-to-pay threshold of $75,000 per quality-adjusted life year for cost-effectiveness in Australia. Inputs and assumptions that produced the top four highest incremental cost-effectiveness ratios include the application of different health resource utilisation source, short time horizon, unweighted regression analyses to determine regression probabilities, and no stopping rule. AbobotulinumtoxinA plus best supportive care has a 74% probability of being cost-effective compared with best supportive care alone at the willingness to pay threshold.ConclusionAbobotulinumtoxinA plus best supportive care treatment is cost-effective in Australia for the management of adult lower limb spasticity in patients treated within 2 years of an acute event.

Project description:BackgroundMaintenance therapy for non-small cell lung cancer (NSCLC) aims to extend disease control after first-line chemotherapy with active and well-tolerated agents. The utility of continuation maintenance therapy requires further research.MethodsThis multicenter, randomized, phase 2 study compared continuation maintenance therapy with pemetrexed (500 mg/m2 every 21 days) and best supportive care (BSC) versus BSC alone in patients with advanced, non-squamous NSCLC who had not progressed after 4 cycles of induction chemotherapy with pemetrexed (500 mg/m2) and cisplatin (75 mg/m2). The primary endpoint was progression-free survival (PFS) from randomization, was analyzed using a Cox model, stratified for the tumor response at the end of induction therapy, at a one-sided alpha of 0.2. Secondary endpoints: response and disease control rates, overall survival (OS), one year survival rates, and treatment-emergent adverse events (TEAEs).ResultsA total of 106 patients commenced induction therapy, of whom 55 patients were randomized to maintenance pemetrexed/BSC (n = 28) or BSC (n = 27). Although the median PFS time for maintenance phase for both arms was 3.2 months, the one-sided p-value for the PFS HR comparison was less than the prespecified limit of 0.2 (HR = 0.76, two-sided 95% confidence interval [CI]: 0.42 to 1.37; one-sided p-value = 0.1815), indicating that PFS was sufficiently long in the pemetrexed/BSC arm to warrant further investigation. Similar PFS results were observed for the overall study period (induction plus maintenance) and when the PFS analysis was adjusted for sex, baseline disease stage, and the ECOG PS prior to randomization. The median OS for the maintenance phase was 12.2 months (95%CI: 5.6 to 20.6) for the pemetrexed/BSC arm and 11.8 months (95% CI: 6.3 to 25.6) for BSC arm. The one-year survival probabilities were similar for both arms for the maintenance phase and the overall study period. Both the induction and continuation maintenance therapies were generally well-tolerated, and similar proportion of patients in each arm experienced at least 1 grade 3/4 TEAE (pemetrexed/BSC, 17.9%; BSC, 18.5%).ConclusionsContinuation pemetrexed maintenance therapy resulted in promising PFS with an acceptable safety profile in a Middle Eastern population with advanced non-squamous NSCLC and is worthy of further investigation.Trial registrationNCT00606021.

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