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Conventional seamless phase 2/3 design with fixed sample size determination (SSD) has gained its popularity in oncology drug development due to attractive features such as significantly shortening the development timeline, minimizing sample size, as well as early decision making. However, this design is not immune to inaccurate treatment effect assumption when only limited efficacy data are available at study design stage. We propose an innovative seamless phase 2/3 study design with flexible SSD for oncology trials, in which the trial is designed under a distribution of treatment effect instead of one single assumption due to huge uncertainty of treatment effect at design stage and the sample size for end of phase 3 analysis is not predetermined at design stage, but rather dynamically determined based on observed treatment effect at phase 2 portion. Some practical sample size determination rules for end of phase 3 analysis will be discussed. The proposed design can lead to reduced sample size or/and improved power compared with conventional seamless phase 2/3 design with fixed SSD. This innovative study design can be especially useful for programs with aggressive development strategy to expedite the process in delivering efficacious treatment to patients. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the safety and efficacy of maintenance therapy with the oral proteasome inhibitor ixazomib in patients with newly diagnosed multiple myeloma (NDMM) not undergoing transplantation. Methods: Data were pooled from four NDMM phase I/II studies; patients received induction therapy with once‐ or twice‐weekly ixazomib plus lenalidomide‐dexamethasone (IRd), melphalan‐prednisone (IMP), or cyclophosphamide‐dexamethasone (ICd), followed by single‐agent ixazomib maintenance, given at the last tolerated dose during induction, until disease progression, death, or unacceptable toxicity. Results: A total of 121 patients achieved stable disease or better after induction (weekly IRd, n = 25; twice‐weekly IRd, n = 18; weekly or twice‐weekly IMP, n = 35; weekly ICd, n = 43) and received ≥ 1 dose of ixazomib maintenance. Grade ≥ 3 drug‐related adverse events occurred in 24% of patients during maintenance; each event was reported in ≤2% of patients. Rates of complete response were 22% after induction and 35% after maintenance. A total of 28 patients (23%) improved their response during maintenance. Conclusions: Ixazomib maintenance following ixazomib‐based induction is associated with deepening of responses and a positive safety profile with no cumulative toxicity in patients with NDMM not undergoing transplantation, suggesting that ixazomib is feasible for long‐term administration. Phase III investigation of ixazomib maintenance is ongoing. [ABSTRACT FROM AUTHOR]

Background: Corticosteroid (CS) injections have been proven to be effective in ameliorating symptoms of plantar fasciitis. Shock-wave (SW) therapy is another common treatment of plantar fasciitis, and several meta-analyses have documented its advantages when compared to placebo treatment. Despite this, few studies have focused on comparing the use of CS and SW in the treatment of plantar fasciitis. The purpose of this meta-analysis is to assess whether SW is superior to CS in managing plantar fasciitis, both in terms of ameliorating pain as well as improving functionality.Methods: A systematic search of the literature was conducted to identify relevant articles that were published in Pubmed, Medline, Embase, the Cochrane Library, SpringerLink, Clinical Trials.gov and OVID from the databases' inception to July 2018. All studies comparing the efficacy of SW and CS in terms of pain levels and functionality improvement were included. Data on the two primary outcomes were collected and analyzed using the Review Manager 5.3.Results: Six studies were included in the current meta-analysis. A significant difference in VAS score (MD = - 0.96, Cl - 1.28 to - 0.63, P < 0.00001, I2 = 96%) was noted between the SW group and the CS group. No significant difference was seen in the Mayo CSS or FFI or HFI or 100 Scoring System score at the 3 months follow-up (Chi2 = 0.62, I2 = 0%, P > 0.05).Conclusions: The clinical relevance of the present study is that both SW and CS were effective and successful in relieving pain and improving self-reported function in the treatment of plantar fasciitis at 3 months. Although inter-group differences were not significant, the VAS score was better improved in the SW group, highlighting that shock-wave therapy may be a better alternative for the management of chronic plantar fasciitis. [ABSTRACT FROM AUTHOR]

Abstract: The failure rate for phase III trials in oncology is high; quantitative predictive approaches are needed. We developed a model‐based meta‐analysis (MBMA) framework to predict progression‐free survival (PFS) from overall response rates (ORR) in relapsed/refractory multiple myeloma (RRMM), using data from seven phase III trials. A Bayesian analysis was used to predict the probability of technical success (PTS) for achieving desired phase III PFS targets based on phase II ORR data. The model demonstrated a strongly correlated (R2 = 0.84) linear relationship between ORR and median PFS. As a representative application of the framework, MBMA predicted that an ORR of ∼66% would be needed in a phase II study of 50 patients to achieve a target median PFS of 13.5 months in a phase III study. This model can be used to help estimate PTS to achieve gold‐standard targets in a target product profile, thereby enabling objectively informed decision‐making. [ABSTRACT FROM AUTHOR]

Purpose Ixazomib is an investigational proteasome inhibitor with demonstrated antitumor activity in xenograft models of multiple myeloma (MM), lymphoma, and solid tumors. This open-label, phase 1 study investigated intravenous (IV) ixazomib, in adult patients with advanced non-hematologic malignancies. Methods Patients received IV ixazomib twice-weekly for up to twelve 21-day cycles. The 0.125 mg/m starting dose was doubled (one patient/dose) until 1.0 mg/m based on dose-limiting toxicities (DLTs) in cycle 1. This was followed by 3 + 3 dose-escalation and expansion at the maximum tolerated dose (MTD). Primary objectives included safety and MTD assessment. Secondary objectives included assessment of pharmacokinetics, pharmacodynamics, and disease response. Results Ixazomib was escalated from 0.125 to 2.34 mg/m to determine the MTD ( n = 23); patients were then enrolled to MTD expansion ( n = 73) and pharmacodynamic ( n = 20) cohorts. Five patients experienced DLTs (1.0 and 1.76 mg/m: grade 3 pruritic rash; 2.34 mg/m: grade 3 and 4 thrombocytopenia, and grade 3 acute renal failure); thus, the MTD was 1.76 mg/m. Drug-related grade ≥3 adverse events (AEs) included thrombocytopenia (23 %), skin and subcutaneous (SC) tissue disorders (16 %), and fatigue (9 %). Among 92 evaluable patients, one (head and neck cancer) had a partial response and 30 had stable disease. Ixazomib terminal half-life was 3.8-7.2 days; plasma exposures increased dose-proportionally and drug was distributed to tumors. Inhibition of whole-blood 20S proteasome activity and upregulation of ATF-3 in tumor biopsies demonstrated target engagement. Conclusions In patients with solid tumors, ixazomib was associated with a manageable safety profile, limited antitumor activity, and evidence of downstream proteasome inhibition effects. [ABSTRACT FROM AUTHOR]

Both parametric and nonparametric sequential designs and estimation methods are implemented in phase I clinical trials. In this article, we take a systematic approach, consisting of a start-up design, a follow-on design, a sequential dose-finding design, and an estimation method, to find an efficient estimate of the maximum tolerated dose under the assumption that the dose-response curve has a true underlying logistic distribution. In particular, for the problem of the nonexistence of the maximum likelihood estimates of the logistic parameters, a constraint on the probability of an undetermined maximum likelihood estimator (MLE) is incorporated into the parametric sequential designs. In addition, this approach can also be extended to incorporate ethical considerations, which prohibit an administered dose from exceeding the maximum acceptable dose. Comparison based on simulation studies between the systematic designs and nonparametric designs are described both for continuous dose spaces and discrete dose spaces, respectively. [ABSTRACT FROM AUTHOR]