On December 3, 2014, the FDA granted accelerated approval of blinatumomab (Blincyto; Amgen, Inc.) for treatment of Philadelphia chromosome-negative relapsed or refractory precursor B-cell acute lymphoblastic leukemia (R/R ALL). Blinatumomab is a recombinant murine protein that acts as a bispecific CD19-directed CD3 T-cell engager. The basis for the approval was a single-arm trial with 185 evaluable adults with R/R ALL. The complete remission (CR) rate was 32% [95% confidence interval (CI), 26%-40%], and the median duration of response was 6.7 months. A minimal residual disease response was achieved by 31% (95% CI, 25%-39%) of all patients. Cytokine release syndrome and neurologic events were serious toxicities that occurred. Other common (>20%) adverse reactions were pyrexia, headache, edema, febrile neutropenia, nausea, tremor, and rash. Neutropenia, thrombocytopenia, and elevated transaminases were the most common (>10%) laboratory abnormalities related to blinatumomab. A randomized trial is required in order to confirm clinical benefit. Clin Cancer Res; 21(18); 4035-9. Ó2015 AACR. Disclosure of Potential Conflicts of InterestNo potential conflicts of interest were disclosed. Editor's DisclosuresThe following editor(s) reported relevant financial relationships: J.L. Abbruzzese is a consultant/advisory board member for Celgene and Halozyme. CME Staff Planners' DisclosuresThe members of the planning committee have no real or apparent conflict of interest to disclose. Learning ObjectivesUpon completion of this activity, the participant should have a better understanding of the mechanism of action of blinatumomab, how the toxicities of blinatumomab reflect the mechanism of action, and the level of evidence supporting use of blinatumomab for the treatment of Philadelphia chromosome-negative relapsed or refractory precursor B-cell acute lymphoblastic leukemia.
On February 22, 2013, the FDA licensed ado-trastuzumab emtansine (Kadcyla; Genentech, Inc.) for use as a single agent for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) who previously received trastuzumab and a taxane, separately or in combination. The clinical basis for licensure was a phase III trial in 991 patients with HER2-positive MBC that randomly allocated patients to receive ado-trastuzumab emtansine (n ¼ 495) or lapatinib in combination with capecitabine (n ¼ 496). The coprimary endpoints were progression-free survival (PFS) based on tumor assessments by an independent review committee and overall survival (OS). Statistically significant improvements in PFS and OS were observed in patients receiving ado-trastuzumab emtansine compared with patients receiving lapatinib plus capecitabine [difference in PFS medians of 3.2 months, HR, 0.65 (95% confidence interval, CI, 0.55-0.77), P < 0.0001 and difference in OS medians of 5.8 months, HR, 0.68 (95% CI, 0.55-0.85), P ¼ 0.0006]. The most common adverse reactions in patients receiving adotrastuzumab emtansine were fatigue, nausea, musculoskeletal pain, thrombocytopenia, headache, increased aminotransferase levels, and constipation. Other significant adverse reactions included hepatobiliary disorders and left ventricular dysfunction. Given the PFS and OS results, the benefit-risk profile was considered favorable. Clin Cancer Res; 20(17); 4436-41. Ó2014 AACR.
On July 3, 2014, the FDA granted accelerated approval for belinostat (Beleodaq; Spectrum Pharmaceuticals, Inc.), a histone deacetylase inhibitor, for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). A single-arm, openlabel, multicenter, international trial in the indicated patient population was submitted in support of the application. Belinostat was administered intravenously at a dose of 1000 mg/m 2 over 30 minutes once daily on days 1 to 5 of a 21-day cycle. The primary efficacy endpoint was overall response rate (ORR) based on central radiology readings by an independent review committee. The ORR was 25.8% [95% confidence interval (CI), 18.3-34.6] in 120 patients that had confirmed diagnoses of PTCL by the Central Pathology Review Group. The complete and partial response rates were 10.8% (95% CI, 5.9-17.8) and 15.0% (95% CI, 9.1-22.7), respectively. The median duration of response, the key secondary efficacy endpoint, was 8.4 months (95% CI, 4.5-29.4). The most common adverse reactions (>25%) were nausea, fatigue, pyrexia, anemia, and vomiting. Grade 3/4 toxicities (!5.0%) included anemia, thrombocytopenia, dyspnea, neutropenia, fatigue, and pneumonia. Belinostat is the third drug to receive accelerated approval for the treatment of relapsed or refractory PTCL.
Differences in clinical pharmacology of the currently marketed phosphodiesterase (PDE)5 inhibitors sildenafil, vardenafil and tadalafil are largely determined by their pharmacokinetic (PK) properties and their PDE5 inhibitory activity profile. This review outlines the basic concepts of pharmacokinetics and pharmacokinetic pharmacodynamic (PK/PD) relationships and their relevance to dose selection and applied pharmacotherapy. It is followed by a detailed comparative discussion on the pharmacokinetics and exposure-response relationship of the currently available PDE5 inhibitors, including known drug-drug interactions and dosage adjustments in special populations. The review is aimed at providing a critical assessment of the pharmacokinetics of PDE5 inhibitors, which may assist clinicians in tailoring drug and/or treatment regimens to the unique needs of each individual patient with erectile dysfunction.
Pharmacometric analyses have become an increasingly important component of New Drug Application (NDA) and Biological License Application (BLA) submissions to the US FDA to support drug approval, labelling and trial design decisions. Pharmacometrics is defined as a science that quantifies drug, disease and trial information to aid drug development, therapeutic decisions and/or regulatory decisions. In this report, we present the results of a survey evaluating the impact of pharmacometric analyses on regulatory decisions for 198 submissions during the period from 2000 to 2008. Pharmacometric review of NDAs included independent, quantitative analyses by FDA pharmacometricians, even when such analysis was not conducted by the sponsor, as well as evaluation of the sponsor's report. During 2000-2008, the number of reviews with pharmacometric analyses increased dramatically and the number of reviews with an impact on approval and labelling also increased in a similar fashion. We also present the impact of pharmacometric analyses on selection of paediatric dosing regimens, approval of regimens that had not been directly studied in clinical trials and provision of evidence of effectiveness to support a single pivotal trial. Case studies are presented to better illustrate the role of pharmacometric analyses in regulatory decision making.
Despite advances in biomedical research that have deepened our understanding of cancer hallmarks, resulting in the discovery and development of targeted therapies, the success rates of oncology drug development remain low. Opportunities remain for objective dose selection informed by exposure-response understanding to optimize the benefit-risk balance of novel therapies for cancer patients. This review article discusses the principles and applications of modeling and simulation approaches across the lifecycle of development of oncology therapeutics. Illustrative examples are used to convey the value gained from integration of quantitative clinical pharmacology strategies from the preclinical-translational phase through confirmatory clinical evaluation of efficacy and safety.
On July 23, 2014, the FDA granted accelerated approval to idelalisib (Zydelig tablets; Gilead Sciences, Inc.) for the treatment of patients with relapsed follicular B-cell non-Hodgkin lymphoma or relapsed small lymphocytic lymphoma (SLL) who have received at least two prior systemic therapies. In a multicenter, single-arm trial, 123 patients with relapsed indolent non-Hodgkin lymphomas received idelalisib, 150 mg orally twice daily. In patients with follicular lymphoma, the overall response rate (ORR) was 54%, and the median duration of response (DOR) was not evaluable; median follow-up was 8.1 months. In patients with SLL, the ORR was 58% and the median DOR was 11.9 months. One-half of patients experienced a serious adverse reaction of pneumonia, pyrexia, sepsis, febrile neutropenia, diarrhea, or pneumonitis. Other common adverse reactions were abdominal pain, nausea, fatigue, cough, dyspnea, and rash. Common treatment-emergent laboratory abnormalities were elevations in alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase, absolute lymphocytes, and triglycerides. Continued approval may be contingent upon verification of clinical benefit in confirmatory trials.
Innovative tools are urgently needed to accelerate the evaluation and subsequent approval of novel treatments that may slow, halt, or reverse the relentless progression of Parkinson disease (PD). Therapies that intervene early in the disease continuum are a priority for the many candidates in the drug development pipeline. There is a paucity of sensitive and objective, yet clinically interpretable, measures that can capture meaningful aspects of the disease. This poses a major challenge for the development of new therapies and is compounded by the considerable heterogeneity in clinical manifestations across patients and the fluctuating nature of many signs and symptoms of PD. Digital health technologies (DHT), such as smartphone applications, wearable sensors, and digital diaries, have the potential to address many of these gaps by enabling the objective, remote, and frequent measurement of PD signs and symptoms in natural living environments. The current climate of the COVID-19 pandemic creates a heightened sense of urgency for effective implementation of such strategies. In order for these technologies to be adopted in drug development studies, a regulatory-aligned consensus on best practices in implementing appropriate technologies, including the collection, processing, and interpretation of digital sensor data, is required. A growing number of collaborative initiatives are being launched to identify effective ways to advance the use of DHT in PD clinical trials. The Critical Path for Parkinson’s Consortium of the Critical Path Institute is highlighted as a case example where stakeholders collectively engaged regulatory agencies on the effective use of DHT in PD clinical trials. Global regulatory agencies, including the US Food and Drug Administration and the European Medicines Agency, are encouraging the efficiencies of data-driven engagements through multistakeholder consortia. To this end, we review how the advancement of DHT can be most effectively achieved by aligning knowledge, expertise, and data sharing in ways that maximize efficiencies.
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