Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse.

In a randomized trial of therapy for FMS-like tyrosine kinase-3 (FLT3) mutant acute myeloid leukemia in first relapse, 224 patients received chemotherapy alone or followed by 80 mg of the FLT3 inhibitor lestaurtinib twice daily. Endpoints included complete remission or complete remission with incomplete platelet recovery (CR/CRp), overall survival, safety, and tolerability. Correlative studies included pharmacokinetics and analysis of in vivo FLT3 inhibition. There were 29 patients with CR/CRp in the lestaurtinib arm and 23 in the control arm (26% vs 21%; P = .35), and no difference in overall survival between the 2 arms. There was evidence of toxicity in the lestaurtinib-treated patients, particularly those with plasma levels in excess of 20 µM. In the lestaurtinib arm, FLT3 inhibition was highly correlated with remission rate, but target inhibition on day 15 was achieved in only 58% of patients receiving lestaurtinib. Given that such a small proportion of patients on this trial achieved sustained FLT3 inhibition in vivo, any conclusions regarding the efficacy of combining FLT3 inhibition with chemotherapy are limited. Overall, lestaurtinib treatment after chemotherapy did not increase response rates or prolong survival of patients with FLT3 mutant acute myeloid leukemia in first relapse. This study is registered at www.clinicaltrials.gov as #NCT00079482.

Value and Implementation of the Aggregate Safety Assessment Plan.

Aggregate safety assessment involves evaluation of the totality of safety data to characterize the emerging safety profile of a product. The Drug Information Association-American Statistical Association Interdisciplinary Safety Evaluation scientific working group recently published an approach to developing an Aggregate Safety Assessment Plan (ASAP). Creation of an ASAP facilitates a consistent approach to safety data collection and analysis across studies and minimizes important missing data at the time of regulatory submission. A critical aspect of the ASAP is identification of the Safety Topics of Interest (STOI). The STOI, as defined in the ASAP, comprises adverse events (AEs), which have the potential to impact the benefit: risk profile of a product and typically require specialized data collection or analyses. While there are clear benefits to developing an ASAP for a drug development program, multiple concerns may be encountered with implementation. This article uses the examples of two STOIs to demonstrate the benefits and efficiencies gained with implementation of the ASAP in safety planning as well as in optimally characterizing the emerging safety profile of a product.

Global Landscape of Benefit-Risk Considerations for Medicinal Products: Current State and Future Directions.

In the last decade there has been a significant increase in the literature discussing the use of benefit-risk methods in medical product (including devices) development. Government agencies, medical product industry groups, academia, and collaborative consortia have extensively discussed the advantages of structured benefit-risk assessments. However, the abundance of information has not resulted in a consistent way to utilize these findings in medical product development. Guidelines and papers on methods, even though well structured, have not led to a firm consensus on a clear and consistent approach. This paper summarizes the global landscape of benefit-risk considerations for product- or program-level decisions from available literature and regulatory guidance, providing the perspectives of three stakeholder groups-regulators, collaborative groups and consortia, and patients. The paper identifies key themes, potential impact on benefit-risk assessments, and significant future trends.

Aggregate Safety Assessment Planning for the Drug Development Life-Cycle.

The Program Safety Analysis Plan (PSAP) was proposed previously as a tool to proactively plan for integrated analyses of product safety data. Building on the PSAP and taking into consideration the evolving regulatory landscape, the Drug Information Association-American Statistical Association (DIA-ASA) Interdisciplinary Safety Evaluation scientific working group herein proposes the Aggregate Safety Assessment Plan (ASAP) process. The ASAP evolves over a product's life-cycle and promotes interdisciplinary, systematic safety planning as well as ongoing data review and characterization of the emerging product safety profile. Objectives include alignment on the safety topics of interest, identification of safety knowledge gaps, planning for aggregate safety evaluation of the clinical trial data and preparing for safety communications. The ASAP seeks to tailor the analyses for a drug development program while standardizing the analyses across studies within the program. The document is intended to be modular and flexible in nature, depending on the program complexity, phase of development and existing sponsor processes. Implementation of the ASAP process will facilitate early safety signal detection, improve characterization of product risks, harmonize safety messaging, and inform program decision-making.

Global Regulatory Landscape for Aggregate Safety Assessments: Recent Developments and Future Directions.

Notwithstanding successful harmonization efforts, the global regulatory framework governing product safety is complex and continually evolving, as evidenced by additional regional guidance and regulations. In this regulatory review, we provide an overview from both global and regional perspectives. A historical perspective, with a focus on recent developments, enables identification of important long-term trends, such as a shift from single-case medical review of serious adverse events to an interdisciplinary evaluation of aggregate data for the purpose of judging product causality and informing benefit-risk assessments. We will show how these trends lead to opportunities for closer interdisciplinary collaboration, for bridging the gap between preand postmarketing surveillance, and for a more proactive determination of patient populations with a positive benefit-risk profile for product use. We will conclude by pointing to ongoing and future work that seeks to provide specific solutions for ongoing aggregate safety evaluation.

A randomized, placebo-controlled study of fentanyl buccal tablet for breakthrough pain in opioid-treated patients with cancer.

OBJECTIVES: Cancer-related breakthrough pain (BTP) is typically managed with a short-acting oral opioid, taken as needed during a fixed-schedule opioid regimen. The conventional approach may not provide the onset of analgesia required for BTP for many patients, because the onset of analgesia with short-acting opioids lags behind the time course of the majority of episodes of BTP. The fentanyl buccal tablet (FBT) employs a novel delivery system that enhances the rate and extent of absorption of fentanyl through the buccal mucosa. This double-blind, randomized, placebo-controlled study evaluated the efficacy, safety, and tolerability of FBT in opioid-treated patients with cancer-related BTP. METHODS: After an open-label titration (N=123) to identify an effective FBT dose to treat BTP episodes, 77 patients were randomly assigned to 1 of 18 prespecified dose sequences of 10 tablets (7 FBT and 3 placebo). Pain intensity, pain relief (PR), and global performance of the medication were recorded at regular time intervals between 15 and 60 minutes. Pain intensity differences (PID), the summed PID (SPID), and summed total PR were calculated. The SPID at 30 minutes (SPID30) was the primary efficacy variable. Adverse events were reported. RESULTS: Sixty-five percent (80/123) of patients were titrated to an effective dose. The mean (SE) SPID30 for FBT was 3.0+/-0.12 versus 1.8+/-0.18 for placebo (P<0.0001). Measures of PR, PID, SPID, summed total PR, and patient ratings of global performance of medication significantly favored FBT over placebo at all time points. Adverse events were typical of opioid drugs. Poor oral tolerability was noted in 2 patients. CONCLUSIONS: FBT is efficacious and safe in the treatment of cancer-related BTP.

A Bayesian adaptive design for multi-dose, randomized, placebo-controlled phase I/II trials.

We present a design for a randomized controlled trial (RCT) featuring two simultaneous iterative processes, dose escalation and cohort expansion. In this design, patient enrollment does not need to stop when transitioning from the evaluation of the dose safety and tolerability to the assessment of its efficacy. The cohort expansion used in dose-finding is adaptive, based on the interim comparisons between each dose and placebo. A set of Bayesian rules guides the decisions about dose cohort expansion. Operating characteristics of this design have been evaluated by simulations designed to mimic the trial conduct and outcome in a variety of dose toxicity and efficacy scenarios. Simulation studies demonstrated that our proposed adaptive design can reduce the total sample size as compared to the conventional approach. The sample size reduction was more profound in scenarios when the testing doses are not effective. Simulation studies also demonstrated that this proposed adaptive design controls the false positive error rate at the specified level and provides adequate statistical power to detect the treatment effect. Compared to the conventional approach, our proposed adaptive design removes ineffective doses, reduces the total sample size, and maintains adequate power for dose-finding. The proposed design has been implemented in an ongoing study and software for trial simulation is available at http://odin.mdacc.tmc.edu/~yuanj/soft.html.

Bendamustine produces durable responses with an acceptable safety profile in patients with rituximab-refractory indolent non-Hodgkin lymphoma.

BACKGROUND: Although initially responsive to therapy, indolent non-Hodgkin lymphomas (NHLs) are generally incurable. Therefore, active and tolerable treatments for patients with relapsed or refractory disease are needed. Bendamustine, a mechlorethamine alkylator with novel mechanisms of action, is approved in the United States for rituximab-refractory indolent B-cell NHL. PATIENTS AND METHODS: Data from 2 North American multicenter studies with similar design, enrollment, and response criteria were pooled to evaluate safety and durability of response. Bendamustine was administered at 120 mg/m2 days 1 and 2 every 21 days for 6-8 cycles. Endpoints included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and safety. RESULTS: The studies enrolled 161 patients with a median of 2 previous chemotherapy regimens. Histologies included follicular (68%), small lymphocytic (20%), marginal zone (11%), and lymphoplasmacytic (1%) lymphoma. Sixty patients (34.1%) were refractory to their last chemotherapy, 53 (30.1%) were alkylating agent refractory. Overall response rate was 76% with 23% complete remissions (CRs) and unconfirmed CR (CRu). The median follow-up was 25.3 months (range, 24-27.8 months) and DOR was 10 months (range, 8.3-14 months). At 1 and 2 years, 45% and 23% of responders continued to respond. Among 127 patients previously treated with alkylators, ORR was 88% (28% CR/CRu) in responsive and 59% (12% CR/CRu) in refractory patients. Fifty opportunistic infections were reported in 48 patients. Second malignancies occurred in 9 patients (5.6%; 5 myelodysplastic syndromes, 2 acute myelogenous leukemia, 1 chronic myelomonocytic leukemia, and 1 squamous cell carcinoma). CONCLUSION: Bendamustine induces durable responses with acceptable long-term safety in rituximab-refractory indolent NHL.

Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia.

PURPOSE: This randomized, open-label, parallel-group, multicenter study was designed to compare the efficacy and safety of bendamustine and chlorambucil in previously untreated patients with advanced (Binet stage B or C) chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: Patients (