Purpose: To describe the clinical studies, chemistry manufacturing and controls, and clinical pharmacology and toxicology that led to Food and Drug Administration approval of nelarabine (Arranon) for the treatment of T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma. Experimental Design: Two phase 2 trials, one conducted in pediatric patients and the other in adult patients, were reviewed. The i.v. dose and schedule of nelarabine in the pediatric and adult studies was 650 mg/m 2 /d daily for 5 days and 1,500 mg/m 2 on days 1, 3, and 5, respectively. Treatments were repeated every 21days. Study end points were the rates of complete response (CR) and CR with incomplete hematologic or bone marrow recovery (CR*). Results: The pediatric efficacy population consisted of 39 patients who had relapsed or had been refractory to two or more induction regimens. CR to nelarabine treatment was observed in 5 (13%) patients and CR+CR* was observed in 9 (23%) patients. The adult efficacy population consisted of 28 patients. CR to nelarabine treatment was observed in 5 (18 %) patients and CR+CR* was observed in 6 (21%) patients. Neurologic toxicity was dose limiting for both pediatric and adult patients. Other severe toxicities included laboratory abnormalities in pediatric patients and gastrointestinal and pulmonary toxicities in adults. Conclusions: On October 28, 2005, the Food and Drug Administration granted accelerated approval for nelarabine for treatment of patients with relapsed or refractoryT-cell acute lymphoblastic leukemia/lymphoblastic lymphoma after at least two prior regimens. This use is based on the induction of CRs. The applicant will conduct postmarketing clinical trials to show clinical benefit (e.g., survival prolongation).
There are several challenging statistical problems identified in the regulatory review of large cardiovascular (CV) clinical outcome trials and central nervous system (CNS) trials. The problems can be common or distinct due to disease characteristics and the differences in trial design elements such as endpoints, trial duration, and trial size. In schizophrenia trials, heavy missing data is a big problem. In Alzheimer trials, the endpoints for assessing symptoms and the endpoints for assessing disease progression are essentially the same; it is difficult to construct a good trial design to evaluate a test drug for its ability to slow the disease progression. In CV trials, reliance on a composite endpoint with low event rate makes the trial size so large that it is infeasible to study multiple doses necessary to find the right dose for study patients. These are just a few typical problems. In the past decade, adaptive designs were increasingly used in these disease areas and some challenges occur with respect to that use. Based on our review experiences, group sequential designs (GSDs) have borne many successful stories in CV trials and are also increasingly used for developing treatments targeting CNS diseases. There is also a growing trend of using more advanced unblinded adaptive designs for producing efficacy evidence. Many statistical challenges with these kinds of adaptive designs have been identified through our experiences with the review of regulatory applications and are shared in this article.
Types I and III interferon (IFN) are co-expressed by respiratory epithelial cells (REC) in response to viral infection. In turn, these IFN stimulate neighboring REC to express a set of interferon-stimulated genes (ISG) through shared signaling pathways. Whether types I and III IFN have non-redundant functions in anti-viral defense of respiratory infections is unknown. Because transcription factors dictate cellular phenotype and function, we hypothesized that ISG that are transcription factors (TF-ISG) mediate non-redundant functions of types I or III IFN. We treated BEAS-2B human REC with increasing doses of IFN-β or IFN-λ1 alone or together, and measured expression of TF-ISG and a set of canonical ISG by qRT-PCR and Western blot. Alone, IFN-β and IFN-λ1 each induced expression of canonical ISG and a subset of TF-ISG. Expression of several ISG differed in response to type I versus type III IFN, either in peak levels or kinetic patterns, or both. Uniquely, IRF1 is induced early in response to IFN-β alone, but is poorly expressed in response to IFN-λ1. Western blots also revealed that while IFN-β alone induced early and transient IRF1 expression, it was lower but sustained (through 24h) after IFN-λ1 alone. In contrast to transcript expression, the two IFN together enhanced expression of IRF1 protein greater than either alone, and IRF1 expression was sustained through 24h. The distinct selective and rapid expression of IRF1 transcript and protein in response to IFN-β suggests that this TF-ISG mediates non-redundant qualitative functional responses of REC to types I and III IFN.
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