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Regulatory Issues: FDA |
Division of Oncology Drug Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Rockville, Maryland, USA
Key Words. Nelarabine • Arranon® • T-cell lymphoblastic leukemia/lymphoma • Relapsed disease
Correspondence: Correspondence: Martin H. Cohen, M.D., Food and Drug Administration, White Oak Campus, 10903 New Hampshire Avenue, Building 22, Room 2102, Silver Spring, Maryland 20993-0002, USA. Telephone: 301-796-1344; Fax: 301-796-9845; e-mail: martin.cohen{at}fda.hhs.gov
Received January 20, 2006; accepted for publication April 18, 2008.
Disclosure: No potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.
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Learning Objectives
Top
Learning Objectives
Abstract
Introduction
Patients and Methods
Results
Safety
Discussion
Author Contributions
Acknowledgments
References
After completing this course, the reader will be able to:
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ABSTRACT |
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TopLearning ObjectivesAbstractIntroductionPatients and MethodsResultsSafetyDiscussionAuthor ContributionsAcknowledgmentsReferences |
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Experimental Design. Two phase II trials, one conducted in pediatric patients and the other in adult patients, were reviewed. Patients were in their first or subsequent relapse and/or were refractory to first-line therapy. The dose and schedule of i.v. nelarabine in the pediatric and adult studies were 650 mg/m2 per day daily for 5 days and 1,500 mg/m2 i.v. on days 1, 3, and 5, respectively. Treatments were repeated every 21 days. Study endpoints 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 after, or had been refractory to, two or more induction regimens. CR to nelarabine treatment was observed in five patients (13%) and CR+CR* was observed in nine patients (23%). The adult efficacy population consisted of 28 patients. CR to nelarabine treatment was observed in five patients (18%) and CR+CR* was observed in six patients (21%).
Neurologic toxicity was dose limiting for both pediatric and adult patients. Other severe toxicities included hematologic, hepatic, and metabolic laboratory abnormalities in pediatric patients and gastrointestinal and pulmonary toxicities in adults.
Conclusions. On October 28, 2005, the FDA granted accelerated approval for nelarabine for treatment of patients with relapsed or refractory T-ALL/T-LBL after at least two prior regimens. This use is based on the induction of CR. The applicant will conduct postmarketing clinical trials to demonstrate clinical benefit, for example, survival prolongation.
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INTRODUCTION |
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The principal route of metabolism for nelarabine is O-demethylation by ADA to form ara-G, which undergoes hydrolysis to form guanine. In addition, some nelarabine is hydrolyzed to form methylguanine, which is O-demethylated to form guanine. Guanine is N-deaminated to form xanthine, which is further oxidized to yield uric acid. Renal elimination of nelarabine and ara-G in humans accounts for approximately 5%–10% and 20%–30%, respectively, of the administered dose [4].
A phase I trial of nelarabine that included 13 adult and 26 pediatric patients with T-cell acute lymphoblastic leukemia/T-cell lymphoblastic lymphoma (T-ALL/T-LBL) was conducted. Nelarabine, at doses of 5–75 mg/kg per day, was administered daily for 5 days as a 1-hour i.v. infusion every 21–28 days. There were two complete responses (CRs) (15%) in adult T-ALL/T-LBL patients and seven CRs (27%) in pediatric T-ALL/T-LBL patients [5].
The present nelarabine U.S. Food and Drug Administration (FDA) submission consists of two multicenter, nonrandomized, open-label, single-arm trials—the first a pediatric study [6], the second an adult study. Patients meeting the criteria of the proposed indication were in second or subsequent relapse and/or were refractory and were not eligible for therapy of higher curative potential.
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PATIENTS AND METHODS |
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50 and had adequate renal (creatinine normal for age or creatinine clearance or glomerular filtration rate 60 ml/min per 1.73 m2) and liver (serum bilirubin 
1.5x the upper limit of normal [ULN] and aspartate aminotransferase and alanine aminotransferase 5x ULN) function.
Patients were not to receive any other anticancer treatment, including radiation therapy, and had to have recovered from the toxicity of all previous chemotherapy. At least 6 weeks had to have elapsed since administration of nitrosoureas or craniospinal or hemipelvic radiation therapy. Pregnant or lactating women and patients with baseline neurotoxicity of grade 2 were excluded.
Pediatric study patients received nelarabine at 650 mg/m2 i.v. over 1 hour daily for five consecutive days, repeated every 21 days. Adult patients received nelarabine at 1,500 mg/m2 i.v. over 2 hours on days 1, 3, and 5, repeated every 21 days. Doses were reduced for nonhematologic or hematologic toxicities in both groups. Depending upon the availability of a donor and other considerations, patients could be removed from study to receive a hematologic stem cell transplant. Intrathecal therapy could be administered, if required.
The primary study endpoint was the rate of CR and the rate of CR*. A CR was defined as bone marrow blast counts 5%, no other evidence of disease, and full recovery of peripheral blood counts (i.e., absolute neutrophil count >1,500/µl, platelets >100,000/µl, hemoglobin [Hb] 10 g/dl for patients <2 years of age or Hb 11 g/dl for patients 2 years of age). CR* was defined as bone marrow blast counts 5% and no other evidence of disease. These patients could have had hypocellular bone marrow or peripheral hemograms that had not completely normalized.
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RESULTS |
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The mean age of the group A and group B pediatric study populations was approximately 11.5 years, with a range of 2 months to 21 years in the former population and 2–21 years in the latter. The majority of study patients were male (group A, 64%; group B, 87%) and white (group A, 64%; group B, 61%). The majority of patients in both groups had a KPS score 80 (group A, 60%; group B, 87%). The large majority of patients had T-ALL (group A, 79%; group B, 90%). Extramedullary involvement was present in 44% of group A patients and 32% of group B patients.
Rates of CR and CR* for pediatric patients receiving nelarabine at 650 mg/m2 are shown in Table 1.
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Stem cell transplantation was performed in four of nine group A CR or CR* patients (44%) and in 10 of 15 group B CR or CR* patients (67%). Two CR or CR* patients (one each from groups A and B) received systemic therapy in preparation for a transplant but were not transplanted. Response duration attributable to nelarabine could not be determined in transplanted patients or in patients receiving pretransplantation chemotherapy. Remission durations for group A and group B patients who were not transplanted and who did not receive systemic therapy during nelarabine-induced remission were 9.3, 6.1, 3.6, and 3.3 weeks and 9.1, 6.3, 2.3, and 1.4+ weeks, respectively.
The adult efficacy population consisted of 28 group A patients who had relapsed or had been refractory to two or more induction regimens and 11 group B patients who had only one prior induction regimen.
The mean age of the group A and group B adult study populations was approximately 30 years, with a range of 16–65 years in the former population and 23–66 years in the latter. The majority of study patients were male (82% in both groups) and white (group A, 61%; group B, 91%). The majority of patients had a performance status score of 0–1 (72% in both groups). The large majority of patients had T-ALL (group A, 61%; group B, 82%). Extramedullary involvement was present in 71% of group A patients and 55% of group B patients. Fourteen percent (4 of 28) of group A patients and 9% (1 of 11) of group B patients had a prior hematopoietic stem cell transplant.
Rates of CR and CR* for adult patients receiving nelarabine at 650 mg/m2 are shown in Table 2. Both T-ALL and T-LBL group A patients achieved a CR or CR* (T-ALL, 24%; T-LBL, 22%).
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SAFETY |
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A variety of laboratory toxicities were also observed, including grade 3 or 4 increased transaminases and bilirubin in 4% and 9% of patients and decreased albumin and potassium in 6% of patients.
Grade 3 or 4 gastrointestinal toxicity was not seen.
Neurologic toxicity was dose limiting (Table 3). Overall, 38% of patients had neurologic events—14% grade 3 and 8% grade 4. The percentage of patients with grade 3 or 4 neurologic toxicity is likely an underestimate because patients were often removed from study if they developed grade 2 neurologic toxicity.
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Other neurologic adverse events, regardless of causality, reported as grade 1, 2, or unknown in pediatric patients, were dysarthria, encephalopathy, hydrocephalus, hyporeflexia, lethargy, mental impairment, paralysis, and sensory loss, each reported in one patient (1%).
The adult safety database included 103 patients who received the recommended nelarabine dose and schedule. As with pediatric patients, hematologic toxicity was the most frequent adverse event. Grade 3 or 4 hematologic toxicity (by National Cancer Institute Common Toxicity Criteria) was observed in approximately 70% of the study population. On occasion, this toxicity was accompanied by febrile neutropenia and infection complicating neutropenia.
Grade 3 or 4 gastrointestinal disorders included nausea, diarrhea, vomiting, constipation, and stomatitis. Each of these grade 3 or 4 toxicities occurred in about 1% of treated patients.
Constitutional symptoms included fatigue (12%) and asthenia (1%). Respiratory disorders included cough and dyspnea (6%).
As was observed in the pediatric study, neurologic toxicity was dose limiting. Overall, 72% of patients had neurologic events—10% grade 3 and 3% grade 4. (As previously indicated, this is likely an underestimate because patients were often removed from the study with grade 2 neurologic toxicity).
Table 4 summarizes the neurologic toxicity seen in adult patients. The most frequent neurologic adverse event, irrespective of causality, was somnolence (all grade 1 or 2). Other frequently recorded toxicities included dizziness, hypoesthesia, headache, paresthesia, ataxia, depressed consciousness, and neuropathy. One patient had status epilepticus. There was also a single report of biopsy-confirmed progressive multifocal leukoencephalopathy.
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DISCUSSION |
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In the present pediatric study, CR to nelarabine treatment was observed in five patients (13%) and CR+CR* was observed in nine patients (23%) who had relapsed or were refractory to two or more prior regimens. Of the nine responding patients, stem cell transplantation was performed in four of nine group A CR or CR* patients (44%). One additional CR or CR* patient received systemic therapy in preparation for a transplant but was not transplanted. For patients who were not transplanted and who did not receive systemic therapy during nelarabine-induced remission, remission durations were 9.3, 6.1, 3.6, and 3.3 weeks.
In the adult study, CR to nelarabine treatment was observed in five patients (18%), and CR* was observed in one additional patient (4%), who had relapsed or were refractory to two or more prior regimens. Stem cell transplantation was performed in one of the six patients (17%). For nontransplanted CR or CR* patients, remission durations were 195+, 30, 19, 15, and 4 weeks.
The primary regulatory issue with this application concerns whether accelerated or regular approval is warranted. Accelerated approval regulations require that a new drug provides benefit over available therapy or that no approved therapy exists. Accelerated approval is granted on the basis of a surrogate endpoint that is reasonably likely to predict clinical benefit. In most cancer trials, the surrogate endpoint is the response rate. Accelerated approval requires that the applicant study the drug further, to verify and describe its clinical benefit (phase IV commitments). The applicant shall carry out any such studies with due diligence (as rapidly as possible) [9].
Regular approval requires that clinical benefit be demonstrated. While survival or symptom improvement are the classic endpoints for regular approval, in acute leukemia regular approval has been granted on the basis of CRs of adequate duration. Pentostatin, cladribine, tretinoin, and arsenic trioxide were all granted regular approval for the treatment of hematologic malignancies on the basis of durable CRs [10]. The rationale for regular approval (based on durable CRs) is that the decrease in transfusion requirements, infections, and bleeding accompanying a CR is of clinical benefit.
In contrast to the above regular approvals, clofarabine was recently granted accelerated approval for the treatment of pediatric patients 1–21 years old with relapsed or refractory ALL after two or more prior regimens. This approval was based on the results of a single-arm phase II study and a supporting phase I study. As was the case with nelarabine, information about response duration data was limited because 40% of responding patients received a stem cell transplant during clofarabine-induced remission.
On October 28, 2005, the FDA granted accelerated approval for nelarabine treatment of patients with T-ALL and T-LBL whose disease has not responded to or has relapsed following treatment with at least two chemotherapy regimens. As indicated, this use is based on the induction of CRs. A phase IV study, to be conducted by the Children's Oncology Group, is currently being reviewed. This pro-posed adequate and well-designed study will verify and describe the clinical benefit of nelarabine therapy.
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AUTHOR CONTRIBUTIONS |
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Manuscript writing: Martin H. Cohen, John R. Johnson, Robert Justice, Richard Pazdur
Final approval of manuscript: Richard Pazdur
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ACKNOWLEDGMENTS |
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REFERENCES |
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314.510 and 21CFR 601.41.
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