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Clinical Cancer Research Vol. 12, 5329-5335, September 15, 2006
© 2006 American Association for Cancer Research

Report from the FDA

Approval Summary: Nelarabine for the Treatment of T-Cell Lymphoblastic Leukemia/Lymphoma

Martin H. Cohen, John R. Johnson, Tristan Massie, Rajeshwari Sridhara, W. David McGuinn, Jr., Sophia Abraham, Brian P. Booth, M. Anwar Goheer, David Morse, Xiao H. Chen, Nallaperumal Chidambaram, Leslie Kenna, Jogarao V. Gobburu, Robert Justice and Richard Pazdur

Authors' Affiliation: Division of Drug Oncology Products, Office of Oncology Drug Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland

Requests for reprints: Martin H. Cohen, Division of Drug Oncology Products, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857. Phone: 301-594-5740; Fax: 301-594-0499; E-mail: martin.cohen{at}fda.hhs.gov.


   Abstract
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 Abstract
Chemistry, Pharmacology and...
 Patients and Methods
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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/m2/d daily for 5 days and 1,500 mg/m2 on days 1, 3, and 5, respectively. Treatments were repeated every 21 days. 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 refractory T-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).

Nelarabine was one of seven purine nucleoside analogues synthesized as potential antiviral drugs (1). Although, it was not effective for that purpose, nelarabine was cytotoxic to MRC-5 human diploid fibroblasts in vitro at the lowest concentration of any of the seven compounds.

Nelarabine, a prodrug of the deoxyguanosine analogue 9-ß-D-arabinofuranosylguanine (ara-G), is demethylated by adenosine deaminase to form the active compound. Intracellular deoxyguanosine kinase and deoxycytidine kinase phosphorylate ara-G sequentially to form ara-GTP (2). Phosphorylation of ara-G to ara-GTP is rapid and intracellular exposure to ara-GTP is much higher than the exposure to intracellular ara-G or nelarabine. After phosphorylation, ara-GTP substitutes for GTP in numerous biological processes, including the replication of DNA (3, 4). This substitution leads to inhibition of DNA synthesis resulting in cell death. This process is lethal to malignant T cells, as it is to other rapidly replicating cells. This mechanism seems so well accepted that little research has been done to determine other potential mechanisms of toxicity. Other mechanisms quite distinct from the inhibition of DNA synthesis are probably responsible for the acute lethal neurotoxicity seen in monkeys and the Guillain-Barre-like syndrome seen clinically (see below).

Nelarabine is cytotoxic in vitro at micromolar concentrations in human bone marrow progenitor cell lines. Experiments in vitro suggest that it is more toxic to human malignant T-cell lines than it is to malignant B-cells, in some cases by at least a factor of 10. Rodriguez et al. (5–7) have shown that this increased toxicity is the result of greater accumulation of ara-GTP in T-cells.

A phase I trial of nelarabine that included 13 adult and 26 pediatric patients with T-cell acute lymphoblastic leukemia (T-ALL)/lymphoblastic lymphoma (T-LBL) was conducted. Nelarabine, at doses of 5 to 75 mg/kg/d was administered daily for 5 days as 1 hour of i.v. infusion every 21 to 28 days. There were 2 (15%) complete responses (CR) in adult T-ALL/T-LBL patients and 7 (27%) CRs in pediatric T-ALL/T-LBL patients (3).

The present nelarabine Food and Drug Administration submission consisted of two multicenter, nonrandomized, open-label, single-arm trials, the first is a pediatric study (8), the second is an adult study. Patients corresponding to the proposed indication were in second or subsequent relapse and/or were refractory and were not eligible for therapy of higher curative potential.


   Chemistry, Pharmacology and Toxicology
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 Chemistry, Pharmacology and...
Patients and Methods
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Chemistry/manufacturing and controls
The chemical name for nelarabine is 2-amino-9-ß-D-arabinofuranosyl-6-methoxy-9H-purine. It has the molecular formula C11H15N5O5 and a molecular weight of 297.27. The chemical structure of nelarabine is shown in Fig. 1 . Nelarabine drug substance is synthesized by enzyme catalyzed reaction using arabinofuranosyl uracil and guanine analogue.


Figure 1
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  		Fig. 1. Nelarabine structural formula.

 
Nelarabine is white to slightly colored amorphous powder. It is slightly soluble to soluble in water depending on pH of the solution. It melts with decomposition between 209°C and 217°C. Arranon injection is supplied as a clear, colorless, sterile solution in glass vials. Each vial contains 250 mg nelarabine and the inactive ingredient sodium chloride in 50 mL Water for Injection, USP. Arranon is intended for i.v. infusion.

Nelarabine clinical pharmacology
Pharmacokinetics. Pharmacokinetic data are available for nelarabine, ara-G, and intracellular ara-GTP in 101 adult patients and 25 pediatric patients with refractory hematologic malignancies who received nelarabine i.v. at doses of 104 to 2,900 mg/m2. Following nelarabine infusion, plasma concentrations of both nelarabine and ara-G decline rapidly in a monoexponential fashion. At the proposed adult dose of 1,500 mg/m2, the mean peak plasma concentration (Cmax) of nelarabine and ara-G [observed in six patients at the end of the 2-hour infusion (day 1)] was 5.0 ± 3.0 and 31.4 ± 5.6 µg/mL, respectively.

Exposure to ara-G is 37 times higher than that for nelarabine after day 1 of nelarabine infusion [area under the concentration-time curve (AUC), 162 ± 49 µg/mL/h versus 4.4 ± 2.2 µg/mL/h, respectively]. Comparable Cmax and AUC values were obtained for nelarabine between days 1 and 5 at the proposed nelarabine adult dose of 1,500 mg/m2, indicating that the pharmacokinetics of nelarabine after multiple dosing is predictable from single dosing. There are not enough data for ara-G to make a comparison between days 1 and 5.

The pharmacokinetics of both nelarabine and ara-G appear to be linear over the nelarabine dosing range of 104 to 2,900 mg/m2 in both pediatric and adult patients.

At the adult nelarabine dose of 1,500 mg/m2, a mean intracellular Cmax for ara-GTP appeared within 3 to 25 hours after nelarabine infusion on day 1. Exposure to intracellular ara-GTP was 532 times higher than that for nelarabine and 14 times higher than that for ara-G (AUC, 2339 ± 2628 µg/mL/h versus 4.4 ± 2.2 and 162 ± 49 µg/mL/h, respectively). Because the intracellular levels of ara-GTP were so prolonged, its elimination half-life could not be estimated. There are no single- or multiple-dose pharmacokinetics data available for pediatric patients at the proposed 650 mg/m2 dose given once daily for 5 consecutive days. There are no multiple-dose data for ara-GTP in adult or pediatric patients. The available pharmacokinetics data indicate that the mean Cmax and AUC values for intracellular ara-GTP were 3- to 4-fold higher in responders than in nonresponders. Comparable mean Cmax and AUC values for both nelarabine and ara-G were obtained in responders and nonresponders. Mean Cmax and AUC values of ara-GTP were 2-fold higher in patients who experienced neurotoxicity than in those who did not. Comparable mean Cmax and AUC values for both nelarabine and ara-G were obtained in patients who experienced neurotoxicity and those who did not.

The pharmacokinetics data at nelarabine of doses of 104 to 2,900 mg/m2 indicate that the mean clearance of nelarabine is ~30% higher in pediatric patients (n = 22) than in adult patients (n = 66; CL, 259 ± 409 L/h/m2 versus 197 ± 189 L/h/m2, respectively) on day 1. The apparent clearance of ara-G is comparable between the two groups (10.5 ± 4.5 L/m2, adult patients; 11.3 ± 4.2 L/m2, pediatric patients) on day 1 after nelarabine administration.

Special populations. Age has no effect on nelarabine or ara-G pharmacokinetics (P > 0.05). No dosing adjustment is required for nelarabine in elderly patients with T-ALL and T-LBL.

Gender has no effect on nelarabine or ara-G pharmacokinetics (P > 0.05).

Most patients enrolled in phase 1 studies were Whites. In general, nelarabine mean clearance and volume of distribution values tend to be higher in Whites (n = 63) than in Blacks (by ~10%; n = 15). The opposite is true for ara-G; mean apparent clearance and volume of distribution values tend to be lower in Whites than in Blacks (by ~15-20%). No differences in safety or effectiveness were observed between these groups.

The effect of renal and hepatic impairment on the pharmacokinetics of nelarabine or ara-G has not been studied. Patients who enrolled in the phase 1 studies (adults and pediatrics) ranged in creatinine clearance from 31 to 363 mL/min. These patients were categorized into three groups: normal with creatinine clearance of >80 mL/min (n = 67), mild with creatinine clearance of 50 to 80 mL/min (n = 15), and moderate with creatinine clearance of <50 mL/min (n = 3). No trend is observed for the change in nelarabine mean clearance and volume of distribution with the degree of renal impairment. However, ara-G mean apparent clearance was about 15% and 40% lower in patients with mild and moderate renal impairment, respectively, than in patients with normal renal function.

Drug-drug interactions. Nelarabine and ara-G are not substrates of cytochrome P450 (CYP) enzymes. Nelarabine and ara-G did not significantly inhibit the activities of the major hepatic CYP enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 at in vitro concentrations of nelarabine and ara-G of >100 µmol/L (IC50 of ~30 µg/mL versus Cmax of 5.0 µg/mL for nelarabine and 31.4 µg/mL for ara-G at the proposed adult nelarabine dose of 1,500 mg/m2). The potential for drug-drug interactions between nelarabine and substrates of these enzymes is unlikely.

Nelarabine and ara-G are not substrates or inhibitors of the efflux transporter, P-glycoprotein.

Pharmacology and toxicology
Comparative pharmacokinetics. All tested animal species, including rat, rabbits, dogs, mice, and monkeys rapidly convert nelarabine to ara-G after i.v. dosing. In the rabbit, the AUC of ara-G was 7- to 10-fold higher than that of nelarabine; AUC and Cmax for both compounds increased linearly with dose and did not change with repeated dosing. The decrease in concentration of both compounds was biphasic. Less information is available for other species, but in the rat, the AUC of ara-G was about six times greater than that of nelarabine. Although humans also rapidly convert nelarabine to ara-G (half-life of nelarabine is ~16 minutes), they do not clear ara-G nearly as readily as rats, mice, or dogs. In humans the, half-life of ara-G is between 2 and 4 hours (Table 1 ). Because the other species eliminate ara-G much more quickly than humans or monkeys do, the sponsor chose to do the major toxicology studies for the development of nelarabine in the monkey.


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  		Table 1. Comparative pharmacokinetics of ara-G

 
Single doses of 3,600 mg/m2 or less in the monkey caused little toxicity but higher doses seemed to cause some saturation of metabolism. The increase in AUC with dose becomes greater than dose normal. Single doses of 4,800 or 6,000 mg/m2 resulted in irreversible neurotoxicity, manifested as a deepening loss of consciousness (see below). An overdose of nelarabine would possibly result in a similar saturation of metabolism and similar neurotoxicity in humans.

Reproductive toxicity and genotoxicity. Nelarabine is fetotoxic at clinically relevant doses. Nelarabine is highly mutagenic but this effect is measurable in vitro only at nonphysiologic concentrations.

Systemic toxicity. With the exception of the two unusual neurotoxicities, Nelarabine caused a spectrum of toxicities that one would expect with a purine antimetabolite. In mice, the LD10 for daily x5 dosing is ~1,500 mg/m2; this dose is associated with shallow breathing, decreased activity, and tremor. Consistent with their rapid elimination of the drug, dogs tolerated single doses of 7,200 mg/m2 with no toxicity. In rabbits given daily doses for 13 days (continuous i.v. infusion), the MTD was 4,320 mg/m2. This dose was associated with reduced appetite and decreased fecal output, decreased total body weight (~11%), and decreased white and red cell variables.

Monkeys tolerated single i.v. doses of 3,600 mg/m2 with few signs of toxicity. As mentioned above, higher doses caused fatal neurotoxicity in some individuals. Monkeys that died from this acute toxicity showed loss of palpebral reflex, shallow respiration, flaccid limbs, and minimal jaw tone. The monkeys that did not recover died within hours after the first or second dose. Monkeys tolerated five daily doses of 1,800 mg/m2, showing dose-dependent decreases in WBC and platelets and a decrease in thymus weight. At this schedule, a dose of 3,600 mg/m2 killed 3 of 4 monkeys by day 13. Moribund monkeys had tremors and convulsions. Most monkeys treated were under ketamine anesthesia and nelarabine dosing was associated with an increase in ketamine recovery time after 5 days of dosing. All monkeys at this dose had tremors and convulsions. Body weight decreased. Aspartate aminotransferase and alanine aminotransferase increased 2- to 12-fold. BUN, triglycerides, and glucose increased. Microscopic damage was found in proliferative tissues, gastrointestinal tract, spleen, marrow, and thymus. There was congestion in the lungs.

In an i.v. study with daily dosing for 30 days, monkeys tolerated doses of only 120 mg/m2 with decreased red and white cell variables. Daily doses of 240 mg/m2 killed 1 of 6 monkeys on day 28. A dose of 480 mg/m2 killed 3 of 10 monkeys despite the cessation of dosing on day 23. Red and white blood cell variables decrease significantly at these higher doses. Significant damage was seen in the brain (cerebellar degeneration and perivascular cuffing in the cerebrum and cerebellum) and in the spine (vacuolization and myelopathy, not reversible in surviving monkeys). Changes in clinical chemistry variables suggested significant liver damage. There was lymphoid infiltration in the bladder, kidney, trachea, salivary gland, lacrimal gland, and heart, suggesting a generalized inflammatory response. In females, there was myocardial degeneration and liver damage (cholangitis, edema, and vacuolization).

The acute neurotoxicity seen in monkeys given one or two doses >3,600 mg/m2 probably results from a secondary pharmacology acting centrally. It could be due to disruption of essential RNA synthesis within the central nervous system after the formation of high intracellular concentrations of ara-GTP or to an ara-GTP-related disruption of signal transmission. The rapid onset and irreversibility suggest that it is distinct from the Guillain-Barre-like syndrome seen in patients. The toxic dose-response curve for lethal neurotoxicity in the monkey is relatively steep, 3,600 mg/m2 is nonlethal but 4,800 mg/m2 killed one monkey within 4 hours.

The neurotoxicity seen in the monkey after 30 days of treatment with relatively low doses probably models the Guillain-Barre-like syndrome seen clinically. Apparently, intracellular ara-GTP disrupts biomolecule transport mechanisms, interfering with GTP-dependant motor proteins in the long axons leading to a generalized degradation in neuronal function. Both of these toxicities are ripe for further investigation.


   Patients and Methods
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Clinical studies
The pediatric study was conducted by the Children's Oncology Group (8), the adult study by The Cancer and Leukemia Group B as an intergroup trial in cooperation with the Southwest Oncology Group. Study patients had T-ALL or T-LBL that was refractory to at least one induction treatment regimen or in first or later relapse after achieving a CR. Patients had a Karnofsky performance status of ≥50, a predicted life expectancy of ≥8 weeks, no severe uncontrolled infection, and adequate renal (creatinine normal for age or creatinine clearance or GFR of ≥60 mL/min/1.73 m2) and liver function (serum bilirubin of ≤1.5x upper limit of normal; aspartate aminotransferase and alanine aminotransferase of ≤5x upper limit of normal).

Subjects must have recovered from toxicity of all previous chemotherapy. At least 6 weeks must have elapsed since administration of nitrosoureas or craniospinal or hemipelvic radiation therapy (X-ray therapy). Pregnant or lactating women, patients not using appropriate contraceptive methods (adult study), and patients with baseline grade ≥2 neurotoxicity were excluded.

Pediatric study patients received nelarabine (650 mg/m2) administered i.v. over 1 hour daily for 5 consecutive days repeated every 21 days. Adult patients received nelarabine (1,500 mg/m2) administered i.v. over 2 hours on days 1, 3, and 5 and repeated every 21 days. Doses were reduced for nonhematologic or hematologic toxicities in both groups. Depending on 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 end point was the rate of CR and the rate of CR with incomplete peripheral blood or bone marrow recovery (CR*). A CR was defined as bone marrow blast counts of ≤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, ≥10 g/dl for subjects <2 years of age; and hemoglobin, ≥11 g/dl for subjects ≥2 years of age). CR* was defined as bone marrow blast counts of ≤5% and no other evidence of disease. These patients may have had hypocellular bone marrow or peripheral blood counts that had not completely normalized.


   Results
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The pediatric efficacy population consisted of 39 patients who had relapsed or had been refractory to two or more induction regimens (group A). Sixty-nine percent of group A patients had received two prior regimens, 18% had received 3 prior regimens, 5% each had received 4 or 5 prior regimens, and 3% had received at least 2 regimens. A supporting efficacy population consisted of 31 patients who had relapsed or had been refractory to one prior induction regimen (group B).

The mean age of the group A and group B pediatric study populations was ~11.5 years with a range of 2 to 20 years in the former population and 3 to 21 years in the latter. The majority of study patients were male (64%, group A; 87%, group B) and Caucasian (64%, group A; 61%, group B). The majority of patients in both groups had a Karnofsky performance status of 80 or better (60%, group A; 87%, group B). The large majority of patients had T-ALL (79%, group A; 90%, group B). Extramedullary involvement was present in 44% of group A patients and 32% of group B patients.

Pediatric efficacy results are summarized in Table 2 (top). Both T-ALL and T-LBL group A patients achieved CR or CR* (23% T-ALL and 25% T-LBL).


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  		Table 2. Efficacy results: pediatric and adult patients

 
Stem cell transplantation was done in 4 of 9 (44%) group A CR or CR* patients and in 10 of 15 (67%) group B CR or CR* patients. Two CR or CR* patients (1 each for group A and group B) received systemic therapy in preparation for a transplant but were not transplanted. Response duration, attributable to nelarabine, could not be determined for transplant patients or for patients undergoing additional chemotherapy during nelarabine-induced remission. For patients who were not transplanted and who did not receive additional systemic therapy remission durations of group A patients were 9.3, 6.1, 3.6, and 3.3 weeks and remission durations of group B patients were 9.1, 6.3, 2.3, and 1.4+ weeks.

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 ~30 years with a range of 16 to 65 years in the former population and 23 to 66 years in the latter. The majority of study patients were male (82% in both groups) and Caucasian (61%, group A; 91%, group B). The majority of patients had a performance status of 0 to 1 (72% in both groups). The large majority of patients had T-ALL (61%, group A; 82%, group B). Extramedullary involvement was present in 71% of group A patients and 55% of group B patients. Group A (14%) and group B (9%) patients had a prior hematologic stem cell transplant.

Adult efficacy results are summarized in Table 2 (bottom). Both T-ALL and T-LBL group A patients achieved CR or CR* (24%, T-ALL; 22%, T-LBL).

Stem cell transplantation was done in 1 of 6 (17%) group A CR or CR* patients and in 1 of 3 (33%) group B CR or CR* patients. For patients who were not transplanted, remission durations of group A patients were 195+, 30, 19, 15, and 4 weeks and remission durations of group B patients were 217 and 5 weeks.

Safety
The pediatric database included 84 pediatric patients who received the recommended nelarabine dose and schedule. Nonneurologic grade 3/4 adverse events, irrespective of causality, included hematologic toxicity manifested by decreased hemoglobin, decreased white blood cell and neutrophil counts, and decreased platelets in ~90% of the study population. Grade 3 neutrophil toxicity was observed in 17% of patients and grade 4 neutrophil decrease in 62% of patients. Febrile neutropenia was reported as was infection complicating neutropenia.

A variety of laboratory toxicities were also observed, including grade 3/4 increased transaminases and bilirubin in 4% and 9% of patients and decreased albumin and potassium in 6% of patients.

Constitutional symptoms included asthenia in 1%. Grade 3/4 gastrointestinal toxicity was not seen.

Neurologic toxicity was dose limiting. Overall, 38% of patients had neurologic events (14%, grade 3; 8% grade 4). These numbers are likely an underestimate as patients were often removed from study if they developed grade 2 neurologic toxicity.

Table 3 summarizes neurologic toxicity in pediatric patients. The most frequent neurologic adverse events, irrespective of causality, was headache. Other toxicities included somnolence, hypoesthesia, and neuropathy. Neuropathies might be sensory, motor, or both. Seizures, paresthesias, tremor, and ataxia also occurred. One patient had status epilepticus.


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  		Table 3. Neurologic adverse events in pediatric patients

 
Other neurologic adverse events, regardless of causality, reported as grades 1 and 2, or unknown in pediatric patients were dysarthria, encephalopathy, hydrocephalus, hyporeflexia, hypertonia, lethargy, mental impairment, paralysis, third nerve paralysis, and sensory loss, each reported in 1 patient.

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 3/4 hematologic toxicity was observed in ~70% of the study population. On occasion, this toxicity was accompanied by febrile neutropenia and infection complicating neutropenia.

Grade 3/4 gastrointestinal disorders included nausea, diarrhea, vomiting, constipation, and stomatitis. Each of these grade 3/4 toxicities occurred in ~1% of treated patients.

Constitutional symptoms included fatigue (12%) and asthenia (1%). Respiratory disorders included dyspnea (6%). Grade 3/4 aspartate aminotransferase increase was noted in 2% of treated patients.

As was observed in the pediatric study, neurologic toxicity was dose limiting. Overall, 72% of patients had neurologic events (10%, grade; 3%, grade 4). (As previously indicated, this is likely an underestimate as patients were often removed from study with grade ≥2 neurologic toxicity).

Table 4 summarizes neurologic toxicity in adult patients. The most frequent neurologic adverse events, irrespective of causality, was somnolence. Other toxicities included dizziness, hypoesthesia, and neuropathy. Neuropathies might be sensory, motor, or both. Headache, paresthesias, ataxia, depressed consciousness, and tremor also occurred.


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  		Table 4. Neurologic adverse events (≥2%) in adult patients

 
Additional grade 3 events were aphasia, convulsion, hemiparesis, and loss of consciousness, each reported in 1 (1%) patient. Additional grade 4+ events were cerebral hemorrhage, coma, intracranial hemorrhage, leukoencephalopathy, and metabolic encephalopathy, each reported in 1 (1%) patient. Blurred vision was reported in 4% of adult patients. There was a single report of biopsy confirmed progressive multifocal leukoencephalopathy in the adult patient population.

There have also been reports of events associated with demyelination and ascending peripheral neuropathies similar in appearance to Guillain-Barre syndrome.


   Discussion
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 Results
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References
 
Pediatric and adult T-ALL and T-LBL patients with relapsed or refractory disease after two or more prior treatment regimens have no proven available therapy. Although T-ALL and T-LBL are chemosensitive diseases, treatment response rates are expected to be low and response durations are short in the multiple resistant population that was studied (9). Further complicating drug evaluation in this group of patients is the recognition that stem cell transplant may produce prolonged remissions in a fraction of patients with CRs (10). Transplants are often done before blood count recovery from treatment and before additional cycles of study treatment can be administered. Consequently, the actual CR rate and the distinction between a CR and a CR without complete bone marrow and/or peripheral blood cell count recovery (CR*) may be uncertain. Further, response duration, attributable to nelarabine, cannot be determined.

In the present pediatric study, CR to nelarabine treatment was observed in 5 (13%) patients and CR+CR* was observed in 9 (23%) patients who had relapsed or were refractory to two or more prior regimens. Of the 9 responding patients, stem cell transplantation was done in 4 of 9 (44%) group A CR or CR* patients. One additional 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 durations were 9.3, 6.1, 3.6, and 3.3 weeks.

In the adult study, CR to nelarabine treatment was observed in 5 (18%) patients and CR+CR* was observed in 6 (21%) patients who had relapsed or were refractory to two or more prior regimens. Stem cell transplantation was done in 1 of the 6 (17%) patients with a CR or CR*. For nontransplanted CR or CR* patients, remission durations were 195+, 30, 19, 15, and 4 weeks.

The primary regulatory issue with this application concerned whether accelerated or regular approval was warranted. Accelerated approval regulations require that a new drug provides benefit over available therapy or that no approved therapy exists. Accelerated approval is granted based on a surrogate end point that is reasonably likely to predict clinical benefit. In most cancer trials, in patients with relapsed/refractory disease, the surrogate end point is response rate. Accelerated approval requires that the applicant study the drug further to verify and describe its clinical benefit (phase 4 commitments). The applicant shall carry out any such studies with due diligence (as rapidly as possible; ref. 11).

Regular approval requires that clinical benefit be shown. Whereas survival or symptom improvement are the classic end points for regular approval, in acute leukemia, regular approval has been granted based on CR rate of adequate duration. Pentostatin, cladribine, tretinoin, and arsenic trioxide were all granted regular approval for treatment of hematologic malignancies based on durable CRs (12). The rationale for regular approval is that the decrease in transfusion requirements, infections, and bleeding accompanying a CR is a clinical benefit.

By contrast to the above regular approvals, clofarabine was recently granted accelerated approval for the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia after two or more prior regimens. This approval was based on the results of a single-arm phase 2 study and a supporting phase 1 study. As was the case with nelarabine response, duration data were limited because 40% of responding patients received a stem cell transplant during clofarabine-induced remission.

On October 28, 2005, the Food and Drug Administration 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. The Food and Drug Administration is in active discussion with the applicant about appropriate postmarketing clinical trials to convert accelerated approval to full approval.


   Footnotes
 
Note: The views expressed are the result of independent work and do not necessarily represent the views and findings of the Food and Drug Administration.

Received 3/14/06; revised 5/ 3/06; accepted 7/ 6/06.


   References
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 Abstract
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 References
 

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