Nelarabine for the Treatment of T-Cell Lymphoblastic Leukemia/Lymphoma Martin H

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, JogaraoV. Gobburu, RobertJustice, and Richard Pazdur

Abstract 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 ofT-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 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).

Nelarabine was one of seven purine nucleoside analogues DNA (3, 4). This substitution leads to inhibition of DNA synthesized as potential antiviral drugs (1). Although, it was synthesis resulting in cell death. This process is lethal to not effective for that purpose, nelarabine was cytotoxic to MRC- malignant T cells, as it is to other rapidly replicating cells. This 5 human diploid fibroblasts in vitro at the lowest concentration mechanism seems so well accepted that little research has been of any of the seven compounds. done to determine other potential mechanisms of toxicity. Nelarabine, a prodrug of the deoxyguanosine analogue 9-h- Other mechanisms quite distinct from the inhibition of DNA D-arabinofuranosylguanine (ara-G), is demethylated by aden- synthesis are probably responsible for the acute lethal osine deaminase to form the active compound. Intracellular neurotoxicity seen in monkeys and the Guillain-Barre-like deoxyguanosine kinase and deoxycytidine kinase phosphory- syndrome seen clinically (see below). late ara-G sequentially to form ara-GTP (2). Phosphorylation of Nelarabine is cytotoxic in vitro at micromolar concentrations ara-G to ara-GTP is rapid and intracellular exposure to ara-GTP in human bone marrow progenitor cell lines. Experiments is much higher than the exposure to intracellular ara-G or in vitro suggest that it is more toxic to human malignant T-cell nelarabine. After phosphorylation, ara-GTP substitutes for GTP lines than it is to malignant B-cells, in some cases by at least a in numerous biological processes, including the replication of 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 Authors’ Affiliation: Division of Drug Oncology Products, Office of Oncology pediatric patients with T-cell acute lymphoblastic leukemia Drug Products, Center for Drug Evaluation and Research, Food and Drug (T-ALL)/lymphoblastic lymphoma (T-LBL) was conducted. Administration, Silver Spring, Maryland Received 3/14/06; revised 5/3/06; accepted 7/6/06. Nelarabine, at doses of 5 to 75 mg/kg/d was administered Note: The views expressed are the result of independent work and do not daily for 5 days as 1 hour of i.v. infusion every 21 to 28 necessarily represent the views and findings of the Food and Drug Administration. days. There were 2 (15%) complete responses (CR) in adult Requests for reprints: Martin H. Cohen, Division of Drug Oncology Products, T-ALL/T-LBL patients and 7 (27%) CRs in pediatric T-ALL/T- Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857. Phone: 301-594-5740; Fax: 301-594-0499; E-mail: [email protected]. LBL patients (3). F 2006 American Association for Cancer Research. The present nelarabine Food and Drug Administration doi:10.1158/1078-0432.CCR-06-0606 submission consisted of two multicenter, nonrandomized,

www.aacrjournals.org 5329 Clin Cancer Res 2006;12(18) September 15, 2006 Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2006 American Association for Cancer Research. Report from the FDA open-label, single-arm trials, the first is a pediatric study (8), At the adult nelarabine dose of 1,500 mg/m2, a mean the second is an adult study. Patients corresponding to the intracellular Cmax for ara-GTP appeared within 3 to 25 hours proposed indication were in second or subsequent relapse and/ after nelarabine infusion on day 1. Exposure to intracellular or were refractory and were not eligible for therapy of higher ara-GTP was 532 times higher than that for nelarabine and curative potential. 14 times higher than that for ara-G (AUC, 2339 F 2628 Ag/ mL/h versus 4.4 F 2.2 and 162 F 49 Ag/mL/h, respectively). Chemistry, Pharmacology and Toxicology Because the intracellular levels of ara-GTP were so prolonged, its elimination half-life could not be estimated. There are no Chemistry/manufacturing and controls single- or multiple-dose pharmacokinetics data available for 2 The chemical name for nelarabine is 2-amino-9-h-D-arabi- pediatric patients at the proposed 650 mg/m dose given once nofuranosyl-6-methoxy-9H-purine. It has the molecular for- daily for 5 consecutive days. There are no multiple-dose data for mula C11H15N5O5 and a molecular weight of 297.27. The ara-GTP in adult or pediatric patients. The available pharma- C chemical structure of nelarabine is shown in Fig. 1. Nelarabine cokinetics data indicate that the mean max and AUCvalues for drug substance is synthesized by enzyme catalyzed reaction intracellular ara-GTP were 3- to 4-fold higher in responders using arabinofuranosyl uracil and guanine analogue. than in nonresponders. Comparable mean Cmax and AUC Nelarabine is white to slightly colored amorphous powder. It values for both nelarabine and ara-G were obtained in is slightly soluble to soluble in water depending on pH of the responders and nonresponders. Mean Cmax and AUCvalues solution. It melts with decomposition between 209jCand of ara-GTP were 2-fold higher in patients who experienced 217jC. Arranon injection is supplied as a clear, colorless, sterile neurotoxicity than in those who did not. Comparable mean solution in glass vials. Each vial contains 250 mg nelarabine Cmax and AUCvalues for both nelarabine and ara-G were and the inactive ingredient sodium chloride in 50 mL Water for obtained in patients who experienced neurotoxicity and those Injection, USP. Arranon is intended for i.v. infusion. who did not. The pharmacokinetics data at nelarabine of doses of 104 Nelarabine clinical pharmacology to 2,900 mg/m2 indicate that the mean clearance of nelara- Pharmacokinetics. Pharmacokinetic data are available for bine is f30% higher in pediatric patients (n = 22) than in nelarabine, ara-G, and intracellular ara-GTP in 101 adult adult patients (n = 66; CL, 259 F 409 L/h/m2 versus 197 F patients and 25 pediatric patients with refractory hematologic 189 L/h/m2, respectively) on day 1. The apparent clearance of malignancies who received nelarabine i.v. at doses of 104 ara-G is comparable between the two groups (10.5 F 4.5 L/m2, 2 to 2,900 mg/m . Following nelarabine infusion, plasma con- adult patients; 11.3 F 4.2 L/m2, pediatric patients) on day 1 centrations of both nelarabine and ara-G decline rapidly in after nelarabine administration. a monoexponential fashion. At the proposed adult dose of Special populations. Age has no effect on nelarabine or ara-G 2 C 1,500 mg/m , the mean peak plasma concentration ( max)of pharmacokinetics (P > 0.05). No dosing adjustment is required nelarabine and ara-G [observed in six patients at the end of the for nelarabine in elderly patients with T-ALL and T-LBL. 2-hour infusion (day 1)] was 5.0 F 3.0 and 31.4 F 5.6 Ag/mL, Gender has no effect on nelarabine or ara-G pharmacokinet- respectively. ics (P > 0.05). Exposure to ara-G is 37 times higher than that for nelarabine Most patients enrolled in phase 1 studies were Whites. In after day 1 of nelarabine infusion [area under the concentra- general, nelarabine mean clearance and volume of distribution-time curve (AUC), 162 F 49 Ag/mL/h versus 4.4 F 2.2 Ag/ tion values tend to be higher in Whites (n = 63) than in Blacks C mL/h, respectively]. Comparable max and AUCvalues were (by f10%; n = 15). The opposite is true for ara-G; mean obtained for nelarabine between days 1 and 5 at the proposed apparent clearance and volume of distribution values tend to be 2 nelarabine adult dose of 1,500 mg/m , indicating that the lower in Whites than in Blacks (by f15-20%). No differences pharmacokinetics of nelarabine after multiple dosing is in safety or effectiveness were observed between these groups. predictable from single dosing. There are not enough data for The effect of renal and hepatic impairment on the ara-G to make a comparison between days 1 and 5. pharmacokinetics of nelarabine or ara-G has not been studied. The pharmacokinetics of both nelarabine and ara-G appear Patients who enrolled in the phase 1 studies (adults and pedia- to be linear over the nelarabine dosing range of 104 to 2,900 trics) ranged in creatinine clearance from 31 to 363 mL/min. 2 mg/m in both pediatric and adult patients. 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, Fig. 1. Nelarabine structural formula. CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 at in vitro

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concentrations of nelarabine and ara-G of >100 Amol/L (IC50 ated with an increase in ketamine recovery time after 5 days of of f30 Ag/mL versus Cmax of 5.0 Ag/mL for nelarabine and dosing. All monkeys at this dose had tremors and convulsions. 31.4 Ag/mL for ara-G at the proposed adult nelarabine dose of Body weight decreased. Aspartate aminotransferase and alanine 1,500 mg/m2). The potential for drug-drug interactions aminotransferase increased 2- to 12-fold. BUN, triglycerides, between nelarabine and substrates of these enzymes is unlikely. and glucose increased. Microscopic damage was found in Nelarabine and ara-G are not substrates or inhibitors of the proliferative tissues, gastrointestinal tract, spleen, marrow, and efflux transporter, P-glycoprotein. thymus. There was congestion in the lungs. In an i.v. study with daily dosing for 30 days, monkeys Pharmacology and toxicology tolerated doses of only 120 mg/m2 with decreased red and Comparative pharmacokinetics. All tested animal species, white cell variables. Daily doses of 240 mg/m2 killed 1 of including rat, rabbits, dogs, mice, and monkeys rapidly convert 6 monkeys on day 28. A dose of 480 mg/m2 killed 3 of nelarabine to ara-G after i.v. dosing. In the rabbit, the AUCof 10 monkeys despite the cessation of dosing on day 23. Red and ara-G was 7- to 10-fold higher than that of nelarabine; AUCand white blood cell variables decrease significantly at these higher C max for both compounds increased linearly with dose and did doses. Significant damage was seen in the brain (cerebellar not change with repeated dosing. The decrease in concentration degeneration and perivascular cuffing in the cerebrum and of both compounds was biphasic. Less information is available cerebellum) and in the spine (vacuolization and myelopathy, for other species, but in the rat, the AUCof ara-G was about six not reversible in surviving monkeys). Changes in clinical times greater than that of nelarabine. Although humans also chemistry variables suggested significant liver damage. There rapidly convert nelarabine to ara-G (half-life of nelarabine is was lymphoid infiltration in the bladder, kidney, trachea, f16 minutes), they do not clear ara-G nearly as readily as rats, salivary gland, lacrimal gland, and heart, suggesting a general- mice, or dogs. In humans the, half-life of ara-G is between ized inflammatory response. In females, there was myocardial 2 and 4 hours (Table 1). Because the other species eliminate degeneration and liver damage (cholangitis, edema, and ara-G much more quickly than humans or monkeys do, the vacuolization). sponsor chose to do the major toxicology studies for the The acute neurotoxicity seen in monkeys given one or two development of nelarabine in the monkey. doses >3,600 mg/m2 probably results from a secondary Single doses of 3,600 mg/m2 or less in the monkey caused pharmacology acting centrally. It could be due to disruption little toxicity but higher doses seemed to cause some saturation of essential RNA synthesis within the central nervous system of metabolism. The increase in AUCwith dose becomes greater after the formation of high intracellular concentrations of ara- than dose normal. Single doses of 4,800 or 6,000 mg/m2 GTP or to an ara-GTP-related disruption of signal transmission. resulted in irreversible neurotoxicity, manifested as a deepening The rapid onset and irreversibility suggest that it is distinct from loss of consciousness (see below). An overdose of nelarabine the Guillain-Barre-like syndrome seen in patients. The toxic would possibly result in a similar saturation of metabolism and dose-response curve for lethal neurotoxicity in the monkey is similar neurotoxicity in humans. relatively steep, 3,600 mg/m2 is nonlethal but 4,800 mg/m2 Reproductive toxicity and genotoxicity. Nelarabine is fetotoxic killed one monkey within 4 hours. at clinically relevant doses. Nelarabine is highly mutagenic but The neurotoxicity seen in the monkey after 30 days of this effect is measurable in vitro only at nonphysiologic treatment with relatively low doses probably models the concentrations. Guillain-Barre-like syndrome seen clinically. Apparently, intra- Systemic toxicity. With the exception of the two unusual cellular ara-GTP disrupts biomolecule transport mechanisms, neurotoxicities, Nelarabine caused a spectrum of toxicities that interfering with GTP-dependant motor proteins in the long one would expect with a purine antimetabolite. In mice, the axons leading to a generalized degradation in neuronal func- 2 LD10 for daily 5 dosing is f1,500 mg/m ; this dose is tion. Both of these toxicities are ripe for further investigation. 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 Patients and Methods rabbits given daily doses for 13 days (continuous i.v. infusion), Clinical studies the MTD was 4,320 mg/m2. This dose was associated with The pediatric study was conducted by the Children’s Oncology reduced appetite and decreased fecal output, decreased total f Group (8), the adult study by The Cancer and Leukemia Group B as an body weight ( 11%), and decreased white and red cell intergroup trial in cooperation with the Southwest Oncology Group. variables. Study patients had T-ALL or T-LBL that was refractory to at least one 2 Monkeys tolerated single i.v. doses of 3,600 mg/m with few induction treatment regimen or in first or later relapse after achieving a signs of toxicity. As mentioned above, higher doses caused fatal CR. Patients had a Karnofsky performance status of z50, a predicted life neurotoxicity in some individuals. Monkeys that died from this expectancy of z8 weeks, no severe uncontrolled infection, and acute toxicity showed loss of palpebral reflex, shallow adequate renal (creatinine normal for age or creatinine clearance or 2 respiration, flaccid limbs, and minimal jaw tone. The monkeys GFR of z60 mL/min/1.73 m ) and liver function (serum bilirubin of V that did not recover died within hours after the first or second 1.5 upper limit of normal; aspartate aminotransferase and alanine aminotransferase of V5 upper limit of normal). dose. Monkeys tolerated five daily doses of 1,800 mg/m2, Subjects must have recovered from toxicity of all previous showing dose-dependent decreases in WBCand platelets and a chemotherapy. At least 6 weeks must have elapsed since administration decrease in thymus weight. At this schedule, a dose of 3,600 of nitrosoureas or craniospinal or hemipelvic radiation therapy (X-ray 2 mg/m killed 3 of 4 monkeys by day 13. Moribund monkeys therapy). Pregnant or lactating women, patients not using appropriate had tremors and convulsions. Most monkeys treated were contraceptive methods (adult study), and patients with baseline grade under ketamine anesthesia and nelarabine dosing was associ- z2 neurotoxicity were excluded.

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Table 1. Comparative pharmacokinetics of ara-G

2 2 Species Injection time (min) Dose (mg/m ) AUC0-1 (Mmol/L/h) C max (Mmol/L) Half-life (min) Clearance (L/h/m ) Mice bolus 369 38 19 50 34 Rabbits 10-20 192 63.4 57.3 52 11 Rats bolus 375 24 39 15 55 Dogs bolus 500 31.3 93.4 14 57 Monkeys bolus 1,800 1,203 288 120-240 5 Humans 120 1,500 579 111 120-240 9

Pediatric study patients received nelarabine (650 mg/m2) adminis- patients who were not transplanted and who did not receive tered i.v. over 1 hour daily for 5 consecutive days repeated every 21 additional systemic therapy remission durations of group A 2 days. Adult patients received nelarabine (1,500 mg/m ) administered patients were 9.3, 6.1, 3.6, and 3.3 weeks and remission dura- i.v. over 2 hours on days 1, 3, and 5 and repeated every 21 days. Doses tions of group B patients were 9.1, 6.3, 2.3, and 1.4+ weeks. were reduced for nonhematologic or hematologic toxicities in both The adult efficacy population consisted of 28 group A groups. Depending on the availability of a donor and other consid- erations, patients could be removed from study to receive a hematologic patients who had relapsed or had been refractory to two or stem cell transplant. Intrathecal therapy could be administered, if more induction regimens and 11 group B patients who had required. only one prior induction regimen. The primary study end point was the rate of CR and the rate of CR The mean age of the group A and group B adult study with incomplete peripheral blood or bone marrow recovery (CR*). A populations was f30 years with a range of 16 to 65 years in the CR was defined as bone marrow blast counts of V5%, no other evidence former population and 23 to 66 years in the latter. The majority of disease, and full recovery of peripheral blood counts (i.e., absolute of study patients were male (82% in both groups) and A A neutrophil count, >1,500/ L; platelets, >100,000/ L; hemoglobin, Caucasian (61%, group A; 91%, group B). The majority of z z 10 g/dl for subjects <2 years of age; and hemoglobin, 11 g/dl for patients had a performance status of 0 to 1 (72% in both subjects z2 years of age). CR* was defined as bone marrow blast counts groups). The large majority of patients had T-ALL (61%, group of V5% and no other evidence of disease. These patients may have had hypocellular bone marrow or peripheral blood counts that had not A; 82%, group B). Extramedullary involvement was present in completely normalized. 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. Results Adult efficacy results are summarized in Table 2 (bottom). Both T-ALL and T-LBL group A patients achieved CR or CR* The pediatric efficacy population consisted of 39 patients (24%, T-ALL; 22%, T-LBL). who had relapsed or had been refractory to two or more Stem cell transplantation was done in 1 of 6 (17%) group A CR induction regimens (group A). Sixty-nine percent of group A or CR* patients and in 1 of 3 (33%) group B CR or CR* patients. patients had received two prior regimens, 18% had received 3 For patients who were not transplanted, remission durations of prior regimens, 5% each had received 4 or 5 prior regimens, group A patients were 195+, 30, 19, 15, and 4 weeks and and 3% had received at least 2 regimens. A supporting efficacy remission durations of group B patients were 217 and 5 weeks. population consisted of 31 patients who had relapsed or had been refractory to one prior induction regimen (group B). Safety The mean age of the group A and group B pediatric study The pediatric database included 84 pediatric patients who populations was f11.5 years with a range of 2 to 20 years in received the recommended nelarabine dose and schedule. the former population and 3 to 21 years in the latter. The Nonneurologic grade 3/4 adverse events, irrespective of causa- majority of study patients were male (64%, group A; 87%, lity, included hematologic toxicity manifested by decreased 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%, Table 2. Efficacy results: pediatric and adult group B). Extramedullary involvement was present in 44% of patients group A patients and 32% of group B patients. Treatment outcome: Group A Group B Pediatric efficacy results are summarized in Table 2 (top). pediatric study (n= 39) (n = 31) Both T-ALL and T-LBL group A patients achieved CR or CR* CR (%), 95% CI 5 (13), 4-27 13 (42), 25-61 (23% T-ALL and 25% T-LBL). CR plus CR*, (%), 95% CI 9 (23), 11-39 15 (48), 30-67 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 Treatment outcome: Group A Group A CR* patients. Two CR or CR* patients (1 each for group A and adult study (n = 28) (n = 11) group B) received systemic therapy in preparation for a CR (%), 95% CI 5 (18), 6-37 2 (18), 2-52 transplant but were not transplanted. Response duration, CR plus CR*, (%), 95% CI 6 (21), 8-41 3 (27), 6-61 attributable to nelarabine, could not be determined for transplant patients or for patients undergoing additional Abbreviation: 95% CI, 95% confidence interval. chemotherapy during nelarabine-induced remission. For

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Table 3. Neurologic adverse events in pediatric patients

Nervous system disorders (preferred term) % Patients (N = 84) Grade 1 Grade 2 Grade 3 Grade 4+ All grades Headache 8 2 4 2 17 Peripheral neurologic disorders, any event 1 4 7 0 12 Peripheral neuropathy 0 4 2 0 6 Peripheral motor neuropathy 1 0 2 0 4 Peripheral sensory neuropathy 0 0 60 6 Somnolence 1 4 1 1 7 Hypoesthesia 1 1 4 0 6 Seizures, any event 0 0 0 66 Convulsions 0 0 0 4 4 Grand mal convulsions 0 0 0 1 1 Status epilepticus 0 0 0 1 1 Motor dysfunction 1 1 1 0 4 Nervous system disorder 1 2 0 0 4 Paresthesia 0 2 1 0 4 Tremor 1 2 0 0 4 Ataxia 1 0 1 0 2

NOTE: Grade 4+ = Grade 4 and grade 5. One patient had a fatal neurologic event, status epilepticus.

hemoglobin, decreased white blood cell and neutrophil counts, Constitutional symptoms included fatigue (12%) and and decreased platelets in f90% of the study population. asthenia (1%). Respiratory disorders included dyspnea (6%). Grade 3 neutrophil toxicity was observed in 17% of patients Grade 3/4 aspartate aminotransferase increase was noted in 2% and grade 4 neutrophil decrease in 62% of patients. Febrile of treated patients. neutropenia was reported as was infection complicating As was observed in the pediatric study, neurologic toxicity neutropenia. was dose limiting. Overall, 72% of patients had neurologic A variety of laboratory toxicities were also observed, events (10%, grade; 3%, grade 4). (As previously indicated, this including grade 3/4 increased transaminases and bilirubin in is likely an underestimate as patients were often removed from 4% and 9% of patients and decreased albumin and potassium study with grade z2 neurologic toxicity). in 6% of patients. Table 4 summarizes neurologic toxicity in adult patients. The Constitutional symptoms included asthenia in 1%. Grade 3/4 most frequent neurologic adverse events, irrespective of gastrointestinal toxicity was not seen. causality, was somnolence. Other toxicities included dizziness, Neurologic toxicity was dose limiting. Overall, 38% of hypoesthesia, and neuropathy. Neuropathies might be sensory, patients had neurologic events (14%, grade 3; 8% grade 4). motor, or both. Headache, paresthesias, ataxia, depressed These numbers are likely an underestimate as patients were consciousness, and tremor also occurred. often removed from study if they developed grade 2 neurologic Additional grade 3 events were aphasia, convulsion, hemi- toxicity. paresis, and loss of consciousness, each reported in 1 (1%) Table 3 summarizes neurologic toxicity in pediatric patients. patient. Additional grade 4+ events were cerebral hemorrhage, The most frequent neurologic adverse events, irrespective of coma, intracranial hemorrhage, leukoencephalopathy, and causality, was headache. Other toxicities included somnolence, metabolic encephalopathy, each reported in 1 (1%) patient. hypoesthesia, and neuropathy. Neuropathies might be sensory, Blurred vision was reported in 4% of adult patients. There was a motor, or both. Seizures, paresthesias, tremor, and ataxia also single report of biopsy confirmed progressive multifocal occurred. One patient had status epilepticus. leukoencephalopathy in the adult patient population. Other neurologic adverse events, regardless of causality, There have also been reports of events associated with reported as grades 1 and 2, or unknown in pediatric patients demyelination and ascending peripheral neuropathies similar were dysarthria, encephalopathy, hydrocephalus, hyporeflexia, in appearance to Guillain-Barre syndrome. hypertonia, lethargy, mental impairment, paralysis, third nerve paralysis, and sensory loss, each reported in 1 patient. Discussion The adult safety database included 103 patients who received the recommended nelarabine dose and schedule. As with Pediatric and adult T-ALL and T-LBL patients with relapsed or pediatric patients, hematologic toxicity was the most frequent refractory disease after two or more prior treatment regimens adverse event. Grade 3/4 hematologic toxicity was observed in have no proven available therapy. Although T-ALL and T-LBL f70% of the study population. On occasion, this toxicity was are chemosensitive diseases, treatment response rates are accompanied by febrile neutropenia and infection complicating expected to be low and response durations are short in the neutropenia. multiple resistant population that was studied (9). Further Grade 3/4 gastrointestinal disorders included nausea, diar- complicating drug evaluation in this group of patients is the rhea, vomiting, constipation, and stomatitis. Each of these recognition that stem cell transplant may produce prolonged grade 3/4 toxicities occurred in f1% of treated patients. remissions in a fraction of patients with CRs (10). Transplants

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Table 4. Neurologic adverse events (z2%) in adult patients

System organ class (preferred term) % Patients (N = 103) Grade 1 Grade 2 Grade 3 Grade 4 All grades Somnolence 20 3 0 0 23 Dizziness 14 8 0 0 21 Peripheral neurologic disorders, any event 8 12 2 0 21 Neuropathy 0 4 0 0 4 Peripheral neuropathy 2 2 1 0 5 Peripheral motor neuropathy 3 3 1 0 7 Peripheral sensory neuropathy 7 60 0 13 Hypoesthesia 5 10 2 0 17 Headache 11 3 1 0 15 Paresthesia 11 4 0 0 15 Ataxia 1 62 0 9 Depressed level of consciousness 4 1 0 1 6 Tremor 2 3 0 0 5 Amnesia 2 1 0 0 3 Dysgeusia 2 1 0 0 3 Balance disorder 1 1 0 0 2 Sensory loss 0 2 0 0 2

NOTE: One patient had a fatal neurologic event, cerebral hemorrhage/coma/leukoencephalopathy. are often done before blood count recovery from treatment and refractory disease, the surrogate end point is response rate. before additional cycles of study treatment can be adminis- Accelerated approval requires that the applicant study the drug tered. Consequently, the actual CR rate and the distinction further to verify and describe its clinical benefit (phase 4 between a CR and a CR without complete bone marrow and/or commitments). The applicant shall carry out any such studies peripheral blood cell count recovery (CR*) may be uncertain. with due diligence (as rapidly as possible; ref. 11). Further, response duration, attributable to nelarabine, cannot Regular approval requires that clinical benefit be shown. be determined. Whereas survival or symptom improvement are the classic end In the present pediatric study, CR to nelarabine treatment points for regular approval, in acute leukemia, regular approval was observed in 5 (13%) patients and CR+CR* was observed in has been granted based on CR rate of adequate duration. 9 (23%) patients who had relapsed or were refractory to two or Pentostatin, cladribine, tretinoin, and arsenic trioxide were all more prior regimens. Of the 9 responding patients, stem cell granted regular approval for treatment of hematologic malig- transplantation was done in 4 of 9 (44%) group A CR or CR* nancies based on durable CRs (12). The rationale for regular patients. One additional patient received systemic therapy in approval is that the decrease in transfusion requirements, preparation for a transplant but was not transplanted. For infections, and bleeding accompanying a CR is a clinical benefit. patients who were not transplanted and who did not receive By contrast to the above regular approvals, clofarabine was systemic therapy during nelarabine-induced remission dura- recently granted accelerated approval for the treatment of tions were 9.3, 6.1, 3.6, and 3.3 weeks. pediatric patients 1 to 21 years old with relapsed or refractory In the adult study, CR to nelarabine treatment was observed acute lymphoblastic leukemia after two or more prior regimens. in 5 (18%) patients and CR+CR* was observed in 6 (21%) This approval was based on the results of a single-arm phase 2 patients who had relapsed or were refractory to two or more study and a supporting phase 1 study. As was the case with prior regimens. Stem cell transplantation was done in 1 of the 6 nelarabine response, duration data were limited because 40% (17%) patients with a CR or CR*. For nontransplanted CR or of responding patients received a stem cell transplant during CR* patients, remission durations were 195+, 30, 19, 15, and clofarabine-induced remission. 4 weeks. On October 28, 2005, the Food and Drug Administration The primary regulatory issue with this application concerned granted accelerated approval for nelarabine treatment of whether accelerated or regular approval was warranted. patients with T-ALL and T-LBL whose disease has not Accelerated approval regulations require that a new drug responded to or has relapsed following treatment with at least provides benefit over available therapy or that no approved two chemotherapy regimens. The Food and Drug Administra- therapy exists. Accelerated approval is granted based on a tion is in active discussion with the applicant about appropriate surrogate end point that is reasonably likely to predict clinical postmarketing clinical trials to convert accelerated approval to benefit. In most cancer trials, in patients with relapsed/ full approval.

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www.aacrjournals.org 5335 Clin Cancer Res 2006;12(18) September 15, 2006 Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2006 American Association for Cancer Research. Approval Summary: Nelarabine for the Treatment of T-Cell Lymphoblastic Leukemia/Lymphoma

Martin H. Cohen, John R. Johnson, Tristan Massie, et al.

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