Summary Basis of Decision for Atriance ™
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
AtrianceTM
Nelarabine, 5 mg/mL, Solution, Intravenous
GlaxoSmithKline Inc.
Submission control no: 099994
Date issued: 2008-05-12
Health Products and Food Branch
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Health Products and Food Branch
Également disponible en français sous le titre : Sommaire des motifs de décision (SMD), PrATRIANCEMD, nélarabine, solution, GlaxoSmithKline Inc.,
No de contrôle de la présentation 099994
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02299925
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On September 22, 2007, Health Canada issued a Notice of Compliance under the Notice of Compliance with Conditions (NOC/c) Policy to GlaxoSmithKline Inc. for the drug product, Atriance™. The product was authorized under the NOC/c Policy on the basis of the promising nature of the clinical evidence, and the need for confirmatory studies to verify the clinical benefit. Patients should be advised of the fact that the market authorization was issued with conditions.
Atriance™ contains the medicinal ingredient nelarabine which is an antineoplastic agent.
Atriance™ is indicated for the treatment of patients with T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma whose disease has not responded to or has relapsed following treatment with at least two chemotherapy regimens.
Refractory and relapsed T-cell acute lymphoblastic leukemia and lymphoblastic lymphoma are both aggressive cancers with very few treatment options. After administration, nelarabine converts to ara-G, which is ultimately converted intracellularly to its active form ara-GTP. Accumulation of ara-GTP in the leukemic cells leads to inhibition of DNA synthesis which results in cell death. In vitro testing has shown T-cells to be more sensitive than B-cells to the cytotoxic effects of nelarabine.
The market authorization was based on quality, non-clinical, and clinical information submitted. The safety and efficacy of Atriance™ were evaluated in two open-label, single-arm, multicentre studies. One study was a pediatric study (n=151) and the other was an adult study (n=39). Market authorization was based on the unconfirmed surrogate endpoint of clinical response only. The consistency of the observed responses in both studies gave credence to the clinical benefit of the drug.
Atriance™ (5 mg/mL, nelarabine) is presented as a solution. The recommended adult dose is 1,500 mg/m²/day administered intravenously over 2 hours on days 1, 3, and 5, repeated every 21 days. The recommended pediatric dose is 650 mg/m²/day administered intravenously over 1 hour on days 1 to 5, repeated every 21 days. The optimal dosing regimen for patients between the ages of 16 and 21 years of age has not been determined. The recommended duration of treatment has not been clearly established. Dosing guidelines are available in the Product Monograph.
Atriance™ is contraindicated in patients who have a history of hypersensitivity to nelarabine or any other component of Atriance™. Atriance™ should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Atriance™ are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and effectiveness, Health Canada considers that the benefit/risk profile of Atriance™ is favourable for the treatment of patients with T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma whose disease has not responded to or has relapsed following treatment with at least two chemotherapy regimens.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Nelarabine, the medicinal ingredient of Atriance™, is an antineoplastic agent. Nelarabine is a pro-drug of deoxyguanosine analogue 9-ß-D-arabinofuranosylguanine (ara-G). After administration, nelarabine converts to ara-G which is ultimately converted intracellularly to the active 5'-triphosphate, ara‑GTP. Accumulation of ara-GTP in the leukemic cells leads to inhibition of deoxyribonucleic acid (DNA) synthesis which results in cell death.
Manufacturing Process and Process Controls
The drug substance is synthetically derived. The manufacturing process is considered to be adequately controlled within justified limits.
Characterization
The route of synthesis of nelarabine supports the chemical structure assigned. Confirmation of the chemical structure was provided by elemental analysis and spectroscopic analysis.
Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were found to be within ICH established limits and/or were qualified from batch analysis or toxicological studies and therefore, are considered to be acceptable.
Control of Drug Substance
The specifications are considered acceptable for the drug substance. Data from the batch analyses were reviewed and are within the proposed acceptance criteria.
The levels of product- and process-related impurities were adequately monitored throughout the manufacturing process. Results from process validation reports and in-process controls indicate that the impurities of the drug substance were adequately under control. The level of impurities reported for the drug substance was found to be within the established limits.
The drug substance packaging is considered acceptable.
Stability
Based on the long-term and accelerated stability data submitted, the proposed retest period for the drug substance is supported and considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Atriance™ (nelarabine) is a clear, colourless solution containing 5 mg nelarabine and 4.5 mg sodium chloride per mL in Water for Injection, USP. Hydrochloric acid and sodium hydroxide may be used to adjust the pH.
Atriance™ is supplied in Type I, clear glass, single-use vials with a gray butyl rubber (latex-free) stopper and a red snap-off aluminum seal containing 250 mg nelarabine in 50 mL Water for Injection, USP.
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The formulation is simple and the proposed excipients are widely used in injectable preparations.
Pharmaceutical Development
Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review.
The formulation used in the Phase I and II clinical studies is the same formulation as proposed for marketing in Canada.
Manufacturing Process and Process Controls
The drug product is formulated, filtered, filled, sealed and capped and then sterilized using conventional pharmaceutical equipment and facilities.
The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.
Control of Drug Product
Atriance™ is tested to verify that the identity, appearance, content, fill volume, pH, and levels of drug-related impurities, foreign particulate matter, and bacterial endotoxins are within acceptance criteria. The test specifications and analytical methods are considered acceptable. Validation results of the analytical method used for the determination of nelarabine and the drug-related impurities are considered acceptable.
Data from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product.
Stability
Based on the long-term and accelerated stability data submitted, the proposed shelf-life of 24 months at 15-30°C for Atriance™ is considered acceptable.
The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.
3.1.3 Facilities and Equipment
The design, operations, and controls of the facility and equipment that are involved in the production are considered suitable for the activities and products manufactured.
All sites are compliant with Good Manufacturing Practices (GMP).
3.1.4 Adventitious Agents Safety Evaluation
Not applicable. There are no excipients of human or animal origin.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Atriance™ has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
Nelarabine is rapidly converted to ara-G which is ultimately converted intracellularly to its active form ara GTP. Accumulation of ara GTP in leukemic cells allows for the incorporation of ara GTP into DNA leading to inhibition of DNA synthesis which results in cell death. Other mechanisms may also contribute to the cytotoxic effects of nelarabine.
3.2.1 Pharmacodynamics
Many of the study reports in this section were largely incomplete, and therefore a detailed review of the methods and data could not be conducted.
Nelarabine and ara-G were cytotoxic specifically to a variety of human T-cells. Specific inhibitors that prevented the conversion of nelarabine to ara-G also prevented the T-cell growth inhibition properties of nelarabine, but not ara-G. This confirms that nelarabine is a bonafide pro-drug of ara-G.
In vitro, human T-cells were more sensitive than human B-cells to the cytotoxic effects of nelarabine. The killing efficiency of nelarabine and ara-G was up to 5.2-fold higher for T-cells compared to B-cells or stem cells. Furthermore, a T-cell line deficient in deoxycytidine kinase (a catalyst for the phosphorylation of ara-G to ara-GTP), showed a significantly diminished sensitivity to cell death induction by nelarabine or ara-G. This supports the hypothesized mechanism of cytotoxicity of ara-G as being via ara-GTP formation. No experiments were conducted that demonstrated a selectivity for nelarabine toxicity in leukemic vs. normal T-cells.
The effectiveness of nelarabine in vivo was demonstrated by administering nelarabine (≥50 or 100 mg/kg/day) to mice implanted with malignant T-cells. In mice that received nelarabine, tumour growth was inhibited by 72 to 91%. Although this methodology is standard for evaluating the growth inhibition potential of test-compounds, nelarabine is indicated for T-cell lymphoma and growth suppression of solid tumours may not be overly relevant.
A number of studies were lacking from this drug submission: experiments to evaluate the binding affinity to non-target proteins or receptors, safety pharmacology studies, and formal drug interaction studies. No studies were provided demonstrating the mechanism of action of nelarabine, nor showing the increased solubility of nelarabine compared to ara-G. Instead, literature references that had detailed explanations were provided. Given the well documented knowledge and understanding of the nucleoside analog class of compounds, in addition to the amount of published data that exists regarding the pharmacodynamics of nelarabine and ara-G, the submitted package is deemed acceptable when considering the palliative nature of the indication. Although, in the absence of safety pharmacology studies, potential cardiac toxicity should be closely monitored in the clinical setting.
3.2.2 Pharmacokinetics
Absorption
Nelarabine had a very short half-life and less systemic exposure compared to ara-G in all species tested, except for the rat. Plasma ara-G concentrations were consistently higher than nelarabine. The findings suggest a rapid conversion of nelarabine to ara-G, and support previous findings that nelarabine is a good pro-drug for ara-G. Systemic exposure of both nelarabine and ara-G in all species examined generally increased in a dose-proportional manner, with no gender differences observed.
Distribution
Nelarabine and ara-G did not bind to human plasma protein to a large extent, therefore the potential for drug-drug interactions based on protein binding is considered unlikely.
Radiolabelled nelarabine administered to pigmented mice distributed rapidly to all major tissues, with the highest concentration in the urinary bladder for the first 6 hours. Low levels of radioactivity were measured in the central nervous system. Concentrations of nelarabine within excretory organs were generally higher than in the blood. No differences in nelarabine distribution were noted between males and females.
Radioactivity levels declined relatively slowly in several tissues, with significant amounts remaining throughout the experiment (240 hours). This suggested a level of incorporation into the tissues, which is not unexpected for this class of compound.
Metabolism
The metabolic pathways for nelarabine and ara-G included N-dealkylation and oxidation. The in vitro metabolic profile of nelarabine assessed from human, monkey, mouse and rabbit hepatocytes was similar among all species. The metabolites observed for nelarabine were ara-G, xanthine, uric acid, and allantoin, with ara-G and allantoin being the major circulating metabolites. The metabolites for ara-G were xanthine, uric acid, and allantoin.
Both nelarabine and ara-G showed little potential to inhibit any of the CYP450 enzymes examined (CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4).
No experiments were performed to determine the nelarabine/ara-G metabolizing enzyme profile. Nelarabine and ara-G did not significantly induce CYPs 1A2, 2B6, or 3A4 activities, however no other CYP enzymes were examined.
Excretion
In both intact and bile-cannulated animals, the predominant route of nelarabine elimination was by renal excretion. Fecal and biliary secretion presented only a minor route of elimination. There were no gender-related differences in the rate or route of elimination of radioactivity in either species.
Drug Interaction Studies
No clinically relevant in vitro or in vivo drug interaction studies were performed. It was noted that animals who were co-administered ketamine as an anaesthetic had higher nelarabine drug exposure values (>3-fold) than those who were given nelarabine alone. Specific toxicities were also potentiated by the concomitant administration of ketamine and nelarabine to all tested animals. This may merit a drug interaction precaution to physicians regarding potential exacerbation of nelarabine side effects upon co-administration with ketamine or structurally-related compounds. Further exploration of nelarabine/ara-G metabolizing enzymes is recommended.
3.2.3 Toxicology
Single-Dose Toxicity
Single-dose toxicity experiments in ketamine-anesthetized monkeys established the suitable levels of 300 mg/kg/day for further repeat-dose studies. Single nelarabine doses of 400 and 500 mg/kg/day resulted in a deepening of anaesthesia followed by death. This suggests that a narrow margin may exist between acceptable and overt toxicity.
Repeat-Dose Toxicity
Neurological toxicity was observed at Day 19 in unanesthetized (restrained) monkeys treated with concentrations of nelarabine lower than that of the proposed human dose. Animals that received 40 mg/kg (480 mg/m2), 3-fold less than the proposed human dose of 1500 mg/m2, were removed from study after Day 23 due to overt neurological toxicity. Decreased absolute white blood cells, neutrophils, monocytes, red blood cells, hematocrit and hemoglobin were also observed.
Neurotoxicity was dose-limiting in monkeys resulting in morbidity and mortality at doses of 3600 mg/m2/day for 5 days and ≥240 mg/m2/day for 30 days. Histopathologic lesions associated with neurotoxicity occurred only in monkeys given 480 mg/m2/day for 23 days and included white matter degeneration and vacuolation in the brain and spinal cord. These findings persisted during a 2-month recovery period.
Monkeys that were administered a combination of fludarabine with nelarabine displayed more severe toxicities compared to monkeys that received either agent alone. This included severe myeloid hypoplasia of the bone marrow which led to death/euthanasia of 4 monkeys due to bacterial septicemia.
Genotoxicity
Nelarabine was mutagenic in the mouse lymphoma mutagenesis assay in the presence and absence of S9 metabolic activation.
Carcinogenicity
Due to the palliative nature of the proposed indication, the absence of carcinogenicity studies is considered acceptable.
Reproductive and Developmental Toxicity
The number of lutea, implantation sites, live fetuses, dead fetuses, sex ratio, and pre-implantation losses in rabbits 6 days post-coital were unaffected by the administered 30, 100, and 300 mg/kg/day doses of nelarabine. These animals, however, had decreased body weight gain, decreased food consumption, and laboured breathing. Fetal malformations were more numerous with increased doses of nelarabine, including decreased fetal weight, delayed ossification, cleft pallet, absent polices, accessory lung lobes and gall bladders, and fused/extra sternebrae. No fertility studies were performed.
3.2.4 Summary and Conclusion
The non-clinical studies have determined that T-cells are more sensitive than B-cells to the cytotoxic action of nelarabine.
Although nelarbine/ara-G is an effective agent in abrogating T-cell growth while leaving B-cells relatively unaffected, the significant neurological toxicities evident at doses less than that proposed for human treatment is cause for concern. Furthermore, the potential for drug interactions leading to enhanced toxicity exists, but currently cannot be precisely addressed as the nelarabine metabolic pathways have not been determined. Given the palliative nature of the indication, the overall benefit of nelarabine treatment for T-cell acute lymphoblastic leukemia and lymphoblastic lymphoma must be carefully evaluated and compared to these toxicities at the clinical level.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
Cytotoxic activity of nelarabine was attributed to intracellular ara-GTP levels. Phase I studies demonstrated that ara-GTP levels were higher in patients who responded than in patients who did not respond. Ara-GTP levels were also higher in female adult patients than in male adult patients, although there were no gender differences in response rates.
Antitumour activity, as evidenced by clinical response, was similar across all dose groups and the frequency of neurotoxicity appeared to increase as the daily nelarabine dose increased.
No Phase I QT studies were submitted. Cardiology adverse events were few and mostly grade 1 or 2. This drug is indicated for an aggressive cancer with a poor prognosis, therefore the absence of any data on QT prolongation is acceptable. A warning stating that there were no QT studies performed has been included in the Product Monograph.
3.3.2 Pharmacokinetics
Absorption
Atriance™ (nelarabine) is administered by intravenous infusion and is rapidly and extensively converted to ara-G. The maximum drug concentration (Cmax) values for nelarabine generally occurred at the end of the infusion. The Cmax values for ara-G also generally occurred at the end of the infusion and were relatively higher than nelarabine Cmax values. The drug exposure (AUC) values were generally dose-proportional. Intracellular ara-GTP AUC and Cmax values were higher in patients who responded (complete or partial response) than in patients who did not respond. Nelarabine and ara-G exposure were not associated with response.
Distribution
Nelarabine and ara-G are extensively distributed throughout the body.
The in vitro protein binding of nelarabine and ara-G in human plasma was low (<25%) and was independent of nelarabine or ara-G concentration over a concentration range of 6-600 μM.
Metabolism
The principal route of metabolism for nelarabine was the O-demethylation by adenosine deaminase (ADA) to form ara-G, which was then hydrolyzed to form guanine. Guanine was N-deaminated and and then oxidized to yield uric arid. Patients who are deficient in ADA will not respond to nelarabine therapy.
Excretion
Nelarabine was rapidly eliminated from plasma with geometric mean half-life values of <30 min. No nelarabine accumulation was seen with daily or every other day administration of nelarabine.
Ara-G was cleared from plasma at a slower rate than nelarabine. Overall, geometric mean half-life values were 2-3 hours. No ara-G accumulation was seen with daily or every other day administration of nelarabine. Renal elimination of nelarabine and ara-G accounted for 5.3% and 23.2% of the administered nelarabine dose, respectively.
Drug Interactions
The involvement of cytochrome P450 enzymes in the metabolism of nelarabine has not been investigated. This is noted in the Product Monograph.
Special Populations
No studies were carried out in patients with hepatic or renal impairment. Patients with reduced creatinine clearance or hepatic impairment should be closely monitored for neurotoxicty.
No pharmacokinetic data are available for pediatric patients at the proposed dose 650 mg/m2/dose.
3.3.3 Clinical Efficacy
Two pivotal studies were submitted for the efficacy evaluation of Atriance™ (nelarabine) in patients with refractory or relapsed T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LBL). Both clinical studies were open-label, single-arm, multicentre Phase II studies. One study enrolled 151 treated pediatric patients (n=151, ≤21 years of age) and the other study enrolled adult patients (n=39). The primary endpoints in both studies were complete and partial response rates. Complete response (CR) was defined as bone marrow blast counts ≤5%, no other evidence of disease, and full recovery of peripheral blood counts. Complete response with or without full hematologic recovery (CR*) was also assessed as a meaningful outcome.
In the pediatric pivotal study, 39 patients received two or more induction regimens prior to the administration of Atriance™ 650 mg/m2/day as an intravenous one-hour infusion for 5 consecutive days, repeated every 21 days. Thirteen percent (5/39) of the patients achieved a CR and 23% (9/39) achieved a CR* (which includes patients who achieved a CR). Of the 9 patients with CR*, 4had a bone marrow transplant; and of the remaining 5, one had additional systemic chemotherapy and intrathecal therapy during the remission period. The median duration for CR* was 12.3 weeks, ranging from 4.7 to 36.4 weeks. After excluding results from patients who were transplanted or took subsequent systemic chemotherapy, the median duration of CR* was 3.3 to 9.3 weeks. In the 650 mg/m2/day dose group, patients whose disease failed to respond to their most recent prior induction, 18% (4/22) achieved a CR with durations from 4.7 to 36.4 weeks. The overall survival ranged from 14.6 to 100.4 weeks, and the one-year survival rate was 14%.
The clinical evidence in the pediatric study was difficult to interpret due to the limited size of the patient population, lack of comparator arm, and confounding factors (transplant and additional chemotherapy given early in remission). However, as in adults, children with refractory or relapsed T-cell ALL and LBL have an aggressive disease with no treatment options. For these reasons, the small CR observed may be considered as clinically beneficial.
The adult pivotal study was composed of 39 patients who had relapsed or refractory T-ALL or T-LBL, 28 of whom had at least two prior induction regimens. Atriance™ 1,500 mg/m2 was administered intravenously over 2 hours on Days 1, 3, and 5 of a 21-day treatment cycle. For patients with ≥2 prior inductions (as per the indication), 18% of the patients experienced a CR and 21% of the patients achieved a CR* (which includes patients who achieved a CR). Of the 6 patients who experienced a CR*, one patient had a transplant and a second patient had a transplant after relapsing. Duration of response ranged from 15.1 to 195.4 weeks and median survival was 20.6 weeks. Concomitant anti-cancer therapy was not permitted. No adult patients received systemic chemotherapy or intrathecal therapy while in a nelarabine-induced CR or CR*.
The proposed indication is for refractory or relapsed T-cell ALL and LBL; diseases that progress rapidly in the absence of effective therapy. T-ALL and T-LBL patients who have relapsed or are refractory to two or more prior induction regimens have no standard, proven treatment options and have a very poor prognosis. There is minimal published research on refractory or relapsed T-cell diseases to make study comparisons and even that would be fraught with difficulty. For these reasons, the small CR observed in the clinical studies may be considered as clinical benefit.
3.3.4 Clinical Safety
The safety profile of Atriance™ (nelarabine) was based on results from a total of 459 patients in four Phase I and three Phase II open-label studies who had refractory hematologic malignancies, as well as supportive data from 522 patients in ongoing or recently completed National Cancer Institute studies.
In the pediatric study population (as assessed in the pivotal Phase II study described in section 3.3.3 Clinical Efficacy), the most frequent adverse event (AE), regardless of causality, reported in patients in the 650 mg/m2 dose group were decreased hematologic parameters: hemoglobin (38%), white blood cells (38%), neutrophils (37%), and platelets (30%), often reaching grades 3 or 4. The sponsor claims these abnormalities were manageable and expected in this population treated with cytotoxic drugs.
Nervous system AEs were common, occurring in 38% of the 84 pediatric patients who received 650 mg/m2. Grade 4 nervous system AEs were primarily seizures, occurring in five patients, one of which was a fatal AE in a patient with a history of seizures. AEs resulted in the withdrawal of 14 patients from the study all due to neurologic events, five of which were peripheral neuropathy and three others described as hypoesthesia or paresthesia. No grade 4 peripheral neuropathies were observed in patients who received the 650 mg/m2 dose. Grade 3 AEs were not uncommon, described as: peripheral sensory neuropathy (6%), peripheral motor neuropathy (2%), peripheral neuropathy (2%), hypoesthesia (4%), and paresthesia (1%). The incidence of grade 3/4 neurologic AEs are likely underestimated since patients were taken off study if neurologic AEs were ≥grade 2.
Deaths in the pediatric study were largely due to progressive disease (59%). Four fatal AEs were considered possibly due to nelarabine (i.e., hypotension/lactic acidosis, acute respiratory distress syndrome, peripheral neuropathy, cortical seizure)
In the adult Phase II studies, most patients (96%) who received the 1500 mg/m2 dose had at least one AE, regardless of causality. Grade 3 AEs were reported by 59% of the patients and grade 4 AEs were reported by 26% of the patients. The most frequently reported grade 3 AEs were fatigue (10%), febrile neutropenia (9%), decreased hemoglobin (7%), decreased platelet count (7%), pleural effusion (5%), and muscle weakness (5%). The most frequently reported grade 4 AEs were decreased neutrophil count (12%), decreased platelet count (10%), fatigue (2%), decreased hemoglobin (2%), and dyspnea (2%).
Serious AEs were reported for 42% of the patients in the adult Phase II studies. The most frequent serious AEs, regardless of causality, were pyrexia (8%), febrile neutropenia (5%), pneumonia (5%), dyspnea (5%), dehydration (4%), and pleural effusion (4%). Serious AEs possibly attributable to treatment with nelarabine that occurred in more than one patient included pyrexia (5%), febrile neutropenia (3%), dehydration (3%), pneumonia (2%), pancytopenia (2%), and ataxia (2%).
The most frequent nervous system AEs, regardless of causality, in the adult Phase II studies for patients who received the 1500 mg/m2 dose were somnolence (23%), dizziness (21%), hypoesthesia (17%), paresthesia (15%), and headache (15%). Most neurologic AEs were determined by the investigator to be possibly drug related and most were evaluated as grade 1 or 2. Resolution of neurologic events was documented in 47% of the cases (103 events of 217 total events). Serious neurologic AEs, regardless of causality, were reported for 8% of the adult patients. Neurologic AEs were likely underestimated since patients were taken off study if they experienced a neurologic AE ≥grade 2.
The studies provide minimal information on the long-term resolution of neurotoxicity. Based on the available data, it is estimated that approximately 50 to 65% of nervous system AEs were resolved. This may have been due to the nature of the studies and their limitations, such as disease progression. The other AEs were expected (hematologic, pulmonary, fatigue, nausea) and appeared to be manageable. With the lack of effective treatment for patients with this aggressive T-cell disease, nelarabine neurotoxicity is manageable with careful vigilance by treating clinicians and appropriate labelling.
3.3.5 Additional Issues
Additional data is required to confirm the clinical benefit and safety of Atriance™. Under the Notice of Compliance with Conditions (NOC/c) policy, the sponsor is required to submit the results of the following confirmatory studies:
- Data from the completed study AALL0434 (Phase III, Pediatric and Adult populations): Intensified Methotrexate, Nelarabine, and Augmented BFM Therapy for Children and Young Adults with Newly Diagnosed T-cell Acute Lymphoblastic Leukemia.
- Data from the completed study PGAA107062 (Phase II, Pediatric and Adult populations): Phase II Study with Nelarabine for Patients with refractory or recurrent T-ALL or T-lymphoblastic lymphoma.
- Data from a Post-Marketing Surveillance Study for Atriance™ in the indicated patient population under 21 years of age receiving the 650 mg/m2 dose of nelarabine.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Refractory or relapsed T-cell LBL and ALL in pediatric and adult patients is an aggressive cancer with no real treatment options. At best, patients are enrolled in Phase I or Phase II clinical trials and hope for a remission long enough to prepare them for a bone marrow transplant. Alternatively, patients are considered palliative and receive comfort measures only.
In the two pivotal studies submitted, the number of patients that achieved complete response (CR) and complete response with or without complete hematologic recovery (CR*) was small. Response durations were confounded in pediatric patients who had a bone marrow transplant or additional chemotherapy during remission. This is not unreasonable since standard practice for relapsed or refractory patients is to achieve a re-induction remission and then proceed to transplant. Therefore, clinical benefit based on response duration is very difficult to interpret. Nevertheless, the consistency of the observed responses in both Phase I and II studies, in pediatric and adult patients, after the first and second relapses or refractory to prior treatments, and the successful transplantation rate, gives credence to its clinical benefit for this patient population.
Some studies (e.g., QT prolongation, and cytochrome P450 studies) were not available and therefore there are a few unanswered questions which may pose varying risks in the use of Atriance™. However, the largest risk involved is neurotoxocity. But given the aggressiveness of the disease and lack of available treatments, the risk appears reasonable. T-cell ALL and LBL are treated by medical specialists who are highly knowledgeable in the potential for toxicity of treatment. Appropriate labelling is provided under the Warning and Precautions section and Adverse Events section of the Product Monograph for Atriance™.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety, and effectiveness, Health Canada considers that the benefit/risk profile of Atriance™ is favourable for the treatment of patients with T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma whose disease has not responded to or has relapsed following treatment with at least two chemotherapy regimens. This New Drug Submission (NDS) qualifies for authorization under the Notice of Compliance with Conditions Policy. The New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations.
Under the Notice of Compliance with Conditions (NOC/c) policy, the sponsor is required to submit the results of the following confirmatory studies:
- Data from the completed study AALL0434 (Phase III, Pediatric and Adult populations): Intensified Methotrexate, Nelarabine, and Augmented BFM Therapy for Children and Young Adults with Newly Diagnosed T-cell Acute Lymphoblastic Leukemia.
- Data from the completed study PGAA107062 (Phase II, Pediatric and Adult populations): Phase II Study with Nelarabine for Patients with refractory or recurrent T-ALL or T-lymphoblastic lymphoma.
- Data from a Post-Marketing Surveillance Study for Atriance™ in the indicated patient population under 21 years of age receiving the 650 mg/m2 dose of nelarabine.
4 Submission Milestones
Submission Milestones: AtrianceTM
| Submission Milestone | Date |
|---|---|
| Request for priority status | |
| Filed | 2005-07-13 |
| Rejection issued by BMORS Bureau | 2005-08-18 |
| Submission filed | 2005-09-28 |
| Screening 1 | |
| Screening Deficiency Notice issued | 2005-11-18 |
| Response filed | 2006-01-16 |
| Screening Acceptance Letter issued | 2006-03-03 |
| Review 1 | |
| Quality Evaluation complete | 2006-12-19 |
| Clinical Evaluation complete | 2006-12-05 |
| NON issued by Director General (quality issues) | 2006-12-22 |
| Response filed | 2007-03-08 |
| Screening 2 | |
| Screening Acceptance Letter issued | 2007-03-15 |
| Review 2 | |
| Quality Evaluation complete | 2007-07-24 |
| Labelling Review complete | 2007-08-01 |
| NOC/c-QN issued | 2007-08-10 |
| Response filed | 2007-08-23 |
| Review 3 | |
| Clinical Evaluation complete | 2007-09-20 |
| Labelling Review complete | 2007-09-20 |
| NOC issued by Director General under the NOC/c Policy | 2007-09-22 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| ATRIANCE | 02299925 | SANDOZ CANADA INCORPORATED | NELARABINE 5 MG / ML |