Atriance - Letter to Health Professionals - 2007

Date: 2007-10-23


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This is duplicated text of a letter from GlaxoSmithKline Canada Inc.
Contact the company for a copy of any references, attachments or enclosures.

20 September 2007

Dear Health Care Professional(s),

GlaxoSmithKline Canada Inc. is pleased to announce that Health Canada has granted a Notice of Compliance under the Notice of Compliance with Conditions (NOC/c) policy for ATRIANCE™ (nelarabine injection, 5 mg/mL) a new antimetabolite for use in 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.

Approval is based on objective response rate from 2 phase II clinical trials.

Health Canada has issued a marketing authorization with conditions under the Notice of Compliance with Conditions policy for ATRIANCE™ to reflect the promising nature of the clinical efficacy and safety of ATRIANCE™ in patients with this serious disease and the need for further follow-up to verify the clinical benefit.

Study demographics and trial design

Pediatric Clinical Study: The safety and efficacy of ATRIANCE™ in pediatric patients were studied in a clinical trial conducted by the Children's Oncology Group (COG). This study included 151 treated patients 21 years of age and younger, 149 of whom had relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LBL). Eighty-four (84) patients, 39 of whom had received two or more prior induction regimens, were treated with 650 mg/m2/day of ATRIANCE™ administered intravenously over 1 hour daily for 5 consecutive days repeated every 21 days (see Table 1). Patients who experienced signs or symptoms of peripheral neuropathy on therapy were to be evaluated for discontinuation of further therapy with ATRIANCE™.

Table 1. Pediatric Clinical Study - Patient Allocation
Patient Population N
Patients treated at 650 mg/m2/day for 5 days every 21 days 84
Patients with T-ALL or T-LBL with two or more prior inductions treated at 650 mg/m2/day for 5 days every 21 days 39

Patients ranged in age from 2.5-21.7 years (overall mean, 11.9 years), 52% were 3 to 12 years of age and most were male (74%) and Caucasian (62%). Seventy seven percent of patients had a diagnosis of T-ALL.

Adult Clinical Study: The safety and efficacy of ATRIANCE™ in adult patients were studied in a clinical trial conducted by the Cancer and Leukemia Group B (CALGB). This study included 39 treated patients, 28 of whom were with T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LBL) that had relapsed following or was refractory to at least two prior induction regimens. ATRIANCE™ 1,500 mg/m2 was administered intravenously over 2 hours on days 1, 3 and 5 repeated every 21 days. Seventeen patients had a diagnosis of T-ALL and 11 had a diagnosis of T-LBL. For patients with ≥2 prior inductions, the age range was 16-65 years (mean 34 years) and most patients were male (82%) and Caucasian (61%). Patients with central nervous system (CNS) disease were not eligible. Patients who experienced grade 2 or greater peripheral neuropathy on therapy were typically discontinued from further therapy with ATRIANCE™.

Study results

Pediatric Clinical Study: Complete response (CR) in the pediatric clinical study 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 this heavily pretreated population. Duration of CR is reported from date of response to date of relapse, and may include subsequent stem cell transplant. Efficacy results, including survival at one year, are presented in Table 2.

Table 2. Efficacy Results in Patients 21 Years of Age and Younger at Diagnosis With ≥2 Prior Inductions Treated with 650 mg/m 2 of ATRIANCE™ Administered Intravenously Over 1 Hour Daily for 5 Consecutive Days Repeated Every 21 Days
  N = 39
CR n (%) [95% CI] 5 (13%) [4%, 27%]
CR* n (%) [95% CI] 9 (23%) [11%, 39%]
Duration of complete response (range in weeks) ** 3.3 to 9.3
Median overall survival (weeks) [95% CI] 13.1 [8.7, 17.4]
Kaplan-Meier Survival estimate at 1 year [95% CI] 14% [3%, 26%]

CR = Complete response
CR* = Complete response with or without hematologic recovery (includes patients who achieved a CR)
** Does not include 5 patients who were transplanted or had subsequent systemic chemotherapy) duration of response in these 5 patients was 4.7 to 42.1 weeks).

The mean number of days on therapy was 46 days (range of 7 to 129 days). Time to complete response ranged from 3.4 to 12 weeks and median time to CR* was 3.4 weeks (95% CI: 3.0, 3.7).

Adult Clinical Study: Complete response (CR) in the adult clinical study 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 complete hematologic recovery (CR*) was also assessed as a meaningful outcome in this heavily pretreated population. The results of the study for patients who had received ≥2 prior inductions are shown in Table 3.

Table 3. Efficacy Results in Adult Patients With ≥2 Prior Inductions Treated with 1,500 mg/m 2 of ATRIANCE™ Administered Intravenously Over 2 Hours on Days 1, 3, and 5 Repeated Every 21 Days
  N = 28
CR n (%) [95% CI] 5 (18%) [6%, 37%]
CR* n (%) [95% CI] 6 (21%) [8%, 41%]
Duration of complete response (range in weeks)** 15 to 195+
Median overall survival (weeks) [95% CI] 20.6 weeks [10.4, 36.4]
Kaplan Meier Survival estimate at 1 year [95% CI] 29% [12%, 45%]

CR = Complete response
CR* = Complete response with or without hematologic recovery (includes patients who achieved a CR)
** Does not include 1 patient who was transplanted (duration of response was 156+ weeks)

The mean number of days on therapy was 56 days (range of 10 to 136 days). Time to complete response and time to CR* ranged from 2.9 to 11.7 weeks.

Indications and Clinical Use

ATRIANCE™ (nelarabine) 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.

Approval is based on the unconfirmed surrogate endpoint of clinical response only.

Patients should be advised about the conditional nature of the market authorization for ATRIANCE in this indication.

Serious Warnings and Precautions

ATRIANCE™ should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. This product is for intravenous use only.

Severe Neurologic Events:

These events included:

  • Altered mental states including severe somnolence
  • Central nervous system effects including convulsions
  • Peripheral neuropathy including numbness, paresthesias, motor weakness, paralysis, craniospinal demyelination, and ascending peripheral neuropathies similar to Guillan-Barré syndrome

Some of these neurologic adverse events are irreversible.

ATRIANCE™ should be discontinued at the first sign of neurologic events of NCI Common Toxicity Criteria grade 2 or greater.

Close monitoring for neurological events is strongly recommended.

Adverse Reactions

The most common adverse events in pediatric patients, regardless of causality, were hematologic disorders (anemia, leukopenia, neutropenia and thrombocytopenia). Of the non-hematologic adverse events in pediatric patients, the most frequent events reported were headache, increased transaminase levels, decreased blood potassium, decreased blood albumin, increased blood bilirubin, and vomiting.

The most common adverse events in adults, regardless of causality, were fatigue; gastrointestinal (GI) disorders (nausea, diarrhea, vomiting, and constipation); hematologic disorders (anemia, leukopenia, neutropenia and thrombocytopenia); respiratory disorders (cough and dyspnea); nervous system disorders (somnolence and dizziness); and pyrexia.

Neurotoxicity is the dose-limiting toxicity of nelarabine. Patients undergoing therapy with ATRIANCE™ should be closely observed for signs and symptoms of neurologic toxicity. See Product Monograph for further details.

Drug Interactions

No formal drug interaction studies have been carried out with nelarabine.

The involvement of cytochrome P450 enzymes in the metabolism of nelarabine has not been investigated.

Dosage and Administration

Adults: The recommended adult dose of ATRIANCE™ is 1,500 mg/m2/day administered intravenously over 2 hours on days 1, 3, and 5, repeated every 21 days.

Children: The recommended pediatric dose of ATRIANCE™ 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.

ATRIANCE™ should be discontinued at the first sign of neurologic events of NCI Common Toxicity Criteria grade 2 or greater. Administration of the next treatment cycle may be delayed for other toxicity including hematologic toxicity.

For enquiries about product availability or medical information regarding ATRIANCE™, please contact our Medical Information Department at 1-800-387-7374.

Original signed by

Tjark Reblin, M.D.
Vice-President and Chief Medical Officer

GlaxoSmithKline Inc.
7333 Mississauga Road
Mississauga, Ontario
L5N 6L4
1-800-397-7374

Any suspected adverse reaction can also be reported to:
Canadian Adverse Drug Reaction Monitoring Program (CADRMP)
Marketed Health Products Directorate
HEALTH CANADA
Address Locator: 0701C
OTTAWA, Ontario, K1A 0K9
Tel: (613) 957 0337 or Fax: (613) 957 0335
Toll free for consumers and health professionals:
Tel: 866 234 2345
Fax: 866 678 6789
cadrmp@hc sc.gc.ca

The Adverse Reaction Reporting Form and the Adverse Reaction Guidelines can be found on the Health Canada web site or in The Canadian Compendium of Pharmaceuticals and Specialties.

For other inquiries related to this communication, please contact Health Canada at:
Bureau of Metabolism, Oncology and Reproductive Sciences (BMORS)
E-mail: bmors_enquiries@hc-sc.gc.ca
Tel: 613-941-3171
Fax: 613-941-1365

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