General Information

Arranon (nelarabine) is a cytotoxic deoxyguanosine analogue prodrug. The drug disrupts DNA synthesis in rapidly dividing cells, inducing cellular apoptosis. Additional mechanisms of cytotoxic activity may also exist.

Arranon is specifically indicated for the treatment of pediatric and adult 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.

Arranon is supplied as a clear, colorless, sterile solution designed for intravenous infusion. Recommended adult dosage is 1,500 mg/m2 delivered as a 2 hour infusion on days 1, 3, and 5 of a 21 day treatment cycle. Recommended pediatric dosage is 650 mg/m2 delivered as a 1 hour infusion daily for days 1 through 5 of a 21 day treatment cycle. Treatment cycles should be repeated until evidence of disease progression is observed.

Clinical Results

FDA Approval
Approval of Arranon was supported by a pair of clinical trials, investigating the drug in both pediatric and adult patients.

Pediatric Patients
Arranon was investigated in a phase II trial of pediatric patients age 21 years and younger. This single-arm, multi-center enrolled 84 patients with refractory T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LBL); 31 of these subjects had received one prior chemotherapy regimen, and 39 had received two or more. All patients received 650 mg/m2 via one hour infusion for 5 consecutive days in 21 day treatment cycles. Results indicated that 13% of subjects (n=5) achieved complete disease response (bone marrow blast counts<5%) and full recovery of peripheral blood counts, and 10% (n=4) achieved complete disease response without full hematological recovery. Response duration was 3.3 to 9.3 weeks, and median overall survival was 13.1 weeks.

Adult Patients
The drug's safety and efficacy in adult patients was investigated was investigated in an additional phase II study. This single-arm, multi-center study enrolled 39 T-ALL and T-LBL patients, 28 of whom had received at least two courses of chemotherapy. Among these subjects, 18% (n=5) achieved complete response and hematological recovery, and 4% (n=1). Duration of complete response was 4 to 195+ weeks, and median overall survival was 20.6 weeks.

Ongoing Study Commitments

• Submit the results of the proposed phase III trial (AALL0434) to be conducted by the Children’s Oncology Group to demonstrate nelarabine’s clinical benefit. First patient enrolled: April 2006
  End of safety phase: 4Q 2009
  Complete accural: 4Q 2012
  Complete 3-year follow-up: 4Q 2015
  Availablity of study report: 4Q 2016

Side Effects

Adverse events associated with the use of Arranon may include, but are not limited to, the following:

• Pediatric Population
• Hematological Toxicities (Anemia, Neutropenia, Thrombocyopenia, Leukopenia)
• Hepatic Enzyme Elevations
• Potassium Deficiencies
• Vomitting
• Calcium Deficiencies
• Asthenia
• Magnesium Deficiencies
• Infection
• 
  Adult Population
• Hematological Toxicities (Anemia, Neutropenia, Thrombocyopenia)
• Fatigue
• Nausea
• Cough
• Asthenia
• Dyspnea
• Petechiae
• Edema
• Febrile Neutropenia

In addition, neurological adverse events were observed in 64% of subjects. Most were mild to moderate (grade 1-2), including headache, somnolence, neuropathy, hypoesthesia. Grade 4 and grade 5 (fatal) adverse neurological events were also obsered, including 3rd and 6th nerve paralysis, progressive multifocal leukoencephalopathy, demyelination similar to Guillain-Barré syndrome, cerebral and intracranial hemorrhage, coma, and metabolic encephalopathy. Close monitoring of such events is recommended, and appearance of moderate (grade 2) or higher neurological toxicities may require discontinuation of treatment.

Mechanism of Action

Arranon is a prodrug of the cytotoxic deoxyguanosine analogue 9-ß-D-arabinofuranosylguanine (ara-G). The drug is ultimately metabolized into the active 5'-triphosphate ara-GTP, which disrupts DNA synthesis and induces apoptosis. Additional cytotoxic activities may exist, but these are not fully understood.

Literature References

Robak T, Korycka A, Kasznicki M, Wrzesien-Kus A, Smolewski P. Purine nucleoside analogues for the treatment of hematological malignancies: pharmacology and clinical applications. Current Cancer Drug Targets 2005 Sep;5(6):421-444

Kurtzberg J, Ernst TJ, Keating MJ, Gandhi V, Hodge JP, Kisor DF, Lager JJ, Stephens C, Levin J, Krenitsky T, Elion G, Mitchell BS. Phase I study of 506U78 administered on a consecutive 5-day schedule in children and adults with refractory hematologic malignancies. Journal of Clinical Oncology 2005 May 20;23(15):3396-3403

Berg SL, Blaney SM, Devidas M, Lampkin TA, Murgo A, Bernstein M, Billett A, Kurtzberg J, Reaman G, Gaynon P, Whitlock J, Krailo M, Harris MB; Children's Oncology Group. Phase II study of nelarabine (compound 506U78) in children and young adults with refractory T-cell malignancies: a report from the Children's Oncology Group. Journal of Clinical Oncology 2005 May 20;23(15):3376-3382

Parker WB, Secrist JA 3rd, Waud WR. Purine nucleoside antimetabolites in development for the treatment of cancer. Current Opinion in Investigational Drugs 2004 Jun;5(6):592-596