The Use of Modified BFM +/- Compound 506U78 (Nelarabine) (NSC# 686673, IND #52611) in an Intensive Chemotherapy Regimen for the Treatment of T-Cell Leukemia

Trial Information

The Use of Modified BFM +/- Compound 506U78 (Nelarabine) (NSC# 686673, IND #52611) in an Intensive Chemotherapy Regimen for the Treatment of T-Cell Leukemia

PRIMARY OBJECTIVES:

I. Determine the feasibility of the addition of nelarabine to modified multiagent
Berlin-Frankfurt-Muenster-86 chemotherapy in patients with newly diagnosed T-cell acute
lymphoblastic leukemia.

SECONDARY OBJECTIVES:

I. Determine the pharmacokinetics and intracellular pharmacology of nelarabine in these
patients.

OUTLINE: This is a pilot, multicenter study.

Prednisone Response Pre-Induction: All patients receive oral prednisone three times daily on
days -7 to -1 and methotrexate intrathecally (IT) on day -7* of week 0. Good prednisone
responders proceed to induction on regimen A. Poor prednisone responders proceed to
induction on regimen C.

NOTE: *Patients who have received cytarabine IT within the week prior to study entry receive
methotrexate IT on day -6.

Regimen A (good prednisone responders) (closed as of 2/27/03):

Induction (weeks 1-5): Patients receive vincristine IV on days 1, 8, and 15; oral prednisone
three times daily on days 1-14; daunorubicin IV over 15 minutes on days 1, 8, 15, and 22;
asparaginase intramuscularly (IM) on days 12, 15, 18, 22, 24, 27, 30, and 33; and
methotrexate IT on day 1.

If bone marrow is M1, week 6 of induction therapy begins on day 36 or when peripheral blood
counts recover. If bone marrow is M2, patients begin week 6 of induction therapy
immediately. If bone marrow is M3, treatment discontinues. Those patients with minimal
residual disease (MRD) on day 36 proceed to regimen B.

Induction (weeks 6-9): Patients receive cyclophosphamide IV over 1 hour on days 36 and 63;
cytarabine IV over 72 hours on days 38-40, 45-47, 52-54, and 59-61; oral mercaptopurine
daily on days 36-63; and methotrexate IT on days 45 and 59.

Consolidation (weeks 10-19): Patients receive oral mercaptopurine on days 64-119;
methotrexate IV over 24 hours and leucovorin calcium IV, or orally as tolerated, on days 71,
85, 99, and 113; and methotrexate IT on days 71, 85, 99, and 113. (Patients begin
methotrexate once blood counts recover and only if bone marrow is M1).

Reinduction (weeks 20-29): Patients receive oral dexamethasone three times daily on days
134-154; vincristine IV on days 141 and 148; doxorubicin IV over 15 minutes on days 134,
141, 148, and 155; and asparaginase IM on days 141, 144, 148, 151, 154, and 157. Beginning
on day 169 or when blood counts recover, patients receive cyclophosphamide IV on day 169,
cytarabine IV over 72 hours on days 171-173 and 178-180; oral thioguanine daily on days
169-182; and methotrexate IT on days 171 and 178. Patients also receive cranial irradiation
for up to 10 days beginning on day 189.

Maintenance (weeks 30-101): Patients receive vincristine IV once; oral prednisone three
times daily for 5 days; oral mercaptopurine daily; and oral methotrexate weekly. Treatment
repeats every 8 weeks for 9 courses.

Regimen B (patients with MRD on day 36 of regimen A) (closed as of 2/27/03):

Induction (weeks 1-9): Patients receive treatment as in induction of regimen A.

Consolidation (weeks 10-19): Patients receive treatment as in consolidation on regimen A.

Reinduction (weeks 20-29): Patients receive treatment as in reinduction on regimen A and
nelarabine IV on days 162-166.

Maintenance (weeks 30-101): Patients receive oral mercaptopurine daily on days 1-28 and
36-56; oral methotrexate weekly; and nelarabine IV on days 29-33. Treatment repeats every 8
weeks for 4 courses. Beginning on week 62, patients receive vincristine IV once; oral
prednisone three times daily for 5 days; oral mercaptopurine daily; and oral methotrexate
weekly. Treatment repeats every 8 weeks for 5 courses.

Regimen C (poor prednisone responders from stage 1 of study and all patients entered during
stage 2 of study) (closed as of 2/27/03):

Induction (weeks 1-5): Patients receive treatment as in induction (weeks 1-5) on regimen A
and nelarabine IV over 1 hour on days 29-33.

If bone marrow is M1, patients begin week 6 of induction therapy on day 36 or when
peripheral blood counts recover. If bone marrow is M2, patients begin week 6 of induction
therapy immediately. If bone marrow is M3, treatment discontinues.

Induction (weeks 6-9): Patients receive treatment as in induction (weeks 6-9) on regimen A.

Consolidation (weeks 10-19): Patients receive treatment as in consolidation on regimen A.

Reinduction (weeks 20-29): Patients receive treatment as in reinduction on regimen B.

Maintenance (weeks 30-101): Patients receive treatment as in maintenance on regimen B.

Regimen D (effective 5/2004):

Induction (weeks 1-5): Patients receive vincristine IV on days 1, 8, and 15; oral prednisone
3 times a day on days 1-14; daunorubicin IV over 15 minutes on days 1, 8, 15, and 22;
nelarabine IV over 1 hour on days 29-33; asparaginase IM on days 12, 15, 18, 22, 24, 27, 30,
and 33; and methotrexate IT on day 1.

If bone marrow is M1, week 6 of induction therapy begins on day 36 or when peripheral blood
counts recover. If bone marrow is M2, patients begin week 6 of induction therapy
immediately. If bone marrow is M3, treatment discontinues.

Induction (weeks 6-9): Patients receive cyclophosphamide IV over 1 hour on days 36 and 50;
cytarabine IV or SC on days 36-39, 43-46, 50-53, and 57-60; oral mercaptopurine once daily
on days 36-63; and methotrexate IT on days 43 and 57.

Patients who are poor responders to prednisone in induction therapy proceed to regimen F.
Patients who are good responders to prednisone but have MRD after induction therapy proceed
to regimen E. Patients who are good responders to prednisone and have no MRD after induction
therapy continue therapy on regimen D.

Consolidation (weeks 10-19): Patients must have M1 marrow to proceed. Patients receive oral
mercaptopurine on days 70-126; methotrexate IV over 24 hours on days 77, 84, 91, and 98;
leucovorin calcium IV or orally every 6 hours on days 78-79, 85-86, 92-93, and 99-100; and
methotrexate IT on days 77, 84, 91, and 98.

Reinduction (weeks 20-29): Patients < 13 years old receive dexamethasone 3 times daily on
days 140-161. Patients ≥ 13 years old receive oral dexamethasone on days 140-146 and
155-161; nelarabine IV on days 169-173; vincristine IV over 15 minutes on days 140, 147, and
153; pegaspargase IM on day 143; cyclophosphamide IV on day 176; cytarabine IV or SC on days
176-179 and 183-186; oral thioguanine on days 176-189; and methotrexate IT on days 176 and
183. Patients with CNS disease undergo craniocervical radiotherapy beginning on day 196 and
continuing for 7-10 days.

Maintenance (weeks 30-61): Patients receive oral mercaptopurine on days 1-28 and 36-56; oral
methotrexate on days 1, 8, 15, 22, 36, 43, and 50; and nelarabine IV on days 29-33.
Treatment repeats every 8 weeks for 4 courses.

Maintenance (weeks 62-101): Patients receive vincristine IV on day 1; oral dexamethasone
twice daily on days 1-5; oral mercaptopurine on days 1-56; and oral methotrexate on days 1,
8, 15, 22, 29, 36, 43, and 50. Treatment repeats every 8 weeks for 5 courses.

Regimen E (good responders to induction prednisone but with MRD) (effective 5/2004):
Patients receive consolidation therapy, reinduction therapy, and maintenance therapy as in
regimen D, but nelarabine is administered at a higher dose.

Regimen F (poor responders to induction prednisone) (effective 5/2004): Patients receive
nelarabine at a higher dose during induction therapy. Patients receive consolidation
therapy, reinduction therapy, and maintenance therapy as in regimen E.

Patients are followed monthly for 1 year, every 2 months for 1 year, every 4 months for 1
year, every 6 months for 1 year, and then annually thereafter.

PROJECTED ACCRUAL: A total of 100 patients (30 for regimens A, B, and C; 70 for regimens D,
E, and F) will be accrued for this study within 9-29 months.