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Title:
A Phase III Randomized Trial for Newly Diagnosed High Risk B-precursor Acute Lymphoblastic Leukemia (ALL) Testing Clofarabine (IND# 73789, NSC# 606869) in the Very High Risk Stratum
Protocol Number:
PAALL1131
Phase:
Phase III
Physician:
Patrick Brown
Purpose:
This randomized phase III trial is studying how well combination chemotherapy works in treating young patients with newly diagnosed high-risk acute lymphoblastic leukemia.
Eligibility:
Ages Eligible for Study: 1 Year to 30 Years Genders Eligible for Study: Both Accepts Healthy Volunteers: No Criteria DISEASE CHARACTERISTICS: Patients must have newly diagnosed B-precursor acute lymphoblastic leukemia (ALL); patients with Down syndrome (DS) are also eligible Patients must have one of the following: NCI high-risk ALL or NCI standard-risk ALL with central nervous system (CNS), testicular leukemia, and/or steroid pre-treatment, and be enrolled in COG AALL08B1; patients that begin therapy on this study (AALL1131) prior to enrollment on COG AALL08B1 are ineligible NCI standard-risk ALL, be enrolled in COG AALL08B1 or COG AALL0932 and completed AALL0932 induction treatment and been classified as high-risk or very high-risk Patients with BCR-ABL1 (Philadelphia chromosome positive) are not eligible for post-induction therapy on this study; non-DS patients may be eligible to enroll in COG AALL0622 or successor COG Ph+ ALL trial by day 15 induction DS HR-ALL patients with induction failure or BCR-ABL1 are not eligible for post-induction No VHR-ALL patients with significant hepatic dysfunction at the time of post-induction randomization defined as: Direct bilirubin greater than 1.5 times upper limit of normal (ULN) for age SGPT (ALT) � 3 times ULN for age Lipase greater than 2.0 times ULN for age Patients cannot have secondary ALL that developed after treatment of a prior malignancy with cytotoxic chemotherapy PATIENT CHARACTERISTICS: White blood cell count (WBC) criteria: Age 1-9.99 years: WBC � 50 000/μL Age 10-30.99 years: Any WBC Age 1-30.99 years: Any WBC with: Testicular leukemia CNS leukemia (CNS3) Steroid pretreatment No very high-risk (VHR) acute lymphoblastic leukemia (ALL) patients with hepatitis B or C infection or history of cirrhosis at the time of post-induction randomization Negative pregnancy test Patients of childbearing potential must agree to use an effective birth control method Female patients who are lactating must agree to stop breast-feeding PRIOR CONCURRENT THERAPY: See Disease Characteristics Patients must not have received any prior cytotoxic chemotherapy for the current diagnosis of acute lymphoblastic leukemia (ALL) or any cancer diagnosed previously, with the exception of steroids and intrathecal cytarabine for the current diagnosis of ALL Patients receiving prior steroid therapy may be eligible No concurrent intensity-modulated radiotherapy
Treatment:
This is a multicenter study. Patients are stratified according to Down syndrome (no vs yes). Induction therapy for ALL patients without Down syndrome (35 days): Patients receive induction chemotherapy comprising cytarabine intrathecally (IT) on day 1; vincristine sulfate IV on days 1, 8, 15, and 22; daunorubicin hydrochloride IV over 1-15 minutes on days 1, 8, 15, and 22; dexamethasone orally (PO) or IV twice daily (BID) on days 1-14 (patients under 10 years old) or prednisone PO or IV BID on days 1-28 (patients at least 10 years old); pegaspargase IV over 1-2 hours on day 4; and methotrexate IT on days 8 and 29 (plus days 15 and 22 for CNS3). Patients are stratified according to NCI ALL risk criteria (high-risk or standard-risk vs very high-risk). High-risk or standard-risk ALL: Patients are randomized to 1 of 2 treatment arms. Consolidation therapy (56 days): Arm I HR-ALL C: Patients receive consolidation therapy comprising cyclophosphamide IV over 30-60 minutes on days 1 and 29; cytarabine IV or subcutaneously (SC) on days 1-4, 8-11, 29-32, and 36-39; mercaptopurine PO on days 1-4 and 29-42, methotrexate IT on days 1, 8, 15, and 22; vincristine sulfate IV on days 15, 22, 43, and 50; and pegaspargase IV over 1-2 hours on days 15 and 43. Patients with continuing clinical evidence of testicular leukemia undergo radiotherapy (RT) once daily, 5 days a week, for approximately 2½ weeks (12 fractions total). Arm II HR-ALL C: Patients receive intrathecal triple therapy (ITT) comprising methotrexate, hydrocortisone sodium succinate, and cytarabine on days 1, 8, 15, and 22. Patients also receive consolidation therapy as patients in arm I HR-ALL C. Patients with testicular leukemia also undergo RT as in arm I HR-ALL C. Interim maintenance therapy (63 days): Arm I HR-ALL IM: Patients receive interim maintenance (IM) therapy comprising vincristine sulfate IV on days 1, 15, 29, and 43; high-dose methotrexate IV over 24 hours on days 1, 15, 29, and 43; leucovorin calcium PO or IV on days 3-4, 17-18, 31-32, and 45-46; methotrexate IT on days 1 and 29; and mercaptopurine PO on days 1-56. Arm II HR-ALL IM: Patients receive ITT on days 1 and 29 and IM therapy as in arm I HR-ALL IM. Delayed intensification therapy (56 days): Arm I HR-ALL DI: Patients receive delayed intensification (DI) therapy comprising vincristine sulfate IV on days 1, 8, 15, 43, and 50; dexamethasone PO or IV BID on days 1-7, and 15-21; doxorubicin hydrochloride IV on days 1, 8, and 15; methotrexate IT on days 1, 29, and 36; pegaspargase IV over 1-2 hours on days 4 and 43; cyclophosphamide IV over 30-60 minutes on day 29; cytarabine IV on days 29-32 and 36-39; and thioguanine PO on days 29-42. Arm II HR-ALL DI: Patients receive ITT on days 1, 29, and 36 and DI therapy as in arm I HR-ALL DI. Maintenance therapy: Arm I HR-ALL M: Patients receive maintenance therapy comprising vincristine sulfate IV on days 1, 29, and 57; methotrexate IT on days 1 (also day 29 of courses 1-4) ; prednisone PO BID on days 1-5, 29-33, and 57-61; mercaptopurine PO on days 1-84; and methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. Treatment repeats every 12 weeks for 2 years (females) or 3 years (males) in the absence of disease progression or unacceptable toxicity. Arm II HR-ALL M: Patients receive ITT on day 1 (also day 29 of courses 1-4) and maintenance therapy as in arm I HR-ALL M. Treatment repeats every 12 weeks for 2 years (females) or 3 years (males) in the absence of disease progression or unacceptable toxicity. Very high-risk ALL: Patients are randomized to 1 of 3 treatment arms. Consolidation therapy part 1 (days 1-28): In all arms, patients receive cyclophosphamide IV over 30-60 minutes on day 1; cytarabine IV or SC on days 1-4 and 8-11; mercaptopurine PO on days 1-14; methotrexate IT on days 1, 8, 15, and 22 (days 1 and 8 only for CNS patients): vincristine sulfate IV on days 15 and 22; and pegaspargase IV over 1-2 hours on day 15. Patients with continuing clinical evidence of testicular leukemia undergo RT once daily, 5 days a week, for approximately 2½ weeks (12 fractions total). Consolidation therapy part 2 (days 29-57): Arm A VHR-ALL C: Patients receive consolidation therapy comprising cyclophosphamide IV over 30-60 minutes on day 29; cytarabine IV over 15-30 minutes or SC on days 29-32 and 36-39; mercaptopurine PO on days 29-42; vincristine IV on days 43 and 50; and pegaspargase IV over 1-2 hours on day 43. Arm B VHR-ALL C: Patients receive consolidation therapy comprising cyclophosphamide IV over 15-30 minutes on days 29-33; etoposide IV over 1-2 hours on days 29-33; vincristine sulfate IV on days 43 and 50; and pegaspargase IV over 1-2 hours on day 43. Arm C VHR-ALL C: Patients receive clofarabine IV over 2 hours on days 29-33 and consolidation therapy as in arm B VHR-ALL C. Interim Maintenance I (63 days): In all arms, patients receive vincristine IV on days 1, 15, 29, and 43; high-dose methotrexate IV over 24 hours on days 1, 15, 29, and 43; leucovorin calcium PO or IV on days 3-4, 17-18, 31-32, and 45-46; mercaptopurine PO on days 1-56; and methotrexate IT on days 1 and 29. Delayed Intensification part 1 (days 1-28): In all arms, patients receive vincristine sulfate IV on days 1, 8, and 15; dexamethasone PO or IV BID on days 1-7 and 15-21; doxorubicin hydrochloride IV over 1-15 minutes on days 1, 8, and 15; methotrexate IT on day 1; and pegaspargase IV over 1-2 hours on day 4. Delayed Intensification part 2 (days 29-57): Arm A VHR-ALL DI: Patients receive DI therapy comprising cyclophosphamide IV over 30-60 minutes on day 29; cytarabine IV over 15-30 minutes or SC on days 29-32 and 36-39; thioguanine PO on days 29-42; methotrexate IT on days 29 and 36; vincristine sulfate IV on days 43 and 50; and pegaspargase IV over 1-2 hours on day 43. Arm B VHR-ALL DI: Patients receive DI therapy comprising cyclophosphamide IV over 15-30 minutes on days 29-33; etoposide IV over 1-2 hours on days 29-33; methotrexate IT on days 29 and 36; vincristine sulfate IV on days 43 and 50; and pegaspargase IV over 1-2 hours on day 43. Arm C VHR-ALL DI: Patients receive clofarabine IV over 2 hours on days 29-33 and DI therapy as in arm II B VHR-ALL DI. Interim Maintenance II (56 days): In all arms, patients receive vincristine sulfate IV and methotrexate IV on days 1, 11, 21, 31, and 41; pegaspargase IV over 1-2 hours on days 2 and 22; and methotrexate IT on days 1 and 31. Maintenance therapy: Patients with CNS3 disease at diagnosis undergo RT once daily over 4 weeks (10 fractions total). In all arms, patients receive vincristine sulfate IV on days 1, 29, and 57; prednisone PO BID on days 1-5, 29-33, and 57-61; methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 (except on methotrexate IT days); mercaptopurine PO on days 1-84; methotrexate IT on day 1 (also day 29 of courses 1 and 2 for CNS patients who did not receive RT). Treatment repeats every 12 weeks for 2 years (females) or 3 years (males) in the absence of disease progression or unacceptable toxicities. High-risk ALL patients with Down syndrome: Patients are stratified according to response to induction therapy (days 1-14) (rapid early responders [RER; M1 day 15 bone marrow] vs slow early responders [SER; M2/M3 day 15 bone marrow]). Induction therapy (days 1-14): All patients receive cytarabine IT on day 1; vincristine sulfate IV on days 1 and 8, dexamethasone PO or IV BID (patients under 10 years old) or prednisone PO BID (patients at least 10 years old) on days 1-14, pegaspargase IV over 1-2 hours on day 4; methotrexate IT on day 8; and leucovorin calcium PO on days 10-11. Induction therapy (day 15-29): RER patients receive induction therapy comprising vincristine sulfate IV on days 15 and 22; dexamethasone PO BID or prednisone PO BID on days 15-28; methotrexate IT on day 29 (also days 15 and 22 for CNS3 pa
Population:
Pediatric
Last Update
08/23/2014 04:02 AM
 

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