Induction Intensification in Treating Infants With Newly Diagnosed Acute Lymphoblastic Leukemia

• ClinicalTrials.gov Identifier: NCT00002756
• Recruitment Status: Completed
• First Posted: January 27, 2003
• Last Update Posted: February 14, 2014
• Sponsor: Children's Oncology Group
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Children's Oncology Group

Tracking Information

• First Submitted Date: November 1, 1999
• First Posted Date: January 27, 2003
• Last Update Posted Date: February 14, 2014
• Study Start Date: June 1996
• Actual Primary Completion Date: September 2007 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 8, 2007)

• Feasibility of intensification
• Event-free survival
• Comparison of event-free survival rates in infants with and without leukemic blasts translocations

• Original Primary Outcome Measures: Not Provided

Current Secondary Outcome Measures (submitted: August 8, 2007)

• Correlation of minimal residual disease at completion of induction, beginning of continuation, and at completion of therapy with patient outcome
• Clinical prognostic features associated with outcome
• Correlation of biologic characteristics of leukemia cells at diagnosis with outcome
• Patterns of gene expression

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Induction Intensification in Treating Infants With Newly Diagnosed Acute Lymphoblastic Leukemia
• Official Title: Induction Intensification in Infant ALL: A Children's Oncology Group Study

Brief Summary

RATIONALE: Drugs used in chemotherapy work in different ways to stop cancer cells from dividing so they stop growing or die. Combining more than one chemotherapy drug and giving them as induction intensification may kill more cancer cells.

PURPOSE: This phase II trial is studying how well induction intensification works in treating infants with newly diagnosed acute lymphocytic leukemia.

Detailed Description

OBJECTIVES:

Primary

• Assess the feasibility of intensification with two courses of high-dose methotrexate followed by one course of cyclophosphamide/etoposide during induction and later as consolidation in infants with newly diagnosed acute lymphoblastic leukemia.
• Determine event-free survival after shortened, intensive therapy in these patients.
• Compare event-free survival rates of infants receiving this regimen whose leukemic blasts have or do not have translocations involving the 11q23 gene MLL.

Secondary

• Correlate the presence of minimal residual disease at completion of induction, beginning of continuation, and at completion of therapy with patient outcome.
• Investigate the clinical prognostic features that may be associated with outcome in infants, such as bone marrow blast content at day 8, white blood cell count, and age.
• Correlate biologic characteristics of the leukemia cells at diagnosis (protocol POG-9900) with outcome in patients treated with this regimen.
• Characterize patterns of gene expression associated with host and disease characteristics and treatment response in patients treated with this regimen.

OUTLINE: This is a multicenter study. Patients are stratified according to participating center and presence of CNS disease (yes vs no).

Patients receive induction chemotherapy comprising vincristine IV on days 1, 8, and 15; oral prednisone three times a day on days 1-21; daunorubicin IV over 30 minutes on days 1-2; cyclophosphamide IV over 30 minutes every 12 hours on days 3-4; and asparaginase intramuscularly (IM) on days 4, 6, 8, 10, 12, 15, 17, and 19. Patients also receive triple intrathecal therapy comprising methotrexate, hydrocortisone, and cytarabine on days 1, 8, and 15 and filgrastim (G-CSF) subcutaneously (SC) or IV beginning on day 5 and continuing until day 20, regardless of blood counts.

Patients receive induction intensification chemotherapy comprising high-dose methotrexate IV over 24 hours; triple intrathecal therapy as per induction therapy on days 22 and 29; and leucovorin calcium IV every 6 hours for 2 doses beginning 42 hours after start of high-dose methotrexate and then orally every 6 hours for 3 doses. Patients also receive etoposide IV over 2 hours and cyclophosphamide IV over 30 minutes on days 36-40. Patients receive G-CSF SC or IV beginning on day 41 and continuing until blood counts recover.

Patients achieving morphologic remission and recovery of blood counts while off G-CSF for 48 hours receive reinduction chemotherapy comprising the same regimen as in induction therapy with the exception of asparaginase IM beginning on day 1 (week 8) and continuing every Monday, Wednesday, and Friday for a total of 8 doses and triple intrathecal therapy on days 1 and 15 only (weeks 8 and 10). Patients receive G-CSF SC or IV beginning on day 5 and continuing until blood counts recover.

After blood count recovery, patients receive consolidation chemotherapy comprising triple intrathecal therapy as per induction therapy on day 1 (week 11); high-dose methotrexate IV over 24 hours on weeks 8 and 12; and leucovorin calcium IV every 6 hours for 2 doses beginning 42 hours after start of high-dose methotrexate and then orally every 6 hours for 3 doses. Patients also receive etoposide IV over 2 hours followed by cyclophosphamide IV over 30 minutes on days 15-19 (week 13). Patients receive G-CSF SC or IV beginning on day 20 and continuing until blood counts recover. On days 29-31 (week 15), patients receive high-dose cytarabine IV over 3 hours every 12 hours for 4 doses and asparaginase IM 6 hours after completion of high-dose cytarabine. Patients receive G-CSF beginning 24 hours after completion of asparaginase and continuing until blood counts recover.

Patients achieving morphologic remission and blood count recovery while off G-CSF for 48 hours receive continuation therapy comprising vincristine IV on day 1; oral prednisone three times a day on days 1-5; and triple intrathecal therapy on day 1 (weeks 18 and 22). Patients also receive methotrexate IM once a week and oral mercaptopurine daily on weeks 19-21, 23, and 24. On week 25, patients receive etoposide IV over 2 hours daily followed by cyclophosphamide IV over 30 minutes daily on days 1-5 and G-CSF SC or IV beginning on day 6 and continuing until blood counts recover. Patients receive an additional course of continuation therapy on weeks 28-35. On weeks 38-48, patients receive another identical course of continuation therapy with the exclusion of the etoposide and cyclophosphamide combination regimen.

Patients are followed monthly for 1 year, every 2 months for 1 year, every 3 months for 1 year, every 6 months for 1 year, and then annually thereafter.

PROJECTED ACCRUAL: Approximately 58-104 patients will be accrued for this study within 2.1 years.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Leukemia

Intervention

• Biological: filgrastim
• Drug: asparaginase
• Drug: cyclophosphamide
• Drug: cytarabine
• Drug: daunorubicin hydrochloride
• Drug: etoposide
• Drug: leucovorin calcium
• Drug: mercaptopurine
• Drug: methotrexate
• Drug: prednisone
• Drug: therapeutic hydrocortisone
• Drug: vincristine sulfate

Study Arms

Experimental: Chemo (Reduced Induction) No BMT (Open February 2004)

Interventions:

• Biological: filgrastim
• Drug: asparaginase
• Drug: cyclophosphamide
• Drug: cytarabine
• Drug: daunorubicin hydrochloride
• Drug: etoposide
• Drug: leucovorin calcium
• Drug: mercaptopurine
• Drug: methotrexate
• Drug: prednisone
• Drug: therapeutic hydrocortisone
• Drug: vincristine sulfate

Publications *

• Dreyer ZE, Dinndorf PA, Camitta B, Sather H, La MK, Devidas M, Hilden JM, Heerema NA, Sanders JE, McGlennen R, Willman CL, Carroll AJ, Behm F, Smith FO, Woods WG, Godder K, Reaman GH. Analysis of the role of hematopoietic stem-cell transplantation in infants with acute lymphoblastic leukemia in first remission and MLL gene rearrangements: a report from the Children's Oncology Group. J Clin Oncol. 2011 Jan 10;29(2):214-22. doi: 10.1200/JCO.2009.26.8938. Epub 2010 Dec 6.
• Fernandez CV, Kodish E, Taweel S, Shurin S, Weijer C; Children's Oncology Group. Disclosure of the right of research participants to receive research results: an analysis of consent forms in the Children's Oncology Group. Cancer. 2003 Jun 1;97(11):2904-9. doi: 10.1002/cncr.11391.
• Kang H, Wilson CS, Harvey RC, Chen IM, Murphy MH, Atlas SR, Bedrick EJ, Devidas M, Carroll AJ, Robinson BW, Stam RW, Valsecchi MG, Pieters R, Heerema NA, Hilden JM, Felix CA, Reaman GH, Camitta B, Winick N, Carroll WL, Dreyer ZE, Hunger SP, Willman CL. Gene expression profiles predictive of outcome and age in infant acute lymphoblastic leukemia: a Children's Oncology Group study. Blood. 2012 Feb 23;119(8):1872-81. doi: 10.1182/blood-2011-10-382861. Epub 2011 Dec 30.
• Salzer WL, Jones TL, Devidas M, Hilden JM, Winick N, Hunger S, Carroll WL, Camitta B, Dreyer ZE. Modifications to induction therapy decrease risk of early death in infants with acute lymphoblastic leukemia treated on Children's Oncology Group P9407. Pediatr Blood Cancer. 2012 Nov;59(5):834-9. doi: 10.1002/pbc.24132. Epub 2012 Apr 5.
• Robinson BW, Devidas M, Carroll AJ, et al.: Specific MLL partner genes in infant acute lymphoblastic leukemia (ALL) associated with outcome are linked to age and white blood cell count (WBC) at diagnosis: A report on the Children's Oncology Group (COG) P9407 trial. [Abstract] Blood 114 (22): A-907, 2009.
• Thompson PA, Murry DJ, Rosner GL, Lunagomez S, Blaney SM, Berg SL, Camitta BM, Dreyer ZE, Bomgaars LR. Methotrexate pharmacokinetics in infants with acute lymphoblastic leukemia. Cancer Chemother Pharmacol. 2007 May;59(6):847-53. doi: 10.1007/s00280-006-0388-1. Epub 2006 Nov 29.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 12, 2014): 221
• Original Enrollment: Not Provided
• Actual Study Completion Date: March 2012
• Actual Primary Completion Date: September 2007 (Final data collection date for primary outcome measure)

Eligibility Criteria

DISEASE CHARACTERISTICS:

• Newly diagnosed acute lymphoblastic leukemia (ALL) or acute undifferentiated leukemia

  • No infants less than 36 weeks' gestation
  • CNS or testicular disease permitted
• No B-cell ALL or acute myeloid leukemia

• Previously untreated except for the following:

  • Steroid treatment within 48 hours of diagnosis allowed with physical examination and differential CBC immediately prior to beginning steroids
• Concurrent registration on protocol POG-9900 (ALL classification study) required
• Patients registered on POG-9407 are eligible for the pharmacokinetic part of the study

PATIENT CHARACTERISTICS:

Age:

• Under 1 at diagnosis

Performance status:

• Not specified

Life expectancy:

• Not specified

Hematopoietic:

• Not specified

Hepatic:

• Not specified

Renal:

• Not specified

Other:

• No uncontrolled infection
• Adequate major organ function

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Not specified

Chemotherapy:

• Not specified

Endocrine therapy:

• See Disease Characteristics
• No concurrent chronic steroid treatment

Radiotherapy:

• Not specified

Surgery:

• Not specified

Other:

• No other concurrent anticancer therapy

Sex/Gender

• Sexes Eligible for Study: All

• Ages: up to 1 Year (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Canada, Switzerland, United States
• Removed Location Countries: Netherlands, New Zealand, Puerto Rico

Administrative Information

• NCT Number: NCT00002756
• Other Study ID Numbers: P9407; COG-P9407 ( Other Identifier: Children's Oncology Group ); POG-9407 ( Other Identifier: Pediatric Oncology Group ); CDR0000064693 ( Other Identifier: Clinical Trials.gov )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Children's Oncology Group
• Original Responsible Party: Not Provided
• Current Study Sponsor: Children's Oncology Group
• Original Study Sponsor: Same as current
• Collaborators: National Cancer Institute (NCI)

Investigators

• Study Chair: Zoann E. Dreyer, MD; Texas Children's Cancer Center

• PRS Account: Children's Oncology Group
• Verification Date: February 2014