LeukemiaPhase 3NCT00002812
Combination Chemotherapy in Treating Children With Acute Lymphocytic Leukemia
A Phase 3 study testing asparaginase, cyclophosphamide and cytarabine in people with Leukemia, run by Children's Oncology Group at 35 sites in 3 countries.
Trial summary
RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining more than one drug and giving the drugs in different combinations may kill more cancer cells. Read more about this study
- Who is it for?
- Ages 1 year to 21 years
- Conditions the study is for
- Leukemia
- What is being tested?
- asparaginase, cyclophosphamide and cytarabine
- Type of treatment
- Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 2,078 participants
- Where
- 35 sitesin 3 countries
- Study dates
- Sep 1996to Mar 2006
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 year to 21 years
- All sexes
- No healthy volunteers
- Child, Adult
DISEASE CHARACTERISTICS: Acute lymphocytic leukemia (ALL) with M3 bone marrow No FAB L3 morphology CNS or overt testicular leukemia at diagnosis allowed High risk status 10-21 years old with any white blood count (WBC) 1-9 years old with WBC of 50,000/mm3 or greater
PATIENT CHARACTERISTICS: Age: 1 to 21 Performance status: Not specified Life expectancy: Not specified Hematopoietic: See Disease Characteristics Hepatic: Not specified Renal: Not specified
PRIOR CONCURRENT THERAPY: No prior therapy for ALL except: Emergency therapy for blast crisis, superior vena cava syndrome, or renal failure due to leukemic infiltration Biologic therapy: Not specified Chemotherapy: Intrathecal cytarabine or methotrexate allowed at diagnostic lumbar puncture Induction therapy must begin within 72 hours after intrathecal injection Endocrine therapy: At least 1-2 months since prior prednisone, for less than 48 hours, for reactive airway disease Inhalational steroids allowed Radiotherapy: Not specified Surgery: Not specified
Trial locations and contacts
35 sites in 3 countries.
35 sites in 3 countries
United States32 sites
University of Michigan Comprehensive Cancer Center
Ann Arbor, Michigan, 48109-0752
Lineberger Comprehensive Cancer Center, UNC
Chapel Hill, North Carolina, 27599-7295
University of Chicago Cancer Research Center
Chicago, Illinois, 60637-1470
Children's Hospital Medical Center - Cincinnati
Cincinnati, Ohio, 45229-3039
Ireland Cancer Center
Cleveland, Ohio, 44106-5065
Children's Hospital of Columbus
Columbus, Ohio, 43205-2696
Children's Hospital of Denver
Denver, Colorado, 80218
University of Texas - MD Anderson Cancer Center
Houston, Texas, 77030-4009
Indiana University Cancer Center
Indianapolis, Indiana, 46202-5289
Holden Comprehensive Cancer Center at The University of Iowa
Iowa City, Iowa, 52242-1009
Children's Mercy Hospital
Kansas City, Missouri, 64108
Long Beach Memorial Medical Center
Long Beach, California, 90806
Children's Hospital Los Angeles
Los Angeles, California, 90027-0700
Jonsson Comprehensive Cancer Center, UCLA
Los Angeles, California, 90095-1781
University of Wisconsin Comprehensive Cancer Center
Madison, Wisconsin, 53792-6164
University of Minnesota Cancer Center
Minneapolis, Minnesota, 55455
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee, 37232-6838
Saint Peter's University Hospital
New Brunswick, New Jersey, 08901-1780
NYU School of Medicine's Kaplan Comprehensive Cancer Center
New York, New York, 10016
Memorial Sloan-Kettering Cancer Center
New York, New York, 10021
Mount Sinai School of Medicine
New York, New York, 10029
Herbert Irving Comprehensive Cancer Center
New York, New York, 10032
University of Nebraska Medical Center
Omaha, Nebraska, 68198-3330
Children's Hospital of Orange County
Orange, California, 92868
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, 19104
Children's Hospital of Pittsburgh
Pittsburgh, Pennsylvania, 15213
Doernbecher Children's Hospital
Portland, Oregon, 97201-3098
Mayo Clinic Cancer Center
Rochester, Minnesota, 55905
UCSF Cancer Center and Cancer Research Institute
San Francisco, California, 94143-0128
Children's Hospital and Regional Medical Center - Seattle
Seattle, Washington, 98105
Fred Hutchinson Cancer Research Center
Seattle, Washington, 98109-1024
Children's National Medical Center
Washington D.C., District of Columbia, 20010-2970
Canada2 sites
IWK Health Centre
Halifax, Nova Scotia, B3J 3G9
British Columbia Children's Hospital
Vancouver, British Columbia, V6H 3V4
Australia1 site
Princess Margaret Hospital for Children
Perth, Western Australia, 6001
About this study
Official title: Treatment of Patients With Acute Lymphoblastic Leukemia With Unfavorable Features: A Phase III Group-wide Study
RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining more than one drug and giving the drugs in different combinations may kill more cancer cells.
PURPOSE: Randomized phase III trial to compare the effectiveness of standard combination chemotherapy treatment with more intensive combination chemotherapy in treating children with acute lymphocytic leukemia.
Read the detailed description
OBJECTIVES: I. Compare the outcomes in children with higher risk acute lymphocytic leukemia (ALL) treated with postinduction chemotherapy based on marrow response on day 7 of induction therapy: for patients with rapid early response (M1/M2), standard vs intensified consolidation chemotherapy and standard vs prolonged duration of intensification chemotherapy; for patients with slow early response, addition of doxorubicin vs idarubicin and cyclophosphamide to intensification chemotherapy. II. Decrease the incidence of avascular necrosis by alternating dexamethasone dosing in patients undergoing 2 courses of delayed intensification. III. Assess the impact of day 7 marrow status on outcome in these patients. IV. Determine prognosis more precisely by supplementing presenting clinical features, immunophenotype, ploidy, cytogenetics, and early marrow response with BAX/BCL-2 ratios, pattern of tyrosine kinase activation, leukemic burden following induction and intensification therapy, and development of high antibody titer to E. coli asparaginase. V. Correlate the traditional prognostic factors of day 7 marrow response, immunophenotype, ploidy, cytogenetics, and early marrow response with BAX/BCL-2 ratios.
OUTLINE: This is a partially randomized, multicenter study. Patients are stratified by center. Patients receive one course of the VPLD regimen comprised of vincristine IV and daunorubicin IV over 15 minutes to 2 hours on days 0 and 7, oral prednisone daily on days 0-7, intrathecal cytarabine on day 0, and asparaginase or pegaspargase intramuscularly on days 3, 5, and 7. Patients are assigned to 1 of 2 two postinduction chemotherapy groups based on bone marrow response on day 7 of induction. Patients with M1/M2 marrow on day 7 are considered rapid early responders. Patients with M3 marrow on day 7 are considered slow early responders. Group 1: Rapid early responders Patients receive 2 additional courses of VPLD induction chemotherapy. Patients are then randomized to 1 of 4 treatment arms: Arm I: Beginning on day 35 of induction therapy, patients receive standard Berlin-Frankfurt-Munster (BFM) regimen with standard delayed intensification. Standard BFM for patients in arm I consists of the following: consolidation over 5 weeks with cyclophosphamide, cytarabine, and mercaptopurine; interim maintenance over 8 weeks with oral methotrexate and mercaptopurine (MTX/MP); and delayed intensification over 7 weeks consisting of reinduction with vincristine, doxorubicin, oral dexamethasone, and asparaginase or pegaspargase followed by reconsolidation with cyclophosphamide, thioguanine, and cytarabine. Arm II: Patients receive standard BFM regimen with double delayed intensification. Patients receive therapy similar to those in arm I, but dexamethasone is interrupted for 1 week during delayed intensification and the intensification regimen is repeated, separated by an 8 week interim maintenance course of oral MTX/MP. Arm III: Patients receive augmented BFM regimen with standard delayed intensification. Patients receive 9 weeks of consolidation therapy with 2 courses of vincristine and pegaspargase alternating with the arm I consolidation therapy. Vincristine, intravenous methotrexate, and pegaspargase (the Capizzi I regimen) are substituted for oral MTX/MP in the interim maintenance regimen. Pegaspargase is substituted for asparaginase and two additional doses of vincristine are administered during delayed intensification. Arm IV: Patients receive augmented BFM regimen with double delayed intensification. Patients receive intensified chemotherapy throughout, combining the additional therapy given to patients in arms II and III. Patients receiving augmented BFM regimen receive pegaspargase instead of asparaginase. Patients with CNS disease at diagnosis are treated only on arm IV. Patients who are Philadelphia chromosome positive and do not have a bone marrow donor are nonrandomly assigned to the treatment group for slow early responders. All RER patients receive the same maintenance therapy with vincristine/prednisone and oral MTX/MP. Intrathecal methotrexate is administered periodically throughout protocol treatment. Group 2: Slow early responders Patients receive augmented BFM consolidation therapy and Capizzi I interim maintenance identical to that received by rapid early responders in arm IV. Patients are then randomized to receive double delayed intensification with either idarubicin or doxorubicin and concurrent cyclophosphamide. All patients receive the same maintenance therapy with vincristine/prednisone and oral MTX/MP. Intrathecal MTX is administered periodically throughout protocol treatment. Patients with CNS disease at entry receive craniospinal irradiation daily for 5 consecutive days beginning on day 0 of consolidation therapy. All slow early responders at diagnosis receive cranial irradiation daily for 5 consecutive days during consolidation therapy. Patients with testicular leukemia at diagnosis receive bilateral testicular irradiation daily for 5 consecutive days during consolidation chemotherapy. Groups 1 and 2: Maintenance therapy continues for 2 years for girls or 3 years for boys beyond completion of consolidation therapy. Patients are followed every 4-6 weeks for 1 year, every 3 months for 1 year, every 6 months for 2 years, and then annually thereafter.
PROJECTED ACCRUAL: Approximately 1,520 patients will be accrued for this study over 4 years.
- Conditions
- Leukemia
- Being tested
- asparaginase, cyclophosphamide, cytarabine, daunorubicin hydrochloride, dexamethasone
- Keywords
- untreated childhood acute lymphoblastic leukemia, L1 childhood acute lymphoblastic leukemia, L2 childhood acute lymphoblastic leukemia
- Medical subject headings
- Leukemia, Precursor Cell Lymphoblastic Leukemia-Lymphoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
asparaginaseDrug
Also called E. coli, Elspar, NSC-109229
Given IV
cyclophosphamideDrug
Also called Cytoxan, NSC-26271
Given IV
cytarabineDrug
Also called Cytosine Arabinoside, Ara-C, Cytosar-U, NSC-63878
Given IV
daunorubicin hydrochlorideDrug
Also called Daunomycin Hydrochloride, Cerrubidine, NSC-82151
Given IV
dexamethasoneDrug
Also called Decadron, NSC-34521
Given IV
Also called Adriamycin, NSC-123127
Given IV
idarubicinDrug
Also called Idarubicin Hydrochloride, Idamycin, NSC-256439
Given IV
mercaptopurineDrug
Also called 6-MP, Purinethol, NSC-755
Given IV
methotrexateDrug
Also called NSC-740
Given PO
pegaspargaseDrug
Also called Asparaginase, Oncaspar
Given IV
prednisoneDrug
Also called NSC-10023
Given PO
thioguanineDrug
Also called 6-TG, NSC-752
Given IV
Also called Oncovin, NSC-67574
Given IV
radiation therapyRadiation
| Study group | Role | What they receive |
|---|---|---|
| Arm A - Standard BFM of Standard Duration (RER) | Experimental | Induction chemotherapy Days 0 - 7. Prednisone 60 mg/m² PO 4 x day. Vincristine sulfate 1.5 mg/m² IV push weekly x 2 Days 0 and 7. Daunomycin (daunorubicin hydrochloride) 25 mg/m² IV push (over 15 min.) weekly x 2 Days 0 and 7. IT Cytosine Arabinoside (cytarabine, Ara-C) Day 0. Asparaginase 6000 IU/m² IM x 3 Days 3, 5, and 7. Day 7 Bone Marrow. Consolidation (Phase II) (5 weeks) Prednisone Taper, cyclophosphamide, cytosine arabinoside (Ara-C), mercaptopurine, vincristine sulfate, pegaspargase, IT Methotrexate and radiation therapy. Receives: Drug: asparaginase; Drug: cyclophosphamide; Drug: cytarabine; Drug: daunorubicin hydrochloride; Drug: dexamethasone; Drug: doxorubicin hydrochloride; Drug: idarubicin; Drug: mercaptopurine; Drug: methotrexate; Drug: pegaspargase; Drug: prednisone; Drug: thioguanine; Drug: vincristine sulfate; Radiation: radiation therapy |
| Arm B - Standard BFM with Double Delayed Intensification (RER) | Experimental | Induction chemotherapy Days 0 - 7. Prednisone 60 mg/m² PO 4 x day. Vincristine sulfate 1.5 mg/m² IV push weekly x 2 Days 0 and 7. Daunomycin (daunorubicin hydrochloride) 25 mg/m² IV push (over 15 min.) weekly x 2 Days 0 and 7. IT Cytosine Arabinoside (cytarabine, Ara-C) Day 0. Asparaginase 6000 IU/m² IM x 3 Days 3, 5, and 7. Day 7 Bone Marrow Consolidation (5 weeks) (Phase II) Prednisone Taper, cyclophosphamide, cytosine arabinoside (Ara-C), mercaptopurine, vincristine sulfate, pegaspargase, IT Methotrexate and radiation therapy. Receives: Drug: asparaginase; Drug: cyclophosphamide; Drug: cytarabine; Drug: daunorubicin hydrochloride; Drug: dexamethasone; Drug: doxorubicin hydrochloride; Drug: idarubicin; Drug: mercaptopurine; Drug: methotrexate; Drug: pegaspargase; Drug: prednisone; Drug: thioguanine; Drug: vincristine sulfate; Radiation: radiation therapy |
| Arm C - Augumented BFM of Standard Duration (RER) | Experimental | Induction chemotherapy Days 0 - 7. Prednisone 60 mg/m² PO 4 x day. Vincristine sulfate 1.5 mg/m² IV push weekly x 2 Days 0 and 7. Daunomycin (daunorubicin hydrochloride) 25 mg/m² IV push (over 15 min.) weekly x 2 Days 0 and 7. IT Cytosine Arabinoside (cytarabine, Ara-C) Day 0. Asparaginase 6000 IU/m² IM x 3 Days 3, 5, and 7. Day 7 Bone Marrow Consolidation (9 weeks) (Phase II) Prednisone Taper, cyclophosphamide, cytosine arabinoside (Ara-C), mercaptopurine, vincristine sulfate, pegaspargase, IT Methotrexate and radiation therapy. Receives: Drug: asparaginase; Drug: cyclophosphamide; Drug: cytarabine; Drug: daunorubicin hydrochloride; Drug: dexamethasone; Drug: doxorubicin hydrochloride; Drug: idarubicin; Drug: mercaptopurine; Drug: methotrexate; Drug: pegaspargase; Drug: prednisone; Drug: thioguanine; Drug: vincristine sulfate; Radiation: radiation therapy |
| Arm D - Augmented BFM with Dbl Delayed Intensification (RER) | Experimental | Induction chemotherapy Days 0 - 7. Prednisone 60 mg/m² PO 4 x day. Vincristine sulfate 1.5 mg/m² IV push weekly x 2 Days 0 and 7. Daunomycin (daunorubicin hydrochloride) 25 mg/m² IV push (over 15 min.) weekly x 2 Days 0 and 7. IT Cytosine Arabinoside (cytarabine, Ara-C) Day 0. Asparaginase 6000 IU/m² IM x 3 Days 3, 5, and 7. Day 7 Bone Marrow Consolidation (9 weeks) (Phase II) Prednisone Taper, cyclophosphamide, cytosine arabinoside (Ara-C), mercaptopurine, vincristine sulfate, pegaspargase, IT Methotrexate and radiation therapy. Receives: Drug: asparaginase; Drug: cyclophosphamide; Drug: cytarabine; Drug: daunorubicin hydrochloride; Drug: dexamethasone; Drug: doxorubicin hydrochloride; Drug: idarubicin; Drug: mercaptopurine; Drug: methotrexate; Drug: pegaspargase; Drug: prednisone; Drug: thioguanine; Drug: vincristine sulfate; Radiation: radiation therapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Event Free Survival
The primary outcome index used in examining most of the randomized treatment groups will be event-free survival (EFS).
Measured: from the time of randomization where the life table events will consist of the first occurrence of the following events: failure to achieve remission, leukemic relapse at any site, death, or occurrence of a second malignancy.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Nov 2003 (estimated)
- Study startSep 1996
- Primary completionMar 2006
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (23)Papers the sponsor has linked to this study.
- Other trials for LeukemiaStudies of the same condition, open and under way.
- More trials run by Children's Oncology GroupThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 2,078 participants (actual)
Sponsor and investigators
- Lead sponsor
- Children's Oncology Group
- Sponsor type
- Research network
- Collaborators
- National Cancer Institute (NCI)
- Responsible party
- Sponsor
- Investigators
- Nita L. Seibel, MD, Study chair, Children's National Research Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00002812
- Sponsor's protocol ID
- 1961
- Other IDs
- CCG-1961, CDR0000064953
- Status last verified
- Aug 2013
- First submitted
- 1 Nov 1999
- Last updated
- 26 Aug 2013
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Nguyen K, Devidas M, Cheng SC, La M, Raetz EA, Carroll WL, Winick NJ, Hunger SP, Gaynon PS, Loh ML; Children's Oncology Group. Factors influencing survival after relapse from acute lymphoblastic leukemia: a Children's Oncology Group study. Leukemia. 2008 Dec;22(12):2142-50. doi: 10.1038/leu.2008.251. Epub 2008 Sep 25.
PubMed 18818707Butturini AM, Dorey FJ, Lange BJ, Henry DW, Gaynon PS, Fu C, Franklin J, Siegel SE, Seibel NL, Rogers PC, Sather H, Trigg M, Bleyer WA, Carroll WL. Obesity and outcome in pediatric acute lymphoblastic leukemia. J Clin Oncol. 2007 May 20;25(15):2063-9. doi: 10.1200/JCO.2006.07.7792.
PubMed 17513811Avramis VI, Panosyan EH. Pharmacokinetic/pharmacodynamic relationships of asparaginase formulations: the past, the present and recommendations for the future. Clin Pharmacokinet. 2005;44(4):367-93. doi: 10.2165/00003088-200544040-00003.
PubMed 15828851Seibel NL, Asselin BL, Nachman JB, et al.: Treatment of high risk T-cell acute lymphoblastic leukemia (T-ALL): comparison of recent experience of the Children's Cancer Group (CCG) and Pediatric Oncology Group (POG). [Abstract] Blood 104 (11): A-681, 2004.
Arce FJ, Seibel N, Gaynon PS, et al.: Pharmacokinetics and pharmacodynamics of asparaginases in antibody-negative pediatric patients with higher risk acute lymphoblastic leukemia (ALL): a report from CCG-1961. [Abstract] J Clin Oncol 24 (Suppl 18): A-9027, 508s, 2006.
Avramis VI, Ettinger L, Martin-Aragon S, et al.: Anti-asparaginase (ASNase) antibody (Ab) in pediatric patients in high risk ALL study (CCG-1961): correlation of Ab and clinical allergy. [Abstract] Proceedings of the American Society of Clinical Oncology 19: A2319, 2000.
Avramis VI, Panosyan E, Avramis IA, et al.: Anti-asparaginase (ASNase) antibody (Ab) and ASNase activity in children with higher risk acute lymphoblastic leukemia (HR ALL) (CCG-1961). [Abstract] Proceedings of the American Society of Clinical Oncology 21: A-1592, 2002.
Bhojwani D, Kang H, Menezes RX, Yang W, Sather H, Moskowitz NP, Min DJ, Potter JW, Harvey R, Hunger SP, Seibel N, Raetz EA, Pieters R, Horstmann MA, Relling MV, den Boer ML, Willman CL, Carroll WL; Children's Oncology Group Study; Dutch Childhood Oncology Group; German Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia. Gene expression signatures predictive of early response and outcome in high-risk childhood acute lymphoblastic leukemia: A Children's Oncology Group Study [corrected]. J Clin Oncol. 2008 Sep 20;26(27):4376-84. doi: 10.1200/JCO.2007.14.4519.
PubMed 18802149Dhall G, Jones T, Radvinsky D, et al.: Adverse reactions to PEG and Erwinia asparaginase and correlation with anti-asparaginase antibody data and survival in children with acute lymphoblastic leukemia (ALL): A report from the Children's Oncology Group study CCG 1961. [Abstract] Blood 114 (22): A-3077, 2009.
Dhall G, Robison NJ, Rubin JI, et al.: Incidence of adverse reactions to post-induction asparaginase (ASP) therapy in children and adolescents with high-risk acute lymphoblastic leukemia (ALL): A report from the Children's Oncology Group Study CCG-1961. [Abstract] J Clin Oncol 26 (Suppl 15): A-10021, 2008.
Freyer DR, Devidas M, La M, Carroll WL, Gaynon PS, Hunger SP, Seibel NL. Postrelapse survival in childhood acute lymphoblastic leukemia is independent of initial treatment intensity: a report from the Children's Oncology Group. Blood. 2011 Mar 17;117(11):3010-5. doi: 10.1182/blood-2010-07-294678. Epub 2010 Dec 30.
PubMed 21193696Freyer DR, Seibel NL, La MK, et al.: Survival after relapse in higher risk acute lymphoblastic leukemia (ALL) in children and adolescents is independent of prior treatment intensity: a report from the Children's Oncology Group (COG). [Abstract] Blood 112 (11): A-917, 2008.
Hastings C, Sather HN, Seibel NL, et al.: Outcomes in children and adolescents with a markedly elevated white blood cell count (>200,000) at diagnosis of high risk acute lymphoblastic leukemia (ALL): a report from the Children's Oncology Group. [Abstract] Blood 108 (11): A-1870, 2006.
Hastings C, Whitlock JA, La M, et al.: Improved outcome of children with Down syndrome (DS) and high risk acute lymphocytic leukemia (HR-ALL): a report of CCG-1961. [Abstract] Blood 110 (11): A-586, 2007.
Henze G. Early postinduction intensification therapy is essential in childhood acute lymphoblastic leukemia. Nat Clin Pract Oncol. 2008 Sep;5(9):502-3. doi: 10.1038/ncponc1184. Epub 2008 Jul 22.
PubMed 18648353
Study at a glance
From the registry record, last updated by the sponsor on 26 Aug 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Treatment of Patients With Acute Lymphoblastic Leukemia With Unfavorable Features: A Phase III Group-wide Study
- ClinicalTrials.gov ID
- NCT00002812
- Acronym / sponsor ID
- 1961
- Conditions
- Leukemia
- Keywords
- untreated childhood acute lymphoblastic leukemia, L1 childhood acute lymphoblastic leukemia, L2 childhood acute lymphoblastic leukemia
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 2,078 participants (actual)
- Lead sponsor
- Children's Oncology GroupResearch network
- Collaborators
- National Cancer Institute (NCI)
- Study start
- Sep 1996
- Primary completion
- Mar 2006 (actual)
- First posted
- 24 Nov 2003 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining more than one drug and giving the drugs in different combinations may kill more cancer cells.
PURPOSE: Randomized phase III trial to compare the effectiveness of standard combination chemotherapy treatment with more intensive combination chemotherapy in treating children with acute lymphocytic leukemia.
Detailed description
OBJECTIVES: I. Compare the outcomes in children with higher risk acute lymphocytic leukemia (ALL) treated with postinduction chemotherapy based on marrow response on day 7 of induction therapy: for patients with rapid early response (M1/M2), standard vs intensified consolidation chemotherapy and standard vs prolonged duration of intensification chemotherapy; for patients with slow early response, addition of doxorubicin vs idarubicin and cyclophosphamide to intensification chemotherapy. II. Decrease the incidence of avascular necrosis by alternating dexamethasone dosing in patients undergoing 2 courses of delayed intensification. III. Assess the impact of day 7 marrow status on outcome in these patients. IV. Determine prognosis more precisely by supplementing presenting clinical features, immunophenotype, ploidy, cytogenetics, and early marrow response with BAX/BCL-2 ratios, pattern of tyrosine kinase activation, leukemic burden following induction and intensification therapy, and development of high antibody titer to E. coli asparaginase. V. Correlate the traditional prognostic factors of day 7 marrow response, immunophenotype, ploidy, cytogenetics, and early marrow response with BAX/BCL-2 ratios.
OUTLINE: This is a partially randomized, multicenter study. Patients are stratified by center. Patients receive one course of the VPLD regimen comprised of vincristine IV and daunorubicin IV over 15 minutes to 2 hours on days 0 and 7, oral prednisone daily on days 0-7, intrathecal cytarabine on day 0, and asparaginase or pegaspargase intramuscularly on days 3, 5, and 7. Patients are assigned to 1 of 2 two postinduction chemotherapy groups based on bone marrow response on day 7 of induction. Patients with M1/M2 marrow on day 7 are considered rapid early responders. Patients with M3 marrow on day 7 are considered slow early responders. Group 1: Rapid early responders Patients receive 2 additional courses of VPLD induction chemotherapy. Patients are then randomized to 1 of 4 treatment arms: Arm I: Beginning on day 35 of induction therapy, patients receive standard Berlin-Frankfurt-Munster (BFM) regimen with standard delayed intensification. Standard BFM for patients in arm I consists of the following: consolidation over 5 weeks with cyclophosphamide, cytarabine, and mercaptopurine; interim maintenance over 8 weeks with oral methotrexate and mercaptopurine (MTX/MP); and delayed intensification over 7 weeks consisting of reinduction with vincristine, doxorubicin, oral dexamethasone, and asparaginase or pegaspargase followed by reconsolidation with cyclophosphamide, thioguanine, and cytarabine. Arm II: Patients receive standard BFM regimen with double delayed intensification. Patients receive therapy similar to those in arm I, but dexamethasone is interrupted for 1 week during delayed intensification and the intensification regimen is repeated, separated by an 8 week interim maintenance course of oral MTX/MP. Arm III: Patients receive augmented BFM regimen with standard delayed intensification. Patients receive 9 weeks of consolidation therapy with 2 courses of vincristine and pegaspargase alternating with the arm I consolidation therapy. Vincristine, intravenous methotrexate, and pegaspargase (the Capizzi I regimen) are substituted for oral MTX/MP in the interim maintenance regimen. Pegaspargase is substituted for asparaginase and two additional doses of vincristine are administered during delayed intensification. Arm IV: Patients receive augmented BFM regimen with double delayed intensification. Patients receive intensified chemotherapy throughout, combining the additional therapy given to patients in arms II and III. Patients receiving augmented BFM regimen receive pegaspargase instead of asparaginase. Patients with CNS disease at diagnosis are treated only on arm IV. Patients who are Philadelphia chromosome positive and do not have a bone marrow donor are nonrandomly assigned to the treatment group for slow early responders. All RER patients receive the same maintenance therapy with vincristine/prednisone and oral MTX/MP. Intrathecal methotrexate is administered periodically throughout protocol treatment. Group 2: Slow early responders Patients receive augmented BFM consolidation therapy and Capizzi I interim maintenance identical to that received by rapid early responders in arm IV. Patients are then randomized to receive double delayed intensification with either idarubicin or doxorubicin and concurrent cyclophosphamide. All patients receive the same maintenance therapy with vincristine/prednisone and oral MTX/MP. Intrathecal MTX is administered periodically throughout protocol treatment. Patients with CNS disease at entry receive craniospinal irradiation daily for 5 consecutive days beginning on day 0 of consolidation therapy. All slow early responders at diagnosis receive cranial irradiation daily for 5 consecutive days during consolidation therapy. Patients with testicular leukemia at diagnosis receive bilateral testicular irradiation daily for 5 consecutive days during consolidation chemotherapy. Groups 1 and 2: Maintenance therapy continues for 2 years for girls or 3 years for boys beyond completion of consolidation therapy. Patients are followed every 4-6 weeks for 1 year, every 3 months for 1 year, every 6 months for 2 years, and then annually thereafter.
PROJECTED ACCRUAL: Approximately 1,520 patients will be accrued for this study over 4 years.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Arm A - Standard BFM of Standard Duration (RER) | Experimental | Drug: asparaginase, Drug: cyclophosphamide, Drug: cytarabine, Drug: daunorubicin hydrochloride, Drug: dexamethasone, Drug: doxorubicin hydrochloride, Drug: idarubicin, Drug: mercaptopurine, Drug: methotrexate, Drug: pegaspargase, Drug: prednisone, Drug: thioguanine, Drug: vincristine sulfate, Radiation: radiation therapyInduction chemotherapy Days 0 - 7. Prednisone 60 mg/m² PO 4 x day. Vincristine sulfate 1.5 mg/m² IV push weekly x 2 Days 0 and 7. Daunomycin (daunorubicin hydrochloride) 25 mg/m² IV push (over 15 min.) weekly x 2 Days 0 and 7. IT Cytosine Arabinoside (cytarabine, Ara-C) Day 0. Asparaginase 6000 IU/m² IM x 3 Days 3, 5, and 7. Day 7 Bone Marrow. Consolidation (Phase II) (5 weeks) Prednisone Taper, cyclophosphamide, cytosine arabinoside (Ara-C), mercaptopurine, vincristine sulfate, pegaspargase, IT Methotrexate and radiation therapy. |
| Arm B - Standard BFM with Double Delayed Intensification (RER) | Experimental | Drug: asparaginase, Drug: cyclophosphamide, Drug: cytarabine, Drug: daunorubicin hydrochloride, Drug: dexamethasone, Drug: doxorubicin hydrochloride, Drug: idarubicin, Drug: mercaptopurine, Drug: methotrexate, Drug: pegaspargase, Drug: prednisone, Drug: thioguanine, Drug: vincristine sulfate, Radiation: radiation therapyInduction chemotherapy Days 0 - 7. Prednisone 60 mg/m² PO 4 x day. Vincristine sulfate 1.5 mg/m² IV push weekly x 2 Days 0 and 7. Daunomycin (daunorubicin hydrochloride) 25 mg/m² IV push (over 15 min.) weekly x 2 Days 0 and 7. IT Cytosine Arabinoside (cytarabine, Ara-C) Day 0. Asparaginase 6000 IU/m² IM x 3 Days 3, 5, and 7. Day 7 Bone Marrow Consolidation (5 weeks) (Phase II) Prednisone Taper, cyclophosphamide, cytosine arabinoside (Ara-C), mercaptopurine, vincristine sulfate, pegaspargase, IT Methotrexate and radiation therapy. |
| Arm C - Augumented BFM of Standard Duration (RER) | Experimental | Drug: asparaginase, Drug: cyclophosphamide, Drug: cytarabine, Drug: daunorubicin hydrochloride, Drug: dexamethasone, Drug: doxorubicin hydrochloride, Drug: idarubicin, Drug: mercaptopurine, Drug: methotrexate, Drug: pegaspargase, Drug: prednisone, Drug: thioguanine, Drug: vincristine sulfate, Radiation: radiation therapyInduction chemotherapy Days 0 - 7. Prednisone 60 mg/m² PO 4 x day. Vincristine sulfate 1.5 mg/m² IV push weekly x 2 Days 0 and 7. Daunomycin (daunorubicin hydrochloride) 25 mg/m² IV push (over 15 min.) weekly x 2 Days 0 and 7. IT Cytosine Arabinoside (cytarabine, Ara-C) Day 0. Asparaginase 6000 IU/m² IM x 3 Days 3, 5, and 7. Day 7 Bone Marrow Consolidation (9 weeks) (Phase II) Prednisone Taper, cyclophosphamide, cytosine arabinoside (Ara-C), mercaptopurine, vincristine sulfate, pegaspargase, IT Methotrexate and radiation therapy. |
| Arm D - Augmented BFM with Dbl Delayed Intensification (RER) | Experimental | Drug: asparaginase, Drug: cyclophosphamide, Drug: cytarabine, Drug: daunorubicin hydrochloride, Drug: dexamethasone, Drug: doxorubicin hydrochloride, Drug: idarubicin, Drug: mercaptopurine, Drug: methotrexate, Drug: pegaspargase, Drug: prednisone, Drug: thioguanine, Drug: vincristine sulfate, Radiation: radiation therapyInduction chemotherapy Days 0 - 7. Prednisone 60 mg/m² PO 4 x day. Vincristine sulfate 1.5 mg/m² IV push weekly x 2 Days 0 and 7. Daunomycin (daunorubicin hydrochloride) 25 mg/m² IV push (over 15 min.) weekly x 2 Days 0 and 7. IT Cytosine Arabinoside (cytarabine, Ara-C) Day 0. Asparaginase 6000 IU/m² IM x 3 Days 3, 5, and 7. Day 7 Bone Marrow Consolidation (9 weeks) (Phase II) Prednisone Taper, cyclophosphamide, cytosine arabinoside (Ara-C), mercaptopurine, vincristine sulfate, pegaspargase, IT Methotrexate and radiation therapy. |
Who may qualify
- Ages
- 1 year to 21 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| asparaginaseAlso: E. coli, Elspar, NSC-109229Given IV | Drug | Arm A - Standard BFM of Standard Duration (RER), Arm B - Standard BFM with Double Delayed Intensification (RER), Arm C - Augumented BFM of Standard Duration (RER), Arm D - Augmented BFM with Dbl Delayed Intensification (RER) |
| cyclophosphamideAlso: Cytoxan, NSC-26271Given IV | Drug | Arm A - Standard BFM of Standard Duration (RER), Arm B - Standard BFM with Double Delayed Intensification (RER), Arm C - Augumented BFM of Standard Duration (RER), Arm D - Augmented BFM with Dbl Delayed Intensification (RER) |
| cytarabineAlso: Cytosine Arabinoside, Ara-C, Cytosar-U, NSC-63878Given IV | Drug | Arm A - Standard BFM of Standard Duration (RER), Arm B - Standard BFM with Double Delayed Intensification (RER), Arm C - Augumented BFM of Standard Duration (RER), Arm D - Augmented BFM with Dbl Delayed Intensification (RER) |
| daunorubicin hydrochlorideAlso: Daunomycin Hydrochloride, Cerrubidine, NSC-82151Given IV | Drug | Arm A - Standard BFM of Standard Duration (RER), Arm B - Standard BFM with Double Delayed Intensification (RER), Arm C - Augumented BFM of Standard Duration (RER), Arm D - Augmented BFM with Dbl Delayed Intensification (RER) |
| dexamethasoneAlso: Decadron, NSC-34521Given IV | Drug | Arm A - Standard BFM of Standard Duration (RER), Arm B - Standard BFM with Double Delayed Intensification (RER), Arm C - Augumented BFM of Standard Duration (RER), Arm D - Augmented BFM with Dbl Delayed Intensification (RER) |
| doxorubicin hydrochlorideAlso: Adriamycin, NSC-123127Given IV | Drug | Arm A - Standard BFM of Standard Duration (RER), Arm B - Standard BFM with Double Delayed Intensification (RER), Arm C - Augumented BFM of Standard Duration (RER), Arm D - Augmented BFM with Dbl Delayed Intensification (RER) |
| idarubicinAlso: Idarubicin Hydrochloride, Idamycin, NSC-256439Given IV | Drug | Arm A - Standard BFM of Standard Duration (RER), Arm B - Standard BFM with Double Delayed Intensification (RER), Arm C - Augumented BFM of Standard Duration (RER), Arm D - Augmented BFM with Dbl Delayed Intensification (RER) |
| mercaptopurineAlso: 6-MP, Purinethol, NSC-755Given IV | Drug | Arm A - Standard BFM of Standard Duration (RER), Arm B - Standard BFM with Double Delayed Intensification (RER), Arm C - Augumented BFM of Standard Duration (RER), Arm D - Augmented BFM with Dbl Delayed Intensification (RER) |
| methotrexateAlso: NSC-740Given PO | Drug | Arm A - Standard BFM of Standard Duration (RER), Arm B - Standard BFM with Double Delayed Intensification (RER), Arm C - Augumented BFM of Standard Duration (RER), Arm D - Augmented BFM with Dbl Delayed Intensification (RER) |
| pegaspargaseAlso: Asparaginase, OncasparGiven IV | Drug | Arm A - Standard BFM of Standard Duration (RER), Arm B - Standard BFM with Double Delayed Intensification (RER), Arm C - Augumented BFM of Standard Duration (RER), Arm D - Augmented BFM with Dbl Delayed Intensification (RER) |
| prednisoneAlso: NSC-10023Given PO | Drug | Arm A - Standard BFM of Standard Duration (RER), Arm B - Standard BFM with Double Delayed Intensification (RER), Arm C - Augumented BFM of Standard Duration (RER), Arm D - Augmented BFM with Dbl Delayed Intensification (RER) |
| thioguanineAlso: 6-TG, NSC-752Given IV | Drug | Arm A - Standard BFM of Standard Duration (RER), Arm B - Standard BFM with Double Delayed Intensification (RER), Arm C - Augumented BFM of Standard Duration (RER), Arm D - Augmented BFM with Dbl Delayed Intensification (RER) |
| vincristine sulfateAlso: Oncovin, NSC-67574Given IV | Drug | Arm A - Standard BFM of Standard Duration (RER), Arm B - Standard BFM with Double Delayed Intensification (RER), Arm C - Augumented BFM of Standard Duration (RER), Arm D - Augmented BFM with Dbl Delayed Intensification (RER) |
| radiation therapy | Radiation | Arm A - Standard BFM of Standard Duration (RER), Arm B - Standard BFM with Double Delayed Intensification (RER), Arm C - Augumented BFM of Standard Duration (RER), Arm D - Augmented BFM with Dbl Delayed Intensification (RER) |
Primary outcome
Event Free Survival
Time frame: from the time of randomization where the life table events will consist of the first occurrence of the following events: failure to achieve remission, leukemic relapse at any site, death, or occurrence of a second malignancy.
The primary outcome index used in examining most of the randomized treatment groups will be event-free survival (EFS).
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Aug 2013.
- Background: PubMed 18818707Nguyen K, Devidas M, Cheng SC, La M, Raetz EA, Carroll WL, Winick NJ, Hunger SP, Gaynon PS, Loh ML; Children's Oncology Group. Factors influencing survival after relapse from acute lymphoblastic leukemia: a Children's Oncology Group study. Leukemia. 2008 Dec;22(12):2142-50. doi: 10.1038/leu.2008.251. Epub 2008 Sep 25.
- Background: PubMed 17513811Butturini AM, Dorey FJ, Lange BJ, Henry DW, Gaynon PS, Fu C, Franklin J, Siegel SE, Seibel NL, Rogers PC, Sather H, Trigg M, Bleyer WA, Carroll WL. Obesity and outcome in pediatric acute lymphoblastic leukemia. J Clin Oncol. 2007 May 20;25(15):2063-9. doi: 10.1200/JCO.2006.07.7792.
- Background: PubMed 15828851Avramis VI, Panosyan EH. Pharmacokinetic/pharmacodynamic relationships of asparaginase formulations: the past, the present and recommendations for the future. Clin Pharmacokinet. 2005;44(4):367-93. doi: 10.2165/00003088-200544040-00003.
- BackgroundSeibel NL, Asselin BL, Nachman JB, et al.: Treatment of high risk T-cell acute lymphoblastic leukemia (T-ALL): comparison of recent experience of the Children's Cancer Group (CCG) and Pediatric Oncology Group (POG). [Abstract] Blood 104 (11): A-681, 2004.
- Results publicationArce FJ, Seibel N, Gaynon PS, et al.: Pharmacokinetics and pharmacodynamics of asparaginases in antibody-negative pediatric patients with higher risk acute lymphoblastic leukemia (ALL): a report from CCG-1961. [Abstract] J Clin Oncol 24 (Suppl 18): A-9027, 508s, 2006.
- Results publicationAvramis VI, Ettinger L, Martin-Aragon S, et al.: Anti-asparaginase (ASNase) antibody (Ab) in pediatric patients in high risk ALL study (CCG-1961): correlation of Ab and clinical allergy. [Abstract] Proceedings of the American Society of Clinical Oncology 19: A2319, 2000.
- Results publicationAvramis VI, Panosyan E, Avramis IA, et al.: Anti-asparaginase (ASNase) antibody (Ab) and ASNase activity in children with higher risk acute lymphoblastic leukemia (HR ALL) (CCG-1961). [Abstract] Proceedings of the American Society of Clinical Oncology 21: A-1592, 2002.
- Results publication: PubMed 18802149Bhojwani D, Kang H, Menezes RX, Yang W, Sather H, Moskowitz NP, Min DJ, Potter JW, Harvey R, Hunger SP, Seibel N, Raetz EA, Pieters R, Horstmann MA, Relling MV, den Boer ML, Willman CL, Carroll WL; Children's Oncology Group Study; Dutch Childhood Oncology Group; German Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia. Gene expression signatures predictive of early response and outcome in high-risk childhood acute lymphoblastic leukemia: A Children's Oncology Group Study [corrected]. J Clin Oncol. 2008 Sep 20;26(27):4376-84. doi: 10.1200/JCO.2007.14.4519.
- Results publicationDhall G, Jones T, Radvinsky D, et al.: Adverse reactions to PEG and Erwinia asparaginase and correlation with anti-asparaginase antibody data and survival in children with acute lymphoblastic leukemia (ALL): A report from the Children's Oncology Group study CCG 1961. [Abstract] Blood 114 (22): A-3077, 2009.
- Results publicationDhall G, Robison NJ, Rubin JI, et al.: Incidence of adverse reactions to post-induction asparaginase (ASP) therapy in children and adolescents with high-risk acute lymphoblastic leukemia (ALL): A report from the Children's Oncology Group Study CCG-1961. [Abstract] J Clin Oncol 26 (Suppl 15): A-10021, 2008.
- Results publication: PubMed 21193696Freyer DR, Devidas M, La M, Carroll WL, Gaynon PS, Hunger SP, Seibel NL. Postrelapse survival in childhood acute lymphoblastic leukemia is independent of initial treatment intensity: a report from the Children's Oncology Group. Blood. 2011 Mar 17;117(11):3010-5. doi: 10.1182/blood-2010-07-294678. Epub 2010 Dec 30.
- Results publicationFreyer DR, Seibel NL, La MK, et al.: Survival after relapse in higher risk acute lymphoblastic leukemia (ALL) in children and adolescents is independent of prior treatment intensity: a report from the Children's Oncology Group (COG). [Abstract] Blood 112 (11): A-917, 2008.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Nita L. Seibel, MD study chair
Children's National Research Institute
35 sites in 3 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing asparaginase, cyclophosphamide and cytarabine in people with Leukemia, run by Children's Oncology Group at 35 sites in 3 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 26 Aug 2013. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 35 sites in United States, Canada, Australia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Event Free Survival (time frame: from the time of randomization where the life table events will consist of the first occurrence of the following events: failure to achieve remission, leukemic relapse at any site, death, or occurrence of a second malignancy.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00002812, which also lists 23 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Aug 2013.