LeukemiaPhase 2/3NCT01228331
Clofarabine or High-Dose Cytarabine and Pegaspargase in Children with ALL
A Phase 2/3 study testing Amsacrine, Clofarabine and Cyclophosphamide in people with Leukemia, run by Universitätsklinikum Hamburg-Eppendorf at 14 sites in Germany.
Trial summary
RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than once drug (combination chemotherapy) may kill more cancer cells. Radiation therapy uses high-energy x-rays to kill cancer cells. Read more about this study
- Who is it for?
- Ages 1 year to 17 years
- Conditions the study is for
- Leukemia
- What is being tested?
- Amsacrine, Clofarabine and Cyclophosphamide
- Type of treatment
- Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 745 participants
- Where
- 14 sitesGermany
- Study dates
- Oct 2010to 20 Nov 2024
- Phase
- Phase 2/3
- 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 17 years
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- diagnosis after the first and before the 18th birthday AND confirmed diagnosis of acute B-precursor or or T-cell leukemia AND parents or guardians/patients give consent for inclusion in the study and transmission of data AND if none of exclusion criteria is accomplished
Who cannot join
- BCR/ABL rearrangement positive OR prior cytostatic treatment lasting > 7 days or prior treatment with cytostatic drugs other than vincristine, daunorubicin and prednisone OR prior severe illnesses which make treatment per the protocol impossible from the outset (BUT trisomy 21 is not an exclusion criterion) OR absence of the baseline data required for assignment to a risk group in accordance with the protocol (BUT patients for whom the MRD value could not be determined for technical reasons will be treated as protocol patients) OR the disease is a secondary malignancy or relapse OR death before the start of treatment
Trial locations and contacts
14 sites in 1 country.
14 sites in 1 country
Germany14 sites
Krankenanstalten Gilead gCmbH Neurochirurgische Klinik
Bielefeld, 33617
Klinikum Bremen-Mitte
Bremen, D-28205
Universitaetsklinikum Duesseldorf
Düsseldorf, D-40225
Klinik und Poliklinik Fuer Kinder-und Jugendmedizin - Universitaetsklinikum Greifswald
Greifswald, 17487
University Medical Center Hamburg - Eppendorf
Hamburg, D-20246
Clinic for Bone Marrow Transplantation and Hematology and Oncology
Idar-Oberstein, D-55743
Klinikum Krefeld GmbH
Krefeld, D-47805
Universitaets - Kinderklinik
Leipzig, D-04317
Johannes Gutenberg University
Mainz, D-55101
Dr. von Haunersches Kinderspital der Universitaet Muenchen
Munich, D-80337
Staedtisches Krankenhaus Muenchen - Harlaching
Munich, D-81545
Klinik St. Hedwig-Kinderklinik
Regensburg, 93049
Dr. Horst-Schmidt-Kliniken
Wiesbaden, D-65199
Helios Kliniken Wuppertal University Hospital
Wuppertal, D-42283
About this study
Official title: A Randomized Multi-Center Treatment Study (COALL 08-09) to Improve the Survival of Children with Acute Lymphoblastic Leukemia on Behalf of the German Society of Pediatric Hematology and Oncology
RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than once drug (combination chemotherapy) may kill more cancer cells. Radiation therapy uses high-energy x-rays to kill cancer cells. It is not yet known whether giving clofarabine or high-dose cytarabine, pegaspargase, and combination chemotherapy followed by daunorubicin hydrochloride or doxorubicin hydrochloride is more effective in treating young patients with acute lymphoblastic leukemia.
PURPOSE: This randomized phase II/III trial is studying the side effects of giving clofarabine compared with giving high-dose cytarabine, pegaspargase, and combination chemotherapy followed by daunorubicin hydrochloride or doxorubicin hydrochloride and to see how well it works in treating young patients with T-cell acute lymphoblastic leukemia or precursor B-cell acute lymphoblastic leukemia.
Read the detailed description
OBJECTIVES:
Primary
- To investigate the safety and efficacy of clofarabine combined with pegaspargase in patients with high-risk acute lymphoblastic leukemia during the first phase of the study. (Phase II)
- To investigate, in terms of minimal-residual disease (MRD), the cytotoxic efficacy of clofarabine compared with high-dose cytarabine in combination with pegaspargase in these patients. (Phase III)
- To compare the incidence of infectious complications after the administration of daunorubicin hydrochloride versus doxorubicin hydrochloride during reinduction.
Secondary
- To compare the safety profiles of clofarabine and pegaspargase versus high-dose cytarabine and pegaspargase in these patients.
- To compare, in terms of MRD, the efficacy of clofarabine and pegaspargase and high-dose cytarabine and pegaspargase, respectively, versus methotrexate, cyclophosphamide, and asparaginase in study GER-COALL-07-03, the historical control group (retrospective comparison).
- To determine the influence of MRD-based stratification in COALL-09 on overall survival and event-free survival in a historical comparison of previous COALL studies.
OUTLINE: This is a multicenter, sequential phase II/III study. Patients are stratified to low risk (LR) or high risk (HR) depending on peripheral white blood cell count on diagnosis, age on diagnosis, and immunological subtype. Patients undergo 2 randomizations (1 during intensification and 1 during reinduction) in the study.
- Preliminary treatment: All patients receive daunorubicin hydrochloride IV over 24 hours on day -7 and methotrexate intrathecally (IT) once on day -9, -8, or -7.
- Induction: All patients receive vincristine IV on days 1, 8, 15, and 22; daunorubicin hydrochloride IV over 24 hours on days 1, 8, and 15; and oral prednisone 3-4 times daily on days 1-28.
Patients are assessed for minimal-residual disease (MRD) status after induction phase. Patients not in remission on day 29 are treated off study. Patients with LR disease are further stratified to LR-reduced (LR-R), LR-standard (LR-S), and LR-intensified (LR-I) groups; patients with HR disease are further stratified to HR-reduced (HR-R), HR-standard (HR-S), and HR-intensified (HR-I) groups. Patients in the LR-R and HR-R groups do not undergo randomization during study.
- Intensification (randomization 1): Patients receive therapy according to risk and disease subtypes. Some patients in different risk group are randomized* to receive high-dose (HD) cytarabine and pegaspargase or clofarabine and pegaspargase.
- LR-R and LR-S: Patients receive medium-high-dose (mHD) methotrexate IV over 24 hours on days 50, 64, and 78; etoposide phosphate IV over 1-2 hours and cytarabine IV over 1 hour on day 66; oral mercaptopurine on days 50-56 and 78-120; oral thioguanine on days 64-70; and methotrexate IT on days 29, 50, 64, and 78. Patients in LR-S group who still have a detectable MRD load on day 29 are randomized (randomization 1) to 1 of 2 arms to receive cytarabine and pegaspargase vs. clofarabine and pegaspargase.
- Arm I (cytarabine and pegaspargase) Patients receive HD cytarabine IV over 3 hours twice daily on days 29-31 and pegaspargase IV over 2 hours on days 31, 52, and 80.
- Arm II (clofarabine and pegaspargase) Patients receive clofarabine IV over 2 hours on days 29-33 and pegaspargase IV over 2 hours on days 33, 52, and 80.
- LR-I and precursor B-cell acute lymphoblastic leukemia (ALL) HR-S and HR-I: Patients receive cyclophosphamide IV over 30 minutes on days 50 and 64; mHD IV over 24 hours on days 51, 65, 78, and 92; etoposide phosphate IV over 1-2 hours and cytarabine IV over 1 hour on days 80 and 94; oral mercaptopurine on days 64-70 and 92-98; oral thioguanine on days 78-84; and methotrexate IT on days 29, 51, 65, 78, and 92. All precursor B-cell ALL patients with a detectable MRD load on day 29 and T-cell ALL patients with an MRD load ≥ 10³ on day 29 are randomized* (randomization 1) to 1 of 2 arms to receive cytarabine and pegaspargase vs. clofarabine and pegaspargase.
- Arm I (cytarabine and pegaspargase) Patients receive HD cytarabine IV over 3 hours twice daily on days 29-31 and 106-108 and pegaspargase IV over 2 hours on days 31, 53, 67, and 108.
- Arm II (clofarabine and pegaspargase) Patients receive clofarabine* IV over 2 hours on days 29-33 and pegaspargase IV over 2 hours on days 33, 53, 67, and 108.
- NOTE: *In phase II, all patients with an MRD load of ≥ 104 (on day 29) receive clofarabine and pegaspargase without randomization.
- T-cell ALL HR (HR-R, HR-S, and HR-I): Patients receive cyclophosphamide IV over 30 minutes on days 29 and 64; mHD methotrexate IV over 24 hours on days 30, 65, 78, and 92; etoposide phosphate IV over 1-2 hours and cytarabine IV over 1 hour on days 80 and 94; oral mercaptopurine on days 64-70 and 92-98; oral thioguanine on days 78-84; and methotrexate IT on days 30, 43, 65, 78, and 92. Patients in HR-S and HR-I group are randomized* (randomization 1) to 1 of 2 arms to receive cytarabine and pegaspargase vs. clofarabine and pegaspargase.
- Arm I (cytarabine and pegaspargase): Patients receive HD cytarabine IV over 3 hours twice daily on days 43-45 and 106-108 and pegaspargase IV over 2 hours on days 32, 45, 67, and 108.
- Arm II (clofarabine and pegaspargase): Patients receive clofarabine IV over 2 hours on days 43-47 and pegaspargase IV over 2 hours on days 32, 47, 67, and 108.
Patients in HR-I group also receive amsacrine IV over 4 hours and etoposide phosphate IV over 2 hours on days 127 and 128, methylprednisolone IV over 30 minutes on days 127-130, and methotrexate IT on day 127, at the end of intensification.
NOTE: *In phase II, all patients with an MRD load of ≥ 103 (on day 43) receive clofarabine and pegaspargase without randomization.
- CNS therapy: All patients with initial CNS involvement undergo cranial radiotherapy for a total of 12 or 18 Gy. HR patients (precursor B-cell ALL with initial WBC count ≥ 200/nL and T-cell ALL with initial WBC count ≥ 100/nL) with no initial CNS involvement also undergo cranial radiotherapy for a total of 12 Gy, beginning 2-3 weeks after the last dose of HD cytarabine or clofarabine. LR patients and HR patients (precursor B-cell ALL with initial WBC count < 200/nL and T-cell ALL with initial WBC count < 100/nL) with no initial CNS involvement do not receive initial cranial radiotherapy. At the beginning of CNS therapy, before cranial radiotherapy, HR-I patients receive vincristine IV on day 1; doxorubicin hydrochloride IV over 24 hours on day 1; oral dexamethasone 3 times daily on days 1-7; and pegaspargase IV over 2 hours on day 7.
All patients receive interim therapy comprising 3 doses (2 in week 1 and 1 in week 3) of methotrexate IT and oral mercaptopurine daily during the 4 weeks between intensification and reinduction.
- Reinduction (randomization 2): Patients undergo reinduction immediately after completion of interim therapy. Patients in LR-S, LR-I, HR-S, and HR-I groups are randomized to 1 of 2 arms (doxorubicin hydrochloride vs. daunorubicin hydrochloride)
- LR-S: Patients receive vincristine IV on days 1 and 8, oral dexamethasone on days 1-14, pegaspargase IV over 2 hours on day 9, cyclophosphamide IV over 30 minutes on day 22, cytarabine IV or intramuscularly (IM) on days 23-26, oral thioguanine on days 22-28, and methotrexate IT on days 1, 22, and 36.
- Arm III (doxorubicin hydrochloride) Patients receive doxorubicin hydrochloride IV over 24 hours on days 1 and 8.
- Arm IV (daunorubicin hydrochloride): Patients receive daunorubicin hydrochloride IV over 24 hours on days 1 and 8.
- LR-R and HR-R: Patients are not randomized. They receive vincristine IV on days 1 and 8, oral dexamethasone on days 1-14, pegaspargase IV over 2 hours on day 8, and methotrexate IT on days 1 and 15.
- LR-I, HR-S, and HR-I: Patients receive vincristine IV on days 1, 8, 22, and 29; oral dexamethasone twice daily on days 1-14 and 22-35; cyclophosphamide IV over 30 minutes on days 43 and 57; cytarabine IV or IM on days 43-46 and 57-60; oral thioguanine on days 43-49 and 57-63; and methotrexate IT* on days 1, 22, and 43.
- Arm III (doxorubicin hydrochloride) Patients receive doxorubicin hydrochloride IV over 24 hours on days 1, 8, 22, and 29.
- Arm IV (daunorubicin hydrochloride) Patients receive daunorubicin hydrochloride IV over 24 hours on days 1, 8, 22, and 29.
NOTE: *Patients who underwent cranial radiotherapy do not receive methotrexate IT.
- Maintenance: Beginning 2-3 weeks after reinduction, all patients receive oral mercaptopurine daily and oral methotrexate weekly for 2 years. Except for LR-R and HR-R, patients also receive pegaspargase IV over 2 hours every 3 weeks for 3 doses. Patients who have not undergone CNS radiotherapy receive methotrexate IT at 3, 6, and 9 months.
Blood and bone marrow samples may be collected periodically for research studies.
After completion of study treatment, patients are followed monthly for 1 year, every 3 months for 2 years, every 6 months for 2 years, and then annually for 5 years.
PROJECTED ACCRUAL: A total of 41 high-risk patients will be accrued for phase II, 296 patients for the first randomization (phase III), and 396 patients for the second randomization will be accrued for this study.
- Conditions
- Leukemia
- Being tested
- Amsacrine, Clofarabine, Cyclophosphamide, Cytarabine, Daunorubicin hydrochloride
- Keywords
- childhood acute lymphoblastic leukemia, untreated 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.
AmsacrineDrug
one block amsacrine together with etoposide and methylprednisolone for very high risk patients
ClofarabineDrug
one block clofarabine with Asparaginase for MRD positive patients after induction
CyclophosphamideDrug
together wit MTX and ASP in consolidation and together with cytarabine and 6-TG in reinduction
CytarabineDrug
part of different chemotherapy blocks in consolidation and reinduction
Daunorubicin hydrochlorideDrug
part of induction and reinduction therapy
DexamethasoneDrug
part of reinduction therapy
part of reinduction therapy
Etoposide phosphateDrug
part of different chemotherapy blocks
MercaptopurineDrug
part of different chemotherapy blocks
MethotrexateDrug
part of different chemotherapy blocks
part of different chemotherapy blocks
PegaspargaseDrug
part of different chemotherapy blocks
ThioguanineDrug
part of different chemotherapy blocks
part of intravenous chemotherapy
Whole-brain radiation therapyRadiation
patients with initial cns involvement receive cranial irradiation
| Study group | Role | What they receive |
|---|---|---|
| Arm I intensification (cytarabine) | Active comparator | LR-S patients receive HD cytarabine IV 4 x 3 g over 12 hours daily on days 29-31 and pegaspargase IV over 2 hours on days 31, 52, and 80.
LR-I and precursor B-cell ALL HR-S and HR-I patients receive HD cytarabine IV 2.500 over 3 hours twice daily on days 29-31 and 106-108 and pegaspargase IV over 2 hours on days 31, 53, 67, and 108.
Followed by standard consolidation therapy regarding to stratification containing:
methotrexate, cyclophosphamide, thioguanin, mercaptopurine, etoposide phosphate, amsacrine, cytarabine, methylprednisolone, dexamethasone, vincristine sulfate; whole-brain radiation therapy only if indicated in patients with cns involvement or T-cell ALL Receives: Drug: Amsacrine; Drug: Cyclophosphamide; Drug: Cytarabine; Drug: Dexamethasone; Drug: Etoposide phosphate; Drug: Methotrexate; Drug: Methylprednisolone; Drug: Pegaspargase; Drug: Thioguanine; Drug: Vincristine sulfate; Radiation: Whole-brain radiation therapy |
| Arm II intensification (clofarabine) | Active comparator | LR-S patients receive clofarabine* IV 5 x 40 mg over 2 hours every day on days 29-33 and pegaspargase IV over 2 hours on days 33, 52, and 80.
LR-I and precursor B-cell ALL HR-S and HR-I patients receive clofarabine* IV over 2 hours on days 29-33 and pegaspargase IV over 2 hours on days 33, 53, 67, and 108.
Followed by standard consolidation therapy regarding to stratification containing:
methotrexate, cyclophosphamide, thioguanin, mercaptopurine, etoposide phosphate, amsacrine, cytarabine, methylprednisolone, dexamethasone, vincristine sulfate; whole-brain radiation therapy only if indicated in patients with cns involvement or T-cell ALL Receives: Drug: Amsacrine; Drug: Clofarabine; Drug: Cyclophosphamide; Drug: Daunorubicin hydrochloride; Drug: Dexamethasone; Drug: Etoposide phosphate; Drug: Methotrexate; Drug: Methylprednisolone; Drug: Pegaspargase; Drug: Thioguanine; Drug: Vincristine sulfate; Radiation: Whole-brain radiation therapy |
| Arm III reinduct.(doxorubicin hydrochl.) | Active comparator | LR-S patients receive doxorubicin hydrochloride IV 30 mg/m2 over 24 hours on days 1 and 8.
LR-I, HR-S and HR-I Patients receive doxorubicin hydrochloride IV 30 mg/m2 over 24 hours on days 1, 8, 22, and 29.
Followed by standard reinduction and maintenance therapy containing:
cyclophophamide, cytarabine, thioguanine, mercaptopurine, methotrexate and pegaspargase, dexamethasone, vincristine sulfate Receives: Drug: Cyclophosphamide; Drug: Cytarabine; Drug: Dexamethasone; Drug: Doxorubicin hydrochloride; Drug: Mercaptopurine; Drug: Methotrexate; Drug: Pegaspargase; Drug: Vincristine sulfate |
| Arm IV reinduct.(daunorubicin hydrochl.) | Active comparator | LR-S patients receive daunorubicin hydrochloride IV 36 mg/m2 over 24 hours on days 1 and 8.
LR-I, HR-S and HR-I Patients receive daunorubicin hydrochloride IV 36 mg/m2 over 24 hours on days 1, 8, 22, and 29.
Followed by standard reinduction and maintenance therapy containing:
cyclophophamide, cytarabine, thioguanine, mercaptopurine, methotrexate and pegaspargase, dexamethasone, vincristine sulfate Receives: Drug: Cyclophosphamide; Drug: Cytarabine; Drug: Daunorubicin hydrochloride; Drug: Dexamethasone; Drug: Mercaptopurine; Drug: Methotrexate; Drug: Pegaspargase; Drug: Vincristine sulfate |
What is being measured
The primary outcome is the main question the study is designed to answer.
Safety and efficacy of clofarabine combined with pegaspargase (phase II)
minimal residual disease diagnostic, toxicity form
Measured: at day 21 after chemotherapy
Secondary outcomes (1)
Incidence of infectious complications after administration of daunorubicin hydrochloride vs doxorubicin hydrochloride
toxicity form
Measured: at the end of reinduction therapy
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Oct 2010 (estimated)
- Study startOct 2010
- Primary completionDec 2019
- Study completion20 Nov 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for LeukemiaStudies of the same condition, open and under way.
- More trials run by Universitätsklinikum Hamburg-EppendorfThe 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 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 745 participants (actual)
Sponsor and investigators
- Lead sponsor
- Universitätsklinikum Hamburg-Eppendorf
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Martin Horstmann, MD, Principal investigator, Universitätsklinikum Hamburg-Eppendorf
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01228331
- Sponsor's protocol ID
- CDR0000686545
- Other IDs
- 2009-012758-18, 2009
- Status last verified
- Jan 2024
- First submitted
- 23 Oct 2010
- Last updated
- 11 Dec 2024
- Results posted
- No
- Data monitoring committee
- Yes
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 11 Dec 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomized Multi-Center Treatment Study (COALL 08-09) to Improve the Survival of Children with Acute Lymphoblastic Leukemia on Behalf of the German Society of Pediatric Hematology and Oncology
- ClinicalTrials.gov ID
- NCT01228331
- Acronym / sponsor ID
- CDR0000686545
- Conditions
- Leukemia
- Keywords
- childhood acute lymphoblastic leukemia, untreated childhood acute lymphoblastic leukemia
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 745 participants (actual)
- Lead sponsor
- Universitätsklinikum Hamburg-EppendorfUniversity, hospital or other
- Study start
- Oct 2010
- Primary completion
- Dec 2019 (actual)
- Study completion
- 20 Nov 2024 (actual)
- First posted
- 26 Oct 2010 (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 work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than once drug (combination chemotherapy) may kill more cancer cells. Radiation therapy uses high-energy x-rays to kill cancer cells. It is not yet known whether giving clofarabine or high-dose cytarabine, pegaspargase, and combination chemotherapy followed by daunorubicin hydrochloride or doxorubicin hydrochloride is more effective in treating young patients with acute lymphoblastic leukemia.
PURPOSE: This randomized phase II/III trial is studying the side effects of giving clofarabine compared with giving high-dose cytarabine, pegaspargase, and combination chemotherapy followed by daunorubicin hydrochloride or doxorubicin hydrochloride and to see how well it works in treating young patients with T-cell acute lymphoblastic leukemia or precursor B-cell acute lymphoblastic leukemia.
Detailed description
OBJECTIVES:
Primary
- To investigate the safety and efficacy of clofarabine combined with pegaspargase in patients with high-risk acute lymphoblastic leukemia during the first phase of the study. (Phase II)
- To investigate, in terms of minimal-residual disease (MRD), the cytotoxic efficacy of clofarabine compared with high-dose cytarabine in combination with pegaspargase in these patients. (Phase III)
- To compare the incidence of infectious complications after the administration of daunorubicin hydrochloride versus doxorubicin hydrochloride during reinduction.
Secondary
- To compare the safety profiles of clofarabine and pegaspargase versus high-dose cytarabine and pegaspargase in these patients.
- To compare, in terms of MRD, the efficacy of clofarabine and pegaspargase and high-dose cytarabine and pegaspargase, respectively, versus methotrexate, cyclophosphamide, and asparaginase in study GER-COALL-07-03, the historical control group (retrospective comparison).
- To determine the influence of MRD-based stratification in COALL-09 on overall survival and event-free survival in a historical comparison of previous COALL studies.
OUTLINE: This is a multicenter, sequential phase II/III study. Patients are stratified to low risk (LR) or high risk (HR) depending on peripheral white blood cell count on diagnosis, age on diagnosis, and immunological subtype. Patients undergo 2 randomizations (1 during intensification and 1 during reinduction) in the study.
- Preliminary treatment: All patients receive daunorubicin hydrochloride IV over 24 hours on day -7 and methotrexate intrathecally (IT) once on day -9, -8, or -7.
- Induction: All patients receive vincristine IV on days 1, 8, 15, and 22; daunorubicin hydrochloride IV over 24 hours on days 1, 8, and 15; and oral prednisone 3-4 times daily on days 1-28.
Patients are assessed for minimal-residual disease (MRD) status after induction phase. Patients not in remission on day 29 are treated off study. Patients with LR disease are further stratified to LR-reduced (LR-R), LR-standard (LR-S), and LR-intensified (LR-I) groups; patients with HR disease are further stratified to HR-reduced (HR-R), HR-standard (HR-S), and HR-intensified (HR-I) groups. Patients in the LR-R and HR-R groups do not undergo randomization during study.
- Intensification (randomization 1): Patients receive therapy according to risk and disease subtypes. Some patients in different risk group are randomized* to receive high-dose (HD) cytarabine and pegaspargase or clofarabine and pegaspargase.
- LR-R and LR-S: Patients receive medium-high-dose (mHD) methotrexate IV over 24 hours on days 50, 64, and 78; etoposide phosphate IV over 1-2 hours and cytarabine IV over 1 hour on day 66; oral mercaptopurine on days 50-56 and 78-120; oral thioguanine on days 64-70; and methotrexate IT on days 29, 50, 64, and 78. Patients in LR-S group who still have a detectable MRD load on day 29 are randomized (randomization 1) to 1 of 2 arms to receive cytarabine and pegaspargase vs. clofarabine and pegaspargase.
- Arm I (cytarabine and pegaspargase) Patients receive HD cytarabine IV over 3 hours twice daily on days 29-31 and pegaspargase IV over 2 hours on days 31, 52, and 80.
- Arm II (clofarabine and pegaspargase) Patients receive clofarabine IV over 2 hours on days 29-33 and pegaspargase IV over 2 hours on days 33, 52, and 80.
- LR-I and precursor B-cell acute lymphoblastic leukemia (ALL) HR-S and HR-I: Patients receive cyclophosphamide IV over 30 minutes on days 50 and 64; mHD IV over 24 hours on days 51, 65, 78, and 92; etoposide phosphate IV over 1-2 hours and cytarabine IV over 1 hour on days 80 and 94; oral mercaptopurine on days 64-70 and 92-98; oral thioguanine on days 78-84; and methotrexate IT on days 29, 51, 65, 78, and 92. All precursor B-cell ALL patients with a detectable MRD load on day 29 and T-cell ALL patients with an MRD load ≥ 10³ on day 29 are randomized* (randomization 1) to 1 of 2 arms to receive cytarabine and pegaspargase vs. clofarabine and pegaspargase.
- Arm I (cytarabine and pegaspargase) Patients receive HD cytarabine IV over 3 hours twice daily on days 29-31 and 106-108 and pegaspargase IV over 2 hours on days 31, 53, 67, and 108.
- Arm II (clofarabine and pegaspargase) Patients receive clofarabine* IV over 2 hours on days 29-33 and pegaspargase IV over 2 hours on days 33, 53, 67, and 108.
- NOTE: *In phase II, all patients with an MRD load of ≥ 104 (on day 29) receive clofarabine and pegaspargase without randomization.
- T-cell ALL HR (HR-R, HR-S, and HR-I): Patients receive cyclophosphamide IV over 30 minutes on days 29 and 64; mHD methotrexate IV over 24 hours on days 30, 65, 78, and 92; etoposide phosphate IV over 1-2 hours and cytarabine IV over 1 hour on days 80 and 94; oral mercaptopurine on days 64-70 and 92-98; oral thioguanine on days 78-84; and methotrexate IT on days 30, 43, 65, 78, and 92. Patients in HR-S and HR-I group are randomized* (randomization 1) to 1 of 2 arms to receive cytarabine and pegaspargase vs. clofarabine and pegaspargase.
- Arm I (cytarabine and pegaspargase): Patients receive HD cytarabine IV over 3 hours twice daily on days 43-45 and 106-108 and pegaspargase IV over 2 hours on days 32, 45, 67, and 108.
- Arm II (clofarabine and pegaspargase): Patients receive clofarabine IV over 2 hours on days 43-47 and pegaspargase IV over 2 hours on days 32, 47, 67, and 108.
Patients in HR-I group also receive amsacrine IV over 4 hours and etoposide phosphate IV over 2 hours on days 127 and 128, methylprednisolone IV over 30 minutes on days 127-130, and methotrexate IT on day 127, at the end of intensification.
NOTE: *In phase II, all patients with an MRD load of ≥ 103 (on day 43) receive clofarabine and pegaspargase without randomization.
- CNS therapy: All patients with initial CNS involvement undergo cranial radiotherapy for a total of 12 or 18 Gy. HR patients (precursor B-cell ALL with initial WBC count ≥ 200/nL and T-cell ALL with initial WBC count ≥ 100/nL) with no initial CNS involvement also undergo cranial radiotherapy for a total of 12 Gy, beginning 2-3 weeks after the last dose of HD cytarabine or clofarabine. LR patients and HR patients (precursor B-cell ALL with initial WBC count < 200/nL and T-cell ALL with initial WBC count < 100/nL) with no initial CNS involvement do not receive initial cranial radiotherapy. At the beginning of CNS therapy, before cranial radiotherapy, HR-I patients receive vincristine IV on day 1; doxorubicin hydrochloride IV over 24 hours on day 1; oral dexamethasone 3 times daily on days 1-7; and pegaspargase IV over 2 hours on day 7.
All patients receive interim therapy comprising 3 doses (2 in week 1 and 1 in week 3) of methotrexate IT and oral mercaptopurine daily during the 4 weeks between intensification and reinduction.
- Reinduction (randomization 2): Patients undergo reinduction immediately after completion of interim therapy. Patients in LR-S, LR-I, HR-S, and HR-I groups are randomized to 1 of 2 arms (doxorubicin hydrochloride vs. daunorubicin hydrochloride)
- LR-S: Patients receive vincristine IV on days 1 and 8, oral dexamethasone on days 1-14, pegaspargase IV over 2 hours on day 9, cyclophosphamide IV over 30 minutes on day 22, cytarabine IV or intramuscularly (IM) on days 23-26, oral thioguanine on days 22-28, and methotrexate IT on days 1, 22, and 36.
- Arm III (doxorubicin hydrochloride) Patients receive doxorubicin hydrochloride IV over 24 hours on days 1 and 8.
- Arm IV (daunorubicin hydrochloride): Patients receive daunorubicin hydrochloride IV over 24 hours on days 1 and 8.
- LR-R and HR-R: Patients are not randomized. They receive vincristine IV on days 1 and 8, oral dexamethasone on days 1-14, pegaspargase IV over 2 hours on day 8, and methotrexate IT on days 1 and 15.
- LR-I, HR-S, and HR-I: Patients receive vincristine IV on days 1, 8, 22, and 29; oral dexamethasone twice daily on days 1-14 and 22-35; cyclophosphamide IV over 30 minutes on days 43 and 57; cytarabine IV or IM on days 43-46 and 57-60; oral thioguanine on days 43-49 and 57-63; and methotrexate IT* on days 1, 22, and 43.
- Arm III (doxorubicin hydrochloride) Patients receive doxorubicin hydrochloride IV over 24 hours on days 1, 8, 22, and 29.
- Arm IV (daunorubicin hydrochloride) Patients receive daunorubicin hydrochloride IV over 24 hours on days 1, 8, 22, and 29.
NOTE: *Patients who underwent cranial radiotherapy do not receive methotrexate IT.
- Maintenance: Beginning 2-3 weeks after reinduction, all patients receive oral mercaptopurine daily and oral methotrexate weekly for 2 years. Except for LR-R and HR-R, patients also receive pegaspargase IV over 2 hours every 3 weeks for 3 doses. Patients who have not undergone CNS radiotherapy receive methotrexate IT at 3, 6, and 9 months.
Blood and bone marrow samples may be collected periodically for research studies.
After completion of study treatment, patients are followed monthly for 1 year, every 3 months for 2 years, every 6 months for 2 years, and then annually for 5 years.
PROJECTED ACCRUAL: A total of 41 high-risk patients will be accrued for phase II, 296 patients for the first randomization (phase III), and 396 patients for the second randomization will be accrued for this study.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Arm I intensification (cytarabine) | Active comparator | Drug: Amsacrine, Drug: Cyclophosphamide, Drug: Cytarabine, Drug: Dexamethasone, Drug: Etoposide phosphate, Drug: Methotrexate, Drug: Methylprednisolone, Drug: Pegaspargase, Drug: Thioguanine, Drug: Vincristine sulfate, Radiation: Whole-brain radiation therapyLR-S patients receive HD cytarabine IV 4 x 3 g over 12 hours daily on days 29-31 and pegaspargase IV over 2 hours on days 31, 52, and 80. LR-I and precursor B-cell ALL HR-S and HR-I patients receive HD cytarabine IV 2.500 over 3 hours twice daily on days 29-31 and 106-108 and pegaspargase IV over 2 hours on days 31, 53, 67, and 108. Followed by standard consolidation therapy regarding to stratification containing: methotrexate, cyclophosphamide, thioguanin, mercaptopurine, etoposide phosphate, amsacrine, cytarabine, methylprednisolone, dexamethasone, vincristine sulfate; whole-brain radiation therapy only if indicated in patients with cns involvement or T-cell ALL |
| Arm II intensification (clofarabine) | Active comparator | Drug: Amsacrine, Drug: Clofarabine, Drug: Cyclophosphamide, Drug: Daunorubicin hydrochloride, Drug: Dexamethasone, Drug: Etoposide phosphate, Drug: Methotrexate, Drug: Methylprednisolone, Drug: Pegaspargase, Drug: Thioguanine, Drug: Vincristine sulfate, Radiation: Whole-brain radiation therapyLR-S patients receive clofarabine* IV 5 x 40 mg over 2 hours every day on days 29-33 and pegaspargase IV over 2 hours on days 33, 52, and 80. LR-I and precursor B-cell ALL HR-S and HR-I patients receive clofarabine* IV over 2 hours on days 29-33 and pegaspargase IV over 2 hours on days 33, 53, 67, and 108. Followed by standard consolidation therapy regarding to stratification containing: methotrexate, cyclophosphamide, thioguanin, mercaptopurine, etoposide phosphate, amsacrine, cytarabine, methylprednisolone, dexamethasone, vincristine sulfate; whole-brain radiation therapy only if indicated in patients with cns involvement or T-cell ALL |
| Arm III reinduct.(doxorubicin hydrochl.) | Active comparator | Drug: Cyclophosphamide, Drug: Cytarabine, Drug: Dexamethasone, Drug: Doxorubicin hydrochloride, Drug: Mercaptopurine, Drug: Methotrexate, Drug: Pegaspargase, Drug: Vincristine sulfateLR-S patients receive doxorubicin hydrochloride IV 30 mg/m2 over 24 hours on days 1 and 8. LR-I, HR-S and HR-I Patients receive doxorubicin hydrochloride IV 30 mg/m2 over 24 hours on days 1, 8, 22, and 29. Followed by standard reinduction and maintenance therapy containing: cyclophophamide, cytarabine, thioguanine, mercaptopurine, methotrexate and pegaspargase, dexamethasone, vincristine sulfate |
| Arm IV reinduct.(daunorubicin hydrochl.) | Active comparator | Drug: Cyclophosphamide, Drug: Cytarabine, Drug: Daunorubicin hydrochloride, Drug: Dexamethasone, Drug: Mercaptopurine, Drug: Methotrexate, Drug: Pegaspargase, Drug: Vincristine sulfateLR-S patients receive daunorubicin hydrochloride IV 36 mg/m2 over 24 hours on days 1 and 8. LR-I, HR-S and HR-I Patients receive daunorubicin hydrochloride IV 36 mg/m2 over 24 hours on days 1, 8, 22, and 29. Followed by standard reinduction and maintenance therapy containing: cyclophophamide, cytarabine, thioguanine, mercaptopurine, methotrexate and pegaspargase, dexamethasone, vincristine sulfate |
Who may qualify
- Ages
- 1 year to 17 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (1 listed)
- diagnosis after the first and before the 18th birthday AND confirmed diagnosis of acute B-precursor or or T-cell leukemia AND parents or guardians/patients give consent for inclusion in the study and transmission of data AND if none of exclusion criteria is accomplished
Key exclusion criteria (1 listed)
- BCR/ABL rearrangement positive OR prior cytostatic treatment lasting > 7 days or prior treatment with cytostatic drugs other than vincristine, daunorubicin and prednisone OR prior severe illnesses which make treatment per the protocol impossible from the outset (BUT trisomy 21 is not an exclusion criterion) OR absence of the baseline data required for assignment to a risk group in accordance with the protocol (BUT patients for whom the MRD value could not be determined for technical reasons will be treated as protocol patients) OR the disease is a secondary malignancy or relapse OR death before the start of treatment
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 |
|---|---|---|
| Amsacrineone block amsacrine together with etoposide and methylprednisolone for very high risk patients | Drug | Arm I intensification (cytarabine), Arm II intensification (clofarabine) |
| Clofarabineone block clofarabine with Asparaginase for MRD positive patients after induction | Drug | Arm II intensification (clofarabine) |
| Cyclophosphamidetogether wit MTX and ASP in consolidation and together with cytarabine and 6-TG in reinduction | Drug | Arm I intensification (cytarabine), Arm II intensification (clofarabine), Arm III reinduct.(doxorubicin hydrochl.), Arm IV reinduct.(daunorubicin hydrochl.) |
| Cytarabinepart of different chemotherapy blocks in consolidation and reinduction | Drug | Arm I intensification (cytarabine), Arm III reinduct.(doxorubicin hydrochl.), Arm IV reinduct.(daunorubicin hydrochl.) |
| Daunorubicin hydrochloridepart of induction and reinduction therapy | Drug | Arm II intensification (clofarabine), Arm IV reinduct.(daunorubicin hydrochl.) |
| Dexamethasonepart of reinduction therapy | Drug | Arm I intensification (cytarabine), Arm II intensification (clofarabine), Arm III reinduct.(doxorubicin hydrochl.), Arm IV reinduct.(daunorubicin hydrochl.) |
| Doxorubicin hydrochloridepart of reinduction therapy | Drug | Arm III reinduct.(doxorubicin hydrochl.) |
| Etoposide phosphatepart of different chemotherapy blocks | Drug | Arm I intensification (cytarabine), Arm II intensification (clofarabine) |
| Mercaptopurinepart of different chemotherapy blocks | Drug | Arm III reinduct.(doxorubicin hydrochl.), Arm IV reinduct.(daunorubicin hydrochl.) |
| Methotrexatepart of different chemotherapy blocks | Drug | Arm I intensification (cytarabine), Arm II intensification (clofarabine), Arm III reinduct.(doxorubicin hydrochl.), Arm IV reinduct.(daunorubicin hydrochl.) |
| Methylprednisolonepart of different chemotherapy blocks | Drug | Arm I intensification (cytarabine), Arm II intensification (clofarabine) |
| Pegaspargasepart of different chemotherapy blocks | Drug | Arm I intensification (cytarabine), Arm II intensification (clofarabine), Arm III reinduct.(doxorubicin hydrochl.), Arm IV reinduct.(daunorubicin hydrochl.) |
| Thioguaninepart of different chemotherapy blocks | Drug | Arm I intensification (cytarabine), Arm II intensification (clofarabine) |
| Vincristine sulfatepart of intravenous chemotherapy | Drug | Arm I intensification (cytarabine), Arm II intensification (clofarabine), Arm III reinduct.(doxorubicin hydrochl.), Arm IV reinduct.(daunorubicin hydrochl.) |
| Whole-brain radiation therapypatients with initial cns involvement receive cranial irradiation | Radiation | Arm I intensification (cytarabine), Arm II intensification (clofarabine) |
Primary outcome
Safety and efficacy of clofarabine combined with pegaspargase (phase II)
Time frame: at day 21 after chemotherapy
minimal residual disease diagnostic, toxicity form
1 secondary outcome
Incidence of infectious complications after administration of daunorubicin hydrochloride vs doxorubicin hydrochloride
Time frame: at the end of reinduction therapy
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 11 Dec 2024.
- Clinical trial summary from the information portal of the German Society of Paediatric Oncology and Haematology (GPOH)Link provided by the sponsor.
- Individual participant dataSharing planned: No
Related trials for Leukemia
RecruitingPhase 2
Tafasitamab With Acalabrutinib and Venetoclax for the Treatment of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Chronic Lymphocytic Leukemia, Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Enrolling by invitationObservational study
Natural History Study of Early Life Exposures in Agriculture (ELEA)
Prostate Cancer, Leukemia
RecruitingPhase 1
A Study of CHM-029 in Participants With NPM1 Mutated, KMT2A or NUP98 Rearranged AML
AML (Acute Myeloid Leukemia)
RecruitingPhase 1
Vididencel in CML-CP Patients With MRD
CML (Chronic Myelogenous Leukemia)
RecruitingPhase 2
Testing New Therapies for Patients With Acute Myeloid Leukemia Who Are Newly Diagnosed and Have Not Yet Started Treatment (A MyeloMATCH Treatment Trial)
Acute Myeloid Leukemia, Acute Myeloid Leukemia Arising From Previous Myelodysplastic/Myeloproliferative Neoplasm
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.
Martin Horstmann, MD principal investigator
Universitätsklinikum Hamburg-Eppendorf
14 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing Amsacrine, Clofarabine and Cyclophosphamide in people with Leukemia, run by Universitätsklinikum Hamburg-Eppendorf at 14 sites in Germany.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 1 exclusion criteria. 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 11 Dec 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 14 sites in Germany. 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 combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
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?
Safety and efficacy of clofarabine combined with pegaspargase (phase II) (time frame: at day 21 after chemotherapy). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 11 Dec 2024.