Bortezomib and Vorinostat in Younger Patients With Refractory or Relapsed MLL Rearranged Hematologic Malignancies
- Conditions
- Acute Lymphoid LeukemiaAcute Myeloid LeukemiaMixed Lineage Acute Leukemia
- Interventions
- Registration Number
- NCT02419755
- Lead Sponsor
- St. Jude Children's Research Hospital
- Brief Summary
This study will test the safety and effectiveness of adding bortezomib and vorinostat to other chemotherapy drugs commonly used to treat relapsed or refractory leukemia. Both drugs have been approved by the Food and Drug Administration (FDA) to treat other cancers in adults, but they have not yet been approved tor treatment younger patients with leukemia.
PRIMARY OBJECTIVE
* To estimate the overall response rate of patients with MLL rearranged (MLLr) hematologic malignancies receiving bortezomib and vorinostat in combination with a chemotherapy backbone.
SECONDARY OBJECTIVES
* Estimate event-free and overall-survival.
* Describe toxicities experienced by participants during treatment.
OTHER PRESPECIFIED OBJECTIVES
* To identify all genomic lesions by comprehensive whole genome, exome and transcriptome sequencing on all patients.
* To compare minimal residual disease (MRD) results by three modalities: flow cytometry, polymerase chain reaction (PCR) and deep sequencing.
- Detailed Description
All participants will undergo diagnostic lumbar puncture and intrathecal (IT) chemotherapy \[Cytarabine, methotrexate, hydrocortisone (ITMHA)\] prior to cycle 1. Throughout all phases of therapy, dexrazoxane will be given as supportive care for all participants prior to receiving mitoxantrone or doxorubicin.
STRATUM 1: MYELOID MALIGNANCIES:
Induction:
* Cytarabine, Days 1-5
* Bortezomib, Days 1, 4, 8, 11, 15, 18
* Vorinostat, Days 1-4, 8-11, 15-18
* ITMHA.for those with CNS1, Day 1
* ITMHA for those with CNS 2/3, Days 1, 4, 8, 11\*, 15\*, 18\* and 22\* (\* Twice weekly until two negative CSF; CNS3 patients must receive at least 6 doses)
* Participants with cumulative anthracycline \<460 mg/m2 also receive Mitoxantrone on Day 1
* Responders may receive up to 6 courses. ITMHA will be limited to day 1 for subsequent courses
Maintenance (bridge) therapy (1 cycle before stem cell transplant if needed)::
* Bortezomib, Days 1, 4, 8, 11, 15, 18
* Vorinostat, Days 1-4, 8-11, 15-18
* ITMHA, Day 1
STRATUM 2: Acute Lymphoid Leukemia (ALL) and Mixed Lineage Malignancies (MLL):
Induction:
* Mitoxantrone, Day 1
* PEG-L-Asparaginase (or Erwinia L-asparaginase), Day 3
* Dexamethasone, Days 1-4, 8-11, 15-18
* Bortezomib, Days 1, 4, 8, 11, 15, 18
* Vorinostat, Days 1-4, 8-11, 15-18
* ITMHA for those with CNS1, Days 1, 8, 15, and 22
* ITMHA for those with CNS2/3, Days 1, 4, 8, 11, 15, and 22
* Participants with \>460 mg/m2 cumulative anthracyclines will not receive mitoxantrone
Consolidation:
* Methotrexate, Days 1 and 15
* Bortezomib, Days 8, 11, 22, 25
* Vorinostat, Days 8-11, and 22-25
* ITMHA, Days 1 and 15
Interim Maintenance:
* Mercaptopurine, Days 1-42
* Doxorubicin, Days 1 and 29
* PEG-L-asparaginase (or Erwinia L-asparaginase), Days 1, 15, and 29
* Dexamethasone, Days 8-11, 22-25, and 36-39
* Bortezomib Days 8,11,22,25,36,39
* Vorinostat, Days 8-11, 22-25, and 36-39
* ITMHA, Day 1
Reinduction:
* Mitoxantrone, Day 1
* PEG-L-asparaginase (or Erwinia L-asparaginase), Day 3
* Dexamethasone, Days 1-4, 8-11, 15-18
* Bortezomib Days 1, 4, 8, 11, 15, 18
* Vorinostat Days 1-4, 8-11, 15-18
* IT MHA Day 1
Maintenance (12 cycles):
* Mercaptopurine, Days 1-28
* Methotrexate, Days 8, 15, and 22
* Dexamethasone, Days 1-4
* Bortezomib, Days 1 and 4
* Vorinostat, Days 1-4
* ITMHA, Day 1
Bridge Therapy (1 cycle before stem cell transplant if needed):
* Bortezomib, Days 1, 4, 8, 11, 15, 18
* Vorinostat, Days 1-4, 8-11, 15-18
* Dexamethasone, Days 1-4, 8-11, 15-18
* ITMHA, Day 1
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 12
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Stratum 2: ALL and MLM Erwinia L-Asparaginase Participants in Stratum 2 \[Acute Lymphoid Leukemia (ALL) and Mixed Lineage Malignancies (MLM)\] receive mitoxantrone, PEG-L-Asparaginase (or Erwinia L-asparaginase), dexamethasone, bortezomib, vorinostat, cytarabine, methotrexate, hydrocortisone, mercaptopurine, and doxorubicin as described in the Detailed Study Description. Stratum 2: ALL and MLM Peg-L-Asparaginase Participants in Stratum 2 \[Acute Lymphoid Leukemia (ALL) and Mixed Lineage Malignancies (MLM)\] receive mitoxantrone, PEG-L-Asparaginase (or Erwinia L-asparaginase), dexamethasone, bortezomib, vorinostat, cytarabine, methotrexate, hydrocortisone, mercaptopurine, and doxorubicin as described in the Detailed Study Description. Stratum 1: Myeloid Malignancies Mitoxantrone Participants receive cytarabine, bortezomib, vorinostat, methotrexate, hydrocortisone, mitoxantrone as described in the Detailed Study Description. Stratum 1: Myeloid Malignancies Bortezomib Participants receive cytarabine, bortezomib, vorinostat, methotrexate, hydrocortisone, mitoxantrone as described in the Detailed Study Description. Stratum 1: Myeloid Malignancies Vorinostat Participants receive cytarabine, bortezomib, vorinostat, methotrexate, hydrocortisone, mitoxantrone as described in the Detailed Study Description. Stratum 1: Myeloid Malignancies Methotrexate Participants receive cytarabine, bortezomib, vorinostat, methotrexate, hydrocortisone, mitoxantrone as described in the Detailed Study Description. Stratum 2: ALL and MLM Bortezomib Participants in Stratum 2 \[Acute Lymphoid Leukemia (ALL) and Mixed Lineage Malignancies (MLM)\] receive mitoxantrone, PEG-L-Asparaginase (or Erwinia L-asparaginase), dexamethasone, bortezomib, vorinostat, cytarabine, methotrexate, hydrocortisone, mercaptopurine, and doxorubicin as described in the Detailed Study Description. Stratum 2: ALL and MLM Vorinostat Participants in Stratum 2 \[Acute Lymphoid Leukemia (ALL) and Mixed Lineage Malignancies (MLM)\] receive mitoxantrone, PEG-L-Asparaginase (or Erwinia L-asparaginase), dexamethasone, bortezomib, vorinostat, cytarabine, methotrexate, hydrocortisone, mercaptopurine, and doxorubicin as described in the Detailed Study Description. Stratum 1: Myeloid Malignancies Cytarabine Participants receive cytarabine, bortezomib, vorinostat, methotrexate, hydrocortisone, mitoxantrone as described in the Detailed Study Description. Stratum 1: Myeloid Malignancies Hydrocortisone Participants receive cytarabine, bortezomib, vorinostat, methotrexate, hydrocortisone, mitoxantrone as described in the Detailed Study Description. Stratum 2: ALL and MLM Mitoxantrone Participants in Stratum 2 \[Acute Lymphoid Leukemia (ALL) and Mixed Lineage Malignancies (MLM)\] receive mitoxantrone, PEG-L-Asparaginase (or Erwinia L-asparaginase), dexamethasone, bortezomib, vorinostat, cytarabine, methotrexate, hydrocortisone, mercaptopurine, and doxorubicin as described in the Detailed Study Description. Stratum 2: ALL and MLM Cytarabine Participants in Stratum 2 \[Acute Lymphoid Leukemia (ALL) and Mixed Lineage Malignancies (MLM)\] receive mitoxantrone, PEG-L-Asparaginase (or Erwinia L-asparaginase), dexamethasone, bortezomib, vorinostat, cytarabine, methotrexate, hydrocortisone, mercaptopurine, and doxorubicin as described in the Detailed Study Description. Stratum 2: ALL and MLM Methotrexate Participants in Stratum 2 \[Acute Lymphoid Leukemia (ALL) and Mixed Lineage Malignancies (MLM)\] receive mitoxantrone, PEG-L-Asparaginase (or Erwinia L-asparaginase), dexamethasone, bortezomib, vorinostat, cytarabine, methotrexate, hydrocortisone, mercaptopurine, and doxorubicin as described in the Detailed Study Description. Stratum 2: ALL and MLM Hydrocortisone Participants in Stratum 2 \[Acute Lymphoid Leukemia (ALL) and Mixed Lineage Malignancies (MLM)\] receive mitoxantrone, PEG-L-Asparaginase (or Erwinia L-asparaginase), dexamethasone, bortezomib, vorinostat, cytarabine, methotrexate, hydrocortisone, mercaptopurine, and doxorubicin as described in the Detailed Study Description. Stratum 2: ALL and MLM Dexamethasone Participants in Stratum 2 \[Acute Lymphoid Leukemia (ALL) and Mixed Lineage Malignancies (MLM)\] receive mitoxantrone, PEG-L-Asparaginase (or Erwinia L-asparaginase), dexamethasone, bortezomib, vorinostat, cytarabine, methotrexate, hydrocortisone, mercaptopurine, and doxorubicin as described in the Detailed Study Description. Stratum 2: ALL and MLM Doxorubicin Participants in Stratum 2 \[Acute Lymphoid Leukemia (ALL) and Mixed Lineage Malignancies (MLM)\] receive mitoxantrone, PEG-L-Asparaginase (or Erwinia L-asparaginase), dexamethasone, bortezomib, vorinostat, cytarabine, methotrexate, hydrocortisone, mercaptopurine, and doxorubicin as described in the Detailed Study Description. Stratum 2: ALL and MLM Mercaptopurine Participants in Stratum 2 \[Acute Lymphoid Leukemia (ALL) and Mixed Lineage Malignancies (MLM)\] receive mitoxantrone, PEG-L-Asparaginase (or Erwinia L-asparaginase), dexamethasone, bortezomib, vorinostat, cytarabine, methotrexate, hydrocortisone, mercaptopurine, and doxorubicin as described in the Detailed Study Description.
- Primary Outcome Measures
Name Time Method Overall Response Rate in All Participants End of first treatment block (up to 2 months) For the purpose of the statistical analysis of the primary objective, response is assessed at the end of first treatment block at maximum tolerated dose of vorinostat (i.e., Induction Ia or Ib for myeloid and Induction for lymphoid and mixed lineage). Any eligible patient who starts first treatment block is considered evaluable. Response of CR, CRi, PR, or PRi is considered a success; otherwise a failure, which will include the cases of No-response, as well as off- treatment or off-study before response can be assessed, except cases found ineligible after enrollment. A patient found ineligible after enrollment will be taken off study and replaced by enrolling an additional MLLr patient.
The rate (probability) of response will be estimated by the sample proportion of patients who responded (CR, CRi, PR, PRi) to Induction, along with the 99% confidence interval and lower confidence bound. Three interim analyses will be performed to monitor the possible lack of efficacy.
- Secondary Outcome Measures
Name Time Method Number of Participants With 3 Year Event Free Survival (EFS) Three years after the last enrollment All eligible patients who started the treatment will be included in this analysis. Patients later found ineligible will be replaced and excluded from the estimation. In addition to death for any reason, no-response (i.e., other than CR, CRi, PR or PRi), off-treatment or off-study (except for the reason of being found ineligible), disease progression, relapse, and second malignancies will be considered as failures. The time to EFS will be set to 0 for patients who fail to respond.
Kaplan-Meier estimates of the OS and EFS functions will be computed, along with estimates of standard errors by the method of Peto. Three-year OS and EFS rates, as well as longer term survival rates (5 year and 10 year) will be estimated with 95% confidence intervals.Number of Participants With 3-year Overall Survival (OS) Three years after the last enrollment All eligible patients who started the treatment will be included in this analysis. Patients later found ineligible will be replaced and excluded from the estimation. Death for any reason is considered as a failure.
Kaplan-Meier estimates of the OS and EFS functions will be computed, along with estimates of standard errors by the method of Peto. Three-year OS and EFS rates, as well as longer term survival rates (5 year and 10 year) will be estimated with 95% confidence intervals.Number of Participant With 10-year Event Free Survival Ten years after the last enrollment All eligible patients who started the treatment will be included in this analysis. Patients later found ineligible will be replaced and excluded from the estimation. In addition to death for any reason, no-response (i.e., other than CR, CRi, PR or PRi), off-treatment or off-study (except for the reason of being found ineligible), disease progression, relapse, and second malignancies will be considered as failures. The time to EFS will be set to 0 for patients who fail to respond.
Kaplan-Meier estimates of the OS and EFS functions will be computed, along with estimates of standard errors by the method of Peto. Three-year OS and EFS rates, as well as longer term survival rates (5 year and 10 year) will be estimated with 95% confidence intervals.Number of Participants With 10-year Overall Survival Ten years after the last enrollment All eligible patients who started the treatment will be included in this analysis. Patients later found ineligible will be replaced and excluded from the estimation. Death for any reason is considered as a failure.
Kaplan-Meier estimates of the OS and EFS functions will be computed, along with estimates of standard errors by the method of Peto. Three-year OS and EFS rates, as well as longer term survival rates (5 year and 10 year) will be estimated with 95% confidence intervals.Number of Participants With 5- Year Event Free Survival Five years after the last enrollment All eligible patients who started the treatment will be included in this analysis. Patients later found ineligible will be replaced and excluded from the estimation. In addition to death for any reason, no-response (i.e., other than CR, CRi, PR or PRi), off-treatment or off-study (except for the reason of being found ineligible), disease progression, relapse, and second malignancies will be considered as failures. The time to EFS will be set to 0 for patients who fail to respond.
Kaplan-Meier estimates of the OS and EFS functions will be computed, along with estimates of standard errors by the method of Peto. Three-year OS and EFS rates, as well as longer term survival rates (5 year and 10 year) will be estimated with 95% confidence intervals.Number of Participants With 5-year Overall Survival Five years after the last enrollment All eligible patients who started the treatment will be included in this analysis. Patients later found ineligible will be replaced and excluded from the estimation. Death for any reason is considered as a failure.
Kaplan-Meier estimates of the OS and EFS functions will be computed, along with estimates of standard errors by the method of Peto. Three-year OS and EFS rates, as well as longer term survival rates (5 year and 10 year) will be estimated with 95% confidence intervals.Number of Relevant Toxicities Related to Therapy From on-therapy date up to 18 months Events were graded using CTCAE v. 4.0. All toxicities will be monitored until the completion of therapy (up to 500 days) for patients that do not go on to bone marrow transplant. If a patient goes on to receive a bone marrow transplant, at that point, they will no longer be monitored for toxicity, as any further toxicities may be secondary to the transplant and not the study regimen.
This outcome reports those toxicities that are that were possibly, probably or definitely related to therapy. Participants were separately monitored for frequency of grade 5 events, grade 4 sepsis, grade 4 hemorrhage, and grade 4 hepatic toxicity across all patients in the stratum. Grade 4 and 5 events that are clearly and incontrovertibly due to extraneous causes or disease progression will be excluded. Higher grade events are considered more severe than lower grade.
Trial Locations
- Locations (1)
St. Jude Children's Research Hospital
🇺🇸Memphis, Tennessee, United States