Clinical Trial: Bortezomib and Vorinostat in Younger Patients With Refractory or Relapsed MLL Rearranged Hematologic Malignancies

Study Status: Terminated
Recruit Status: Terminated
Study Type: Interventional

Official Title: A Phase II Study of Bortezomib and Vorinostat in Patients With Refractory or Relapsed MLL Rearranged Hematologic Malignancies

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 Summary:

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-asparagin
    Sponsor: St. Jude Children's Research Hospital

    Current Primary Outcome: Overall response rate in all participants [ Time Frame: 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.



    Original Primary Outcome: Overall response rate in all participants [ Time Frame: 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 the first treatment block (i.e., Induction Ia or Ib for myeloid and Induction for lymphoid and mixed lineage). Any eligible patient who starts the first treatment block is considered as evaluable. A response of CR, CRi, PR, or PRi is considered as 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 the 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.



    Current Secondary Outcome:

    • 3 year event free survival (EFS) [ Time Frame: 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.

    • 5 year event free survival [ Time Frame: 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.

    • 10 year event free survival [ Time Frame: 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.

    • 3 year overall survival (OS) [ Time Frame: 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.

    • 5 year overall survival [ Time Frame: 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.

    • 10 year overall survival [ Time Frame: 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 relevant toxicities related to therapy [ Time Frame: From on-therapy date up to 18 months ]

      Therapy-related 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 toxic

      Original Secondary Outcome: Same as current

      Information By: St. Jude Children's Research Hospital

      Dates:
      Date Received: April 14, 2015
      Date Started: April 2015
      Date Completion: October 2026
      Last Updated: January 5, 2017
      Last Verified: January 2016