Bortezomib and Vorinostat in Younger Patients With Refractory or Relapsed MLL Rearranged Hematologic Malignancies
Condition: Mixed Lineage Acute Leukemia; Acute Myeloid Leukemia; Acute Lymphoid Leukemia
MeSH terms: Leukemia; Hematologic Neoplasms; Leukemia, Lymphoid; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Biphenotypic, Acute
Intervention: Bortezomib; Vorinostat; Mitoxantrone; Cytarabine; Methotrexate; Hydrocortisone; Peg-L-Asparaginase; Erwinia L-Asparaginase; Dexamethasone; Mercaptopurine; Doxorubicin
Intervention description: Bortezomib will be given as a 1 mg/mL solution intravenous (IV) push over 3 to 5 seconds. For subcutaneous (SQ) administration, bortezomib will be mixed at 2.5 mg/ml.; Vorinostat should be taken orally (PO) with food.; Given by intravenous (IV) injection.; Given by intravenous (IV) injection.; Methotrexate will be given intrathecally (IT) along with hydrocortisone and cytarabine.; Hydrocortisone will be given intrathecally (IT) along with methotrexate and cytarabine.; Given by intravenous (IV) or intramuscular (IM) injection.; To be used in case of allergy or intolerance to PEG-Asparaginase. Given by intravenous (IV) or intramuscular (IM) injection.; Given orally (PO) or intravenously (IV).; Given orally (PO).; Given intravenously (IV).
Intervention MeSH terms: Cytarabine; Dexamethasone; Hydrocortisone; Doxorubicin; Methotrexate; Bortezomib; Asparaginase; Mitoxantrone; Mercaptopurine; Vorinostat; Pegaspargase
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 12.0
Sex: All
Maximum age: 21 Years
Healthy volunteers: No
Keywords: Infant leukemia; ALL; AML; Biphenotypic leukemia; Pediatric

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.
    

Eligibility criteria:

        INCLUSION CRITERIA:

          -  Age: Patient is ≤ 21 years of age (i.e., eligible until 22nd birthday).

          -  Diagnosis: Participant has a hematologic malignancy that is positive for MLLr as
             determined by fluorescent in situ hybridization (FISH) or RT-PCR, and disease meets at
             least one of the following criteria:

               -  Relapsed after or is refractory to chemotherapy

               -  Relapsed after hematopoietic stem cell transplantation (HSCT)

               -  Relapsed or refractory secondary leukemia (Relapse is defined as reappearance of
                  leukemia cells after the attainment of complete remission and refractory is
                  defined as ≥5% blasts at the end of induction. Patients that achieved MRD
                  negative status followed by reappearance of blasts at less than 5% are eligible.)

          -  Patients must have had verification of the malignancy at relapse, including
             immunophenotyping, to confirm diagnosis.

          -  Performance Level: Karnofsky ≥50% for patients >16 years of age and Lansky ≥50 for
             patients ≤16 years of age (See Appendix III). Patients who are unable to walk because
             of paralysis, but who are up in a wheelchair, will be considered ambulatory for the
             purpose of assessing the performance score.

          -  Prior therapy:

               -  Patients who relapse while receiving standard ALL maintenance chemotherapy
                  consisting of daily 6MP, weekly methotrexate, monthly vincristine, and monthly
                  steroid pulse will not be required to have a waiting period before entry onto
                  this study.

               -  Patients who relapse on therapy other than standard ALL maintenance therapy must
                  have fully recovered from the acute toxic effects of all prior chemotherapy,
                  immunotherapy, or radiotherapy prior to entering this study.

               -  Cytotoxic therapy: At least 14 days since the completion of cytotoxic therapy
                  with the exception of hydroxyurea, low dose cytarabine, and intrathecal
                  chemotherapy which is permitted up to 24 hours prior to the start of protocol
                  therapy. For patients with aggressive disease that is in the peripheral blood and
                  rising, this 14 day washout period may be omitted.

               -  Biologic (anti-neoplastic) agent: At least 7 days since the completion of therapy
                  with a biologic agent or donor lymphocyte infusions (DLI). For agents that have
                  known adverse events occurring beyond 7 days after administration, this period
                  must be extended beyond the time during which adverse events are known to occur.

               -  Stem cell transplant or rescue: ≥2 months must have elapsed since the time of
                  transplant. Patients with active graft-vs-host disease (GVHD) are not eligible.

          -  Organ function requirements: All patients must have:

               -  Adequate renal function defined as: Creatinine clearance or radioisotope GFR ≥70
                  mL/min/1.73 m^2, OR adequate serum creatinine based on age/gender.

               -  Adequate liver function defined as: Total bilirubin ≤ ULN for age, or if total
                  bilirubin is > ULN, direct bilirubin is ≤ 1.4 mg/dL, AND SGPT (ALT) ≤4 x ULN for
                  age, unless elevation due to leukemic infiltration

               -  Adequate cardiac function defined as: Shortening fraction of ≥27% by
                  echocardiogram OR Ejection fraction of ≥50% by gated radionuclide study

               -  Central nervous system (CNS) function defined as: Patients with seizure disorder
                  may be enrolled if on allowed anti-convulsants and well controlled.
                  Benzodiazepines and gabapentin are acceptable. CNS toxicity ≤ Grade 2.

               -  Adequate pulmonary function defined as FVC>50% predicted OR, if unable to perform
                  pulmonary function testing, must maintain pulse oximetry oxygen saturation >92%
                  on room air.

        EXCLUSION CRITERIA:

          -  Patients requiring anticonvulsants known to activate the cytochrome p450 system, in
             particular anticonvulsants such as phenytoin, carbamazepine, and phenobarbital, are
             not eligible. Benzodiazepines and gabapentin are acceptable. Please see Appendix I for
             a list of drugs known to be potent inducers/inhibitors of the cytochrome p450 system
             and Appendix II for a list of anticonvulsants based on CYP3A4/5 enzyme induction.

          -  ALL patients who cannot receive any asparaginase products (E. Coli, PEG-asparaginase,
             or Erwinia asparaginase) on this study (eg, due to prior severe pancreatitis, stroke
             or other toxicity) are not eligible. Patients with clinically significant prior
             allergies to PEG-asparaginase are eligible if Erwinia L-asparaginase can be
             substituted.

          -  Pregnancy and breast feeding: patients who are pregnant or breast-feeding are not
             eligible for this study as there is as yet no available information regarding human
             fetal or teratogenic toxicities. Negative pregnancy tests must be obtained in girls
             who are post-menarchal. Males or females of reproductive potential may not participate
             unless they have agreed to use an effective birth control method.

          -  Investigational drugs: Patients who are currently receiving another investigational
             drug are not eligible.

          -  Anti-cancer agents: Patients who are currently receiving other anti-cancer agents with
             the exception of those delineated in the eligibility criteria.

          -  Infection: Patients who have an uncontrolled infection are not eligible. Infections
             controlled on concurrent anti-microbial agents are acceptable, and anti-microbial
             prophylaxis per institutional guidelines are acceptable.

          -  Known human immunodeficiency virus (HIV) infection (pre-study testing not required).

          -  Any significant concurrent disease, illness, or psychiatric disorder that would
             compromise patient safety or compliance, study participation, follow up, or
             interpretation of study research.

          -  Patients with Fanconi anemia, Kostmann syndrome, Shwachman syndrome, or other
             inherited bone marrow failure syndromes are not eligible.

          -  Patients who in the opinion of the investigator may not be able to comply with the
             safety monitoring requirements of the study are not eligible.