Re-Induction Therapy for Relapsed Pediatric T-Cell Acute Lymphoblastic Leukemia or Lymphoma
Condition: Acute Lymphoblastic Leukemia; Lymphoma, Non-Hodgkin's; Leukemia, T-Cell; Leukemia, B-Cell
MeSH terms: Lymphoma; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Lymphoma, Non-Hodgkin; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, B-Cell; Leukemia, T-Cell
Intervention: Dexamethasone; Panobinostat; Liposomal vincristine; Mitoxantrone; Peg-asparaginase; Bortezomib; Intrathecal Triples; High-dose methotrexate; 6-Mercaptopurine; High-dose cytarabine; Nelarabine; Cyclophosphamide; Etoposide; Clofarabine
Intervention description: Given orally (PO).; Given PO.; For intravenous (IV) use only.; Given IV.; Given IV or intramuscularly (IM).
In case of allergy or intolerance to Peg-asparaginase, Erwinia L-asparaginase (Erwinase®) will be used. Erwinia L-asparaginase is given by either IV or IM injection.; Given by IV push over 3 to 5 seconds. For IV use only.; Given IT as ITMHA.; Given intrathecally (IT) or IV.; Given PO at consistent time each day.; Given IT or IV.; Given IV; Given IV.; Given IV.
In case of etoposide reactions, IV etoposide phosphate (Etopophos®) will be used.; Given IV.
Clofarabine will be given instead of nelarabine for patients with B-lymphoblastic leukemia and lymphoma in stratum II.
Intervention MeSH terms: Cytarabine; Dexamethasone; Hydrocortisone; Cyclophosphamide; Methotrexate; Etoposide; Vincristine; Bortezomib; Asparaginase; Mitoxantrone; Mercaptopurine; Clofarabine; Panobinostat; Pegaspargase
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 3.0
Sex: All
Maximum age: 21 Years
Healthy volunteers: No
Keywords: Hematopoietic Stem Cell Transplantation; Salvage Regimen; Re-Induction Therapy; Multi-agent chemotherapy

Summary:

      This is a phase-II study to evaluate the efficacy of a salvage regimen in children with
      relapsed T-cell ALL or lymphoma. Peg-asparaginase, mitoxantrone, intrathecal triples (IT)
      (intrathecal methotrexate/hydrocortisone/cytarabine) (ITMHA) and dexamethasone are commonly
      used drugs to treat relapsed or refractory acute lymphocytic leukemia or lymphoma (ALL). In
      this study, the investigators want to know if adding three drugs called panobinostat,
      bortezomib and liposomal vincristine (VSLI) to this regimen will result in remission (no
      signs or symptoms of leukemia or lymphoma).

        -  Panobinostat has been approved by the FDA for treating adults with multiple myeloma, but
           it has not been approved for use in children and has not been given together with the
           other drugs used in this study. It has not been widely studied in children.

        -  VSLI has been approved by the FDA for adults with relapsed or refractory ALL, but has
           not yet been approved for treating children with leukemia or lymphoma.

        -  Bortezomib has been approved by the FDA for treating adults with a cancer called
           multiple myeloma and adults with relapsed mantle cell lymphoma; it has not been approved
           for treating children.

      PRIMARY OBJECTIVE:

        -  To estimate the complete remission (CR) rate for patients with T-cell lymphoblastic
           leukemia and lymphoma in first relapse.

      SECONDARY OBJECTIVES:

        -  To evaluate minimal residual disease (MRD) levels at end of each block of therapy.

        -  To describe the toxicities of vincristine sulfate liposome injection (VSLI) when used in
           combination with chemotherapy and bortezomib.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Participants must have relapsed or refractory acute lymphoblastic leukemia or lymphoma
             (ALL):

               -  Stratum I: T-cell lymphoblastic leukemia or lymphoma in first relapse or
                  refractory to one or two courses of frontline induction therapy.

               -  Stratum II: B-cell or T-cell lymphoblastic leukemia or lymphoma in second or
                  third relapse or refractory to 2 or 3 induction or re-induction attempts.
                  Patients with Ph+ ALL must be refractory or relapsed after treatment with regimen
                  that included a tyrosine kinase inhibitor (TKI).

          -  Relapse in ALL is defined as the reappearance (in a patient who has previously
             achieved remission) of leukemic blasts in the bone marrow.

               -  Should flow cytometric analyses suggest relapse (by the reappearance of a similar
                  immunophenotype to the original leukemia) in the presence of <5% blasts
                  morphologically, a repeat bone marrow test is recommended to confirm relapse.

               -  Molecular or genetic relapse is characterized by the reappearance of a
                  cytogenetic or molecular abnormality.

          -  Age is ≤ 21 years (participant has not yet reached 22nd birthday).

          -  Able to swallow capsules.

          -  Karnofsky or Lansky performance score is ≥ 60%. The Lansky performance score should be
             used for participants < 16 years and the Karnofsky performance score for participants
             ≥ 16 years.

          -  Prior therapy:

               -  There is no waiting period for participants who relapse while receiving therapy
                  if they are free from side effects attributable to such therapy.

               -  Emergent radiation therapy, one dose of intrathecal chemotherapy and up to 7 days
                  of steroids or hydroxyurea are permitted before start of treatment in
                  participants who relapse after completion of frontline therapy. Other
                  circumstances must be cleared by PI or medical designee.

               -  At least 90 days have elapsed since bone marrow transplant and participant is off
                  immune suppression for ≥ 2 weeks, if applicable.

          -  Adequate renal function defined as glomerular filtration rate ≥ 60 cc/min/1.73m^2 or
             serum creatinine based on age as follows:

               -  If age is 1 to 2 years, then maximum serum creatinine (mg/dL) is 0.6 for males or
                  females.

               -  If age is 2 to 6 years, then maximum serum creatinine (mg/dL) is 0.8 for males or
                  females.

               -  If age is 6 to 10 years, then maximum serum creatinine (mg/dL) is 1 for males or
                  females.

               -  If age is 10 to <13 years, then maximum serum creatinine (mg/dL) is 1.2 for males
                  or females.

               -  If age is 13 to 16 years, then maximum serum creatinine (mg/dl) is 1.5 for males
                  or 1.4 for females.

               -  If age is > 16 years, then maximum serum creatinine (mg/dl) is 1.7 for males or
                  1.4 for females.

          -  Adequate hepatic function defined as:

               -  Direct bilirubin ≤ 1.4 mg/dL (if total bilirubin > 1.4 mg/dL) AND

               -  AST and ALT < 5 x ULN for age.

          -  Adequate cardiac function defined as shortening fraction of ≥ 27% or ejection fraction
             ≥ 45%.

          -  Lymphoma participants without bone marrow involvement must have:

               -  Absolute neutrophil count (ANC) >1,000/mm3, AND

               -  Platelet count ≥50,000/mm^3 (without transfusion support)

               -  NOTE: These criteria are waived for participants with leukemia or lymphoma
                  participants with bone marrow involvement.

          -  Written, informed consent and assent following Institutional Review Board, NCI, FDA
             and OHRP guidelines.

        Exclusion Criteria:

          -  Prior histone deacytylases (HDAC), DAC, HSP90 inhibitors or valproic acid for
             treatment of cancer.

          -  Patients who will need valproic acid for any medical condition during the study or
             within 5 days prior to first panobinostat treatment.

          -  Impaired cardiac function or clinically significant cardiac diseases, history of
             arrhythmia (including ventricular fibrillation or torsade de pointes), bradycardia <50
             bpm, screening ECG with prolonged QTc or uncontrolled hypertension.

          -  Impairment of gastrointestinal (GI) function or GI disease that may significantly
             alter the absorption of panobinostat.

          -  Patients with diarrhea > CTCAE grade 2.

          -  Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled
             diabetes or active or uncontrolled infection) including abnormal laboratory values,
             that could cause unacceptable safety risks or compromise compliance with the protocol.

          -  Patients using medications that have a relative risk of prolonging the QT interval or
             inducing torsade de pointes if treatment cannot be discontinued or switched to a
             different medication prior to starting treatment.

          -  Patients who have received targeted agents within 2 weeks or within 5 half-lives of
             the agent and active metabolites (whichever is longer) and who have not recovered from
             side effects of those therapies.

          -  Patients who have undergone major surgery ≤ 4 weeks prior to starting treatment or who
             have not recovered from side effects of such therapy.

          -  Patients with known positivity for human immunodeficiency virus (HIV) or hepatitis
             B/C.

          -  Inability to swallow capsules.

          -  Active, uncontrolled infection or severe concurrent medical disease, including but not
             limited to congestive heart failure, cardiac arrhythmias, or psychiatric illness.

          -  Isolated extramedullary relapse (leukemia) or isolated CNS lymphoma.

          -  Pregnant or lactating (female participant of childbearing potential must have negative
             serum or urine pregnancy test required within 7 days prior to start of treatment).
             Male or female of reproductive potential has agreed to use effective contraception
             method for duration of study treatment.

          -  Down syndrome.

          -  Inability or unwillingness or research participant or legal guardian/representative to
             give written informed consent.