Bortezomib, Vorinostat and Dexamethasone for Relapsed/Refractory Acute Lymphoblastic Leukemia (ALL)
Condition: Acute Lymphoblastic Leukemia
MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid
Intervention: Bortezomib; Vorinostat; Dexamethasone; Methotrexate; Imatinib mesylate
Intervention description: 1.3 mg/m^2 by intravenous pyelogram (IVP) over 3-5 seconds on days 1, 4, 8 and 11.; 180 mg/m^2 (max dose 400mg) by mouth (PO) divided twice a day (BID) on days 1-14; 6 mg/m^2 by mouth (PO) divided twice a day (BID) on days 4-15.; Intrathecal Methotrexate at age based dose on day 1 (repeat on day 15 or 16 for CNS positive patients only); For Ph+ acute lymphoblastic leukemia (ALL) patients only:
Imatinib Mesylate is allowable at 340 mg/m2 PO once a day (rounded to the nearest 100 mg) for age ≤18 years and 400 mg for >18 years on Days 1-16.
Intervention MeSH terms: Dexamethasone; Methotrexate; Bortezomib; Imatinib Mesylate; Vorinostat
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 2.0
Sex: All
Minimum age: 2 Years
Maximum age: 30 Years
Healthy volunteers: No

Summary:

      Both of bortezomib and vorinostat have identified Phase II doses for pediatric and adult
      patients of which no grade 4 dose limiting toxicities have been observed in prior studies.
      The pre-clinical synergy of these 2 agents when used in combination along with the lack of
      over-riding toxicities and different mechanisms of action provide strong rationale for a
      clinical trial investigating bortezomib and vorinostat in combination. This trial will use
      the identified Phase II dose which is at or below the maximum tolerated dose for both agents
      which have very acceptable toxicity profiles and such should prove feasible and tolerable in
      this relapsed/refractory ALL population.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Diagnosis of lymphoblastic lymphoma or acute lymphoblastic leukemia (ALL) with ≥ 5%
             blasts in the bone marrow (M2/M3) with or without extramedullary disease that meets
             one of the following criteria:

               -  Refractory Disease/Induction Failure: Failure to achieve initial remission after
                  2 attempts of standard induction therapy

               -  Relapsed Disease: Patients in relapse #1 or higher for whom standard curative
                  therapies or therapies to prolong survival do not exist.

        Patients who are Philadelphia chromosome-positive (Ph + ALL) are eligible provided they are
        not imatinib resistant or intolerant.

        Patients with CNS positive disease will be eligible.

          -  Age 2 to 30 years

          -  Karnofsky ≥ 50% for patients 16 years and older and Lansky status ≥ 50 for patients
             under 16 years of age.

          -  Patients must have a life expectancy ≥ 8 weeks as determined by the enrolling
             investigator.

          -  Have acceptable organ function as defined within 7 days of starting treatment:

               -  Renal: creatinine clearance ≥ 70ml/min/1.73m^2 or serum creatinine based on
                  age/gender as follows: Maximum serum creatinine (mg/dl) 0.8 for 2 years to <6
                  years; 1.0 for 6 years to <10 years; 1.2 for 10 years to <13 years; 1.5 male and
                  1.4 female for 13 years to <16 years; 1.7 male and 1.4 female for ≥ 16 years

               -  Hepatic: ALT < 5 x upper limit of normal (ULN) and total bilirubin ≤ 1.5x upper
                  limit of normal (ULN) for age.

               -  Cardiac: left ventricular ejection fraction ≥ 40% by echocardiogram/multi gated
                  acquisition scan (ECHO/MUGA). Normal QTc on electrocardiogram (EKG) (not to
                  exceed upper limit of normal - men: 430 milliseconds (ms); women: 450 ms;
                  children up to 15 years: 440 ms).

          -  Prior Therapy:

               -  Patients must have recovered from the non-hematologic toxic effects of all prior
                  therapy before entry onto this trial. Recovery is defined as a Common Toxicity
                  Criteria for Adverse Events (CTCAE) version 4.0 toxicity grade <2, unless
                  otherwise specified in the Inclusion and Exclusion Criteria.

        Cytotoxic therapy: Patients must have had their last dose of chemotherapy at least two
        weeks prior to study entry.

          -  Hematopoietic growth factors: At least 7 days since the completion of therapy with a
             growth factor and at least 14 days since pegfilgrastim (Neulasta®) administration.

          -  Biologic (anti-neoplastic) therapy: At least 7 days since the completion of therapy
             with a biologic agent. 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. The duration of this interval must be discussed
             with the study chair.

          -  Monoclonal antibodies: At least 3 half-lives of the antibody after the last
             administration of a monoclonal antibody.

          -  Hematopoietic Stem Cell Transplant (HSCT): Patients who have experienced their relapse
             after a HSCT are eligible, provided they have no evidence of Graft-versus-Host Disease
             (GVHD).

               -  Women of child bearing potential must agree to use adequate contraception
                  (diaphragm, birth control pills, injections, intrauterine device [IUD], surgical
                  sterilization, subcutaneous implants, or abstinence, etc.) for the duration of
                  treatment and for 2 months after the last dose of chemotherapy. Sexually active
                  men must agree to use barrier contraceptive for the duration of treatment and for
                  2 months after the last dose of chemotherapy.

               -  Voluntary written consent before performance of any study-related procedure not
                  part of normal medical care, with the understanding that consent may be withdrawn
                  by the subject/guardian at any time without prejudice to future medical care.

        Exclusion Criteria:

          -  Pregnant or lactating. The agents used in this study are known to be teratogenic to a
             fetus and there is no information on the excretion of agents into breast milk.
             Confirmation that the subject is not pregnant must be established by a negative serum
             beta-human chorionic gonadotropin (beta-hCG) pregnancy test result obtained during
             screening. Pregnancy testing is not required for surgically sterilized women.

          -  Known hypersensitivity to bortezomib, boron or mannitol or any of the agents or their
             ingredients used in this study.

          -  Inability to swallow capsules.

          -  Grade 2 or greater peripheral neuropathy within 14 days before study registration.

          -  Patients with untreated positive blood cultures or progressive infections as assessed
             by radiographic studies.

          -  Myocardial infarction within 6 months prior to enrollment or has New York Heart
             Association (NYHA) Class III or IV heart failure (appendix VI), uncontrolled angina,
             severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute
             ischemia or active conduction system abnormalities. Prior to study entry, any ECG
             abnormality at Screening has to be documented by the investigator as not medically
             relevant.

          -  Serious concomitant medical or psychiatric disorders (e.g., active infection,
             uncontrolled diabetes) that, in the opinion of the investigator, would compromise the
             safety of the patient or likely to interfere with participation in this clinical
             study.

          -  Diagnosed or treated for another malignancy within 3 years of enrollment, with the
             exception of complete resection of basal cell carcinoma or squamous cell carcinoma of
             the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy.

          -  Patient has received investigational drugs within the 14 days before study
             registration.

          -  Radiation therapy within 3 weeks before registration. Enrollment of patients who
             require concurrent radiotherapy (which must be localized in its field size) should be
             deferred until the radiotherapy is completed and 3 weeks have elapsed since the last
             date of therapy.