S0919 Idarubicin, Cytarabine, and Pravastatin in Treating Patients With Relapsed Acute Myeloid Leukemia
Condition: Leukemia
MeSH terms: Leukemia
Intervention: cytarabine; idarubicin; pravastatin sodium
Intervention description: 1.5 g/m2/day given by continuous IV on days 4-7; 12 mg/m2/day given intravenously over 10-15 minutes on days 4-6; 1,280 mg/day given orally on days 1-8
Intervention MeSH terms: Cytarabine; Idarubicin; Pravastatin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 115.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: recurrent adult acute myeloid leukemia; adult acute myeloid leukemia with 11q23 (MLL) abnormalities; adult acute myeloid leukemia with inv(16)(p13;q22); adult acute myeloid leukemia with t(15;17)(q22;q12); adult acute myeloid leukemia with t(16;16)(p13;q22); adult acute myeloid leukemia with t(8;21)(q22;q22)

Summary:

      RATIONALE: Drugs used in chemotherapy, such as idarubicin and cytarabine, work in different
      ways to stop the growth of cancer cells, either by killing the cells or by stopping them from
      dividing. Pravastatin may stop the growth of cancer cells by blocking some of the enzymes
      needed for cell growth. Pravastatin may also help idarubicin and cytarabine work better by
      making cancer cells more sensitive to the drugs. Giving idarubicin and cytarabine together
      with pravastatin may kill more cancer cells.

      PURPOSE: This phase II trial is studying how well giving idarubicin and cytarabine together
      with pravastatin works in treating patients with relapsed acute myeloid leukemia (AML).

      ADDITIONAL BACKGROUND: S0919 was initially designed for patients with relapsed acute myeloid
      leukemia (AML), where the patient's preceding remission had lasted ≥ 3 months. The null
      response rate was 30%. The study closed to accrual on Nov 1, 2012 after meeting the defined
      criterion for a positive study; and the results are being submitted to the American Society
      of Clinical Oncology meeting. Based on the promising results from this trial, the trial has
      now been amended to evaluate this therapeutic regimen in poor-risk patients (patients with
      newly diagnosed acute myeloid leukemia (AML) arising out of myelodysplastic syndrome (MDS),
      primary refractory acute myeloid leukemia (AML), and relapsed acute myeloid leukemia (AML)
      with the patient's preceding remission lasting < 6 months).
    

Eligibility criteria:

        Cohort 1 (Initial cohort: Relapsed AML with previous remission >/= 3 months) is permanently
        closed to accrual DISEASE CHARACTERISTICS

          -  Patients must have a previous morphologically confirmed diagnosis of acute myeloid
             leukemia (AML). Note: This protocol uses the World Health Organization (WHO)
             diagnostic criteria for acute myeloid leukemia (AML) (see Section 4.1). Patients with
             acute promyelocytic leukemia (APL, FAB, M3) or blastic transformation of chronic
             myelogenous leukemia (CMML) are not eligible.

          -  Patients must have received at least one prior chemotherapy regimen for their acute
             myeloid leukemia (AML) and they may have received any type of chemotherapy. They must
             have achieved complete remission (CR), lasting at least three months with their last
             induction regimen and they must have relapsed after the last regimen. Relapse must be
             documented by a bone marrow examination demonstrating > 5% blasts in the bone marrow
             not attributable to another cause. Refractory patients and patients who have received
             autologous or allogeneic stem cell transplantation are not eligible. Administration of
             hydroxyurea to control high white blood cell (WBC) count prior to, during and after
             registration is permitted.

          -  Patients must not have symptomatic congestive heart failure, coronary artery disease,
             cardiomyopathy, or uncontrolled arrhythmias. Either an echocardiogram or
             multiple-gated acquisition (MUGA) scan with an ejection fraction ≥ 45% must be
             obtained within 28 days prior to registration. (Either method for measuring cardiac
             function is acceptable, however, the same scan must be used throughout treatment and
             follow-up to monitor the patient for cardiac toxicity.) If patient has symptoms
             suggestive of ischemia or congestive heart failure after that cardiac evaluation was
             done, a repeat study must be obtained prior to registration.

          -  Patients must have a serum creatinine < 2.0 mg/dl within 14 days prior to
             registration.

          -  Patients must have a total bilirubin ≤ 2.0 x Institutional Upper Limit of Normal
             (IULN) within 14 days prior to registration, unless the elevation is due primarily to
             elevated unconjugated hyperbilirubinemia secondary to Gilbert's syndrome or hemolysis
             and not to liver dysfunction.

          -  Patients must have SGOT (AST) ≤ 3.0 x IULN and SGPT (ALT) ≤ 3.0 x IULN within 14 days
             prior to registration. Treatment may begin with SGOT/SGPT above those limits, if the
             abnormalities are thought to be due to the patient's leukemia.

          -  Patients must have Zubrod performance status of 0-2 (see Section 10.8).

          -  Patients must be ≥ 18 years of age.

          -  Patients must not have clinical evidence of leptomeningeal disease (a spinal tap does
             not need to be performed).

          -  Patients not known to be HIV+ must be tested for HIV infection (the human
             immunodeficiency virus) within 14 days prior to registration (see Section 2.0 for
             justification). Patients who are HIV+ may be eligible providing they meet all of the
             following additional criteria within 14 days prior to registration:

               1. Patient must have no history of AIDS defining events.

               2. CD4 cells ≥ 500/mm3.

               3. Viral load of < 50 copies HIV mRNA/mm3 if on cART or < 25,000 copies HIV mRNA if
                  not on cART.

               4. No zidovudine or stavudine as part of cART. Patients who are HIV+ and do not meet
                  all of these criteria will not be eligible for this study.

          -  Patients with prior malignancy (other than AML) are eligible. However, the patient
             must be in remission from the prior malignancy and have completed all chemotherapy and
             radiotherapy at least 6 months prior to registration and all treatment related
             toxicities must have been resolved. NOTE: For patients with prior history of
             malignancy who have received anthracyclines or mediastinal/pericardial radiation in
             the past, the risk versus benefit of therapy should be weighed, particularly in the
             setting of receiving consolidation therapy.

          -  Patients must not have a systemic fungal, bacterial, viral or other infection that is
             not controlled (defined as exhibiting ongoing signs/symptoms related to the infection
             and without improvement, despite appropriate antibiotics or other treatment).

          -  Southwest Oncology Group patients must be registered on SWOG-9007 ("Cytogenetic
             Studies in Leukemia Patients"). Collection of pretreatment marrow specimens must be
             completed within 28 days prior to registration. Pretreatment specimens of bone marrow
             (or peripheral blood if the marrow aspirate is a dry tap) must be submitted to an
             approved Southwest Oncology Group Cytogenetics Laboratory for cytogenetics analysis.
             Note that protocol SWOG-9007 also requires submission of specimens at additional
             timepoints.

          -  Southwest Oncology Group patients must be offered participation in S9910 ("Leukemia
             Centralized Reference Laboratories and Tissue Repositories Ancillary"). If consent is
             given, collection of pretreatment blood and/or marrow specimens must be completed
             within 28 days prior to registration. If the patient consents to participate in S9910,
             pretreatment specimens of marrow and/or peripheral blood must be submitted to the
             Southwest Oncology Group Myeloid Repository at the University of New Mexico for
             cellular and molecular studies. Note that protocol S9910 also requests submission of
             specimens at additional timepoints.

          -  Women of reproductive potential must have a negative pregnancy test within 14 days
             prior to registration. Patients must not be pregnant or nursing because of the
             teratogenic potential of the drugs used in this study. Women/men of reproductive
             potential must have agreed to use an effective contraceptive method.

          -  All patients must be informed of the investigational nature of this study and must
             sign and give written informed consent in accordance with institutional and federal
             guidelines.

          -  At the time of patient registration, the treating institution's name and ID number
             must be provided to the Data Operations Center in Seattle in order to ensure that the
             current (within 365 days) date of institutional review board approval for this study
             has been entered into the data base.

        Cohort 2 (MDS transformed to AML) is permanently closed to accrual AND Cohort 3
        (relapsed/refractory AML) is permanently closed to accrual

        DISEASE CHARACTERISTICS:

          -  For patients registered to relapsed/refractory (Cohort 3), morphologically confirmed
             diagnosis of acute myeloid leukemia (AML)

          -  Patient registered to the myelodysplastic syndrome (MDS) transformed to acute myeloid
             leukemia (AML) cohort (Cohort 2) patients must have a previous morphologically
             confirmed diagnosis of myelodysplastic syndrome/chronic myelomonocytic leukemia
             (MDS/CMML). Patients may have received previous non-intensive therapy (such as:
             azacitidine, decitabine, low-dose cytarabine, lenalidomide) given treatment of
             myelodysplastic syndrome/chronic myelomonocytic leukemia (MDS/CMML) (with up to 20%
             blasts). At time of registration, patient must have morphologically confirmed
             diagnosis of acute myeloid leukemia (AML).

          -  Patients with acute promyelocytic leukemia (i.e., APL, FAB M3) or blastic
             transformation of chronic myelogenous leukemia are not eligible

          -  Patients must not have received autologous or allogeneic stem cell transplant.

          -  Patients in the relapsed/refractory acute myeloid leukemia (AML) cohort (Cohort 3)
             must:

               -  Have received ≥ 1 prior chemotherapy regimen for acute myeloid leukemia (AML)

                    -  Any type of prior chemotherapy allowed

                    -  Administration of hydroxyurea to control high white blood cell (WBC) prior
                       to, during, and after registration is permitted

               -  Relapse must be documented by a bone marrow examination demonstrating > 5% blasts
                  in the bone marrow not attributable to another cause

               -  Patient must not have received chemo within 14 days prior to registration

          -  Primary refractory patients eligible if, on Day 14 of previous chemo regimen, they
             have significant residual disease. Patients who received only hypomethylating agent or
             low dose therapy for Induction are not considered primary refractory for this study
             and are not eligible.

          -  Relapsed patients must have achieved a complete remission (CR) or CR with incomplete
             blood count recovery that lasted < 6 months after the last induction regimen

          -  No clinical evidence of leptomeningeal disease

          -  Pretreatment (collected within 28 days of registration) cytogenetics must be performed
             on all patients.

          -  Patients must have complete history and physical exam within 28 days prior to
             registration.

        PATIENT CHARACTERISTICS:

          -  No symptomatic congestive heart failure, coronary artery disease, cardiomyopathy, or
             uncontrolled arrhythmias

               -  Ejection fraction ≥ 45% by echocardiogram or MUGA scan within 28 days prior to
                  registration (or within 14 days prior to registration if the patient has received
                  anthracycline in the 28 day window)

          -  Zubrod performance status 0-2

          -  Serum creatinine ≤ 2.0 times upper limit of normal (ULN)

          -  Total bilirubin ≤ 2.0 times ULN (unless elevation is primarily due to elevated
             unconjugated hyperbilirubinemia secondary to Gilbert's syndrome or hemolysis AND not
             due to liver dysfunction)

          -  AST and ALT ≤ 3.0 times ULN

          -  Not pregnant or nursing and negative pregnancy test within 14 days prior to
             registration. Females of child-bearing potential must agree to use effective
             contraception

          -  No HIV positivity unless the following criteria are met:

               -  No history of AIDS-defining events

               -  CD4 count ≥ 500/mm³

               -  Viral load < 25,000 copies (< 50 copies if on combination antiretroviral therapy)

               -  Not receiving zidovudine or stavudine as part of combination antiretroviral
                  therapy

          -  No uncontrolled systemic fungal, bacterial, viral, or other infection, defined as
             exhibiting ongoing signs/symptoms related to the infection with no improvement despite
             appropriate antibiotics or other treatment

          -  Patients with prior malignancy (other than AML and MDS/CMML) eligible provided patient
             is in remission from that malignancy at least 6 months prior to registration. Except
             for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) treatment, all
             treatment related toxicities must have been resolved.