S0919 Idarubicin, Cytarabine, and Pravastatin in Treating Patients With Relapsed Acute Myeloid Leukemia

Study Overview
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Brief Summary
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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).

Detailed Description
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COHORTS: Cohort 1 (Initial cohort: Relapsed AML with previous remission ≥ 3 months), Cohort 2 (Poor-risk cohort: MDS transformed to AML), Cohort 3 (Poor-risk cohort: Refractory or relapsed AML with previous remission < 6 months) OBJECTIVES: To test whether the complete remission (CR) rate (including CR with incomplete recovery) in patients with relapsed acute myeloid leukemia (AML) treated with idarubicin and cytarabine in combination with pravastatin is sufficiently high to warrant a phase III investigation. To estimate relapse-free survival and overall survival rates in these patients. To estimate the frequency and severity of toxicities of this regimen in these patients. To evaluate, in a preliminary manner, whether pre-study cytogenetic features correlate with response in these patients. OUTLINE: This is a multicenter study. Induction therapy: Patients receive oral pravastatin once daily on days 1-8, idarubicin IV over 10-15 minutes on days 4-6, and cytarabine IV continuously on days 4-7. Patients achieving complete remission proceed to consolidation therapy. Consolidation therapy: Beginning 30-60 days after the start of induction therapy, patients receive oral pravastatin once daily on days 1-6 and idarubicin IV over 10-15 minutes and cytarabine IV continuously on days 4 and 5. Treatment repeats approximately every 5 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed periodically for 5 years.

Official Title
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S0919, A Phase II Study of Idarubicin and Ara-C in Combination With Pravastatin for Poor-Risk Acute Myelogenous Leukemia

Conditions
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Leukemia

Intervention / Treatment
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* Drug: cytarabine
* Drug: idarubicin
* Drug: pravastatin sodium


Participation Criteria
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Eligibility Criteria
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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: Patient must have no history of AIDS defining events. CD4 cells ≥ 500/mm3. Viral load of < 50 copies HIV mRNA/mm3 if on cART or < 25,000 copies HIV mRNA if not on cART. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: treatment<br>Induction (1 cycle): pravastatin 1280 mg/d PO D 1-8 idarubicin 12 mg/m2/d IV D 4-6 cytarabine 1.5 g/m2/d continuous IV D 4-7 Consolidation (up to 2 cycles): pravastatin 1280 mg/d PO D 1-6 idarubicin 12 mg/m2/d IV D 4-5 cytarabine 1.5 g/m2/d continuous IV D 4-5 | Drug: cytarabine<br>* 1.5 g/m2/day given by continuous IV on days 4-7<br>Drug: idarubicin<br>* 12 mg/m2/day given intravenously over 10-15 minutes on days 4-6<br>Drug: pravastatin sodium<br>* 1,280 mg/day given orally on days 1-8<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Remission (CR) Rate (Including CR With Incomplete Recovery) | Participants who achieved morphological complete remission with or without incomplete blood count recovery. Per the Revised Recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia, morphologic complete remission requires that the patient achieve the morphologic leukemia-free state and have an absolute neutrophil count of more than 1,000/μL and platelets of ≥ 100,000/μL. | Up to 5 years after registration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency and Severity of Toxicity as Assessed by NCI CTCAE Version 3.0 | Number of patients with Grade 3-5 adverse events that were possibly, probably or definitely related to study drug are reported by given type of adverse event | Up to 5 years post registration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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)