Cyclosporine, Pravastatin Sodium, Etoposide, and Mitoxantrone Hydrochloride in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

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Brief Title

Cyclosporine, Pravastatin Sodium, Etoposide, and Mitoxantrone Hydrochloride in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

Official Title

Cyclosporine Modulation of Drug Resistance in Combination With Pravastatin, Mitoxantrone, and Etoposide for Adult Patients With Relapsed/Refractory Acute Myeloid Leukemia (AML): A Phase 1/2 Study

Brief Summary

      This phase I/II trial studies the side effects and best dose of etoposide and mitoxantrone
      hydrochloride when given together with cyclosporine and pravastatin sodium and to see how
      well they work in treating patients with relapsed or refractory acute myeloid leukemia (AML).
      Cyclosporine may inhibit efflux of cancer drugs out of cancer cells and may thereby improve
      chemotherapy treatment for AML. Pravastatin sodium may stop the growth of cancer cells by
      blocking some of the nutrients needed for cell growth. Drugs used in chemotherapy, such as
      etoposide and mitoxantrone hydrochloride, work in different ways to stop the growth of cancer
      cells, either by killing the cells or by stopping them from dividing. Giving cyclosporine
      together with pravastatin sodium, etoposide, and mitoxantrone hydrochloride may kill more
      cancer cells
    

Detailed Description

      PRIMARY OBJECTIVES:

      I. Determine the maximum tolerated doses of mitoxantrone (mitoxantrone hydrochloride) and
      etoposide in combination with pravastatin (pravastatin sodium) and cyclosporine.

      SECONDARY OBJECTIVES:

      I. Describe the complete remission (CR)/CR with incomplete peripheral blood count recovery
      (CRi) rate after up to 2 cycles of induction therapy.

      II. Describe the disease-free survival of patients that achieve CR/CRi. III. Estimate the
      frequency and severity of regimen-associated toxicities, along with 28-day mortality after
      start of study treatment.

      OUTLINE: This is a phase I/II, dose-escalation study of etoposide and mitoxantrone
      hydrochloride in combination with pravastatin sodium and cyclosporine.

      Patients receive cyclosporine intravenously (IV) continuously on days 5-9. Patients also
      receive pravastatin sodium orally (PO) every 6 hours on days 1-10, etoposide IV continuously
      on days 5-9, and mitoxantrone hydrochloride IV continuously on days 5-9. Treatment repeats
      for up to 2 courses in the absence of disease progression or unacceptable toxicity. Patients
      achieving CR/CRi may receive 2 additional courses in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, patients are followed up for 1 month.
    

Study Phase

Phase 1/Phase 2

Study Type

Interventional


Primary Outcome

Maximum Tolerated Doses Mitoxantrone Hydrochloride and Etoposide When Combined With Cyclosporine and Pravastatin Sodium

Secondary Outcome

 CR/CRi

Condition

Adult Acute Megakaryoblastic Leukemia (M7)

Intervention

cyclosporine

Study Arms / Comparison Groups

 Treatment (immunosuppression, enzyme inhibitor, and chemo)
Description:  Patients receive cyclosporine IV continuously on days 5-9. Patients also receive pravastatin sodium PO every 6 hours on days 1-10, etoposide IV continuously on days 5-9, and mitoxantrone hydrochloride IV continuously on days 5-9. Treatment repeats for up to 2 courses in the absence of disease progression or unacceptable toxicity. Patients achieving CR/CRi may receive 2 additional courses in the absence of disease progression or unacceptable toxicity.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

6

Start Date

April 2011

Completion Date

March 2012

Primary Completion Date

March 2012

Eligibility Criteria

        Inclusion Criteria:

          -  Treatment-related mortality (TRM) score =< 9.2 as calculated with simplified model

          -  Prior morphological diagnosis of AML according to the 2008 World Health Organization
             (WHO) diagnostic criteria; patients with biphenotypic AML are eligible; patients with
             acute promyelocytic leukemia with t(15;17)(q22;q12) and variants are ineligible

          -  Relapsed/persistent disease as defined by International Working Group criteria;
             outside diagnostic material is acceptable as long as peripheral blood and/or bone
             marrow slides are reviewed at the study institution; flow cytometric analysis of
             peripheral blood and/or bone marrow should be performed according to institutional
             practice guidelines

          -  Patients with prior autologous or allogeneic hematopoietic cell transplantation (HCT)
             are eligible if relapse occurs > 180 days post-transplant provided symptoms of
             graft-versus host disease are well controlled with stable use of immunosuppressive
             agents

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-3, assessed at time
             of registration

          -  Should be off any active therapy for AML with the exception of hydroxyurea or low-dose
             cytarabine (=< 100 mg/m^2) for at least 14 days prior to study registration unless
             patient has rapidly progressive disease, and all Grade 2-4 non-hematologic toxicities
             must have resolved

          -  Bilirubin =< 2 x Institutional Upper Limit of Normal (IULN) unless elevation is
             thought to be due to hepatic infiltration by AML, Gilbert's syndrome, or hemolysis
             (assessed within 7 days prior to registration)

          -  Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and
             serum glutamic pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 2 x
             IULN unless elevation is thought to be due to hepatic infiltration by AML (assessed
             within 7 days prior to registration)

          -  Serum creatinine =< 1.5 x IULN (assessed within 7 days prior to registration)

          -  Left ventricular ejection fraction >= 40%, assessed within 28 days prior to
             registration, e.g. by multi gated acquisition scan (MUGA) scan or echocardiography, or
             other appropriate diagnostic modality, and no clinical evidence of congestive heart
             failure; if the patient had anthracycline-based therapy since the most recent cardiac
             assessment, cardiac evaluation should be repeated if there is clinical or
             radiographical suspicion of cardiac dysfunction, or if the previous cardiac assessment
             was abnormal

          -  Patients with symptoms/signs of hyperleukocytosis or white blood cell (WBC) >
             100,000/uL can be treated with leukapheresis prior to enrollment

          -  Women of childbearing potential and men must agree to use adequate contraception
             (hormonal or barrier method of birth control; abstinence) prior to study entry and for
             the duration of study participation

          -  Ability to understand and the willingness to sign a written informed consent document;
             the consent can be obtained from a legally authorized representative if the patient is
             unable to provide informed consent

        Exclusion Criteria:

          -  Diagnosis of another malignancy, unless the patient was diagnosed at least 2 years
             earlier and has been disease-free for at least 6 months following the completion of
             curative intent therapy with the following exceptions:

               -  Patients with treated non-melanoma skin cancer, in situ carcinoma, or cervical
                  intraepithelial neoplasia, regardless of the disease-free duration, are eligible
                  for this study if definitive treatment for the condition has been completed

               -  Patients with organ-confined prostate cancer with no evidence of recurrent or
                  progressive disease based on prostate-specific antigen (PSA) values are also
                  eligible for this study if hormonal therapy has been initiated or a radical
                  prostatectomy has been performed

          -  Refractory/relapsing blast crisis of chronic myelogenous leukemia (CML)

          -  Known hypersensitivity to any study drug

          -  Human immunodeficiency virus (HIV)-positive patients are excluded if their cluster of
             differentiation (CD)4 count is below 200 cells/uL or if they have active acquired
             immune deficiency syndrome (AIDS)-related complications, as these patients are at
             increased risk of lethal infections when treated with marrow-suppressive therapy

          -  Pregnancy or lactation; women of childbearing potential must undergo pregnancy test
             within 7 days prior to registration

          -  Uncontrolled systemic fungal, bacterial, viral, or other infection (defined as
             exhibiting progressive signs/symptoms related to the infection and without
             improvement, despite appropriate antibiotics or other treatment)

          -  Patients may not be receiving any other investigational agents
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Roland Walter, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT01342887

Organization ID

2409.00

Secondary IDs

NCI-2011-00657

Responsible Party

Principal Investigator

Study Sponsor

Fred Hutchinson Cancer Research Center

Collaborators

 National Cancer Institute (NCI)

Study Sponsor

Roland Walter, Principal Investigator, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium


Verification Date

June 2017