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

This study has been terminated.
Sponsor:
Collaborator:
Information provided by:
Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier:
NCT01342887
First received: April 22, 2011
Last updated: June 18, 2012
Last verified: June 2012
  Purpose

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


Condition Intervention Phase
Adult Acute Megakaryoblastic Leukemia (M7)
Adult Acute Minimally Differentiated Myeloid Leukemia (M0)
Adult Acute Monoblastic Leukemia (M5a)
Adult Acute Monocytic Leukemia (M5b)
Adult Acute Myeloblastic Leukemia With Maturation (M2)
Adult Acute Myeloblastic Leukemia Without Maturation (M1)
Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
Adult Acute Myeloid Leukemia With Del(5q)
Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
Adult Acute Myelomonocytic Leukemia (M4)
Adult Erythroleukemia (M6a)
Adult Pure Erythroid Leukemia (M6b)
Recurrent Adult Acute Myeloid Leukemia
Drug: cyclosporine
Drug: pravastatin sodium
Drug: mitoxantrone hydrochloride
Drug: etoposide
Procedure: bone marrow aspiration
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Fred Hutchinson Cancer Research Center:

Primary Outcome Measures:
  • Maximum tolerated doses mitoxantrone hydrochloride and etoposide when combined with cyclosporine and pravastatin sodium [ Time Frame: After completion of first 2 courses ] [ Designated as safety issue: Yes ]
    Assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

  • CR/CRi rate [ Time Frame: After completion of first 2 courses ] [ Designated as safety issue: No ]
    Categorized according to criteria recommended by an International Working Group.


Secondary Outcome Measures:
  • Disease-free survival of patients that achieve CR/CRi [ Time Frame: Up to 4.5 years ] [ Designated as safety issue: No ]
  • Frequency and severity of regimen-associated toxicities [ Time Frame: Up to 1 month after completion of study treatment ] [ Designated as safety issue: Yes ]
  • Treatment-related mortality score [ Time Frame: At 28 days ] [ Designated as safety issue: No ]

Enrollment: 6
Study Start Date: April 2011
Study Completion Date: March 2012
Primary Completion Date: March 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (immunosuppression, enzyme inhibitor, and chemo)
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.
Drug: cyclosporine
Given IV
Other Names:
  • ciclosporin
  • cyclosporin
  • cyclosporin A
  • CYSP
  • Sandimmune
Drug: pravastatin sodium
Given PO
Other Names:
  • PRAV
  • Pravachol
Drug: mitoxantrone hydrochloride
Given IV
Other Names:
  • CL 232315
  • DHAD
  • DHAQ
  • Novantrone
Drug: etoposide
Given IV
Other Names:
  • EPEG
  • VP-16
  • VP-16-213
Procedure: bone marrow aspiration
Correlative studies

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01342887

Locations
United States, Washington
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Seattle, Washington, United States, 98109
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Investigators
Principal Investigator: Roland Walter Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
  More Information

No publications provided

Responsible Party: Walter, Roland, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
ClinicalTrials.gov Identifier: NCT01342887     History of Changes
Other Study ID Numbers: 2409.00, NCI-2011-00657
Study First Received: April 22, 2011
Last Updated: June 18, 2012
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Leukemia
Leukemia, Myelomonocytic, Acute
Leukemia, Myelomonocytic, Chronic
Leukemia, Monocytic, Acute
Leukemia, Megakaryoblastic, Acute
Leukemia, Erythroblastic, Acute
Neoplasms by Histologic Type
Neoplasms
Myelodysplastic-Myeloproliferative Diseases
Bone Marrow Diseases
Hematologic Diseases
Myeloproliferative Disorders
Etoposide
Mitoxantrone
Etoposide phosphate
Cyclosporins
Cyclosporine
Pravastatin
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors

ClinicalTrials.gov processed this record on October 16, 2014