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

Primary Purpose

Adult Acute Megakaryoblastic Leukemia (M7), Adult Acute Minimally Differentiated Myeloid Leukemia (M0), Adult Acute Monoblastic Leukemia (M5a)

Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
cyclosporine
pravastatin sodium
mitoxantrone hydrochloride
etoposide
bone marrow aspiration
Sponsored by
Fred Hutchinson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Adult Acute Megakaryoblastic Leukemia (M7)

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (immunosuppression, enzyme inhibitor, and chemo)

Arm 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.

Outcomes

Primary Outcome Measures

Maximum Tolerated Doses Mitoxantrone Hydrochloride and Etoposide When Combined With Cyclosporine and Pravastatin Sodium
Determine the doses of mitoxantrone and etoposide that, when combined with CSA and pravastatin, meet minimum standards for both efficacy and toxicity and have the highest efficacy rate among several mitoxantrone and etoposide doses. Assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

Secondary Outcome Measures

CR/CRi
Describe the disease-free survival of patients that achieve Complete Remission (CR)/CR with inadequate recovery of peripheral blood cell counts (CRi). Categorized according to criteria recommended by an International Working Group.
Disease-free Survival of Patients That Achieve CR/CRi
Describe the disease-free survival of patients that achieve CR/CRi.
Frequency and Severity of Regimen-associated Toxicities
Estimate the frequency and severity of regimen-associated toxicities, along with 28-day mortality after start of study treatment

Full Information

First Posted
April 22, 2011
Last Updated
June 27, 2017
Sponsor
Fred Hutchinson Cancer Center
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT01342887
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
Study Type
Interventional

2. Study Status

Record Verification Date
June 2017
Overall Recruitment Status
Terminated
Study Start Date
April 2011 (undefined)
Primary Completion Date
March 2012 (Actual)
Study Completion Date
March 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Fred Hutchinson Cancer Center
Collaborators
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
6 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (immunosuppression, enzyme inhibitor, and chemo)
Arm Type
Experimental
Arm 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.
Intervention Type
Drug
Intervention Name(s)
cyclosporine
Other Intervention Name(s)
ciclosporin, cyclosporin, cyclosporin A, CYSP, Sandimmune
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
pravastatin sodium
Other Intervention Name(s)
PRAV, Pravachol
Intervention Description
Given PO
Intervention Type
Drug
Intervention Name(s)
mitoxantrone hydrochloride
Other Intervention Name(s)
CL 232315, DHAD, DHAQ, Novantrone
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
etoposide
Other Intervention Name(s)
EPEG, VP-16, VP-16-213
Intervention Description
Given IV
Intervention Type
Procedure
Intervention Name(s)
bone marrow aspiration
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Maximum Tolerated Doses Mitoxantrone Hydrochloride and Etoposide When Combined With Cyclosporine and Pravastatin Sodium
Description
Determine the doses of mitoxantrone and etoposide that, when combined with CSA and pravastatin, meet minimum standards for both efficacy and toxicity and have the highest efficacy rate among several mitoxantrone and etoposide doses. Assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Time Frame
After completion of first 2 courses, up to 22 weeks
Secondary Outcome Measure Information:
Title
CR/CRi
Description
Describe the disease-free survival of patients that achieve Complete Remission (CR)/CR with inadequate recovery of peripheral blood cell counts (CRi). Categorized according to criteria recommended by an International Working Group.
Time Frame
After completion of first 2 courses, up to 22 weeks
Title
Disease-free Survival of Patients That Achieve CR/CRi
Description
Describe the disease-free survival of patients that achieve CR/CRi.
Time Frame
Up to 4.5 years
Title
Frequency and Severity of Regimen-associated Toxicities
Description
Estimate the frequency and severity of regimen-associated toxicities, along with 28-day mortality after start of study treatment
Time Frame
At 28 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Roland Walter
Organizational Affiliation
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Official's Role
Principal Investigator
Facility Information:
Facility Name
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States

12. IPD Sharing Statement

Learn more about this trial

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

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