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

Sponsor
Fred Hutchinson Cancer Center (Other)
Overall Status
Terminated
CT.gov ID
NCT01342887
Collaborator
National Cancer Institute (NCI) (NIH)
6
1
1
11
0.5

Study Details

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:
  1. Determine the maximum tolerated doses of mitoxantrone (mitoxantrone hydrochloride) and etoposide in combination with pravastatin (pravastatin sodium) and cyclosporine.
SECONDARY OBJECTIVES:
  1. Describe the complete remission (CR)/CR with incomplete peripheral blood count recovery (CRi) rate after up to 2 cycles of induction therapy.

  2. 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 Design

Study Type:
Interventional
Actual Enrollment :
6 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (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
Study Start Date :
Apr 1, 2011
Actual Primary Completion Date :
Mar 1, 2012
Actual Study Completion Date :
Mar 1, 2012

Arms and Interventions

Arm Intervention/Treatment
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

    Outcome Measures

    Primary Outcome Measures

    1. Maximum Tolerated Doses Mitoxantrone Hydrochloride and Etoposide When Combined With Cyclosporine and Pravastatin Sodium [After completion of first 2 courses, up to 22 weeks]

      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

    1. CR/CRi [After completion of first 2 courses, up to 22 weeks]

      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.

    2. Disease-free Survival of Patients That Achieve CR/CRi [Up to 4.5 years]

      Describe the disease-free survival of patients that achieve CR/CRi.

    3. Frequency and Severity of Regimen-associated Toxicities [At 28 days]

      Estimate the frequency and severity of regimen-associated toxicities, along with 28-day mortality after start of study treatment

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Locations

    Site City State Country Postal Code
    1 Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium Seattle Washington United States 98109

    Sponsors and Collaborators

    • Fred Hutchinson Cancer Center
    • National Cancer Institute (NCI)

    Investigators

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

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Roland Walter, Principal Investigator, Fred Hutchinson Cancer Center
    ClinicalTrials.gov Identifier:
    NCT01342887
    Other Study ID Numbers:
    • 2409.00
    • NCI-2011-00657
    First Posted:
    Apr 27, 2011
    Last Update Posted:
    Jul 2, 2017
    Last Verified:
    Jun 1, 2017

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Treatment (Immunosuppression, Enzyme Inhibitor, and Chemo)
    Arm/Group 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. cyclosporine: Given IV pravastatin sodium: Given PO mitoxantrone hydrochloride: Given IV etoposide: Given IV bone marrow aspiration: Correlative studies
    Period Title: Overall Study
    STARTED 6
    COMPLETED 4
    NOT COMPLETED 2

    Baseline Characteristics

    Arm/Group Title Treatment (Immunosuppression, Enzyme Inhibitor, and Chemo)
    Arm/Group 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. cyclosporine: Given IV pravastatin sodium: Given PO mitoxantrone hydrochloride: Given IV etoposide: Given IV bone marrow aspiration: Correlative studies
    Overall Participants 6
    Age (years) [Mean (Full Range) ]
    Mean (Full Range) [years]
    51
    Sex: Female, Male (Count of Participants)
    Female
    4
    66.7%
    Male
    2
    33.3%

    Outcome Measures

    1. Primary Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Treatment (Immunosuppression, Enzyme Inhibitor, and Chemo)
    Arm/Group 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. cyclosporine: Given IV pravastatin sodium: Given PO mitoxantrone hydrochloride: Given IV etoposide: Given IV bone marrow aspiration: Correlative studies
    Measure Participants 6
    Number [doses tolerated]
    0
    2. Secondary Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Treatment (Immunosuppression, Enzyme Inhibitor, and Chemo)
    Arm/Group 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. cyclosporine: Given IV pravastatin sodium: Given PO mitoxantrone hydrochloride: Given IV etoposide: Given IV bone marrow aspiration: Correlative studies
    Measure Participants 6
    CR
    0
    0%
    CRi
    0
    0%
    CR/CRi not achieved
    6
    100%
    3. Secondary Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Treatment (Immunosuppression, Enzyme Inhibitor, and Chemo)
    Arm/Group 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. cyclosporine: Given IV pravastatin sodium: Given PO mitoxantrone hydrochloride: Given IV etoposide: Given IV bone marrow aspiration: Correlative studies
    Measure Participants 6
    0-6month survival of those achieving CR/CRi
    0
    0%
    >6month survival of those achieving CR/CRi
    0
    0%
    Participants who do not achieve CR/CRi
    6
    100%
    4. Secondary Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Treatment (Immunosuppression, Enzyme Inhibitor, and Chemo)
    Arm/Group 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. cyclosporine: Given IV pravastatin sodium: Given PO mitoxantrone hydrochloride: Given IV etoposide: Given IV bone marrow aspiration: Correlative studies
    Measure Participants 6
    Early death (within 28 days)
    2
    33.3%
    Experienced Dose-Limiting Toxicity
    1
    16.7%
    Persistent Disease
    3
    50%

    Adverse Events

    Time Frame
    Adverse Event Reporting Description
    Arm/Group Title Treatment (Immunosuppression, Enzyme Inhibitor, and Chemo)
    Arm/Group 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. cyclosporine: Given IV pravastatin sodium: Given PO mitoxantrone hydrochloride: Given IV etoposide: Given IV bone marrow aspiration: Correlative studies
    All Cause Mortality
    Treatment (Immunosuppression, Enzyme Inhibitor, and Chemo)
    Affected / at Risk (%) # Events
    Total / (NaN)
    Serious Adverse Events
    Treatment (Immunosuppression, Enzyme Inhibitor, and Chemo)
    Affected / at Risk (%) # Events
    Total 5/6 (83.3%)
    Blood and lymphatic system disorders
    Febrile Neutropenia 1/6 (16.7%) 1
    Infections and infestations
    Sepsis 4/6 (66.7%) 4
    Renal and urinary disorders
    Acute Kidney Injury 1/6 (16.7%) 1
    Other (Not Including Serious) Adverse Events
    Treatment (Immunosuppression, Enzyme Inhibitor, and Chemo)
    Affected / at Risk (%) # Events
    Total 6/6 (100%)
    Blood and lymphatic system disorders
    Anemia 1/6 (16.7%) 1
    Febrile Neutropenia 4/6 (66.7%) 7
    Pancytopenia 3/6 (50%) 3
    Cardiac disorders
    Palpitation 1/6 (16.7%) 1
    Tachycardia 6/6 (100%) 6
    Ear and labyrinth disorders
    Ear pain to palpitation 1/6 (16.7%) 1
    Eye disorders
    Extraocular muscle paresis, worsening 1/6 (16.7%) 1
    Gastrointestinal disorders
    Diarrhea 3/6 (50%) 4
    Esophageal pain 1/6 (16.7%) 1
    Heartburn 1/6 (16.7%) 1
    Mucositis oral 6/6 (100%) 6
    Nausea 6/6 (100%) 6
    Oral Thrush 1/6 (16.7%) 1
    Vomiting 2/6 (33.3%) 2
    General disorders
    Chest pain 2/6 (33.3%) 2
    Chills 2/6 (33.3%) 2
    Fatigue 5/6 (83.3%) 5
    Hypothermia 1/6 (16.7%) 2
    Malaise 1/6 (16.7%) 1
    Edema, bilateral hand and feet 2/6 (33.3%) 2
    Edema, face 1/6 (16.7%) 1
    Gait disturbance 1/6 (16.7%) 1
    Volume Retention 1/6 (16.7%) 1
    Hepatobiliary disorders
    Transaminitis 1/6 (16.7%) 1
    Immune system disorders
    Pulmonary Aspergillosis 1/6 (16.7%) 1
    Infections and infestations
    Cellulitis 1/6 (16.7%) 1
    Coagulase Negative Staphylococcus Bacteremia 1/6 (16.7%) 1
    E. Coli Urinary Tract Infection 1/6 (16.7%) 1
    Rash, chest 3/6 (50%) 3
    Sinus Infection 1/6 (16.7%) 1
    Vancomycin-Resistant Enterococci Bacteremia 2/6 (33.3%) 2
    Viral upper respiratory infection 1/6 (16.7%) 1
    Injury, poisoning and procedural complications
    Bruising 1/6 (16.7%) 1
    Burning sensation during infusion 3/6 (50%) 3
    Febrile nonhemolytic transfusion reaction 1/6 (16.7%) 1
    Investigations
    Blood bilirubin increased 2/6 (33.3%) 2
    Jaundice 1/6 (16.7%) 1
    Weight Gain 1/6 (16.7%) 1
    Metabolism and nutrition disorders
    Hypokalemia 4/6 (66.7%) 4
    Hypomagnesemia 1/6 (16.7%) 1
    Hyponatremia 2/6 (33.3%) 2
    Hypophosphatemia 1/6 (16.7%) 1
    Anorexia 6/6 (100%) 7
    Metabolic acidosis 2/6 (33.3%) 2
    Musculoskeletal and connective tissue disorders
    Back Pain 1/6 (16.7%) 1
    Leg Pain 3/6 (50%) 3
    Weakness 4/6 (66.7%) 4
    Nervous system disorders
    Acute toxic-metabolic encephalopathy 1/6 (16.7%) 1
    Dizziness 2/6 (33.3%) 2
    Headache 3/6 (50%) 3
    Restlessness 1/6 (16.7%) 1
    Tremors 1/6 (16.7%) 1
    Psychiatric disorders
    Altered Mental Status 4/6 (66.7%) 4
    Anxiety 1/6 (16.7%) 1
    Insomnia 1/6 (16.7%) 1
    Nervousness/agitation 1/6 (16.7%) 1
    Withdrawn/Unwilling to communicate 1/6 (16.7%) 1
    Renal and urinary disorders
    Acute Kidney Injury 3/6 (50%) 4
    Anuria 1/6 (16.7%) 1
    Burning sensation during urination 1/6 (16.7%) 1
    Hematuria 2/6 (33.3%) 2
    Rhabdomyolysis 1/6 (16.7%) 1
    Reproductive system and breast disorders
    Pain on left areola, superficial 1/6 (16.7%) 1
    Respiratory, thoracic and mediastinal disorders
    Bronchospasms 1/6 (16.7%) 1
    Cough 1/6 (16.7%) 1
    Epistaxis 3/6 (50%) 3
    Hypoxia 1/6 (16.7%) 1
    Multifocal pneumonia 2/6 (33.3%) 2
    Pleural Effusion 2/6 (33.3%) 2
    Rhinovirus 2/6 (33.3%) 2
    Dyspnea 2/6 (33.3%) 2
    Tachypnea 2/6 (33.3%) 2
    Skin and subcutaneous tissue disorders
    Blanched buttocks 1/6 (16.7%) 1
    Periobital Edema 2/6 (33.3%) 2
    Scalp rash 1/6 (16.7%) 1
    Leukemia cutis 1/6 (16.7%) 1
    Pain, right axillary area 2/6 (33.3%) 2
    Vascular disorders
    Hypertension 6/6 (100%) 6
    Hypotension 2/6 (33.3%) 2

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Roland B. Walter, MD, PhD, MS
    Organization Fred Hutch Cancer Research Center
    Phone
    Email rwalter@fredhutch.org
    Responsible Party:
    Roland Walter, Principal Investigator, Fred Hutchinson Cancer Center
    ClinicalTrials.gov Identifier:
    NCT01342887
    Other Study ID Numbers:
    • 2409.00
    • NCI-2011-00657
    First Posted:
    Apr 27, 2011
    Last Update Posted:
    Jul 2, 2017
    Last Verified:
    Jun 1, 2017