Bortezomib and Doxil for the Treatment of Patients With Acute Myelogenous Leukemia

Sponsor
Joseph Tuscano (Other)
Overall Status
Completed
CT.gov ID
NCT01736943
Collaborator
Millennium Pharmaceuticals, Inc. (Industry)
25
1
1
77
0.3

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether bortezomib in combination with doxil/lipodox is effective in the treatment of Acute Myeloid Leukemia.

Condition or Disease Intervention/Treatment Phase
Phase 2

Detailed Description

Acute myeloid leukemia (AML) remains largely incurable despite advances that have been made in recent years into increasing the complete response (CR) rates. In elderly patients (over the age of 60), CR rates are lower, 40 to 50%, and long term disease-free and overall survival is less than 10%. The therapeutic options for relapsed/refractory AML are significantly limited. Bortezomib has shown promising activity in patients with advanced hematologic malignancies, including those with leukemia and non-Hodgkin's lymphoma.

Given the available data suggesting efficacy of bortezomib in combination with doxil in patients with relapsed multiple myeloma (MM), chronic lymphocytic leukemia (CLL), and Non Hodgkin's lymphoma (NHL) as well as the known sensitivity of AML to anthracyclines and in vitro data demonstrating the sensitivity of multiply resistant AML cells to bortezomib, we are proposing the use of this combination in patients with relapsed/refractory AML or elderly patients who are not candidates for standard induction therapy.

Using the subcutaneous formulation of bortezomib would provide patients with reduced neurotoxicity and easier schedule due to decreased time in the infusion room and it would decrease overall cost of care.

Study Design

Study Type:
Interventional
Actual Enrollment :
25 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Phase II Trial of the Combination of Subcutaneous (SQ) Bortezomib and Pegylated Liposomal Doxorubicin (PLD or Doxil or LipoDox) for the Treatment of Patients With Relapsed/Refractory Acute Myelogenous Leukemia (AML)
Actual Study Start Date :
Dec 19, 2012
Actual Primary Completion Date :
May 20, 2019
Actual Study Completion Date :
May 20, 2019

Arms and Interventions

Arm Intervention/Treatment
Experimental: Bortezomib + Doxil

Bortezomib will be given subcutaneously at 1.5mg/m2 on days 1, 4, 8 and 11 of a 3 week cycle. Doxil will be administered once every three weeks as a single intravenous infusion at a dose of 40 mg/m2 (day 4 of each cycle).

Drug: Bortezomib
Bortezomib will be given twice a week subcutaneously (under the skin) for two weeks in every 3 week cycle.
Other Names:
  • Velcade
  • Drug: Doxil
    Doxil or LipoDox will also be given through a venous catheter (inside your vein). Doxil or LipoDox will be given over 60 to 90 minutes on Day 4 of every 21-day cycle.
    Other Names:
  • LipoDox; pegylated liposomal doxorubicin
  • Outcome Measures

    Primary Outcome Measures

    1. Progression Free Survival [Up to 2 years]

      The time from first day of treatment to the first observation of disease progression or death due to any cause. If a patient has not progressed or died, progression-free survival is censored at the time of last follow-up.

    Secondary Outcome Measures

    1. Overall Survival [Up to two years]

      Overall survival wil be measured as the time from start of treatment to the Date of death or the last date the patient was known to be alive

    2. Toxicity Information Recorded Will Include the Type, Severity, Time of Onset, Time of Resolution, and the Probable Association With the Study Regimen. [Up to two years]

      Toxicity will be evaluated based on the standard NCI Common Toxicity Criteria for Adverse Effects CTCAE) V.4.0 grading criteria.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 80 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Written informed consent

    • Female subjects must be either postmenopausal for at least 1 year before the screening visit, is surgically sterilized or if they are of childbearing potential, agree to practice 2 effective methods of contraception from the time of signing the informed consent form through 30 days after the last dose of SQ VELCADE, or agree to completely abstain from heterosexual intercourse.

    • Male subjects, even if surgically sterilized must agree to 1 of the following: practice effective barrier contraception during the entire study treatment period and through a minimum of 30 days after the last dose of study drug, or completely abstain from heterosexual intercourse.

    • Adults (age 18 to 80) with AML, excluding the M3 subtype, that are not likely to respond to conventional therapy

    • Bone marrow and peripheral blood studies must be available for confirmation of diagnosis.

    • Performance status of 60% or greater by the Karnofsky scale

    • A minimum of 4 weeks must have elapsed since the completion of prior chemotherapy.

    • Patients may have had autologous transplant.

    • There are no minimum hematological parameter requirements prior to the first two cycles, as patients with AML and myelodysplastic syndrome (MDS) are understood to have low absolute neutrophil count (ANC) and platelet counts when the disease is active. However, patients with white blood cell count (WBC) greater than 30,000 will receive hydroxyurea to reduce the WBC count to below 30,000 at which point they may begin treatment.

    • A pretreatment calculated creatinine clearance (absolute value) of ≥ 40 ml/minute or serum creatinine of < 1.5 x upper limit of normal is required.

    • Patients must have a serum bilirubin ≤1.5 mg/dl, serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamic-pyruvic transaminase (SGPT) ≤2.5 times the institutional upper limits of normal.

    Exclusion Criteria:
    • There is no specific platelet and absolute neutrophil count that will exclude patients from this study given the natural history of AML.

    • Patient has greater than or equal to Grade 2 peripheral neuropathy

    • Patient had myocardial infarction within 6 months prior to enrollment or has New York Heart Association Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at screening must be documented by the investigator as not medically relevant. An left ventricular ejection fraction (LVEF) must be > 50

    • Patient has hypersensitivity to VELCADE, boron, or mannitol.

    • Female subject is pregnant or lactating.

    • Female patients who are lactating or have a positive serum pregnancy test during the screening period, or a positive urine pregnancy test on Day 1 before first dose of study drug, if applicable.

    • Serious medical or psychiatric illness likely to interfere with participation in this clinical study.

    • Diagnosed or treated for another malignancy within 3 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy.

    • Participation in clinical trials with other investigational agents not included in this trial, within 14 days of the start of this trial and throughout the duration of this trial.

    • Radiation therapy within 3 weeks before randomization. Enrollment of subjects who require concurrent radiotherapy (which must be localized in its field size) should be deferred until the radiotherapy is completed and 3 weeks have elapsed since the last date of therapy.

    • Patients with active/uncontrolled central nervous system (CNS) leukemia

    • Patients eligible, at the time of starting treatment, for curative therapeutic approaches (such as allogeneic transplant) are not eligible for the trial.

    • Patients may not receive any other anti-cancer therapy (cytotoxic, biologic, radiation, or hormonal other than for replacement) while on this study other than hydroxyurea for control of counts.

    • Human Immunodeficiency Virus (HIV)-positive.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 University of California Comprehensive Cancer Center Sacramento California United States 95817

    Sponsors and Collaborators

    • Joseph Tuscano
    • Millennium Pharmaceuticals, Inc.

    Investigators

    • Principal Investigator: Joseph Tuscano, MD, University of California, Davis

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Joseph Tuscano, Principal Investigator, University of California, Davis
    ClinicalTrials.gov Identifier:
    NCT01736943
    Other Study ID Numbers:
    • 322070
    • UCDCC#230
    • X05385
    First Posted:
    Nov 29, 2012
    Last Update Posted:
    Feb 24, 2021
    Last Verified:
    Feb 1, 2021
    Keywords provided by Joseph Tuscano, Principal Investigator, University of California, Davis
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Bortezomib + Doxil
    Arm/Group Description Bortezomib will be given subcutaneously at 1.5mg/m2 on days 1, 4, 8 and 11 of a 3 week cycle. Doxil will be administered once every three weeks as a single intravenous infusion at a dose of 40 mg/m2 (day 4 of each cycle). Bortezomib: Bortezomib will be given twice a week subcutaneously (under the skin) for two weeks in every 3 week cycle. Doxil: Doxil or LipoDox will also be given through a venous catheter (inside your vein). Doxil or LipoDox will be given over 60 to 90 minutes on Day 4 of every 21-day cycle.
    Period Title: Overall Study
    STARTED 25
    COMPLETED 25
    NOT COMPLETED 0

    Baseline Characteristics

    Arm/Group Title Bortezomib + Doxil
    Arm/Group Description Bortezomib will be given subcutaneously at 1.5mg/m2 on days 1, 4, 8 and 11 of a 3 week cycle. Doxil will be administered once every three weeks as a single intravenous infusion at a dose of 40 mg/m2 (day 4 of each cycle). Bortezomib: Bortezomib will be given twice a week subcutaneously (under the skin) for two weeks in every 3 week cycle. Doxil: Doxil or LipoDox will also be given through a venous catheter (inside your vein). Doxil or LipoDox will be given over 60 to 90 minutes on Day 4 of every 21-day cycle.
    Overall Participants 25
    Age (Count of Participants)
    <=18 years
    0
    0%
    Between 18 and 65 years
    14
    56%
    >=65 years
    11
    44%
    Sex: Female, Male (Count of Participants)
    Female
    12
    48%
    Male
    13
    52%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    Asian
    1
    4%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    Black or African American
    3
    12%
    White
    20
    80%
    More than one race
    0
    0%
    Unknown or Not Reported
    1
    4%
    Region of Enrollment (participants) [Number]
    United States
    25
    100%

    Outcome Measures

    1. Primary Outcome
    Title Progression Free Survival
    Description The time from first day of treatment to the first observation of disease progression or death due to any cause. If a patient has not progressed or died, progression-free survival is censored at the time of last follow-up.
    Time Frame Up to 2 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Bortezomib + Doxil
    Arm/Group Description Bortezomib will be given subcutaneously at 1.5mg/m2 on days 1, 4, 8 and 11 of a 3 week cycle. Doxil will be administered once every three weeks as a single intravenous infusion at a dose of 40 mg/m2 (day 4 of each cycle). Bortezomib: Bortezomib will be given twice a week subcutaneously (under the skin) for two weeks in every 3 week cycle. Doxil: Doxil or LipoDox will also be given through a venous catheter (inside your vein). Doxil or LipoDox will be given over 60 to 90 minutes on Day 4 of every 21-day cycle.
    Measure Participants 10
    Median (95% Confidence Interval) [days]
    21
    2. Secondary Outcome
    Title Overall Survival
    Description Overall survival wil be measured as the time from start of treatment to the Date of death or the last date the patient was known to be alive
    Time Frame Up to two years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Bortezomib + Doxil
    Arm/Group Description Bortezomib will be given subcutaneously at 1.5mg/m2 on days 1, 4, 8 and 11 of a 3 week cycle. Doxil will be administered once every three weeks as a single intravenous infusion at a dose of 40 mg/m2 (day 4 of each cycle). Bortezomib: Bortezomib will be given twice a week subcutaneously (under the skin) for two weeks in every 3 week cycle. Doxil: Doxil or LipoDox will also be given through a venous catheter (inside your vein). Doxil or LipoDox will be given over 60 to 90 minutes on Day 4 of every 21-day cycle.
    Measure Participants 10
    Median (95% Confidence Interval) [Days]
    50
    3. Secondary Outcome
    Title Toxicity Information Recorded Will Include the Type, Severity, Time of Onset, Time of Resolution, and the Probable Association With the Study Regimen.
    Description Toxicity will be evaluated based on the standard NCI Common Toxicity Criteria for Adverse Effects CTCAE) V.4.0 grading criteria.
    Time Frame Up to two years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Bortezomib + Doxil
    Arm/Group Description Bortezomib will be given subcutaneously at 1.5mg/m2 on days 1, 4, 8 and 11 of a 3 week cycle. Doxil will be administered once every three weeks as a single intravenous infusion at a dose of 40 mg/m2 (day 4 of each cycle). Bortezomib: Bortezomib will be given twice a week subcutaneously (under the skin) for two weeks in every 3 week cycle. Doxil: Doxil or LipoDox will also be given through a venous catheter (inside your vein). Doxil or LipoDox will be given over 60 to 90 minutes on Day 4 of every 21-day cycle.
    Measure Participants 25
    Abdominal pain
    4
    16%
    Alanine aminotransferase increased
    3
    12%
    Anemia
    17
    68%
    Anorexia
    7
    28%
    Aspartate aminotransferase increased
    4
    16%
    Chills
    4
    16%
    Constipation
    4
    16%
    Cough
    4
    16%
    Diarrhea
    9
    36%
    Dizziness
    8
    32%
    Dyspnea
    10
    40%
    Edema limbs
    3
    12%
    Epitaxis
    4
    16%
    Fatigue
    15
    60%
    Febrile neutopenia
    12
    48%
    Gastrointestinal disorders - Other, gum tenderness
    3
    12%
    Generalized muscle weakness
    4
    16%
    Headache
    5
    20%
    Hypoalbuminemia
    6
    24%
    Hypocalcemia
    4
    16%
    Hypokalemia
    3
    12%
    Hyponatremia
    7
    28%
    Hypotension
    4
    16%
    Infections and infestations - Other, bacteremia
    3
    12%
    Insomnia
    4
    16%
    Lymphocyte count decreased
    12
    48%
    Malaise
    4
    16%
    Mucositis oral
    4
    16%
    Nausea
    15
    60%
    Neutrophil count decreased
    10
    40%
    Peripheral sensory neuropathy
    4
    16%
    Platelet count decreased
    18
    72%
    Respiratory, thoracic and mediastinal disorders - Other, tachypnea
    3
    12%
    Skin and subcutaneous tissue disorders - Other, Ecchymoses
    4
    16%
    Vomiting
    8
    32%
    White blood cell decreased
    14
    56%

    Adverse Events

    Time Frame Up to 30 days after discontinuation of study drugs.
    Adverse Event Reporting Description Incidence of adverse events.
    Arm/Group Title Bortezomib + Doxil
    Arm/Group Description Bortezomib will be given subcutaneously at 1.5mg/m2 on days 1, 4, 8 and 11 of a 3 week cycle. Doxil will be administered once every three weeks as a single intravenous infusion at a dose of 40 mg/m2 (day 4 of each cycle). Bortezomib: Bortezomib will be given twice a week subcutaneously (under the skin) for two weeks in every 3 week cycle. Doxil: Doxil or LipoDox will also be given through a venous catheter (inside your vein). Doxil or LipoDox will be given over 60 to 90 minutes on Day 4 of every 21-day cycle.
    All Cause Mortality
    Bortezomib + Doxil
    Affected / at Risk (%) # Events
    Total 1/25 (4%)
    Serious Adverse Events
    Bortezomib + Doxil
    Affected / at Risk (%) # Events
    Total 10/25 (40%)
    Blood and lymphatic system disorders
    Febrile neutropenia 1/25 (4%)
    Cardiac disorders
    Atrial fibrillation 1/25 (4%)
    Heart failure 1/25 (4%)
    Sinus bradycardia 1/25 (4%)
    Gastrointestinal disorders
    Rectal hemorrhage 1/25 (4%)
    Infections and infestations
    Bronchial infection 1/25 (4%)
    Catheter related infection 1/25 (4%)
    Infections and infestations - Other, Bacteremia 1/25 (4%)
    Injury, poisoning and procedural complications
    Fracture 1/25 (4%)
    Musculoskeletal and connective tissue disorders
    Back pain 1/25 (4%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    neoplasms benign, malignant and unspecified (incl cysts and polyps) - other, specify 1/25 (4%)
    Nervous system disorders
    Vasovagal reaction 1/25 (4%)
    Respiratory, thoracic and mediastinal disorders
    bronchopulmonary hemorrhage 1/25 (4%)
    Respiratory failure 1/25 (4%)
    Other (Not Including Serious) Adverse Events
    Bortezomib + Doxil
    Affected / at Risk (%) # Events
    Total 18/25 (72%)
    Blood and lymphatic system disorders
    Anemia 17/25 (68%)
    Febrile neutropenia 12/25 (48%)
    Cardiac disorders
    Heart failure 2/25 (8%)
    Sinus tachycardia 2/25 (8%)
    Gastrointestinal disorders
    Abdominal pain 4/25 (16%)
    Bloating 2/25 (8%)
    Colitis 2/25 (8%)
    Constipation 4/25 (16%)
    Diarrhea 9/25 (36%)
    Gastrointestinal disorders - Other, Gum tenderness 3/25 (12%)
    Mucositis oral 4/25 (16%)
    Nausea 15/25 (60%)
    Vomiting 8/25 (32%)
    General disorders
    Chills 4/25 (16%)
    Edema limbs 3/25 (12%)
    Fatigue 15/25 (60%)
    Fever 2/25 (8%)
    Malaise 4/25 (16%)
    Pain 2/25 (8%)
    Infections and infestations
    Catheter related infection 2/25 (8%)
    Injury, poisoning and procedural complications
    Bruising 2/25 (8%)
    Fall 2/25 (8%)
    Infusion related reaction 2/25 (8%)
    Investigations
    Alanine aminotransferase increased 3/25 (12%)
    Aspartate aminotransferase increased 4/25 (16%)
    Blood bilirubin increased 2/25 (8%)
    Creatinine increased 2/25 (8%)
    Lymphocyte count decreased 12/25 (48%)
    neutrophil count decreased 10/25 (40%)
    Platelet count decreased 18/25 (72%)
    Weight gain 2/25 (8%)
    Weight loss 2/25 (8%)
    White blood cell decreased 14/25 (56%)
    Metabolism and nutrition disorders
    Anorexia 7/25 (28%)
    Dehydration 2/25 (8%)
    Hypoalbuminemia 6/25 (24%)
    Hypocalcemia 4/25 (16%)
    hypokalemia 3/25 (12%)
    Hyponatremia 7/25 (28%)
    Hypophosphatemia 2/25 (8%)
    Musculoskeletal and connective tissue disorders
    Generalized muscle weakness 4/25 (16%)
    Muscle weakness lower limb 2/25 (8%)
    Musculoskeletal and connective tissue disorder - Other: body/pain sore 2/25 (8%)
    Pain extremity 2/25 (8%)
    Nervous system disorders
    Dizziness 8/25 (32%)
    Headache 5/25 (20%)
    Lethargy 2/25 (8%)
    Peripheral sensory neuropathy 4/25 (16%)
    presyncope 2/25 (8%)
    Psychiatric disorders
    Insomnia 4/25 (16%)
    Respiratory, thoracic and mediastinal disorders
    Cough 4/25 (16%)
    Dyspnea 10/25 (40%)
    Epitaxis 4/25 (16%)
    Respiratory failure 3/25 (12%)
    Respiratory, thoracic and mediastinal disorders - Other, specify: Tachypnea 3/25 (12%)
    Sore throat 2/25 (8%)
    Wheezing 2/25 (8%)
    Skin and subcutaneous tissue disorders
    Skin and subcutaneous tissue disorders - Other, specify: Ecchymoses 4/25 (16%)
    Vascular disorders
    Hematoma 2/25 (8%)

    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 Analyst
    Organization University of California, Davis
    Phone 916-734-8053
    Email nlogihara@ucdavis.edu
    Responsible Party:
    Joseph Tuscano, Principal Investigator, University of California, Davis
    ClinicalTrials.gov Identifier:
    NCT01736943
    Other Study ID Numbers:
    • 322070
    • UCDCC#230
    • X05385
    First Posted:
    Nov 29, 2012
    Last Update Posted:
    Feb 24, 2021
    Last Verified:
    Feb 1, 2021