Bortezomib and Doxil for the Treatment of Patients With Acute Myelogenous Leukemia
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
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:
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:
|
Outcome Measures
Primary Outcome Measures
- 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
- 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
- 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
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.- 322070
- UCDCC#230
- X05385
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
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
|
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
|
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
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 |
nlogihara@ucdavis.edu |
- 322070
- UCDCC#230
- X05385