Refractory Acute Leukemia, Relapsed Acute Leukemia
Conditions
Keywords
Leukemia, Acute Myeloid Leukemia, Acute Lymphoid / Lymphoblastic Leukemia
Brief summary
Based on what is known about it's mechanism of action, bortezomib is presumed to make other chemotherapy drugs work better. This study examines the use of bortezomib in combination with an already effective chemotherapy regimen that is used to treat leukemias that have relapsed or been refractory to treatment.
Detailed description
VELCADE is a drug that blocks growth of cancer cells and helps destroy them. This research will help us to determine if VELCADE when combined with chemotherapy is useful in treating the leukemia with which you have been diagnosed. Your leukemia is a type that did not respond to chemotherapy or has come back after successful therapy. VELCADE is approved by the Food and Drug Administration (FDA) for the treatment of multiple myeloma for patients that have received at least one prior therapy. Multiple Myeloma is a type of cancer that develops from blood cells. The dose of the drug being used in this research study is the same as what is used for the treatment of myeloma but the number of injections is less. VELCADE has, however not been approved by the FDA for use in acute leukemia. Mitoxantrone and etoposide, the other two chemotherapy drugs are also used for treating leukemia. In the first part of the study, we are going to test the safety of VELCADE at different doses when given with mitoxantrone and etoposide. You may be enrolled at any one of three doses. In the second part, we are going to assess the response to the combination of VELCADE and chemotherapy drugs. You will receive VELCADE at the chosen dose based on safety assessment from Phase I. It will be administered as an intravenous (through the vein) injection on day-1 and day-4 of the 5-day schedule. In addition, you will also receive mitoxantrone over 15 minutes and etoposide over 45 minutes from days 1-5. The first 28 days from the beginning of the treatment will be called a treatment cycle. On day-14 of the treatment cycle, you will have a bone marrow biopsy done to see if all the leukemia cells have disappeared. If there is no evidence of leukemia, then you may receive growth factors to help your marrow recover faster. If there is still presence of leukemia, in the same amount or more, then the treatment will be considered a failure and you will not receive any more of this treatment. If there is a partial improvement then you will receive additional cycles of VELCADE with chemotherapy as described above until there are no signs of your disease. This is called a complete remission. Therapy will be withheld at any time if there is concern that you are having side-effects that are not medically acceptable. Once the side-effects have resolved, VELCADE therapy may be re-started at a lower dose. It is estimated that you may require about two to three cycles of therapy.
Interventions
DRUGBortezomib with mitoxantrone, etoposide and cytarabine
All patients receive bortezomib in combination with mitoxantrone, etoposide and cytarabine. This is a 5 day chemotherapy regimen that is administered in the hospital.
DRUGBortezomib 1.0mg/m^2
All patients receive bortezomib in combination with mitoxantrone, etoposide and cytarabine. This is a 5 day chemotherapy regimen that is administered in the hospital.
DRUGBortezomib 1.3mg/m^2
All patients receive bortezomib in combination with mitoxantrone, etoposide and cytarabine. This is a 5 day chemotherapy regimen that is administered in the hospital.
Sponsors
Millennium Pharmaceuticals, Inc.
Sidney Kimmel Cancer Center at Thomas Jefferson University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control (ie, a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study. * Male subject agrees to use an acceptable method for contraception for the duration of the study. * Patients who have had a diagnosis of Acute Myeloid Leukemia (AML) or Acute Lymphoblastic Leukemia (ALL) will be eligible for the study. * Patients must have failed initial therapy that may manifest in either of the following ways: * Demonstration of Primary Refractory Disease (Primary Induction Failure) as evidenced by a mid-cycle bone marrow analysis showing lack of complete tumor clearance (CTC). * Relapse of initial disease after a period of attaining complete remission. * Patients must be \> 18 years of age, with no upper age limit. * ECOG performance status of 0 or 1. * Patients have no symptomatic cardiac or pulmonary disease and adequate hepatic and renal function as measured by the following criteria: * Cardiac: Left ventricular ejection fraction at rest must be \>40% (MUGA preferred) * Hepatic: ALT and AST \< 3x the upper limits of normal range as specified by the institution's clinical laboratory. * Renal: Serum creatinine within the normal range (\< 1.4 mg/dL) or if creatinine outside normal range then creatinine clearance \> 60 mL/min/m2 * Patients who have had a diagnosis of Acute Myeloid Leukemia (AML) or Acute Lymphoblastic Leukemia (ALL) will be eligible for the study. * Patients must have failed initial therapy that may manifest in either of the following ways: * Demonstration of Primary Refractory Disease (Primary Induction Failure) as evidenced by a mid-cycle bone marrow analysis showing lack of complete tumor clearance (CTC). * Relapse of initial disease after a period of attaining complete remission. * Patients must be \> 18 years of age, with no upper age limit. * ECOG performance status of 0 or 1. * Patients have no symptomatic cardiac or pulmonary disease and adequate hepatic and renal function as measured by the following criteria: * Cardiac: Left ventricular ejection fraction at rest must be \>40% (MUGA preferred) * Hepatic: ALT and AST \< 3x the upper limits of normal range as specified by the institution's clinical laboratory. * Renal: Serum creatinine within the normal range (\< 1.4 mg/dL) or if creatinine outside normal range then creatinine clearance \> 60 mL/min/m2
Exclusion criteria
* Patient has \> Grade 2 peripheral neuropathy within 14 days before enrollment. * Myocardial infarction within 6 months prior to enrollment or has New York Hospital Association (NYHA) Class III or IV heart failure (see section 8.4), 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 has to be documented by the investigator as not medically relevant. * Patient has hypersensitivity to bortezomib, boron or mannitol. * Female subject is pregnant or breast-feeding. Confirmation that the subject is not pregnant must be established by a negative serum or urinary pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women. * Patient has received other investigational drugs within 14 days before enrollment * Serious medical or psychiatric illness likely to interfere with participation in this clinical study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicity in Phase I | 30-90 days | Dose limiting toxicity (DLT) is defined as grade-3 toxicity definitely related to bortezomib or grade-4 toxicity probably or definitely related to bortezomib. |
| Complete Response Rate to 1.3mg/m^2 of Bortezomib With Mitoxantrone and Etoposide in Phase II | Up to 7 years | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions. The percentage of participants that experienced complete response will be reported. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Bortezomib Bortezomib in combination with mitoxantrone, etoposide and cytarabine
Bortezomib with mitoxantrone, etoposide and cytarabine: All patients receive bortezomib in combination with mitoxantrone, etoposide and cytarabine. This is a 5 day chemotherapy regimen that is administered in the hospital. | 55 |
| Total | 55 |
Baseline characteristics
| Characteristic | Bortezomib |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 11 Participants |
| Age, Categorical Between 18 and 65 years | 44 Participants |
| Age, Continuous | 51.39 years STANDARD_DEVIATION 15.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 30 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 22 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 8 Participants |
| Race (NIH/OMB) White | 35 Participants |
| Region of Enrollment United States | 55 participants |
| Sex: Female, Male Female | 29 Participants |
| Sex: Female, Male Male | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 38 / 38 |
| serious Total, serious adverse events | 10 / 38 |
Outcome results
Primary
Complete Response Rate to 1.3mg/m^2 of Bortezomib With Mitoxantrone and Etoposide in Phase II
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions. The percentage of participants that experienced complete response will be reported.
Time frame: Up to 7 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 - Bortezomib 0.7mg/m^2 | Complete Response Rate to 1.3mg/m^2 of Bortezomib With Mitoxantrone and Etoposide in Phase II | 27 percentage of participants |
Primary
Number of Participants With Dose Limiting Toxicity in Phase I
Dose limiting toxicity (DLT) is defined as grade-3 toxicity definitely related to bortezomib or grade-4 toxicity probably or definitely related to bortezomib.
Time frame: 30-90 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1 - Bortezomib 0.7mg/m^2 | Number of Participants With Dose Limiting Toxicity in Phase I | 0 Participants |
| Phase 1 - Bortezomib 1.0 mg/m^2 | Number of Participants With Dose Limiting Toxicity in Phase I | 0 Participants |
| Phase 1 - Bortezomib 1.3mg/m^2 | Number of Participants With Dose Limiting Toxicity in Phase I | 0 Participants |