Acute Lymphoblastic Leukemia in Remission, B Acute Lymphoblastic Leukemia, B Acute Lymphoblastic Leukemia, Philadelphia Chromosome Negative
Conditions
Brief summary
This phase II trial studies how well combination chemotherapy and inotuzumab ozogamicin work in treating patients with B acute lymphoblastic leukemia. Drugs used in chemotherapy, such as cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, dexamethasone, methotrexate and cytarabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as inotuzumab ozogamicin, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving combination chemotherapy and inotuzumab ozogamicin may work better at treating B acute lymphoblastic leukemia.
Detailed description
PRIMARY OBJECTIVES: I. To evaluate the clinical efficacy of the sequential combination of hyper-CVAD (hyperfractionated cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, dexamethasone, methotrexate and cytarabine) + inotuzumab ozogamicin in patients with newly diagnosed B-cell acute lymphocytic leukemia (ALL) in terms of event-free survival (EFS). SECONDARY OBJECTIVES: I. To evaluate other efficacy endpoints such as overall survival, overall response rate, minimal residual disease (MRD) negativity rate as well as the safety of this combination. OUTLINE: INTENSIVE CHEMOTHERAPY: Patients receive cyclophosphamide intravenously (IV) over 3 hours every 12 hours on days 1-3 and dexamethasone IV or orally (PO) on days 1-4 and 11-14 of courses 1 and 3. Patients may receive ofatumumab IV over 2 hours on days 1, 2 and 11 of course 1, days 1 and 8 of courses 2 and 4, and days 1 and 11 of course 3, or rituximab IV over 2 hours on days 1 and 11 of courses 1 and 3, and days 1 and 8 of courses 2 and 4. Patients also receive methotrexate intrathecally (IT) on day 2 of courses 1 and 3, IV over 24 hours on day 1 and IT on day 8 of courses 2 and 4, doxorubicin hydrochloride IV over 24 hours on day 4 of courses 1 and 3, vincristine sulfate IV over 1 hour on days 4 and 11 of courses 1 and 3, cytarabine IT on day 7 of courses 1 and 3, and IV over 2 hours every 12 hours on days 2 and 3, and IT on day 5 of courses 2 and 4, leucovorin calcium IV 4 times a days on day 2 of courses 2 and 4. Patients then receive inotuzumab ozogamicin IV over 1 hour on days 1 and 8 of courses 5-8. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive mercaptopurine PO thrice a day, methotrexate PO once a week, vincristine sulfate IV over 1 hour on day 1 and prednisone PO on days 1-5. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days and every 6 months.
Interventions
DRUGCyclophosphamide
Given IV
DRUGCytarabine
Given IT or IV
DRUGDexamethasone
Given IV or PO
DRUGDoxorubicin Hydrochloride
Given IV
BIOLOGICALInotuzumab Ozogamicin
Given IV
OTHERLaboratory Biomarker Analysis
Correlative studies
DRUGLeucovorin Calcium
Given IV
DRUGMercaptopurine
Given PO
DRUGMethotrexate
Given IT, IV or PO
BIOLOGICALOfatumumab
Given IV
DRUGPrednisone
Given PO
BIOLOGICALRituximab
Given IV
DRUGVincristine Sulfate
Given IV
Sponsors
M.D. Anderson Cancer Center
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with newly diagnosed, previously untreated B-lineage ALL, or having achieved complete remission (CR) with one course of induction chemotherapy * Patients with extramedullary disease only are eligible * Failure to one induction course of chemotherapy (these patients will be analyzed separately) * Performance status of 0-3 * Creatinine less than or equal to 2.0 mg/dL (unless considered tumor related) * Bilirubin less than or equal to 2.0 mg/dL (unless considered tumor related) * Adequate cardiac function as assessed by history and physical examination * No active or co-existing malignancy with life expectancy less than 12 months * Women of childbearing potential (WOCBP) or male subjects with a partner who is WOCBP must agree to use contraception during the study, if sexually active
Exclusion criteria
* Pregnant or nursing women * Known to be human immunodeficiency virus (HIV)-positive * Philadelphia chromosome (Ph)-positive ALL * Active and uncontrolled disease/infection as judged by the treating physician * Unable or unwilling to sign the consent form * Subjects who have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver involvement or stable chronic liver disease per investigator assessment) * Chronic or current infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment such as, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis, tuberculosis and active hepatitis C
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event-Free Survival | Start of treatment up to 2 years | Event-free survival defined as the time interval from date of treatment start until the date of death, disease progression or relapse. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Start of treatment up to 2 years | Time from date of treatment start until date of death due to any cause or last Follow-up. |
| Participants to Achieve Complete Remission (CR): | Start of treatment up to 2 years | Complete Remission (CR) is defined as - Normalization of the peripheral blood and bone marrow blasts \</= 5% in normocellular or hypercellular marrow, granulocyte count of 1x10\^9/L or above and platelets \>/= 100X10\^9/L and complete resolution of all sites of extramedullary disease. |
| Number of Participants With Minimal Residual Disease (MRD) Negativity | Start of treatment up to 2 years | MRD levels continuously assessed during induction and consolidation therapy by 6-color multiparameter flow. MRD negativity defined by a value of at least 10-4 and confirmed on a second bone marrow aspiration/biopsy performed after a subsequent cycle. |
| Number of Participants With Adverse Events | Start of treatment up to 30 days after last dose received. | For the purpose of toxicity monitoring, toxicities are defined as any treatment -related grade 3 or 4 non-hematologic AEs occurred any time during the trial.NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 utilized for adverse event reporting. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORElias Jabbour
M.D. Anderson Cancer Center
Participant flow
Recruitment details
Recruitment Period: March 2018 to January 2019
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Hyper-CVAD, Inotuzumab Ozogamicin) See detailed description.
Cyclophosphamide: Given IV
Cytarabine: Given IT or IV
Dexamethasone: Given IV or PO
Doxorubicin Hydrochloride: Given IV
Inotuzumab Ozogamicin: Given IV
Laboratory Biomarker Analysis: Correlative studies
Leucovorin Calcium: Given IV
Mercaptopurine: Given PO
Methotrexate: Given IT, IV or PO
Ofatumumab: Given IV
Prednisone: Given PO
Rituximab: Given IV
Vincristine Sulfate: Given IV | 4 |
| Total | 4 |
Baseline characteristics
| Characteristic | Treatment (Hyper-CVAD, Inotuzumab Ozogamicin) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants |
| Age, Continuous | 29 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 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 | 1 Participants |
| Race (NIH/OMB) White | 3 Participants |
| Region of Enrollment United States | 4 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 4 |
| other Total, other adverse events | 4 / 4 |
| serious Total, serious adverse events | 3 / 4 |
Outcome results
Primary
Event-Free Survival
Event-free survival defined as the time interval from date of treatment start until the date of death, disease progression or relapse.
Time frame: Start of treatment up to 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Hyper-CVAD, Inotuzumab Ozogamicin) | Event-Free Survival | 24 Months |
Secondary
Number of Participants With Adverse Events
For the purpose of toxicity monitoring, toxicities are defined as any treatment -related grade 3 or 4 non-hematologic AEs occurred any time during the trial.NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 utilized for adverse event reporting.
Time frame: Start of treatment up to 30 days after last dose received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment (Hyper-CVAD, Inotuzumab Ozogamicin) | Number of Participants With Adverse Events | Neutropenic Fever | 2 Participants |
| Treatment (Hyper-CVAD, Inotuzumab Ozogamicin) | Number of Participants With Adverse Events | Peripheral Sensory Neuropathy | 1 Participants |
| Treatment (Hyper-CVAD, Inotuzumab Ozogamicin) | Number of Participants With Adverse Events | Allergic Reaction | 1 Participants |
| Treatment (Hyper-CVAD, Inotuzumab Ozogamicin) | Number of Participants With Adverse Events | Muscle Weakness | 1 Participants |
Secondary
Number of Participants With Minimal Residual Disease (MRD) Negativity
MRD levels continuously assessed during induction and consolidation therapy by 6-color multiparameter flow. MRD negativity defined by a value of at least 10-4 and confirmed on a second bone marrow aspiration/biopsy performed after a subsequent cycle.
Time frame: Start of treatment up to 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Hyper-CVAD, Inotuzumab Ozogamicin) | Number of Participants With Minimal Residual Disease (MRD) Negativity | 4 Participants |
Secondary
Overall Survival
Time from date of treatment start until date of death due to any cause or last Follow-up.
Time frame: Start of treatment up to 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Hyper-CVAD, Inotuzumab Ozogamicin) | Overall Survival | 24 Months |
Secondary
Participants to Achieve Complete Remission (CR):
Complete Remission (CR) is defined as - Normalization of the peripheral blood and bone marrow blasts \</= 5% in normocellular or hypercellular marrow, granulocyte count of 1x10\^9/L or above and platelets \>/= 100X10\^9/L and complete resolution of all sites of extramedullary disease.
Time frame: Start of treatment up to 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Hyper-CVAD, Inotuzumab Ozogamicin) | Participants to Achieve Complete Remission (CR): | 4 Participants |