Low-Intensity Chemotherapy and Blinatumomab in Treating Patients With Philadelphia Chromosome Negative Relapsed or Refractory Acute Lymphoblastic Leukemia
Study Details
Study Description
Brief Summary
This phase II trial studies how well low-intensity chemotherapy and blinatumomab work in treating patients with Philadelphia chromosome negative acute lymphoblastic leukemia that has come back or does not respond to treatment. Drugs used in chemotherapy, such as dexamethasone, filgrastim, pegfilgrastim, cyclophosphamide, methotrexate, cytarabine and vincristine sulfate, 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 blinatumomab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving low-intensity chemotherapy and blinatumomab may work better at treating acute lymphoblastic leukemia.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
PRIMARY OBJECTIVE:
- To evaluate the combined effect of blinatumomab and mini-hyper-CVD (low-intensity chemotherapy) on event-free survival.
SECONDARY OBJECTIVES:
-
Evaluating other clinical efficacy endpoints (minimal residual disease [MRD] negativity, duration of response, the overall response rate [complete response (CR) + CR with inadequate count recovery (CRi)]) of the regimen occurred any time during the treatment.
-
Overall survival. III. Determining the safety of the combination regimen.
OUTLINE:
INDUCTION PHASE: Patients receive blinatumomab intravenously (IV) continuously on days 1-28 and dexamethasone orally (PO) or IV over 30 minutes on days -3 to day 0 and 7-10. Patients also receive filgrastim subcutaneously (SC) on days 1-42 or pegfilgrastim SC on days 1 and 25, cyclophosphamide IV over 3 hours twice daily (BID) on days -3 to -1, methotrexate intrathecally (IT) on day 2 and IV over 24 hours on day 22, cytarabine IT on day 7 and IV over 3 hours BID on days 23 and 24, and vincristine sulfate IV over 15 minutes on days 0 and 7. At the discretion of the treating physician, patients may receive rituximab IV over 4-6 hours on days -3, 0, 22 and 29, and leucovorin calcium IV over 15 minutes or PO 4 times daily (QID) for 8 doses.
CONSOLIDATION PHASE: Patients receive blinatumomab IV continuously on days 1-28 and dexamethasone PO or IV over 30 minutes on days 1-4 and 11-14. Patients also receive cyclophosphamide IV over 3 hours BID on days 1-3, vincristine sulfate IV over 15 minutes on days 1 and 11, filgrastim SC on days 1-4 and 22-42 or pegfilgrastim SC on day 5 and 25, methotrexate IT on day 2 and IV over 24 hours on day 22, cytarabine IT on day 7 and IV over 3 hours BID on days 23 and 24. At the discretion of the treating physician, patients may receive rituximab IV over 4-6 hours on days 1, 8, 22 and 29, and leucovorin calcium IV over 15 minutes or PO QID for 8 doses. Treatment repeats every 42 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity.
MAINTENANCE PHASE: Patients receive prednisone PO and vincristine sulfate IV over 15 minutes on days 1-5 of cycles 5-9, 7-11 and 13-24, and mercaptopurine PO BID on days 1-28 of cycles 1-5, 7-11, and 13-24. Patients also receive methotrexate PO once a week and blinatumomab IV continuously on days 1-28 of cycles 6 and 12. Cycles repeat every 28 days for up to 24 cycles (2 years) in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Treatment (blinatumomab, combination chemotherapy) See detailed description. |
Biological: Blinatumomab
Given IV
Other Names:
Drug: Cyclophosphamide
Given IV
Other Names:
Drug: Cytarabine
Given IT or IV
Other Names:
Drug: Dexamethasone
PO or IV
Other Names:
Biological: Filgrastim
Given SC
Other Names:
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Leucovorin Calcium
Given IV
Other Names:
Drug: Mercaptopurine
Given PO
Other Names:
Drug: Methotrexate
Given IT or IV
Other Names:
Biological: Pegfilgrastim
Given SC
Other Names:
Biological: Rituximab
Given IV
Other Names:
Drug: Vincristine Sulfate
Given IV
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Event free survival (EFS) where events defined as no response, loss of response, or death [From the first day of treatment assessed up to 2 years]
The median EFS time will be estimated by Bayesian posterior estimates, along with the 95% credible intervals. Will be estimated using the Kaplan-Meier method, and log rank test will be used to compare the differences in the time-to-event variables between subgroups (e.g. different patient characteristics).
Secondary Outcome Measures
- Minimal residual disease (MRD) negativity [Up to 2 years]
Will be summarized using descriptive statistics, including means with standard deviations, or medians with ranges, histograms and box-plot.
- Duration of response [From date on initial response assessed up to 2 years]
Defined as the number of days from the date of initial response (partial response [PR] or better) to the date of first documented disease progression/relapse or death. Will be estimated using the Kaplan-Meier method, and log rank test will be used to compare the differences in the time-to-event variables between subgroups (e.g. different patient characteristics).
- Overall response rate [Up to 2 years]
defined as the percentage of patients achieving complete response (CR) or CR with inadequate count recovery (CRi). Will be estimated along with 95% confidence interval. Overall response rate will be compared between subgroups (e.g. different patient characteristics) by Fisher's exact test and minimal residual disease difference will be assessed by Wilcoxon rank test, respectively.
- Overall survival [Time from the first day of treatment assessed up to 2 years]
defined as the time from treatment start till death or last follow-up. Will be estimated using the Kaplan-Meier method, and log rank test will be used to compare the differences in the time-to-event variables between subgroups (e.g. different patient characteristics).
- Incidence of adverse events [Up to 2 years]
Toxicity will be reported by type, frequency and severity. Highest toxicity grades per patient per course will be tabulated for selected adverse events and laboratory measurements.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Patients with first or second relapsed/refractory B-cell acute lymphoblastic leukemia (ALL)
-
Performance status =< 3 (Eastern Cooperative Oncology Group [ECOG] scale)
-
Total serum bilirubin =< 2 x upper limit of normal (ULN), unless due to Gilbert's syndrome, hemolysis or the underlying leukemia approved by the principal investigator (PI)
-
Alanine aminotransferase (ALT) =< 3 x ULN, unless due to the underlying leukemia approved by the PI
-
Aspartate aminotransferase (AST) =< 3 x ULN unless due to the underlying leukemia approved by the PI
-
Signed informed consent
-
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:
-
Patients with Philadelphia chromosome (Ph)-positive ALL or Burkitt leukemia
-
Active, uncontrolled central nervous system (CNS) leukemia involvement
-
Active serious infection not controlled by oral or intravenous antibiotics
-
Active secondary malignancy other than skin cancer (e.g., basal cell carcinoma or squamous cell carcinoma) that in the investigator's opinion will shorten survival to less than 1 year
-
Known hepatitis B or C infection, or known seropositivity for human immunodeficiency virus (HIV)
-
Active grade III-V cardiac failure as defined by the New York Heart Association criteria
-
Patients with a cardiac ejection fraction (as measured by either multi-gated acquisition [MUGA] or echocardiogram) < 40%
-
Prior history of treatment with blinatumomab
-
Treatment with any investigational antileukemic agents or chemotherapy agents in the last two weeks, unless full recovery from side effects has occurred or patient has rapidly progressive disease judged to be life-threatening by the investigator
-
Pregnant and lactating women will not be eligible; women of childbearing potential should have a negative pregnancy test prior to entering on the study and be willing to practice methods of contraception; women do not have childbearing potential if they have had a hysterectomy or are postmenopausal without menses for 12 months; in addition, men enrolled on this study should understand the risks to any sexual partner of childbearing potential and should practice an effective method of birth control
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | M D Anderson Cancer Center | Houston | Texas | United States | 77030 |
Sponsors and Collaborators
- M.D. Anderson Cancer Center
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: Elias Jabbour, M.D. Anderson Cancer Center
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- 2017-0127
- NCI-2018-00737
- 2017-0127