Acute Lymphoblastic Leukemia
Conditions
Keywords
Infants
Brief summary
The purpose of this study is to test the good and bad effects of the study drugs bortezomib and vorinostat when they are given in combination with chemotherapy commonly used to treat acute lymphoblastic leukemia (ALL) in infants. For example, adding these drugs could decrease the number of leukemia cells, but it could also cause additional side effects. Bortezomib and vorinostat have been approved by the US Food and Drug Administration (FDA) to treat other cancers in adults, but they have not been approved for treating children with leukemia. With this research, we plan to meet the following goals: PRIMARY OBJECTIVE: * Determine the tolerability of incorporating bortezomib and vorinostat into an ALL chemotherapy backbone for newly diagnosed infants with ALL. SECONDARY OBJECTIVES: * Estimate the event-free survival and overall survival of infants with ALL who are treated with bortezomib and vorinostat in combination with an ALL chemotherapy backbone. * Measure minimal residual disease (MRD) positivity using both flow cytometry and PCR. * Compare end of induction, end of consolidation, and end of reinduction MRD levels to Interfant99 (ClinicalTrials.gov registration ID number NCT00015873) participant outcomes.
Detailed description
Treatment will consist of 4 main phases: Remission Induction, Consolidation, Reinduction, and Maintenance. High risk patients will receive a reintensification phase prior to transplant in first remission. REMISSION INDUCTION: Chemotherapy will be given in an attempt to induce the participant's leukemia into remission. Drugs given are intrathecal triple drug treatment with methotrexate, hydrocortisone and Ara-C (ITMHA); dexamethasone; vorinostat; bortezomib; PEG-asparaginase; mitoxantrone; cyclophosphamide; cytarabine; and 6-mercaptopurine. CONSOLIDATION PHASE: After the participant's blood counts have recovered from Remission Induction, he/she will move to the consolidation phase. This therapy is given to kill any remaining leukemia cells. Drugs given are ITMHA, high-dose methotrexate, and 6-mercaptopurine. RE-INDUCTION: This phase aims to improve the participant's overall response to therapy by again seeking to bring his/her leukemia into remission. Drugs given are ITMHA, mitoxantrone, peg-asparaginase, dexamethasone, bortezomib, and vorinostat.Participants that achieve MRD negative status following Re-Induction may proceed directly to stem cell transplant (SCT) (SCT not part of this study). RE-INTENSIFICATION: Participants that remain MRD positive following Consolidation or Reinduction may receive Chimeric Antigen Receptor T-Cell therapy (CART), if available (CART is not part of this study), or proceed to a Reintensification phase then go on to stem cell transplant (SCT). MAINTENANCE PHASE: Participants with negative MRD after consolidation will skip the re-intensification phase and proceed to receive maintenance therapy to keep the leukemia from returning. Drugs given are ITMHA, dexamethasone, vincristine, 6-mercaptopurine and methotrexate. Each cycle of these drugs lasts 28 days and will be repeated up to 20 times as long as there are no serious side effects.
Interventions
DRUGITMHA
Given intrathecally (IT).
DRUGDexamethasone
Given orally (PO) or naso-gastrically (NG) or intravenously (IV).
DRUGMitoxantrone
Given IV.
DRUGPegaspargase
Given IV. If participant is allergic to pegaspargase, Asparaginase Erwinia Chrysanthemi will be used.
Asparaginase Erwinia Chrysanthemi will be used in case of allergy or intolerance of participant to PEG-asparaginase. Given IV (preferred) or intramuscularly (IM).
DRUGBortezomib
Given IV.
DRUGVorinostat
Taken PO or NG.
DRUGCyclophosphamide
Given IV.
DRUGMercaptopurine
Given PO or NG.
DRUGMethotrexate
Given IV, IM or PO.
DRUGLeucovorin Calcium
Leucovorin rescue PO or IV.
DRUGCytarabine
Given IV.
DRUGEtoposide
Given IV. In case of participant allergy, etoposide phosphate (Etopophos®) will be given.
DRUGVincristine
Given IV.
Sponsors
Gateway for Cancer Research
Baylor College of Medicine
St. Jude Children's Research Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 365 Days
Healthy volunteers
No
Inclusion criteria
* Patient is ≤ 365 days of age at the time of diagnosis. * Patient has newly diagnosed acute lymphoblastic leukemia (ALL) or acute undifferentiated leukemia with ≥25% blasts in the bone marrow (M3), with or without extramedullary disease. Patients with T-cell ALL are eligible. Patients with bilineage or biphenotypic acute leukemia are eligible, provided the morphology and immunophenotype are predominantly lymphoid. * Limited prior therapy, including hydroxyurea for 72 hours or less, systemic glucocorticoids for one week or less, one dose of vincristine, and one dose of intrathecal chemotherapy. * Written informed consent following Institutional Review Board, NCI, FDA, and Office for Human Research Protections (OHRP) Guidelines.
Exclusion criteria
* Patients with prior therapy, other than therapy specified in the Inclusion Criteria. * Patients with mature B-cell ALL or acute myelogenous (AML). * Patients with Down syndrome. * Inability or unwillingness of legal guardian/representative to give written informed consent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Treatment-related Mortality (TRM) | At the end of reinduction (up to 5 months after start of therapy) | Number of treatment related deaths divided by total number of patients during induction or reinduction therapy. Presented as percentage |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With 3-year Event Free Survival (EFS) | 3 years after completion of therapy (up to 5 years after start of therapy) | Event-free survival (EFS) will be estimated by the Kaplan-Meier estimator. For EFS, relapse and second malignancies will be considered as failures in addition to death in complete remission. The time to EFS will be set to 0 for patients who fail to achieve complete remission. EFS probability will be estimated with 95% confidence intervals. |
| Percentage of Participants With 5-year Overall Survival (OS) | 5 years after completion of therapy (up to 7 years after start of therapy) | Overall survival (OS) will be estimated by the Kaplan-Meier estimator with 95% confidence intervals. |
| Minimal Residual Disease (MRD) Positivity Using Flow Cytometry or PCR at Induction Day 22, End of Induction, End of Consolidation, and End of Maintenance. | At the end of induction day 22 (approximately 3 weeks), end of induction (approximately 6 weeks), end of consolidation (approximately 14 weeks), and end of maintenance therapy (approximately 2 years) | Proportion of participants with positive MRD at the end of each therapy block. The proportion of MRD positive patients is determined by the number of patients that are MRD positive at the end of each therapy block divided by the number of patients that completed each therapy block. |
Countries
Canada, United States
Participant flow
Recruitment details
Fifty patients were enrolled between January 2016 to November 2021.
Participants by arm
| Arm | Count |
|---|---|
| Stratum 1 Patient is \< 365 days of age at the time of diagnosis. Patient has newly diagnosed acute lymphoblastic leukemia (ALL) or acute undifferentiated leukemia with ≥25% blasts in the bone marrow (M3), with or without extramedullary disease. Patients with T-cell ALL are eligible. Patients with bilineage or biphenotypic acute leukemia are eligible, provided the morphology and immunophenotype are predominantly lymphoid. Limited prior therapy, including hydroxyurea for 72 hours or less, systemic glucocorticoids for one week or less, one dose of vincristine, and one dose of intrathecal chemotherapy. Written informed consent following Institutional Review Board, NCI, FDA, and OHRP Guidelines. | 50 |
| Total | 50 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | CAR T cells | 2 |
| Overall Study | Death | 3 |
| Overall Study | Development of unacceptable toxicity during treatment | 1 |
| Overall Study | No response to treatment | 2 |
| Overall Study | Relapse or Transplant | 14 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Stratum 1 |
|---|---|
| Age, Continuous | 5.32 months STANDARD_DEVIATION 3.33 |
| Race/Ethnicity, Customized Black | 4 Participants |
| Race/Ethnicity, Customized Other | 15 Participants |
| Race/Ethnicity, Customized White | 31 Participants |
| Region of Enrollment Canada | 13 Participants |
| Region of Enrollment United States | 37 Participants |
| Sex: Female, Male Female | 24 Participants |
| Sex: Female, Male Male | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 17 / 50 |
| other Total, other adverse events | 50 / 50 |
| serious Total, serious adverse events | 27 / 50 |
Outcome results
Primary
Percentage of Treatment-related Mortality (TRM)
Number of treatment related deaths divided by total number of patients during induction or reinduction therapy. Presented as percentage
Time frame: At the end of reinduction (up to 5 months after start of therapy)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stratum 1 | Percentage of Treatment-related Mortality (TRM) | 1 Participants |
Secondary
Minimal Residual Disease (MRD) Positivity Using Flow Cytometry or PCR at Induction Day 22, End of Induction, End of Consolidation, and End of Maintenance.
Proportion of participants with positive MRD at the end of each therapy block. The proportion of MRD positive patients is determined by the number of patients that are MRD positive at the end of each therapy block divided by the number of patients that completed each therapy block.
Time frame: At the end of induction day 22 (approximately 3 weeks), end of induction (approximately 6 weeks), end of consolidation (approximately 14 weeks), and end of maintenance therapy (approximately 2 years)
Population: The number analyzed is different from the overall number analyzed because the patient(s) MRD at that time period was not evaluated due to induction failure, death, or relapse.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Stratum 1 | Minimal Residual Disease (MRD) Positivity Using Flow Cytometry or PCR at Induction Day 22, End of Induction, End of Consolidation, and End of Maintenance. | MRD positivity at Day 22 | 13 Participants |
| Stratum 1 | Minimal Residual Disease (MRD) Positivity Using Flow Cytometry or PCR at Induction Day 22, End of Induction, End of Consolidation, and End of Maintenance. | MRD positivity at End of Induction | 13 Participants |
| Stratum 1 | Minimal Residual Disease (MRD) Positivity Using Flow Cytometry or PCR at Induction Day 22, End of Induction, End of Consolidation, and End of Maintenance. | MRD positivity at End of Consolidation | 11 Participants |
| Stratum 1 | Minimal Residual Disease (MRD) Positivity Using Flow Cytometry or PCR at Induction Day 22, End of Induction, End of Consolidation, and End of Maintenance. | MRD positivity at End of Maintenance | 0 Participants |
Secondary
Percentage of Participants With 3-year Event Free Survival (EFS)
Event-free survival (EFS) will be estimated by the Kaplan-Meier estimator. For EFS, relapse and second malignancies will be considered as failures in addition to death in complete remission. The time to EFS will be set to 0 for patients who fail to achieve complete remission. EFS probability will be estimated with 95% confidence intervals.
Time frame: 3 years after completion of therapy (up to 5 years after start of therapy)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stratum 1 | Percentage of Participants With 3-year Event Free Survival (EFS) | 49.96 percentage of participants |
Secondary
Percentage of Participants With 5-year Overall Survival (OS)
Overall survival (OS) will be estimated by the Kaplan-Meier estimator with 95% confidence intervals.
Time frame: 5 years after completion of therapy (up to 7 years after start of therapy)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stratum 1 | Percentage of Participants With 5-year Overall Survival (OS) | 62.8 percentage of participants |