Description:
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.
Title
- Brief Title: Total Therapy for Infants With Acute Lymphoblastic Leukemia (ALL) I
- Official Title: Total Therapy for Infants With Acute Lymphoblastic Leukemia (ALL) I
Clinical Trial IDs
- ORG STUDY ID:
TINI
- SECONDARY ID:
NCI-2015-01493
- NCT ID:
NCT02553460
Conditions
- Acute Lymphoblastic Leukemia
Interventions
| Drug | Synonyms | Arms |
|---|
| ITMHA | Intrathecal Triples, Methotrexate/hydrocortisone/cytarabine | Treatment |
| Dexamethasone | Decadron®, Hexadrol®, Dexone®, Dexameth® | Treatment |
| Mitoxantrone | Novantrone®, Mitozantrone | Treatment |
| Pegaspargase | PEG-asparaginase, Oncaspar® | Treatment |
| Asparaginase Erwinia Chrysanthemi | Erwinia chrysanthemi, Erwinase®, Erwinaze^T^M, Crisantaspase | Treatment |
| Bortezomib | Velcade®, PS-341, MLN341, LDP-341 | Treatment |
| Vorinostat | Solinza®, Suberoylanidide Hydroxamic Acid, SAHA | Treatment |
| Cyclophosphamide | Cytoxan® | Treatment |
| Mercaptopurine | 6-MP, Purinethol® | Treatment |
| Methotrexate | MTX, High Dose MTX | Treatment |
| Leucovorin Calcium | Wellcovorin®, Folinic acid | Treatment |
| Cytarabine | Ara-C, Cytosar-U® | Treatment |
| Etoposide | VP-16, Vepesid® | Treatment |
| Vincristine | Oncovin® | Treatment |
Purpose
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.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| Treatment | Experimental | Participants who meet eligibility requirements will receive remission induction, consolidation treatment, reinduction, reintensification and maintenance therapy.
Interventions: ITMHA, dexamethasone, mitoxantrone, pegaspargase or asparaginase Erwinia chrysanthemi, bortezomib, vorinostat, cyclophosphamide, mercaptopurine, methotrexate, leucovorin calcium, cytarabine, etoposide, and vincristine. | - ITMHA
- Dexamethasone
- Mitoxantrone
- Pegaspargase
- Asparaginase Erwinia Chrysanthemi
- Bortezomib
- Vorinostat
- Cyclophosphamide
- Mercaptopurine
- Methotrexate
- Leucovorin Calcium
- Cytarabine
- Etoposide
- Vincristine
|
Eligibility Criteria
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.
| Maximum Eligible Age: | 365 Days |
| Minimum Eligible Age: | N/A |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Probability of treatment-related mortality (TRM) during induction or reinduction therapy |
| Time Frame: | At the end of reinduction (up to 5 months after start of therapy) |
| Safety Issue: | |
| Description: | Tolerability will be measured by the probability of toxic death (Treatment-Related Mortality, TRM) during Induction or Reinduction. As a safety precaution, the study team will suspend enrollment to the study intermittently to prevent more than 10 patients being treated simultaneously with induction and/or re-induction therapy. The study team will consider a < 10% TRM rate as clinically tolerable and will be used as a benchmark. |
Secondary Outcome Measures
| Measure: | 3-year event free survival (EFS) |
| Time Frame: | 3 years after completion of therapy (up to 5 years after start of therapy) |
| Safety Issue: | |
| Description: | 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. |
| Measure: | 5-year event free survival (EFS) |
| Time Frame: | 5 years after completion of therapy (up to 7 years after start of therapy) |
| Safety Issue: | |
| Description: | 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. |
| Measure: | 10-year event free survival (EFS) |
| Time Frame: | 10 years after completion of therapy (up to 12 years after start of therapy) |
| Safety Issue: | |
| Description: | 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. |
| Measure: | 3-year overall survival (OS) |
| Time Frame: | 3 years after completion of therapy (up to 5 years after start of therapy) |
| Safety Issue: | |
| Description: | Overall survival (OS) will be estimated by the Kaplan-Meier estimator. OS probability at years 3, 5, 10 will be estimated with 95% confidence intervals. |
| Measure: | 5-year overall survival (OS) |
| Time Frame: | 5 years after completion of therapy (up to 7 years after start of therapy) |
| Safety Issue: | |
| Description: | Overall survival (OS) will be estimated by the Kaplan-Meier estimator. OS probability at years 3, 5, 10 will be estimated with 95% confidence intervals. |
| Measure: | 10-year overall survival (OS) |
| Time Frame: | 10 years after completion of therapy (up to 12 years after start of therapy) |
| Safety Issue: | |
| Description: | Overall survival (OS) will be estimated by the Kaplan-Meier estimator. OS probability at years 3, 5, 10 will be estimated with 95% confidence intervals. |
| Measure: | Compare minimal residual disease (MRD) positivity using flow cytometry |
| Time Frame: | At end of induction (approximately 6 weeks), end of consolidation (approximately 14 weeks), end of reinduction (approximately 19 weeks), end of reintensification (approximately 23 weeks), and end of maintenance therapy (approximately 2 years) |
| Safety Issue: | |
| Description: | Proportion of participants with positive MRD at the end of each therapy block. |
| Measure: | Compare minimal residual disease (MRD) positivity using PCR |
| Time Frame: | At end of induction (approximately 6 weeks), end of consolidation (approximately 14 weeks), end of reinduction (approximately 19 weeks), end of reintensification (approximately 23 weeks), and end of maintenance therapy (approximately 2 years) |
| Safety Issue: | |
| Description: | Proportion of participants with positive MRD at the end of each therapy block. |
| Measure: | Mean MRD levels compared to the Interfant99 study (NCT00015873) |
| Time Frame: | At end of induction (approximately 6 weeks), end of consolidation (approximately 11 weeks), and end of reinduction (approximately 19 weeks) |
| Safety Issue: | |
| Description: | The two-sample two-sided Z test at the 5% significance level will be utilized for this comparison. |
| Measure: | Median MRD levels compared to the Interfant99 study (NCT00015873) |
| Time Frame: | At end of induction (approximately 6 weeks), end of consolidation (approximately 11 weeks), and end of reinduction (approximately 19 weeks) |
| Safety Issue: | |
| Description: | The two-sample two-sided Z test at the 5% significance level will be utilized for this comparison. |
Details
| Phase: | Phase 1/Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Recruiting |
| Lead Sponsor: | St. Jude Children's Research Hospital |
Trial Keywords
Last Updated
April 29, 2021
