Total Therapy for Infants With Acute Lymphoblastic Leukemia (ALL) I
Study Details
Study Description
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:
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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.
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Measure minimal residual disease (MRD) positivity using both flow cytometry and PCR.
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Compare end of induction, end of consolidation, and end of reinduction MRD levels to Interfant99 (ClinicalTrials.gov registration ID number NCT00015873) participant outcomes.
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
|
Phase 1/Phase 2 |
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.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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Experimental: Treatment 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. |
Drug: ITMHA
Given intrathecally (IT).
Other Names:
Drug: Dexamethasone
Given orally (PO) or naso-gastrically (NG) or intravenously (IV).
Other Names:
Drug: Mitoxantrone
Given IV.
Other Names:
Drug: Pegaspargase
Given IV. If participant is allergic to pegaspargase, Asparaginase Erwinia Chrysanthemi will be used.
Other Names:
Drug: Asparaginase Erwinia Chrysanthemi
Asparaginase Erwinia Chrysanthemi will be used in case of allergy or intolerance of participant to PEG-asparaginase. Given IV (preferred) or intramuscularly (IM).
Other Names:
Drug: Bortezomib
Given IV.
Other Names:
Drug: Vorinostat
Taken PO or NG.
Other Names:
Drug: Cyclophosphamide
Given IV.
Other Names:
Drug: Mercaptopurine
Given PO or NG.
Other Names:
Drug: Methotrexate
Given IV, IM or PO.
Other Names:
Drug: Leucovorin Calcium
Leucovorin rescue PO or IV.
Other Names:
Drug: Cytarabine
Given IV.
Other Names:
Drug: Etoposide
Given IV. In case of participant allergy, etoposide phosphate (Etopophos®) will be given.
Other Names:
Drug: Vincristine
Given IV.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Probability of treatment-related mortality (TRM) during induction or reinduction therapy [At the end of reinduction (up to 5 months after start of therapy)]
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
- 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.
- 5-year event free survival (EFS) [5 years after completion of therapy (up to 7 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.
- 10-year event free survival (EFS) [10 years after completion of therapy (up to 12 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.
- 3-year overall survival (OS) [3 years after completion of therapy (up to 5 years after start of therapy)]
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.
- 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. OS probability at years 3, 5, 10 will be estimated with 95% confidence intervals.
- 10-year overall survival (OS) [10 years after completion of therapy (up to 12 years after start of therapy)]
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.
- Compare minimal residual disease (MRD) positivity using flow cytometry [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)]
Proportion of participants with positive MRD at the end of each therapy block.
- Compare minimal residual disease (MRD) positivity using PCR [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)]
Proportion of participants with positive MRD at the end of each therapy block.
- Mean MRD levels compared to the Interfant99 study (NCT00015873) [At end of induction (approximately 6 weeks), end of consolidation (approximately 11 weeks), and end of reinduction (approximately 19 weeks)]
The two-sample two-sided Z test at the 5% significance level will be utilized for this comparison.
- Median MRD levels compared to the Interfant99 study (NCT00015873) [At end of induction (approximately 6 weeks), end of consolidation (approximately 11 weeks), and end of reinduction (approximately 19 weeks)]
The two-sample two-sided Z test at the 5% significance level will be utilized for this comparison.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Patient is ≤ 365 days of age at the time of diagnosis.
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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.
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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.
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Written informed consent following Institutional Review Board, NCI, FDA, and Office for Human Research Protections (OHRP) Guidelines.
Exclusion Criteria:
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Patients with prior therapy, other than therapy specified in the Inclusion Criteria.
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Patients with mature B-cell ALL or acute myelogenous (AML).
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Patients with Down syndrome.
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Inability or unwillingness of legal guardian/representative to give written informed consent.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | Children's Hospital Los Angeles | Los Angeles | California | United States | 90027 |
2 | Children's Hospital of Orange County | Orange | California | United States | 92868 |
3 | Lucile Packard Children's Hospital Stanford University | Palo Alto | California | United States | 94304 |
4 | Rady Children's Hospital and Health Center | San Diego | California | United States | 92123 |
5 | Children's Hospital and Clinics of Minnesota | Minneapolis | Minnesota | United States | 55404 |
6 | St. Jude Affiliate-Charlotte | Charlotte | North Carolina | United States | 28204 |
7 | Cincinnati Children's Hospital | Cincinnati | Ohio | United States | 45229 |
8 | Rainbow Babies & Children's Hospital | Cleveland | Ohio | United States | 44106 |
9 | Oregon Health and Science University | Portland | Oregon | United States | 97239 |
10 | St. Jude Children's Research Hospital | Memphis | Tennessee | United States | 38105 |
11 | Children's Hospital of the King's Daughters (CHKD) | Norfolk | Virginia | United States | 23507 |
12 | Alberta Children's Hospital | Calgary | Alberta | Canada | T3A 6A8 |
13 | Stollery Children's Hospital | Edmonton | Alberta | Canada | T6G 2B7 |
14 | Children's & Women's Health Centre of British Columbia | Vancouver | British Columbia | Canada | V6H 3V4 |
15 | McMaster Children's Hospital at Hamilton Health Sciences | Hamilton | Ontario | Canada | L85 4J9 |
16 | Centre Hospitalier Universitaire Sainte-Justine | Montreal | Quebec | Canada | H3T 1C5 CAN |
17 | The Montreal Children's Hospital (MUHC-McGill) | Montreal | Quebec | Canada | H4A 3J1 |
18 | Centre Hospitalier Universitaire de Quebec | Québec | Quebec | Canada | G1V 4G2 |
Sponsors and Collaborators
- St. Jude Children's Research Hospital
- Gateway for Cancer Research
- Baylor College of Medicine
Investigators
- Study Chair: Tanja Gruber, MD, PhD, Lucile Packard Children's Hospital Stanford University
- Principal Investigator: Sima Jeha, MD, St. Jude Children's Research Hospital
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- TINI
- NCI-2015-01493