Total Therapy for Infants With Acute Lymphoblastic Leukemia (ALL) I
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The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. |
| ClinicalTrials.gov Identifier: NCT02553460 |
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Recruitment Status :
Active, not recruiting
First Posted : September 17, 2015
Results First Posted : June 7, 2023
Last Update Posted : June 7, 2023
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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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Acute Lymphoblastic Leukemia | Drug: ITMHA Drug: Dexamethasone Drug: Mitoxantrone Drug: Pegaspargase Drug: Asparaginase Erwinia Chrysanthemi Drug: Bortezomib Drug: Vorinostat Drug: Cyclophosphamide Drug: Mercaptopurine Drug: Methotrexate Drug: Leucovorin Calcium Drug: Cytarabine Drug: Etoposide Drug: Vincristine | Phase 1 Phase 2 |
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 Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 50 participants |
| Allocation: | N/A |
| Intervention Model: | Single Group Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Total Therapy for Infants With Acute Lymphoblastic Leukemia (ALL) I |
| Actual Study Start Date : | January 29, 2016 |
| Actual Primary Completion Date : | May 10, 2022 |
| Estimated Study Completion Date : | October 2031 |
| 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 Name: Cytoxan® 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 Name: Oncovin® |
- Percentage of Treatment-related Mortality (TRM) [ Time Frame: 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
- 3-year Event Free Survival (EFS) [ Time Frame: 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 Overall Survival (OS) [ Time Frame: 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.
- Minimal Residual Disease (MRD) Positivity Using Flow Cytometry at Day 22, End of Induction, End of Consolidation, and End of Maintenance. [ 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) ]Proportion of participants with positive MRD at the end of each therapy block.
- Minimal Residual Disease (MRD) Positivity Using PCR End of Induction, End of Consolidation, and End of Maintenance. [ 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) ]Proportion of participants with positive MRD at the end of each therapy block.
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| Ages Eligible for Study: | up to 365 Days (Child) |
| Sexes Eligible for Study: | All |
| Accepts 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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02553460
Show 17 study locations
| Study Chair: | Tanja Gruber, MD, PhD | Lucile Packard Children's Hospital Stanford University | |
| Principal Investigator: | Sima Jeha, MD | St. Jude Children's Research Hospital |
Documents provided by St. Jude Children's Research Hospital:
| Responsible Party: | St. Jude Children's Research Hospital |
| ClinicalTrials.gov Identifier: | NCT02553460 |
| Other Study ID Numbers: |
TINI NCI-2015-01493 ( Registry Identifier: NCI Clinical Trial Registration Program ) |
| First Posted: | September 17, 2015 Key Record Dates |
| Results First Posted: | June 7, 2023 |
| Last Update Posted: | June 7, 2023 |
| Last Verified: | June 2023 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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Infants |
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Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid Neoplasms by Histologic Type Neoplasms Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Leucovorin Cytarabine Dexamethasone Hydrocortisone Cyclophosphamide Methotrexate |
Etoposide Vincristine Bortezomib Asparaginase Mitoxantrone Mercaptopurine Vorinostat Pegaspargase Levoleucovorin Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Antirheumatic Agents Antineoplastic Agents, Alkylating Alkylating Agents |