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Total Therapy for Infants With Acute Lymphoblastic Leukemia (ALL) I

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ClinicalTrials.gov Identifier: NCT02553460
Recruitment Status : Recruiting
First Posted : September 17, 2015
Last Update Posted : June 21, 2018
Sponsor:
Collaborators:
Gateway for Cancer Research
Texas Children's Hospital
Information provided by (Responsible Party):
St. Jude Children's Research Hospital

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.

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

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.

RE-INTENSIFICATION: If the participant's maximum residual disease (MRD) is not negative after consolidation, he/she will receive intensification therapy, then go on to stem cell transplant (SCT) (SCT not part of this study).

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)
Estimated Enrollment : 50 participants
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
Estimated Primary Completion Date : February 2020
Estimated Study Completion Date : October 2031


Arm Intervention/treatment
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:
  • Intrathecal Triples
  • Methotrexate/hydrocortisone/cytarabine

Drug: Dexamethasone
Given orally (PO) or naso-gastrically (NG) or intravenously (IV).
Other Names:
  • Decadron®
  • Hexadrol®
  • Dexone®
  • Dexameth®

Drug: Mitoxantrone
Given IV.
Other Names:
  • Novantrone®
  • Mitozantrone

Drug: Pegaspargase
Given IV. If participant is allergic to pegaspargase, Asparaginase Erwinia Chrysanthemi will be used.
Other Names:
  • PEG-asparaginase
  • Oncaspar®

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:
  • Erwinia chrysanthemi
  • Erwinase®
  • Erwinaze^T^M
  • Crisantaspase

Drug: Bortezomib
Given IV.
Other Names:
  • Velcade®
  • PS-341
  • MLN341
  • LDP-341

Drug: Vorinostat
Taken PO or NG.
Other Names:
  • Solinza®
  • Suberoylanidide Hydroxamic Acid
  • SAHA

Drug: Cyclophosphamide
Given IV.
Other Name: Cytoxan®

Drug: Mercaptopurine
Given PO or NG.
Other Names:
  • 6-MP
  • Purinethol®

Drug: Methotrexate
Given IV.
Other Names:
  • MTX
  • High Dose MTX

Drug: Leucovorin Calcium
Leucovorin rescue PO or IV.
Other Names:
  • Wellcovorin®
  • Folinic acid

Drug: Cytarabine
Given IV.
Other Names:
  • Ara-C
  • Cytosar-U®

Drug: Etoposide
Given IV. In case of participant allergy, etoposide phosphate (Etopophos®) will be given.
Other Names:
  • VP-16
  • Vepesid®

Drug: Vincristine
Given IV.
Other Name: Oncovin®




Primary Outcome Measures :
  1. 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) ]
    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 :
  1. 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.

  2. 5-year event free survival (EFS) [ Time Frame: 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.

  3. 10-year event free survival (EFS) [ Time Frame: 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.

  4. 3-year overall survival (OS) [ Time Frame: 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. 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.

  6. 10-year overall survival (OS) [ Time Frame: 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.

  7. 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) ]
    Proportion of participants with positive MRD at the end of each therapy block.

  8. 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) ]
    Proportion of participants with positive MRD at the end of each therapy block.

  9. 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) ]
    The two-sample two-sided Z test at the 5% significance level will be utilized for this comparison.

  10. 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) ]
    The two-sample two-sided Z test at the 5% significance level will be utilized for this comparison.



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Ages Eligible for Study:   up to 365 Days   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 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.

Information from the National Library of Medicine

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


Contacts
Contact: Tanja A. Gruber, MD, PhD 866-278-5833 tanja.gruber@stjude.org
Contact: St. Jude Referral Office 866-278-5833 referralinfo@stjude.org

Locations
United States, California
Children's Hospital Los Angeles Recruiting
Los Angeles, California, United States, 90027
Contact: Paul Gaynon, MD    323-361-4110    pgaynon@chla.usc.edu   
Principal Investigator: Paul Gaynon, MD         
Children's Hospital of Orange County Recruiting
Orange, California, United States, 92868
Contact: Ivan Kirov, MD    714-997-3000    ikirov@choc.org   
Principal Investigator: Ivan Kirov, MD         
Lucile Packard Children's Hospital Stanford University Recruiting
Palo Alto, California, United States, 94304
Contact: Norman J. Lacayo, MD    650-497-8953    lacayon@stanford.edu   
Principal Investigator: Norman J. Lacayo, MD         
Rady Children's Hospital and Health Center Recruiting
San Diego, California, United States, 92123
Contact: Deborah Schiff, MD    858-966-5983    dschiff@chsd.org   
Principal Investigator: Deborah Schiff, MD         
United States, Minnesota
Children's Hospital and Clinics of Minnesota Recruiting
Minneapolis, Minnesota, United States, 55102
Contact: Michael Richards, MD    612-813-5193    Michael.richards@childrensmn.org   
Principal Investigator: Michael Richards, MD         
United States, North Carolina
St. Jude Affiliate-Charlotte Recruiting
Charlotte, North Carolina, United States, 28204
Contact: Christine Bolen, MD    704-384-1900    cybolen@novanthealth.org   
Principal Investigator: Christine Bolen, MD         
United States, Ohio
Cincinnati Children's Hospital Recruiting
Cincinnati, Ohio, United States, 45229
Contact: Erin Breese, MD, PhD    513-636-2799    erin.breese@cchmc.org   
Principal Investigator: Erin Breese, MD, PhD         
Rainbow Babies & Children's Hospital Recruiting
Cleveland, Ohio, United States, 44106
Contact: Yousif Matloub, MD    216-844-5437    yousif.matloub@uhhospitals.org   
Principal Investigator: Yousif Matloub, MD         
United States, Oregon
Oregon Health and Science University Recruiting
Portland, Oregon, United States, 97239
Contact: Bill Chang, MD    503-494-1080    changb@ohsu.edu   
Principal Investigator: Bill Chang, MD         
United States, Tennessee
St. Jude Children's Research Hospital Recruiting
Memphis, Tennessee, United States, 38105
Contact: Tanja A. Gruber, MD, PhD    866-278-5833    tanja.gruber@stjude.org   
Contact: Referral Office    866-278-5833    referralinfo@stjude.org   
Principal Investigator: Tanja A. Gruber, MD, PhD         
United States, Virginia
Children's Hospital of the King's Daughters (CHKD) Recruiting
Norfolk, Virginia, United States, 23507
Contact: Eric Lowe, MD    757-668-7243    eric.lowe@chkd.org   
Principal Investigator: Eric Lowe, MD         
Canada, Alberta
Alberta Children's Hospital Recruiting
Calgary, Alberta, Canada, T3A 6A8
Contact: Victor A. Lewis, MD    403-220-6898    victor.lewis@ahs.ca   
Principal Investigator: Victor A. Lewis, MD         
Stollery Children's Hospital Recruiting
Edmonton, Alberta, Canada, T6G 2B7
Contact: Sunil Desai, M.B.Ch.B., FRCP(c)    780-248-5415    sunil.desai@ahs.ca   
Principal Investigator: Sunil Desai, M.B.Ch.B., FRCP(c)         
Canada, British Columbia
Children's & Women's Health Centre of British Columbia Recruiting
Vancouver, British Columbia, Canada, V6H 3V4
Contact: Kirk R. Schultz, MD    604-875-2345 ext 6477    kschultz@mail.ubc.ca   
Principal Investigator: Kirk R. Schultz, MD         
Canada, Ontario
McMaster Children's Hospital at Hamilton Health Sciences Recruiting
Hamilton, Ontario, Canada, L85 4J9
Contact: Uma Athale, MD    905-521-2100 ext 73376    athaleu@mcmaster.ca   
Principal Investigator: Uma Athale, MD         
Canada, Quebec
The Montreal Children's Hospital (MUHC-McGill) Recruiting
Montreal, Quebec, Canada, H4A 3J1
Contact: Catherine Vezina, MD    514-412-4445    catherine.vezina@muhc.mcgill.ca   
Principal Investigator: Catherine Vezina, MD         
Centre Hospitalier Universitaire Sainte-Justine Recruiting
Montreal, Quebec, Canada, HcT 1C5
Contact: Henrique Bittencourt, MD    514-345-4931    henrique.bittencourt.hsj@ssss.gouv.qc.ca   
Contact: Yvan Samson       yvan.samson@umontreal.ca   
Principal Investigator: Henrique Bittencourt, MD         
Centre Hospitalier Universitaire de Quebec Recruiting
Québec, Quebec, Canada, G1V 4G2
Contact: Bruno Michon, MD    418-525-4444    bruno.michon@mail.chuq.qc.ca   
Principal Investigator: Bruno Michon, MD         
Sponsors and Collaborators
St. Jude Children's Research Hospital
Gateway for Cancer Research
Texas Children's Hospital
Investigators
Principal Investigator: Tanja A. Gruber, MD, PhD St. Jude Children's Research Hospital

Additional Information:
Responsible Party: St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier: NCT02553460     History of Changes
Other Study ID Numbers: TINI
NCI-2015-01493 ( Registry Identifier: NCI Clinical Trial Registration Program )
First Posted: September 17, 2015    Key Record Dates
Last Update Posted: June 21, 2018
Last Verified: February 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by St. Jude Children's Research Hospital:
Infants

Additional relevant MeSH terms:
Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Dexamethasone acetate
Dexamethasone
Hydrocortisone
Etoposide phosphate
Vorinostat
Pegaspargase
Cyclophosphamide
Methotrexate
Bortezomib
Etoposide
Cytarabine
Vincristine
Mitoxantrone
Asparaginase
6-Mercaptopurine
BB 1101
Levoleucovorin
Leucovorin
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents