- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT05955261
A Study of Venetoclax in Combination With Conventional Chemotherapy in Pediatric Patients With Acute Myeloid Leukemia
A Collaboration Phase 2 Study of Venetoclax in Combination With Conventional Chemotherapy in Pediatric Patients With Acute Myeloid Leukemia
This is a phase 2 study to test the hypothesis that venetoclax in combination with standard chemotherapy will be tolerable and active in pediatric patients with newly diagnosed acute myeloid leukemia (AML).
Primary Objectives:
- Establish the tolerability adding venetoclax to standard chemotherapy in pediatric patients with AML
- Estimate the proportion of patients who become minimal residual disease (MRD) negative by flow cytometry after one course of venetoclax-based induction therapy
Secondary Objectives:
- Estimate the rates of complete remission (CR), event-free survival (EFS), and overall survival (OS) in pediatric patients who receive venetoclax-based chemotherapy
Study Overview
Status
Conditions
Detailed Description
Treatment will be based on genetic characteristics and response to therapy. Venetoclax will be given with each course of therapy. Low-risk patients will receive four courses of chemotherapy and intermediate-risk patients will receive five courses. High-risk patients who do not have a suitable stem cell donor or who decline HCT will receive five courses of chemotherapy. The definition of suitable stem cell donor and the conditioning regimens used for HCT will be determined by local institutional protocols or guidelines.
Intervention:
Low Risk
Induction 1: Venetoclax orally (PO) once daily (QD) on days -2 to 11, cytarabine intravenously (IV) over 30 minutes every 12 hours on days 1-8, daunorubicin hydrochloride IV over 1 hour QD on days 1, 3, and 5, etoposide IV over one hour QD on days 1-5, and gemtuzumab ozogamicin IV over 2 hours on day 6.
Induction 2: Venetoclax PO QD on days 1-14, cytarabine IV over 30 minutes every 12 hours on days 1-8, daunorubicin hydrochloride IV over 1 hour QD on days 1, 3, and 5, and etoposide IV over 1 hour QD on days 1-5.
Intensification: Venetoclax PO QD on days 1-7, cytarabine IV over 1-2 hours every 12 hours on days 1-4, and mitoxantrone hydrochloride IV over 1 hour QD on days 2-4 during intensification 1 and then venetoclax PO QD on days 1-7 and high-dose cytarabine IV over 3 hours every 12 hours on days 1, 3, and 5 during intensification 2. Patients with FLT3 activation receive sorafenib PO QD on days 8-28 during intensification 1 and 2.
Intermediate Risk
Induction 1: Venetoclax orally (PO) once daily (QD) on days -2 to 11, cytarabine intravenously (IV) over 30 minutes every 12 hours on days 1-8, daunorubicin hydrochloride IV over 1 hour QD on days 1, 3, and 5, etoposide IV over one hour QD on days 1-5, and gemtuzumab ozogamicin IV over 2 hours on day 6.
Induction 2: Venetoclax PO QD on days 1-14, fludarabine phosphate IV over 30 minutes QD on days 1-5, cytarabine IV over 3 hours QD starting 4 hours after each dose of fludarabine on days 1-5, idarubicin hydrochloride IV over 15 minutes QD on days 3-5. Patients with FLT3 activation receive sorafenib PO QD on days 8-28.
Intensification: Venetoclax PO QD on days 1-7, cytarabine IV over 1-2 hours every 12 hours on days 1-4, and mitoxantrone hydrochloride IV over 1 hour QD on days 2-4 during intensification 1, venetoclax PO QD on days 1-7 and high-dose cytarabine IV over 3 hours every 12 hours on days 1, 3, and 5 during intensification 2, and then venetoclax PO QD on days 1-7, cytarabine IV over 1-2 hours every 12 hours on days 1-5, and etoposide IV over 1 hour QD on days 1-5 during intensification 3. Patients with FLT3 activation receive sorafenib PO QD on days 8-28 during intensification 1-3.
High Risk
Induction 1: Venetoclax orally (PO) once daily (QD) on days -2 to 11, cytarabine intravenously (IV) over 30 minutes every 12 hours on days 1-8, daunorubicin hydrochloride IV over 1 hour QD on days 1, 3, and 5, etoposide IV over one hour QD on days 1-5, and gemtuzumab ozogamicin IV over 2 hours on day 6.
Induction 2: Venetoclax PO QD on days 1-14, fludarabine phosphate IV over 30 minutes QD on days 1-5, cytarabine IV over 3 hours QD starting 4 hours after each dose of fludarabine on days 1-5, idarubicin hydrochloride IV over 15 minutes QD on days 3-5. Patients with FLT3 activation receive sorafenib PO QD on days 8-28.
Intensification: Patients with MRD < 0.1% proceed directly to HCT if donor is available. If a donor is not yet available, patients with MRD < 0.1% may receive ventoclax PO QD on days 1-21 and azacitidine IV over 30 minutes QD on days 1-5 or venetoclax PO QD on days 1-7, cytarabine IV over 1-2 hours every 12 hours on days 1-5, and etoposide IV over 1 hour QD on days 1-5. Patients with MRD 0.1% to < 1% may receive ventoclax PO QD on days 1-21 and azacitidine IV over 30 minutes QD on days 1-5 or venetoclax PO QD on days 1-7, cytarabine IV over 1-2 hours every 12 hours on days 1-5, and etoposide IV over 1 hour QD on days 1-5. Patients with MRD >= 1% may receive venetoclax PO QD on days 1-10, azacitidine IV over 30 minutes QD on days 1-5, and high-dose cytarabine IV over 3 hours every 12 hours on days 6, 8, and 10. Patients with FLT3 activation receive sorafenib PO QD on days 8-28.
Study Type
Enrollment (Estimated)
Phase
- Phase 2
Contacts and Locations
Study Contact
- Name: Jeffrey E. Rubnitz, MD, PhD
- Phone Number: 866-278-5833
- Email: referralinfo@stjude.org
Study Locations
-
-
Tennessee
-
Memphis, Tennessee, United States, 38105
- Recruiting
- St. Jude Children's Research Hospital
-
Contact:
- Jeffrey E. Rubnitz, MD, PhD
- Phone Number: 866-278-5833
- Email: referralinfo@stjude.org
-
Principal Investigator:
- Jeffrey E. Rubnitz, MD, PhD
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Child
- Adult
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Diagnosis of AML fulfilling the criteria of the WHO classification of myeloid neoplasms or < 20% marrow myeloblasts and evidence of a clonal de novo AML genetic abnormality or myeloid sarcoma or primary myelodysplastic syndrome (MDS) with ≥ 10% blasts
- Age > 28 days and < 22 years
- No prior therapy for this malignancy except for one dose of intrathecal therapy and the use of hydroxyurea or low-dose cytarabine (≤ 200 mg/m^2 per day for ≤ 7 days)
- Female patients of childbearing potential must have a negative pregnancy test within 2 weeks prior to enrollment
- Male and female participants of reproductive potential must agree to use an effective contraceptive method during the study and for 6 months after study treatment
- Written informed consent from the patient and/or parent/legal guardian
- Direct bilirubin ≤ 1.5 x institutional upper limit of normal
Exclusion Criteria:
- Patients with treatment-related AML, Down syndrome, acute promyelocytic leukemia, chronic myeloid leukemia in blast crisis, juvenile myelomonocytic leukemia, Fanconi anemia, Kostmann syndrome, Shwachman syndrome, or other bone marrow failure syndromes are not eligible
- Uncontrolled systemic fungal, bacterial, or viral infection or significant concurrent disease that would compromise patient safety or compliance, study participation, follow up, or interpretation of study results
- Prior exposure to any dose of anthracycline or anthracenedione
- Patients may not receive strong or moderate CYP3A inducers, such as rifampin, within 3 days of enrollment
- Patients may not receive moderate or strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, voriconazole, posaconazole) within 3 days of enrollment.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Non-Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Low Risk
All eligible patients receive intervention according to the Detailed Description section with the following: Venetoclax, Cytabrine, Danunorubicin Hydrochloride, Gemtuzumab Ozogamicin, Etoposide, Mitoxantrone Hydrochloride, Gilteritinib |
Given IV
Other Names:
Venetoclax will be given with each course of therapy.
Patients with low-risk AML will receive four courses of therapy, intermediate-risk patients will receive five courses of therapy, and high-risk patients will receive two or three courses of therapy followed by hematopoietic stem cell transplantation.
Other Names:
Given IV over 30 minutes q12 hours on days 1-8 (16 doses)
Other Names:
IV over 1 hour on days 1, 3, and 5
Other Names:
Given IV over 15 minutes on days 3-5
Other Names:
IV over 1 hour on days 2-4
Other Names:
Given IV over 1 hour on days 1-5
Other Names:
PO on days 8-28 (21 doses)
Other Names:
|
Experimental: Intermediate Risk
All eligible patients receive intervention according to the Detailed Description section with the following: Venetoclax, Cytabrine, Danunorubicin Hydrochloride, Fludarabine Phosphate, Gemtuzumab Ozogamicin, Etoposide, Idarubin Hydrochloride, Mitoxantrone Hydrochloride, Gilteritinib |
Given IV
Other Names:
Venetoclax will be given with each course of therapy.
Patients with low-risk AML will receive four courses of therapy, intermediate-risk patients will receive five courses of therapy, and high-risk patients will receive two or three courses of therapy followed by hematopoietic stem cell transplantation.
Other Names:
Given IV over 30 minutes q12 hours on days 1-8 (16 doses)
Other Names:
IV over 1 hour on days 1, 3, and 5
Other Names:
Given IV over 15 minutes on days 3-5
Other Names:
IV over 1 hour on days 2-4
Other Names:
Given IV over 1 hour on days 1-5
Other Names:
PO on days 8-28 (21 doses)
Other Names:
Given IV over 30 minutes on days 1-5
Other Names:
|
Experimental: High Risk
All eligible patients receive intervention according to the Detailed Description section with the following: Venetoclax, Azacitidine, Cytabrine, Danunorubicin Hydrochloride, Fludarabine Phosphate, Gemtuzumab Ozogamicin, Etoposide, Idarubin Hydrochloride, Gilteritinib |
Given IV
Other Names:
Venetoclax will be given with each course of therapy.
Patients with low-risk AML will receive four courses of therapy, intermediate-risk patients will receive five courses of therapy, and high-risk patients will receive two or three courses of therapy followed by hematopoietic stem cell transplantation.
Other Names:
Given IV over 30 minutes q12 hours on days 1-8 (16 doses)
Other Names:
IV over 1 hour on days 1, 3, and 5
Other Names:
Given IV over 15 minutes on days 3-5
Other Names:
Given IV over 1 hour on days 1-5
Other Names:
PO on days 8-28 (21 doses)
Other Names:
Given IV over 30 minutes on days 1-5
Other Names:
Given IV over 30 minutes on days 1-5
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Minimal residual disease (MRD)-negativity rate
Time Frame: At day 29 after induction 1
|
Will compute a binomial confidence interval for the proportion of MRD-evaluable patients who become MRD-negative (defined as MRD < 0.1%) after induction 1.
|
At day 29 after induction 1
|
Incidence of death or unacceptable adverse event
Time Frame: From initiation to completion of each course of therapy, an average of 6 weeks
|
A patient is deemed to have tolerated a course of therapy if they complete that course without death or an unacceptable adverse event.
Will monitor the tolerability or each course using multi-stage binomial stopping rules.
Will use the method of Jung and Kim to compute 95% confidence intervals that adjust for the multi-stage monitoring.
|
From initiation to completion of each course of therapy, an average of 6 weeks
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Event-free survival
Time Frame: From study enrollment to disease resistance, relapse, development of a second malignancy, or death due to any cause (up to 3 years after the last enrollment).
|
The Kaplan-Meier method will be used and 95% confidence intervals will be computed for event-free survival at 3 years.
|
From study enrollment to disease resistance, relapse, development of a second malignancy, or death due to any cause (up to 3 years after the last enrollment).
|
Overall survival
Time Frame: From protocol enrollment until death (up to 3 years after the last enrollment).
|
The Kaplan-Meier method will be used and 95% confidence intervals will be computed for overall survival at 3 years.
|
From protocol enrollment until death (up to 3 years after the last enrollment).
|
Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: Jeffrey E. Rubnitz, MD, PhD, St. Jude Children's Research Hospital
Publications and helpful links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Estimated)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Neoplasms by Histologic Type
- Neoplasms
- Leukemia
- Leukemia, Myeloid
- Leukemia, Myeloid, Acute
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Peripheral Nervous System Agents
- Antiviral Agents
- Enzyme Inhibitors
- Analgesics
- Sensory System Agents
- Antimetabolites, Antineoplastic
- Antimetabolites
- Antineoplastic Agents
- Immunosuppressive Agents
- Immunologic Factors
- Antineoplastic Agents, Phytogenic
- Topoisomerase II Inhibitors
- Topoisomerase Inhibitors
- Antineoplastic Agents, Immunological
- Antibiotics, Antineoplastic
- Immunoconjugates
- Immunotoxins
- Etoposide
- Venetoclax
- Azacitidine
- Fludarabine
- Fludarabine phosphate
- Cytarabine
- Daunorubicin
- Idarubicin
- Mitoxantrone
- Gemtuzumab
Other Study ID Numbers
- AML23
- NCI-2023-04138 (Registry Identifier: NCI Clinical Trial Registration Program)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
IPD Sharing Time Frame
IPD Sharing Access Criteria
IPD Sharing Supporting Information Type
- STUDY_PROTOCOL
- SAP
- ICF
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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