A Study of Venetoclax in Combination With Conventional Chemotherapy in Pediatric Patients With Acute Myeloid Leukemia
Study Details
Study Description
Brief Summary
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
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
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 Design
Arms and Interventions
| 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 |
Drug: Venetoclax
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:
Drug: Cytarabine
Given IV over 30 minutes q12 hours on days 1-8 (16 doses)
Other Names:
Drug: Gemtuzumab Ozogamicin
Given IV
Other Names:
Drug: Daunorubicin Hydrochloride
IV over 1 hour on days 1, 3, and 5
Other Names:
Drug: Idarubicin Hydrochloride
Given IV over 15 minutes on days 3-5
Other Names:
Drug: Mitoxantrone Hydrochloride
IV over 1 hour on days 2-4
Other Names:
Drug: Etoposide
Given IV over 1 hour on days 1-5
Other Names:
Drug: Gilteritinib
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 |
Drug: Venetoclax
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:
Drug: Cytarabine
Given IV over 30 minutes q12 hours on days 1-8 (16 doses)
Other Names:
Drug: Gemtuzumab Ozogamicin
Given IV
Other Names:
Drug: Daunorubicin Hydrochloride
IV over 1 hour on days 1, 3, and 5
Other Names:
Drug: Fludarabine Phosphate
Given IV over 30 minutes on days 1-5
Other Names:
Drug: Idarubicin Hydrochloride
Given IV over 15 minutes on days 3-5
Other Names:
Drug: Mitoxantrone Hydrochloride
IV over 1 hour on days 2-4
Other Names:
Drug: Etoposide
Given IV over 1 hour on days 1-5
Other Names:
Drug: Gilteritinib
PO on days 8-28 (21 doses)
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 |
Drug: Venetoclax
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:
Drug: Azacitidine
Given IV over 30 minutes on days 1-5
Other Names:
Drug: Cytarabine
Given IV over 30 minutes q12 hours on days 1-8 (16 doses)
Other Names:
Drug: Gemtuzumab Ozogamicin
Given IV
Other Names:
Drug: Daunorubicin Hydrochloride
IV over 1 hour on days 1, 3, and 5
Other Names:
Drug: Fludarabine Phosphate
Given IV over 30 minutes on days 1-5
Other Names:
Drug: Idarubicin Hydrochloride
Given IV over 15 minutes on days 3-5
Other Names:
Drug: Etoposide
Given IV over 1 hour on days 1-5
Other Names:
Drug: Gilteritinib
PO on days 8-28 (21 doses)
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Minimal residual disease (MRD)-negativity rate [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.
- Incidence of death or unacceptable adverse event [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.
Secondary Outcome Measures
- Event-free survival [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.
- Overall survival [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.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Diagnosis of AML (de novo, MDS-related, or treatment-related) 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 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/m2 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
-
Patient must be fit for protocol therapy
-
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 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 the first dose of venetoclax or during the administration of venetoclax.
-
Patients may not receive moderate or strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, voriconazole, posaconazole) within 3 days of the first dose of venetoclax or during the administration of venetoclax in induction 1.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | St. Jude Children's Research Hospital | Memphis | Tennessee | United States | 38105 |
Sponsors and Collaborators
- St. Jude Children's Research Hospital
- AbbVie
Investigators
- Principal Investigator: Jeffrey E. Rubnitz, MD, PhD, St. Jude Children's Research Hospital
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- AML23
- NCI-2023-04138