A Study of Venetoclax in Combination With Conventional Chemotherapy in Pediatric Patients With Acute Myeloid Leukemia

Study Overview
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Brief Summary
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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

Detailed Description
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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.

Official Title
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A Collaboration Phase 2 Study of Venetoclax in Combination With Conventional Chemotherapy in Pediatric Patients With Acute Myeloid Leukemia

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Venetoclax
* Drug: Azacitidine
* Drug: Cytarabine
* Drug: Gemtuzumab Ozogamicin
* Drug: Daunorubicin Hydrochloride
* Drug: Fludarabine Phosphate
* Drug: Idarubicin Hydrochloride
* Drug: Mitoxantrone Hydrochloride
* Drug: Etoposide
* Drug: Gilteritinib


Participation Criteria
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Eligibility Criteria
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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.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low Risk<br>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<br>* 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.<br>* Other names: ABT-99;Drug: Cytarabine<br>* Given IV over 30 minutes q12 hours on days 1-8 (16 doses)<br>* Other names: Cytosar-U®;Drug: Gemtuzumab Ozogamicin<br>* Given IV<br>* Other names: Mylotarg;Drug: Daunorubicin Hydrochloride<br>* IV over 1 hour on days 1, 3, and 5<br>* Other names: L-lyxo-Hexopyranoside;Drug: Idarubicin Hydrochloride<br>* Given IV over 15 minutes on days 3-5<br>* Other names: Zavedos;Drug: Mitoxantrone Hydrochloride<br>* IV over 1 hour on days 2-4<br>* Other names: Novantrone;Drug: Etoposide<br>* Given IV over 1 hour on days 1-5<br>* Other names: Vepesid®;Drug: Gilteritinib<br>* PO on days 8-28 (21 doses)<br>* Other names: Xospata;|
| Experimental: Intermediate Risk<br>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<br>* 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.<br>* Other names: ABT-99;Drug: Cytarabine<br>* Given IV over 30 minutes q12 hours on days 1-8 (16 doses)<br>* Other names: Cytosar-U®;Drug: Gemtuzumab Ozogamicin<br>* Given IV<br>* Other names: Mylotarg;Drug: Daunorubicin Hydrochloride<br>* IV over 1 hour on days 1, 3, and 5<br>* Other names: L-lyxo-Hexopyranoside;Drug: Fludarabine Phosphate<br>* Given IV over 30 minutes on days 1-5<br>* Other names: SH T 586;Drug: Idarubicin Hydrochloride<br>* Given IV over 15 minutes on days 3-5<br>* Other names: Zavedos;Drug: Mitoxantrone Hydrochloride<br>* IV over 1 hour on days 2-4<br>* Other names: Novantrone;Drug: Etoposide<br>* Given IV over 1 hour on days 1-5<br>* Other names: Vepesid®;Drug: Gilteritinib<br>* PO on days 8-28 (21 doses)<br>* Other names: Xospata;|
| Experimental: High Risk<br>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<br>* 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.<br>* Other names: ABT-99;Drug: Azacitidine<br>* Given IV over 30 minutes on days 1-5<br>* Other names: Vidaza;Drug: Cytarabine<br>* Given IV over 30 minutes q12 hours on days 1-8 (16 doses)<br>* Other names: Cytosar-U®;Drug: Gemtuzumab Ozogamicin<br>* Given IV<br>* Other names: Mylotarg;Drug: Daunorubicin Hydrochloride<br>* IV over 1 hour on days 1, 3, and 5<br>* Other names: L-lyxo-Hexopyranoside;Drug: Fludarabine Phosphate<br>* Given IV over 30 minutes on days 1-5<br>* Other names: SH T 586;Drug: Idarubicin Hydrochloride<br>* Given IV over 15 minutes on days 3-5<br>* Other names: Zavedos;Drug: Etoposide<br>* Given IV over 1 hour on days 1-5<br>* Other names: Vepesid®;Drug: Gilteritinib<br>* PO on days 8-28 (21 doses)<br>* Other names: Xospata;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Minimal residual disease (MRD)-negativity rate | 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 | 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 | 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 | 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). |