Clinical Trials/NCT05955261

NCT05955261

Suspended

Phase 2

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

St. Jude Children's Research Hospital13 sites in 1 country70 target enrollmentJuly 25, 2023

Overview

Phase: Phase 2
Intervention: Cytarabine
Conditions: Acute Myeloid Leukemia
Sponsor: St. Jude Children's Research Hospital
Enrollment: 70
Locations: 13
Primary Endpoint: Minimal residual disease (MRD)-negativity rate
Status: Suspended
Last Updated: 19 days ago

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

Overview

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

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 gilteritinib 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 gilteritinib 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 gilteritinib 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 gilteritinib 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 gilteritinib PO QD on days 8-28.

Registry

clinicaltrials.gov

Start Date

July 25, 2023

End Date

March 1, 2034

Last Updated

19 days ago

Study Type

Interventional

Study Design

Parallel

Sex

All

Investigators

Sponsor

St. Jude Children's Research Hospital

Responsible Party

Sponsor

Eligibility Criteria

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 or a complete blood count with the presence of at least 1,000 blasts/μL (e.g., a WBC count ≥ 10,000/μL with ≥ 10% blasts or a WBC count ≥ 5,000/μL with ≥ 20% blasts
•Age \> 28 days and \< 22 years
•No prior therapy for this malignancy except for one dose of intrathecal therapy and 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.

Arms & Interventions

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

Intervention: Cytarabine

Low Risk

Intervention: Gemtuzumab Ozogamicin

Low Risk

Intervention: Daunorubicin Hydrochloride

Low Risk

Intervention: Mitoxantrone Hydrochloride

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

Intervention: Cytarabine

Intermediate Risk

Intervention: Etoposide

Intermediate Risk

Intervention: Gilteritinib

High Risk

High Risk

Intervention: Azacitidine

Outcomes

Primary Outcomes

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.

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.

Secondary Outcomes

Overall survival(From protocol enrollment until death (up to 3 years after the last enrollment).)
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).)