Gentuzumab Ozogamicin and Midostaurin Combination With Standard Cytarabine and Danunorubi Midostaurin as a Novel Approach to Treating Patients With Newly Diagnosed FLT-3 Mutated Acute Myeloid Leukemia

Study Overview
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Brief Summary
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This phase I study hopes to explore how safe and tolerable is the combination of gemtuzumab ozogamicin (GO) and midostaurin, with the standard induction therapy (cytarabine and daunorubicin) in patients with newly diagnosed FLT-3 mutated Acute Myeloid Leukemia (AML). GO is FDA approved for the treatment of adults with newly diagnosed CD33 positive AML and used in combination with chemotherapy, cytarabine and daunorubicin. Midostaurin is FDA approved for use with cytarabine and daunorubicin in patients with FLT3-mutated AML. By combining standard induction therapy with GO and midostaurin, our aim is to investigate a novel approach to treating patients with newly diagnosed FLT3-mutated AML.

Detailed Description
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PRIMARY OBJECTIVE: I. To assess the maximum tolerated dose (MTD) of combining gemtuzumab ozogamicin (GO) to the induction regimen of cytarabine and daunorubicin (DA) and midostaurin. SECONDARY OBJECTIVES: I. To assess the frequency of early death associated with study treatment. II. To evaluate the preliminary efficacy of the study treatment. III. To assess the safety profile of the study treatment. EXPLORATORY OBJECTIVES: I. Quantify CD33 expression on acute myeloid leukemia (AML) blasts. II. Determine the CD33 single-nucleotide polymorphism (SNP) status previously reported to correlate with response and correlate clinical outcomes of patients with the CD33 genotype. OUTLINE: This is a dose finding study to identify the maximum tolerated dose (MTD) schedule of GO, and its safety and tolerability in combination with midostaurin in FLT3-mutated newly diagnosed AML patients. INDUCTION THERAPY: Patients receive cytarabine intravenously (IV) on days 1-7, daunorubicin IV on days 1-3 and midostaurin 50mg orally (PO) twice daily (BID) on days 8-21. Patients also receive gemtuzumab ozogamicin IV either on day or days 1 and 4 or days 1, 4 and 7 depending on dose level in the absence of disease progression or unacceptable toxicity. RE-INDUCTION THERAPY: Between days 14 and 21 of Induction Therapy, patients who achieve at least 5% bone marrow blasts after an optional bone marrow biopsy may receive a single 28-day cycle of cytarabine and daunorubicin with or without midostaurin per the treating physician. Patients who achieve a complete remission (CR) or complete remission with incomplete blood count recovery (CRi) may undergo allogeneic stem cell transplantation (SCT) or receive consolidation therapy. CONSOLIDATION THERAPY: PATIENTS < 60 YEARS: Patients receive high dose cytarabine (HiDAC) IV on days 1, 3, and 5 and gemtuzumab ozogamicin IV on day 1 of cycle 1 and midostaurin 50mg PO BID on days 8-21. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. PATIENTS >= 60 YEARS: Patients receive cytarabine (MiDAC) IV on days 1, 3, and 5 and gemtuzumab ozogamicin IV on day 1 of cycle 1 and midostaurin 50mg PO BID on days 8-21. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 24 months.

Official Title
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A Phase I Study to Evaluate the Safety and Tolerability of Gemtuzumab Ozogamicin and Midostaurin When Used in Combination With Standard Cytarabine and Daunorubicin Induction for Newly Diagnosed FLT3-mutated Acute Myeloid Leukemia

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
* Drug: Cytarabine
* Drug: Daunorubicin Hydrochloride
* Drug: Gemtuzumab Ozogamicin
* Drug: Midostaurin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to understand and the willingness to sign a written informed consent document Eastern Cooperative Oncology Group (ECOG) performance status =< 2 Newly diagnosed AML as confirmed by bone marrow and/or peripheral blood examination as indicated, with: Confirmed CD33 positivity, per institutional standards Presence of FLT3 internal tandem duplication (ITD) or tyrosine kinase domain (TKD) mutation as confirmed by next-generation sequencing (NGS) or other molecular method Aspartate aminotransferase (AST) < 2.5 x upper limit of normal (ULN; local laboratory) Alanine aminotransferase (ALT) < 2.5 x ULN Total bilirubin < 2 x ULN (except for patients with known Gilbert's syndrome) Calculated creatinine clearance (according to the Cockcroft-Gault equation) > 40 mL/min OR serum creatinine < 1.5 x the ULN Female patients of childbearing potential must agree to use adequate contraception (2 forms of contraception or abstinence) from the screening visit until 6 months following the last dose of study treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately Male patients of childbearing potential having intercourse with females of childbearing potential must agree to abstain from heterosexual intercourse or have their partner use 2 forms of contraception from the screening visit until 3 months following the last dose of study treatment. They must also refrain from sperm donation from the screening visit until 90 days following the last dose of study treatment Exclusion Criteria: Isolated myeloid sarcoma (meaning, patients must have blood or marrow involvement to enter study) Acute promyelocytic leukemia (per World Health Organization classification) Active central nervous system (CNS) involvement by AML, as assessed at discretion of principal investigator (PI) or treating physician and confirmed by lumbar puncture Except for hydroxyurea, no other prior systemic anti-AML therapies may have been received prior to starting study therapy Known history of veno-occlusive disease Known active human immunodeficiency virus (HIV), active hepatitis B or active hepatitis C infection Patients with the following will be excluded: uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, serious cardiac arrhythmia, myocardial infarction within 6 months prior to enrollment, New York Heart Association (NYHA) class III or IV heart failure, severe uncontrolled ventricular arrhythmias Patients with uncontrolled infection will not be enrolled until infection is treated Any concurrent condition that, in the investigator's opinion, would jeopardize the safety of the patient or compliance with the protocol Inability to take oral medication Hypersensitivity to any study agent, or its excipients, when administered alone Pregnancy or breastfeeding at the time of enrollment

Ages Eligible for Study
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Minimum Age: 18 Years

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (gemtuzumab ozogamicin, cytarabine, daunorubicin)<br>INDUCTION THERAPY: Cytarabine intravenously (IV) on days 1-7, daunorubicin IV on days 1-3 and midostaurin 50 mg orally (PO) twice daily (BID) on days 8-21. Gemtuzumab ozogamicin IV may be given either on days 1, or days 1 and 4 or days 1, 4 and 7. RE-INDUCTION THERAPY: Between days 14 and 21 of Induction Therapy, patients may receive a single 28-day cycle of cytarabine and daunorubicin with or without midostaurin per the treating physician. Patients may also undergo allogeneic stem cell transplantation (SCT) or receive consolidation therapy. CONSOLIDATION THERAPY: PATIENTS < 60 YEARS: high dose cytarabine (HiDAC) IV on days 1, 3, and 5 and gemtuzumab ozogamicin IV on day 1 of cycle 1 and midostaurin 50 mg PO BID on days 8-21. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. PATIENTS >= 60 YEARS: Same as above except cytarabine (MiDAC) IV on days 1, 3, and 5. | Procedure: Allogeneic Hematopoietic Stem Cell Transplantation<br>* Undergo allogeneic SCT<br>* Other names: Stem Cell Transplantation, Allogeneic;Drug: Cytarabine<br>* Given IV<br>* Other names: WR-28453;Drug: Daunorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubilem;Drug: Gemtuzumab Ozogamicin<br>* Given IV<br>* Other names: WAY-CMA-676;Drug: Midostaurin<br>* Given PO<br>* Other names: Rydapt;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum-tolerated dose (MTD) of combining gemtuzumab ozogamicin with cytarabine, daunorubicin, and midostaurin | The MTD will be estimated using isotonic regression. An incidence of dose limiting toxicity at each dose level will be summarized. | 42 days after start of last induction (i.e. induction or re-induction) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of 30-day treatment-related mortality | Will be estimated with exact confidence intervals. | Up to 30 days after receiving initial induction therapy | 
| Rate of complete composite remission (CCR) | Complete composite remission is defined as meeting criteria for complete remission (CR), complete remission with incomplete blood count recovery (CRi), or complete remission with incomplete platelet recovery (CRp). Will be measured and reported with 95% exact confidence intervals. | At end of consolidation treatment (up to 120 days) | 
| Objective response rate (ORR) | ORR is defined as the sum of CR, CRi, Morphologic leukemia-free state (MLFS), and Partial remission (PR). Will be measured and reported with 95% exact confidence intervals. | At end of consolidation treatment (up to 120 days) | 
| Event free survival | EFS will be measured from start of on-study therapy (i.e., Day 1) to the date of primary refractory disease, relapse from CR or CRi, or death from any cause. Participants not known to have failed induction therapy, relapsed, or died at time of last follow-up will be censored on the date they were last examined (i.e., 2 years following completion of on-study therapy). The Kaplan-Meier method will be used. Mean and/or median survival and 95% confidence intervals will be reported, if available. | From date of primary refractory disease, or relapse from complete response (CR) or complete remission with incomplete blood count recovery (CRi) , or death from any cause, assessed up to 24 months | 
| Duration of response | For only participants that achieve CR or CRi, the DoR is measured from the date of first documented response (CR, CRi) until the date of relapse. Participants not known to have relapsed at time of last follow-up will be censored on the date they were last examined (i.e., 2 years following completion of on-study therapy). The Kaplan-Meier method will be used. Mean and/or median survival and 95% confidence intervals will be reported, if available. | From date of first documented response (CR, CRi) to date of documented relapse, assessed up to 24 months | 
| Relapse-free survival | For only participants that achieve CR or CRi, RFS will be measured from the date of first documented response (CR, CRi) to the date of relapse or death from any cause. Participants not known to have relapsed or died at time of last follow-up will be censored on the date they were last examined (i.e., 2 years following completion of on-study therapy). The Kaplan-Meier method will be used. Mean and/or median survival and 95% confidence intervals will be reported, if available. | From date of first documented response (CR, CRi) to date of relapse or death from any cause, assessed up to 24 months | 
| Overall survival | The Kaplan-Meier method will be used. Mean and/or median survival and 95% confidence intervals will be reported, if available. | From start of treatment until death, assessed up to 24 months | 
| Incidence of adverse events and serious adverse events | Will be tabulated and summarized by severity and major organ site according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. | Up to 90 days after last dose of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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FLT, FLT-3, Acute Myeloid Leukemia