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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

Primary Purpose

Acute Myeloid Leukemia

Status

Recruiting

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Allogeneic Hematopoietic Stem Cell Transplantation

Cytarabine

Daunorubicin Hydrochloride

Gemtuzumab Ozogamicin

Midostaurin

About this trial

This is an interventional treatment trial for Acute Myeloid Leukemia focused on measuring FLT, FLT-3, Acute Myeloid Leukemia

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Ohio State University Comprehensive Cancer CenterRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (gemtuzumab ozogamicin, cytarabine, daunorubicin)

Arm Description

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Incidence of 30-day treatment-related mortality

Will be estimated with exact confidence intervals.

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.

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.

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.

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.

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.

Overall survival

The Kaplan-Meier method will be used. Mean and/or median survival and 95% confidence intervals will be reported, if available.

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.

Full Information

NCT ID

NCT03900949

First Posted

April 1, 2019

Last Updated

February 2, 2023

Sponsor

Uma Borate

1. Study Identification

Unique Protocol Identification Number

NCT03900949

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

February 2023

Overall Recruitment Status

Recruiting

Study Start Date

March 13, 2019 (Actual)

Primary Completion Date

January 1, 2024 (Anticipated)

Study Completion Date

January 1, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Uma Borate

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Acute Myeloid Leukemia

Keywords

FLT, FLT-3, Acute Myeloid Leukemia

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

18 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Treatment (gemtuzumab ozogamicin, cytarabine, daunorubicin)

Arm Type

Experimental

Arm Description

Intervention Type

Procedure

Intervention Name(s)

Allogeneic Hematopoietic Stem Cell Transplantation

Other Intervention Name(s)

Allogeneic, Allogeneic Hematopoietic Cell Transplantation, Allogeneic Stem Cell Transplantation, HSC, HSCT, Stem Cell Transplantation, Allogeneic

Intervention Description

Undergo allogeneic SCT

Intervention Type

Drug

Intervention Name(s)

Cytarabine

Other Intervention Name(s)

.beta.-Cytosine arabinoside, 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-.beta.-D-Arabinofuranosylcytosine, 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-Beta-D-arabinofuranosylcytosine, 1.beta.-D-Arabinofuranosylcytosine, 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-, 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-, Alexan, Ara-C, ARA-cell, Arabine, Arabinofuranosylcytosine, Arabinosylcytosine, Aracytidine, Aracytin, Aracytine, Beta-Cytosine Arabinoside, CHX-3311, Cytarabinum, Cytarbel, Cytosar, Cytosine Arabinoside, Cytosine-.beta.-arabinoside, Cytosine-beta-arabinoside, Erpalfa, Starasid, Tarabine PFS, U 19920, U-19920, Udicil, WR-28453

Intervention Description

Given IV

Intervention Type

Drug

Intervention Name(s)

Daunorubicin Hydrochloride

Other Intervention Name(s)

Cerubidin, Cerubidine, Cloridrato de Daunorubicina, Daunoblastin, Daunoblastina, Daunoblastine, Daunomycin Hydrochloride, Daunomycin, hydrochloride, Daunorubicin.HCl, Daunorubicini Hydrochloridum, FI-6339, Ondena, RP-13057, Rubidomycin Hydrochloride, Rubilem

Intervention Description

Given IV

Intervention Type

Drug

Intervention Name(s)

Gemtuzumab Ozogamicin

Other Intervention Name(s)

Calicheamicin-Conjugated Humanized Anti-CD33 Monoclonal Antibody, CDP-771, CMA-676, gemtuzumab, hP67.6-Calicheamicin, Mylotarg, WAY-CMA-676

Intervention Description

Given IV

Intervention Type

Drug

Intervention Name(s)

Midostaurin

Other Intervention Name(s)

CGP 41251, CGP41251, N-Benzoyl-Staurosporine, N-Benzoylstaurosporine, PKC-412, PKC412, Rydapt

Intervention Description

Given PO

Primary Outcome Measure Information:

Title

Maximum-tolerated dose (MTD) of combining gemtuzumab ozogamicin with cytarabine, daunorubicin, and midostaurin

Description

The MTD will be estimated using isotonic regression. An incidence of dose limiting toxicity at each dose level will be summarized.

Time Frame

42 days after start of last induction (i.e. induction or re-induction)

Secondary Outcome Measure Information:

Title

Incidence of 30-day treatment-related mortality

Description

Will be estimated with exact confidence intervals.

Time Frame

Up to 30 days after receiving initial induction therapy

Title

Rate of complete composite remission (CCR)

Description

Time Frame

At end of consolidation treatment (up to 120 days)

Title

Objective response rate (ORR)

Description

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.

Time Frame

At end of consolidation treatment (up to 120 days)

Title

Event free survival

Description

Time Frame

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

Title

Duration of response

Description

Time Frame

From date of first documented response (CR, CRi) to date of documented relapse, assessed up to 24 months

Title

Relapse-free survival

Description

Time Frame

From date of first documented response (CR, CRi) to date of relapse or death from any cause, assessed up to 24 months

Title

Overall survival

Description

The Kaplan-Meier method will be used. Mean and/or median survival and 95% confidence intervals will be reported, if available.

Time Frame

From start of treatment until death, assessed up to 24 months

Title

Incidence of adverse events and serious adverse events

Description

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.

Time Frame

Up to 90 days after last dose of treatment

Other Pre-specified Outcome Measures:

Title

CD33 expression

Description

Will be summarized descriptively. CD33 expression will be correlated with CCR and ORR using Fisher's exact test and with time-to-event endpoints using a log-rank test.

Time Frame

Up to 24 months

Title

CD33 single nucleotide polymorphism (SNP)

Description

Will be summarized descriptively. The presence/absence of CD33 SNPs will be correlated with CCR and ORR using Fisher's exact test and with time-to-event endpoints using a log-rank test.

Time Frame

Up to 24 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

The Ohio State University Comprehensive Cancer Center

Phone

800-293-5066

OSUCCCClinicaltrials@osumc.edu

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Uma Borate, M.D.

Organizational Affiliation

The Ohio State Comprehensive Cancer Center

Official's Role

Principal Investigator

Facility Information:

Facility Name

Ohio State University Comprehensive Cancer Center

City

Columbus

State/Province

Ohio

ZIP/Postal Code

43210

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Ana Swatzell

Phone

614-685-9573

adriana.swatzell@osumc.edu

First Name & Middle Initial & Last Name & Degree

Uma Borate, MD

12. IPD Sharing Statement

Plan to Share IPD

Links:

URL

http://cancer.osu.edu

Description

The Jamesline

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