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.
- Brief Title: Testing the Combination of Standard Induction Therapy With Gemtuzumab Ozogamicin and 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 Preliminary Efficacy of Gemtuzumab Ozogamicin and Midostaurin When Used in Combination With Standard Cytarabine and Daunorubicin Induction for Newly Diagnosed FLT3-mutated AML.
Clinical Trial IDs
- ORG STUDY ID:
- SECONDARY ID:
- SECONDARY ID:
- NCT ID:
This study is being done to evaluate the safety and tolerability of using the combination of
gemtuzumab ozogamicin and midostaurin together with standard induction chemotherapy
(cytarabine and daunorubicin) in the treatment of patients with newly diagnosed FLT-3 mutated
acute myeloid leukemia (AML). The study will evaluate the benefit of adding gemtuzumab
ozogamicin and midostaurin to standard induction chemotherapy efficacy, compared to standard
induction for treating AML.
I. To assess the maximum tolerated dose of combining GO to the induction regimen of DA and
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
I. Quantify CD33 expression on AML blasts. II. Determine the CD33 SNP status previously
reported to correlate with response and correlate clinical outcomes of patients with the CD33
Potential participants will undergo a screening bone marrow examination with complete
cytogenetic and molecular studies to evaluate disease. In general, individuals with
confirmatory mutations to FLT3 ITD or TKD will be considered eligible to participate in this
The induction portion of this study is comprised of 4 dose levels, with dose levels 1-3
consisting of an incremental increase in the number of fractionated gemtuzumab ozogamicin
doses and dose level 4 being identical to dose level 3, except the daunorubicin dosage is
increased to 90 mg/m2. A dose cohort consists of 3 patients, after assessment the cohort an
escalation/de-escalation decision is made, over a total of 8 dose cohorts (n=24 patients).
Except for the change in daunorubicin dosing between dose levels 3 and 4 (i.e., 60 mg/m2 to
90 mg/m2), the doses of all other drug agents will remain the same across dose levels.
Treatment Plan - Induction:
Eligible participants will initiate a single course of standard '7+3' induction with
cytarabine, which will be consecutively administered on Days 1 to 7 and daunorubicin
consecutively administered on Days 1 to 3. Participants will also concurrently receive
fixed-dose gemtuzumab ozogamicin (3 mg/m2) given at varying time intervals, with the lowest
dose fraction being a single dose given on Day 1, and the highest dose fraction consisting of
gemtuzumab ozogamicin administered on Days 1, 4, and 7. Participants will continue this
initial induction course by receiving midostaurin (50 mg b.i.d) on Days 8 through 21 of the
28 day cycle.
Participants may repeat induction a second time if results of the Day 14 bone marrow biopsy
show a residual blast count ≥5% with adequate cellularity. A bone marrow evaluation after
first induction will be performed after count recovery (between days 23-days 35). If results
of the bone marrow examination after peripheral blood count recovery are consistent with
complete remission (CR) or complete remission with incomplete blood count recovery (CRi),
then participants may undergo allogenic stem cell transplantation (if a suitable donor is
available) or proceed to consolidation therapy.
Treatment Plan - Consolidation:
Gemtuzumab ozogamicin is only administered as part of the first course of the consolidation
regimen. Individuals aged < 60 years will receive standard high-dose cytarabine (HiDAC, 3
g/m2 IV, b.i.d) given on Days 1, 3, and 5, along with gemtuzumab ozogamicin (3 mg/m2) given
on Day 1 (first consolidation course only), and midostaurin administered on Days 8 through 21
of a 28 day cycle. Participants aged ≥ 60 years will consist of cytarabine (1.5 to 2 g/m2)
given on Days 1, 3, 5, gemtuzumab ozogamicin (3 mg/m2) given Day 1 (first consolidation
course only), then midostaurin administered on Days 8 through 21 of a 28 day cycle.
Participants may receive a total of 2 courses of consolidation therapy.
Participants who proceed to allogeneic stem cell transplantation and those who develop
progressive disease will be removed from clinical trial treatment and will be followed for
disease status and survival, together with those participants who complete induction and
consolidation, up to 24 months after end of treatment.
|Experimental||Experimental||Participants receive one or two induction chemotherapy cycles, followed by one or two consolidation therapy cycles.
Induction includes daunorubicin (IV) days 1, 2, 3 at either 60 mg/m2 (Dose Levels 1, 2, 3) or 90 mg/m2 (Dose Level 4); cytarabine (IV) given days 1 through 7 (100 mg/m2) for 1-3 hours; ozogamuzumab ozogamicin (IV) (days 1, 4, 7), followed by midostaurin (oral) taken twice daily on Days 8 through 21. Induction may be repeated once.
Consolidation 1 consists of a 28 day cycle with high dose cytarabine (IV) (3 g/m2) given every 12 hours on Days 1, 3, and 5, with gemtuzumab ozogamicin (IV) given on Day 1, followed by midostaurin (50 mg, oral) taken twice daily on Days 8 through 21.
Consolidation 2 consists of a 28 day cycle with high dose cytarabine (IV) (3 g/m2) given every 12 hours on Days 1, 3, and 5, followed by midostaurin (50 mg, oral) taken twice daily on Days 8 through 21.|
- Gemtuzumab Ozogamicin
1. Ability to understand and the willingness to sign a written informed consent document.
2. Aged ≥ 18 years at time of informed consent. Both men and women and members of all
races and ethnic groups will be included.
3. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
4. Newly diagnosed AML as confirmed by bone marrow and/or peripheral blood examination as
1. Confirmed CD33 positivity, per institutional standards
2. Presence of FLT3 ITD or TKD mutation as confirmed by NGS or other molecular
5. Participants must have the following clinical laboratory values:
1. Aspartate aminotransferase (AST) <2.5 × upper limit of normal (ULN; local
2. Alanine aminotransferase (ALT) < 2.5 × ULN, and
3. Total bilirubin < 2 × ULN (except for patients with known Gilbert's syndrome).
4. Adequate renal function as defined by calculated creatinine clearance (according
to the Cockcroft-Gault equation) > 40 mL/min OR serum creatinine < 1.5 × the ULN.
6. 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.
7. 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.
1. Isolated myeloid sarcoma (meaning, patients must have blood or marrow involvement to
2. Acute promyelocytic leukemia (per World Health Organization classification50)
3. Active central nervous system (CNS) involvement by AML, as assessed at discretion of
PI or treating physician and confirmed by lumbar puncture.
4. Except for hydroxyurea, no other prior systemic anti-AML therapies may have been
received prior to starting study therapy.
5. Known history of veno-occlusive disease
6. Known active human immunodeficiency virus (HIV), active hepatitis B or active
hepatitis C infection
7. 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
8. Patients with uncontrolled infection will not be enrolled until infection is treated
9. Any concurrent condition that, in the Investigator's opinion, would jeopardize the
safety of the patient or compliance with the protocol.
10. Inability to take oral medication
11. Hypersensitivity to any study agent, or its excipients, when administered alone
12. Pregnancy or breastfeeding at the time of enrollment
|Maximum Eligible Age:||N/A|
|Minimum Eligible Age:||18 Years|
Primary Outcome Measures
|Measure:||Dose limiting toxicity during first treatment cycle|
|Time Frame:||42 days after start of therapy|
|Description:||A dose limiting toxicity (DLT) during the first treatment cycle, which is defined as: 1) any Grade 3+ non-hematological toxicity based on NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0. and additional protocol-defined criteria; 2) a hematologic toxicity defined as: failure to recover ANC > 500/μL or platelet count > 50,000/μL (by 6 weeks after first induction or re-induction) in participants with < 5% blasts in the bone marrow, absence of myelodysplastic changes, and/or absence of evidence of disease (i.e., flow cytometry of bone marrow).|
Secondary Outcome Measures
|Measure:||Incidents of serious adverse events|
|Time Frame:||90 days after last day of study treatment or until participant receives alternative AML treatment|
|Description:||Incidence and type of serious adverse events (SAEs) based on the NCI CTCAE v5.0|
|Measure:||Incidence of 30-day mortality|
|Time Frame:||30 days after start of initial induction|
|Description:||30 day mortality|
|Measure:||Rate of complete composite remission (CCR)|
|Time Frame:||End of consolidation treatment (up to 120 days)|
|Description:||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).|
|Measure:||Objective response rate (ORR)|
|Time Frame:||End of consolidation treatment (up to 120 days)|
|Description:||ORR is defined as the sum of CR, CRi, Morphologic leukemia-free state (MLFS), and Partial remission (PR)|
|Measure:||Event free survival (EFS)|
|Time Frame:||Date of primary refractory disease, relapse, or death from any cause (up to 24 months following end of treatment)|
|Description:||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)|
|Measure:||Duration of response (DoR)|
|Time Frame:||Date of documented relapse (up to 24 months following end of treatment)|
|Description:||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).|
|Measure:||Relapse free survival (RFS)|
|Time Frame:||Date of relapse or death from any cause (up to 24 months following end of treatment)|
|Description:||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).|
|Measure:||Overall survival (OS)|
|Time Frame:||Date of death (up to 24 months following end of treatment)|
|Lead Sponsor:||OHSU Knight Cancer Institute|
- Acute Myeloid Leukemia