Gemtuzumab + Midostaurin for Acute Myeloid Leukemia

No longer recruiting at 3 trial locations

Overseen By The Ohio State University Comprehensive Cancer Center

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: OHSU Knight Cancer Institute

Must be taking: Hydroxyurea

Disqualifiers: HIV, Hepatitis B, Heart failure, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment combination for patients with Acute Myeloid Leukemia (AML) that has a FLT3 mutation. The study tests the safety and tolerability of combining two drugs, gemtuzumab ozogamicin (Mylotarg) and midostaurin (Rydapt), with standard chemotherapy drugs. People recently diagnosed with FLT3-mutated AML and possessing the CD33 protein are suitable candidates for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it mentions that no prior systemic anti-AML therapies, except for hydroxyurea, are allowed before starting the study treatment. It's best to discuss your current medications with the study team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the combination of gemtuzumab ozogamicin (GO) and midostaurin is generally well-tolerated by patients with acute myeloid leukemia (AML). Studies have found that adding midostaurin to chemotherapy, which includes GO, is safe for both younger and older patients with the FLT3 mutation in AML. Reports also indicate that GO can be safely used with strong chemotherapy, including midostaurin, in newly diagnosed AML cases.

GO has already received FDA approval for treating adults with AML when used with certain chemotherapy drugs. Midostaurin is also FDA-approved for patients with a specific AML mutation. This existing approval provides some reassurance about their safety when used together. However, as this is a phase 1 trial, the researchers are still in the early stages of understanding the full safety of this combination therapy. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of gemtuzumab ozogamicin and midostaurin for acute myeloid leukemia (AML) because it offers a novel approach compared to traditional chemotherapy options like cytarabine and daunorubicin. Gemtuzumab ozogamicin is unique because it is an antibody-drug conjugate, which specifically targets leukemia cells, potentially reducing harm to healthy cells. Midostaurin adds another layer of innovation by inhibiting specific enzymes that promote cancer cell growth, offering a targeted approach that differs from the broad action of standard chemotherapy. This combination aims to improve treatment effectiveness and safety, offering new hope for patients with AML.

What evidence suggests that this trial's treatments could be effective for FLT3-mutated Acute Myeloid Leukemia?

Research shows that adding gemtuzumab ozogamicin (GO) to standard chemotherapy improves outcomes for patients with newly diagnosed Acute Myeloid Leukemia (AML). This approach has been particularly effective in enhancing survival for certain AML types. In this trial, participants will receive a combination of gemtuzumab ozogamicin, cytarabine, and daunorubicin. Additionally, midostaurin, another treatment option in this trial, has significantly increased survival rates for patients with FLT3-mutated AML, as studies have shown. For instance, one study found that after four years, 51.4% of patients taking midostaurin were still alive, compared to 44.3% of those who did not take it. Using these treatments together offers a promising strategy for treating FLT3-mutated AML. ^{4 6 7 8 9}

Who Is on the Research Team?

Uma Borate, MD

Principal Investigator

The Ohio State Comprehensive Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with newly diagnosed FLT-3 mutated Acute Myeloid Leukemia (AML) who can sign consent, have an ECOG status of ≤2, and CD33 positive AML. They must not have had previous AML treatments, no active HIV or hepatitis B/C, and agree to contraception use. Those with severe heart issues, uncontrolled infections or certain allergies are excluded.

Inclusion Criteria

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

I can take care of myself but might not be able to do heavy physical work.

Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

I have only used hydroxyurea for my AML, no other treatments.

I do not have active HIV, hepatitis B, or hepatitis C.

My AML has spread to my brain or spinal cord, confirmed by a spinal tap.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Therapy

Patients receive cytarabine IV on days 1-7, daunorubicin IV on days 1-3, midostaurin 50mg PO BID on days 8-21, and gemtuzumab ozogamicin IV on specified days depending on dose level

3 weeks

Re-Induction Therapy

Patients with at least 5% bone marrow blasts may receive a single 28-day cycle of cytarabine and daunorubicin with or without midostaurin

4 weeks

Consolidation Therapy

Patients receive high dose cytarabine and gemtuzumab ozogamicin, with midostaurin for up to 2 cycles

8 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

What Are the Treatments Tested in This Trial?

Interventions

• Cytarabine
• Daunorubicin Hydrochloride
• Gemtuzumab Ozogamicin
• Midostaurin

Trial Overview The study tests a combination of gemtuzumab ozogamicin (GO) and midostaurin with standard cytarabine and daunorubicin chemotherapy in patients with new FLT-3 mutated AML. It aims to find out if this novel approach is safe and how well patients tolerate it.

How Is the Trial Designed?

Group I: Treatment (gemtuzumab ozogamicin, cytarabine, daunorubicin) Experimental Treatment 5 Interventions

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.

Cytarabine is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Cytosar-U for:

• Acute myeloid leukemia
• Acute lymphocytic leukemia
• Chronic myeloid leukemia
• Meningeal leukemia

Approved in European Union as Depocyt for:

• Lymphomatous meningitis

Approved in Canada as Cytosar-U for:

• Acute myeloid leukemia
• Acute lymphocytic leukemia
• Chronic myeloid leukemia

Who Is Running the Clinical Trial?

OHSU Knight Cancer Institute

Lead Sponsor

Trials

239

Recruited

2,089,000+

Uma Borate

Lead Sponsor

Trials

7

Recruited

310+

Published Research Related to This Trial

In a phase I study involving patients with acute myeloid leukemia (AML), the combination of the tyrosine kinase inhibitor midostaurin with bortezomib and chemotherapy showed a 56.5% complete response (CR) rate and an 82.5% overall response rate, indicating significant efficacy in treating refractory or relapsed AML.

While the treatment was effective, it was also associated with expected drug-related toxicities, including peripheral neuropathy, decreased ejection fraction, and diarrhea, particularly at higher dose levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Midostaurin, bortezomib and MEC in relapsed/refractory acute myeloid leukemia. Walker, AR., Wang, H., Walsh, K., et al.[2022]

Gemtuzumab ozogamicin (Mylotarg) has been approved for treating acute myeloid leukemia (AML) in patients aged 15 and older, showing significant improvements in event-free survival and reduced relapse risk based on a meta-analysis of 3,325 patients.

While Mylotarg is effective, it is associated with common side effects such as hemorrhage and infection, particularly when used in combination with other chemotherapy drugs like daunorubicin and cytarabine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The EMA Review of Mylotarg (Gemtuzumab Ozogamicin) for the Treatment of Acute Myeloid Leukemia. Ali, S., Dunmore, HM., Karres, D., et al.[2020]

Midostaurin, when combined with standard chemotherapy (cytarabine and daunorubicin), significantly improves event-free survival, disease-free survival, and overall survival in patients with newly diagnosed FLT3-mutated acute myeloid leukemia (AML), based on a phase III trial.

The treatment with midostaurin is considered safe, showing no significant difference in overall toxicity compared to placebo, although it was associated with a higher incidence of grade 3 to 5 anemia and rash.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Midostaurin in Combination With Standard Chemotherapy for Treatment of Newly Diagnosed FMS-Like Tyrosine Kinase 3 (FLT3) Mutation-Positive Acute Myeloid Leukemia. Kim, M., Williams, S.[2019]

Midostaurin, a multikinase inhibitor, was found to have a manageable safety profile in a study of 103 patients with FLT3 mutation-positive acute myeloid leukemia, with no new safety events reported during treatment.

The treatment showed promising outcomes, including high rates of transplant success and low relapse rates during maintenance therapy, indicating its efficacy when combined with chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Updated safety of midostaurin plus chemotherapy in newly diagnosed FLT3 mutation-positive acute myeloid leukemia: the RADIUS-X expanded access program. Roboz, GJ., Strickland, SA., Litzow, MR., et al.[2021]

The combination treatment of gemtuzumab ozogamicin, intermediate-dose cytarabine, and mitoxantrone (MIDAM) resulted in a 63% overall response rate in 62 patients with refractory or relapsed CD33(+) acute myeloid leukemia, with 50% achieving complete remission.

While the MIDAM regimen showed promising efficacy, it also had safety concerns, including a 16% rate of severe hyperbilirubinemia and four early toxic deaths, highlighting the need for further randomized trials to establish its safety and effectiveness as a standard treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term disease-free survival after gemtuzumab, intermediate-dose cytarabine, and mitoxantrone in patients with CD33(+) primary resistant or relapsed acute myeloid leukemia. Chevallier, P., Delaunay, J., Turlure, P., et al.[2019]

Midostaurin is an oral Type III receptor tyrosine kinase inhibitor that effectively targets FLT3 mutations in acute myeloid leukemia (AML), showing robust anti-blast responses in relapsed/refractory patients and potentially bridging them to transplant.

While generally well tolerated as a single agent, midostaurin's hematologic toxicity increases when combined with standard chemotherapy, but it may prolong survival in patients with FLT3-ITD mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Midostaurin: an emerging treatment for acute myeloid leukemia patients. Gallogly, MM., Lazarus, HM.[2020]

In a study of 90 patients with acute myeloid leukemia (AML) in first relapse, combining gemtuzumab ozogamycin (GO) with intermediate- to high-dose cytarabine (IHDAraC) resulted in a significantly higher response rate (68% vs 45%) and improved overall survival (median 35 months vs 6 months) compared to IHDAraC alone.

The benefits of the IHDAraC + GO combination were particularly evident in patients with low- or intermediate-risk cytogenetics, suggesting that this treatment strategy could be more effective for these specific patient groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved outcome of patients with low- and intermediate-risk cytogenetics acute myeloid leukemia (AML) in first relapse with gemtuzumab and cytarabine versus cytarabine: results of a retrospective comparative study. Prebet, T., Etienne, A., Devillier, R., et al.[2019]

Gemtuzumab ozogamicin (Mylotarg) is an FDA-approved treatment for older patients (60+) with CD33+ acute myeloid leukemia (AML) who cannot undergo chemotherapy, targeting the CD33 antigen found on over 80% of AML cases.

The treatment has shown clinical remissions in patients, although it can cause side effects like fever, chills, and low blood cell counts, indicating the need for careful monitoring during administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mylotarg approved for patients with CD33+ acute myeloid leukemia. Sorokin, P.[2012]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10813452/

Gemtuzumab Ozogamicin in Acute Myeloid Leukemia A study showed that when GO was administered as a single agent, it appeared to be an effective option for treating relapsed AML, with a 31.6% ...

2. ashpublications.org ashpublications.org/blood/article/142/20/1673/498629/Gemtuzumab-ozogamicin-in-AML-the-next-chapter

Gemtuzumab ozogamicin in AML: the next chapter | Blood Gemtuzumab ozogamicin for de novo acute myeloid leukemia: final efficacy and safety updates from the open-label, phase III ALFA-0701 trial .

3. sciencedirect.com sciencedirect.com/science/article/pii/S2213048925000275

Real-World Efficacy and Safety of Gemtuzumab ... Gemtuzumab ozogamicin plus standard induction chemotherapy “3 + 7″ has been reported to improve outcomes of newly diagnosed intermediate cytogenetic risk AML, ...

4. catalogues.ema.europa.eu catalogues.ema.europa.eu/node/3618/administrative-details

GO-First: Real-world treatment patterns and effectiveness ... The 'GO-First' study will retrospectively identify real-world patients from Austria, Belgium and Germany who have been treated with GO in a first-line AML ...

5. nature.com nature.com/articles/s41375-025-02700-9

Gemtuzumab ozogamicin in first-line treatment of CBF-AML In a contemporary cohort, our data show an absolute survival advantage of 10% at 2 years with GO-containing induction therapy and acceptable ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03900949?term=FI-6339&rank=9

Gentuzumab Ozogamicin and Midostaurin Combination ... This phase I study hopes to explore how safe and tolerable is the combination of gemtuzumab ozogamicin (GO) and midostaurin, ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10542832/

Gemtuzumab ozogamicin plus midostaurin in conjunction ... Our study highlights the excellent effectiveness of GO plus midostaurin in addition to standard IC for newly diagnosed FLT3-mutated/CD33+ AML patients: the ...

8. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/2907/533102/Gemtuzumab-Based-Induction-Chemotherapy-Combined

Gemtuzumab Based Induction Chemotherapy Combined with ... The addition of Midostaurin to DAGO1 and DAGO2 chemotherapy was well tolerated and safe in both younger and older patients with FLT3mut AML with ...

9. sciencedirect.com sciencedirect.com/science/article/pii/S2950328025001062

Safety of Gemtuzumab Ozogamicin with Cytarabine ... Our results show that GO can safely be combined with intensive chemotherapy with midostaurin in newly diagnosed acute myeloid leukemia.