Combining Midostaurin and Gemtuzumab Ozogamicin for Treating Acute Myeloid Leukemia

MidOStaurin + Gemtuzumab OzogAmIcin Combination in First-line Standard Therapy for Acute Myeloid Leukemia (MOSAIC)

This study is testing a new combination of two drugs to see if it can help newly diagnosed acute myeloid leukemia patients with certain genetic mutations respond better to treatment.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 214 (estimated)
• Ages: 18 Years to 75 Years
• Sex: All
• Sponsor: Technische Universität Dresden (Academic / other)
• Drugs / interventions: gemtuzumab, quizartinib, chemotherapy, dasatinib
• Locations: 21 sites (München, Bavaria and 20 other locations)
• Trial ID: NCT04385290 on ClinicalTrials.gov

What this trial studies

This clinical trial evaluates the safety and efficacy of combining midostaurin, a potent c-KIT inhibitor, with gemtuzumab ozogamicin in newly diagnosed acute myeloid leukemia (AML) patients who have specific genetic mutations or cytogenetic abnormalities. The study is designed in two phases, with the first phase focusing on patients with FLT3 mutations and the second phase targeting those with core-binding factor (CBF) gene mutations. The goal is to enhance the effectiveness of standard chemotherapy by addressing the underlying genetic factors that contribute to treatment resistance and relapse in AML. By inhibiting key signaling pathways involved in cell proliferation and survival, the trial aims to improve patient outcomes.

Who should consider this trial

Good fit: Ideal candidates for this study are adults aged 18 to 75 with newly diagnosed acute myeloid leukemia exhibiting specific genetic mutations or cytogenetic abnormalities.

Not a fit: Patients without the specified genetic mutations or those with advanced age or poor health status may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment combination could significantly improve survival rates and reduce relapse in patients with acute myeloid leukemia.

How similar studies have performed: Previous studies with other c-KIT inhibitors have shown promising results, suggesting that this approach may be effective, although the specific combination being tested is novel.

Eligibility criteria

Inclusion Criteria:

* Written informed consent
* Newly diagnosed AML according to the criteria of the World Health Organisation plus the following molecular or cytogenetic specifications:

  * Phase I Trial - MODULE:

    * t(8;21)/RUNX1-RUNX1T1 or
    * inv(16) or t(16;16)/CBFB-MYH11 or
    * FLT3-ITD or
    * FLT3-tyrosine kinase domain (FLT3-TKD)
  * Phase II Trial - MAGNOLIA

    * t(8;21)/RUNX1-RUNX1T1 or
    * inv(16) or t(16;16)/CBFB-MYH11
  * Phase II Trial - MAGMA

    * FLT3-ITD or
    * FLT3-TKD
    * Absence of mutations in CBF genes (i.e. t(8;21)/RUNX1-RUNX1T1 or inv(16) or t(16;16)/CBFB-MYH11)
* Male and female patients aged

  * 18 - ≤ 75 years in Phase I Trial - MODULE
  * 18 - ≤ 70 years in Phase II Trials - MAGMA and MAGNOLIA
* Eastern Cooperative Oncology Group (ECOG) Score of 0-2
* Life expectancy \> 14 days
* Adequate hepatic and renal function

  * alanine aminotransferase / aspartate transaminase ≤ 2.5 x ULN
  * Bilirubin \< 2 x upper limits of normal
  * Creatinine \< 1.5 x upper limits of normal or Creatinine clearance \> 40 ml/min
* White blood cell count \< 30 × 10\^9/L. Note: Hydroxyurea and/or a dose of 100-200 mg/m\^2 cytarabine per day for up to 3 days (for emergency use for clinical stabilization) is permitted to meet this criterion.

Exclusion Criteria (all study parts):

* Previous antineoplastic treatment for AML other than hydroxyurea and/or cytarabine for emergency use (100-200 mg/m\^2 per day on maximal 3 days)
* Previous treatment with anthracyclines
* central nervous system involvement
* Isolated extramedullary AML
* Uncontrolled infection
* AML after antecedent myelodysplasia (MDS) with prior cytotoxic treatment (e.g., azacytidine or decitabine)
* Any investigational agent within 30 days or 5 half-lives, whichever is greater, prior to day 1. An investigational agent is defined as an agent with no approved medical use in adults or in pediatric patients
* Prior treatment with a FLT3 inhibitor (e.g., midostaurin, quizartinib, sorafenib)
* Strong CYP3A4/5 enzyme inducing drugs unless they can be discontinued or replaced prior to enrollment
* Any other known disease or concurrent severe and/or uncontrolled medical condition (e.g., cardiovascular disease including congestive heart failure or active uncontrolled infection) that could compromise participation in the study
* Impairment of gastrointestinal (GI) function or GI disease that might alter significantly the absorption of midostaurin
* Confirmed diagnosis of HIV infection,
* Active viral hepatitis unless serology demonstrates clearance of infection. Occult or prior hepatitis B virus (HBV) infection, defined as negative hepatitis B surface antigen and positive total hepatitis core antibodies, may be included if HBV DNA is undetectable, provided that patients are willing to undergo monthly DNA testing. Patients who have protective titers of hepatitis B surface antibody after vaccination or prior cured hepatitis B are eligible. Patients for hepatitis C virus (HCV) antibody are eligible provided PCR is negative for HCV RNA.
* Cardiovascular abnormalities, including any of the following:

  * History of myocardial infarction, angina pectoris, Coronary Artery Bypass Grafting within 6 months prior to starting study treatment
  * Clinically uncontrolled cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade atrioventricular block (e.g., bifascicular block, Mobitz type II and third degree atrioventricular block)
  * Uncontrolled congestive heart failure
  * Left ventricular ejection fraction of \< 50%
  * Poorly controlled arterial hypertension
* Pregnant or nursing (lactating) women
* Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they fulfill at least one of the following criteria:

  * Post-menopausal (12 months of natural amenorrhea or 6 months of amenorrhea with serum follicule stimulating hormone \> 40 U/ml)
  * Postoperative (i.e. 6 weeks) after bilateral ovariectomy with or without hysterectomy
  * Women of childbearing potential must have a negative serum pregnancy test performed within 7 days before the first dose of study drug
  * Continuous and correct application of a contraception method with a Pearl Index of \< 1% (e.g. implants, depots, oral contraceptives, intrauterine device) from initial study drug administration until at least 7 months after the last dose of gemtuzumab ozogamicin and at least 4 months after the last dose of midostaurin, whichever period is longer. A hormonal contraception method must always be combined with a barrier method (e.g. condom)
  * Sexual abstinence
  * Vasectomy of the sexual partner
* Sexually active males unless they use a condom during intercourse while taking the drug during treatment, and for at least 4 months after stopping treatment and should not father a child in this period. A condom is required to be used also by vasectomized men as well as during intercourse with a male partner in order to prevent delivery of the drug via semen
* Unwillingness or inability to comply with the protocol
* Known hypersensitivity to midostaurin, GO, cytarabine or daunorubicin or to any of the excipients of midostaurin, GO, cytarabine or daunorubicin.

Where this trial is running

München, Bavaria and 20 other locations

• LMU Klinikum, Campus Großhadern — München, Bavaria, Germany (Recruiting)
• Universitätsklinikum Essen — Essen, North Rhine-Westphalia, Germany (Recruiting)
• Universitätsklinikum Aachen — Aachen, Germany (Recruiting)
• Universitätsklinikum Augsburg — Augsburg, Germany (Not_yet_recruiting)
• Klinikum Chemnitz gGmbH — Chemnitz, Germany (Recruiting)
• Universitätsklinikum Dresden — Dresden, Germany (Recruiting)
• Johann Wolfgang Goethe-Universität — Frankfurt am Main, Germany (Recruiting)
• Universitätsklinikum Halle — Halle, Germany (Recruiting)
• Universitätsklinikum Heidelberg — Heidelberg, Germany (Recruiting)
• Universitätsklinikum Jena — Jena, Germany (Recruiting)
• Universitätsklinikum Schleswig-Holstein — Kiel, Germany (Recruiting)
• Gemeinschaftsklinikum Mittelrhein gGmbH — Koblenz, Germany (Recruiting)
• Universitätsklinikum Leipzig — Leipzig, Germany (Recruiting)
• Klinikum Mannheim gGmbH — Mannheim, Germany (Recruiting)
• Philipps-Universität Marburg Fachbereich Medizin — Marburg, Germany (Recruiting)
• Rotkreuzklinikum München gGmbH — München, Germany (Recruiting)
• Universitätsklinikum Münster — Münster, Germany (Recruiting)
• Klinikum Nürnberg-Nord — Nuremberg, Germany (Not_yet_recruiting)
• Krankenhaus Barmherzige Brüder — Regensburg, Germany (Recruiting)
• Robert-Bosch-Krankenhaus — Stuttgart, Germany (Recruiting)
• Rems-Murr-Klinikum Winnenden — Winnenden, Germany (Recruiting)

Study contacts

• Principal investigator: Christoph Röllig, Prof. Dr. — Technische Universität Dresden, Medical Faculty Carl Gustav Carus
• Study coordinator: Christoph Röllig, Prof. Dr.

Conditions Acute Myeloid Leukemia; AML; FLT3 mutation; CBF; midostaurin; gemtuzumab ozogamicin