Combination of Midostaurin and Gemtuzumab Ozogamicin in First-line Standard Therapy for Acute Myeloid Leukemia (MOSAIC)

• Status: Active, not recruiting
• Trial end date: 2028-04-01
• Target enrollment: 0
• Participant gender: All

Summary

This phase I/II clinical trial evaluates the safety and efficacy of the combined administration of midostaurin and gemtuzumab ozogamicin in the frame of first-line standard chemotherapy in newly diagnosed acute myeloid leukemia (AML) patients displaying a cytogenetic aberration or fusion transcript in the core-binding factor (CBF) genes or FMS-like tyrosine Kinase 3 (FLT3) mutation.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Technische Universität Dresden
• Collaborators: Novartis Pharmaceuticals; Pfizer
• Treatments: Cytarabine; Daunorubicin; Gemtuzumab; Midostaurin; Staurosporine

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

• FLT3 wild-type

• Phase II Trial - MAGMA

• FLT3-ITD or

• FLT3-TKD

• Male and female patients with age

• 18 - ≤ 75 years in Phase I Trial - MODULE or Phase II Trial - MAGNOLIA

• 18 - ≤ 60 years in Phase II Trial - MAGMA

• 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 is permitted to meet this criterion.

Exclusion Criteria (all study parts):

• Previous antineoplastic treatment for AML other than hydroxyurea

• 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 or active viral hepatitis

• 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/placebo, GO, cytarabine or daunorubicin.