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.

Acute myeloid leukemia is a malignancy that is still fatal for the majority of patients. Besides age, the genetic configuration of AML blasts is one of the strongest prognostic factors. Patients with mutations in the core-binding factor (CBF) genes have the best prognosis, however a considerable proportion of 35-60% will eventually relapse. Mutation and overexpression of receptor tyrosinkinases (RTK) have been proposed as main reasons for relapse development or chemoresistance in CBF AMLs. RTKs like stem cell factor receptor (c-KIT) and FLT3 are of high clinical relevance as they mediate proliferation and differentiation of hematopoietic stem cells. There is evidence that c-Kit mutations and high levels of c-KIT in CBF-AML have adverse effects on survival endpoints indicating c-KIT as potential therapeutic target in this special AML population. Midostaurin can be considered a potent c-KIT inhibitor besides having multi-kinase inhibitory activity for several other kinases of documented or potential pathogenetic relevance for AML, most importantly mutated FLT3. The kinase inhibition ultimately leads to inhibition of proliferation, cell cycle arrest, and apoptosis. Previous studies with other c-KIT inhibitors such as dasatinib showed promising results with respect to survival end points in newly diagnosed CBF AML patients. Midostaurin is considered a more potent c-KIT inhibitor than dasatinib and may be able to potentiate the inhibitory effect on leukemic cell growth.

Another important therapeutical target in CBF AML is the sialic acid-binding immunoglobulin-like lectin (CD33) which is expressed on the majority of AML blasts. Gemtuzumab Ozogamicin (GO) is a therapeutic CD33 antibody linked to a strong cytostatic drug (calicheamicin) which causes apoptosis of cancer cells upon internalization. For the combination of GO and standard intensive chemotherapy, metaanalyses of randomized trials have shown that i) a low-dose fractionated administration results in the best tolerability, and ii) among AML subgroups, patients with CBF AML have the greatest benefit from GO in addition to standard therapy. Subgroup analyses within the ALFA-0701 (A Randomized Study of Gemtuzumab Ozogamicin With Daunorubicine and Cytarabine in Untreated Acute Myeloid Leukemia Aged of 50-70 Years Old) trial population showing beneficial effects of GO on overall survival, relapse-free survival and event-free survival in patients positive for FLT3 mutation as compared to those negative for FLT3 mutation. Subgroup analyses of the GO registration trial ALFA-0701 showed a significant clinical benefit of the patients displaying a mutation in the FLT3 gene compared to those without this mutation. In Addition, CBF AML patients with FLT3 mutations expressed particularly high levels of CD33 antigen and that CD33 antigen levels were positively correlated to the improved survival after GO treatment. Furthermore, recently published data of two paediatric populations with internal tandem mutation in the FLT3 gene showed reduced relapse rates in GO recipients compared to the control group only receiving standard chemotherapy. These results suggest that GO is a particularly beneficiary agent in FLT3 mutated patients who would currently receive midostaurin in addition to intensive chemotherapy as a standard of care. Hence, from a clinical point of view there is an unambiguous rationale supporting the combination of midostaurin and GO for treatment of AML in the two cytogenetic subgroups: CBF AML and FLT3 mutated AML.

GO has become the new treatment standard for patients with CBF AML. The hypothesized positive effect of midostaurin is likely but randomized proof is laking.

Midostaurin has become the new treatment standard for AML patients with mutations in the FLT3 gene. The positive effect of GO is shown in a post-hoc subgroup analysis of the ALFA-0701 trial, but prospective randomized proof is lacking.

Therefore, the proposed trial intends i) to explore and establish the safe combination of GO plus midostaurin (MODULE) and ii) to evaluate the effect of midostaurin versus no midostaurin added to standard AML chemotherapy plus GO in CBF AML (MAGNOLIA) and iii) to evaluate the effect of GO versus no GO added to standard AML chemotherapy plus midostaurin in FLT3 mutated AML (MAGMA).

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.

The subtrials are not blinded.