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Phase I (Trial part MODULE): The treatment plan combines increasing doses levels of midostaurin (25/50 mg BID) and gemtuzumab ozogamicin (3 mg/m\^2 i.v. max 4.5 mg on day(s) 1, (4, 7)) with 7+3 standard chemotherapy scheme using cytarabine (200 mg/m\^2 cont. inf. i.v. on days 1 to 7) and daunorubicin (60 mg/m\^2 i.v. on days 1 to 3).

Phase II (Trial part MAGNOLIA): midostaurin (recommended phase II dose, RP2D) is combined with treatment standard (7+3 standard chemotherapy scheme using cytarabine 200 mg/m\^2 cont. inf. i.v. and daunorubicin 60 mg/m\^2 i.v.) plus GO (recommended phase II dose, RP2D) in CBF AML

Phase II (Trial part MAGNOLIA): treatment standard of CBF AML (7+3 standard chemotherapy scheme using cytarabine 200 mg/m\^2 cont. inf. i.v. and daunorubicin 60 mg/m\^2 i.v. plus GO (3 mg/m\^2 i.v. max 4.5 mg) on days 1, 4, 7). No additional Midostaurin is given.

Phase II (Trial part MAGMA): GO (recommended phase II dose, RP2D) is combined with treatment standard (7+3 standard chemotherapy scheme using cytarabine 200 mg/m\^2 cont. inf. i.v. and daunorubicin 60 mg/m\^2 i.v.) plus Midostaurin (recommended phase II dose, RP2D) in FLT3 mutated AML

Phase II Trial (MAGMA): treatment standard of FLT3 mutated AML (7+3 standard chemotherapy scheme using cytarabine 200 mg/m\^2 cont. inf. i.v. and daunorubicin 60 mg/m\^2 i.v plus midostaurin). No additional GO is given.

Midostaurin (IMP) induction: 25 mg or 50 mg peroral BID, days 8 to 21 depending on assigned dose level

GO (IMP) induction: 3 mg/m\^2 i.v. max 4.5 mg, on day1, or on days 1, 4, or days 1, 4, 7 depending on assigned dose level

Daunorubicin (DNR, non-IMP) induction: 60 mg/m\^2/day i.v., days 1 to 3

Cytarabine (AraC, non-IMP) induction: 200 mg/m\^2/day cont. infusion, days 1 to 7

MODULE: conventional chemotherapy (Cytarabine+Daunorubicin) in combination with midostaurin+GO

Midostaurin (IMP):

RP2D peroral, days 8 to 21, induction cycle 1; 50 mg peroral BID, days 8 to 21 induction cycle 2; 50 mg peroral BID, days 8 to 21, 3 consolidation cycles; 50 mg peroral BID, days 1 to 28, 12 maintenance cycles;

GO (IMP): 3 mg/m\^2 i.v. max 4.5 mg, RP2D, 1 induction cycle only

Daunorubicin (DNR, non-IMP):

60 mg/m\^2 i.v., days 1 to 3 of induction cycle 1 and 2 in good and moderate responders; 50 mg/m\^2/day i.v., days 1 to 3 of induction cycle 2 in non-responders

Cytarabine (AraC, non-IMP):

200 mg/m\^2/day cont. infusion, days 1 to 7 of induction cycles 1 and 2 in good and moderate responders; 3000/1500 mg/m\^2/day i.v. BID, days 1 to 3 of induction cycle 2 in non-responders; 3000/1500 mg/m\^2 i.v. BID, days 1, 3, 5 of consolidation, 3 cycles

MAGNOLIA-trial: Midostaurin associated with conventional chemotherapy (AraC+DNR)+GO

GO (IMP): 3 mg/m\^2 i.v. max 4.5 mg on days 1, 4, 7; 1 induction cycle only

Daunorubicin (DNR, non-IMP):

60 mg/m\^2/day i.v., days 1 to 3 of induction cycle 1 and 2 in good and moderate responders; 50 mg/m\^2/day i.v., days 1 to 3 of induction cycle 2 in non-responders

Cytarabine (AraC, non-IMP):

200 mg/m\^2/day cont. infusion, days 1 to 7 of induction cycles 1 and 2 in good and moderate responders; 3000/1500 mg/m\^2/day i.v. BID, days 1 to 3 of induction cycle 2 in non-responders; 3000/1500 mg/m\^2 i.v. BID, days 1, 3, 5 of consolidation, 3 cycles

MAGNOLIA-trial: conventional chemotherapy (AraC+DNR)+GO

Midostaurin (IMP):

RP2D peroral, days 8 to 21, induction cycle 1; 50 mg peroral BID, days 8 to 21, induction cycle 2; 50 mg peroral BID, days 8 to 21, 3 consolidation cycles; 50 mg peroral BID, days 1 to 28, 12 maintenance cycles;

GO (IMP): 3 mg/m\^2 i.v. max 4.5 mg, RP2D, 1 induction cycle only

Daunorubicin (DNR, non-IMP):

60 mg/m\^2/day i.v., days 1 to 3 of induction cycles 1-2 in good and moderate responders; 50 mg/m\^2/day i.v., days 1 to 3 of induction cycle 2 in non-responders

Cytarabine (AraC, non-IMP):

200 mg/m\^2/day cont. infusion, days 1 to 7 of induction cycles 1 and 2 in good and moderate responders; 3000/1500 mg/m\^2/day i.v. BID, days 1 to 3 of induction cycle 2 in non-responders; 3000/1500 mg/m\^2 i.v. BID, days 1, 3, 5 of consolidation, 3 cycles

MAGMA-trial:GO associated with conventional chemotherapy (AraC+DNR)+Midostaurin

Midostaurin (IMP):

RP2D peroral, days 8 to 21, induction cycle 1; 50 mg peroral BID, days 8 to 21 induction cycle 2; 50 mg peroral BID, days 8 to 21, 3 consolidation cycles; 50 mg peroral BID, days 1 to 28, 12 maintenance cycles

Daunorubicin (DNR, non-IMP):

60 mg/m\^2/day i.v., days 1 to 3 of induction cycle 1 and 2 in good and moderate responders; 50 mg/m\^2/day i.v., days 1 to 3 of induction cycle 2 in non-responders

Cytarabine (AraC, non-IMP):

200 mg/m\^2/day cont. infusion, days 1 to 7 of induction cycles 1 and 2 in good and moderate responders; 3000/1500 mg/m\^2/day i.v. BID, days 1 to 3 of induction cycle 2 in non-responders; 3000/1500 mg/m\^2 i.v. BID, days 1, 3, 5 of consolidation, 3 cycles

MAGMA-trial: conventional chemotherapy (AraC+DNR)+Midostaurin

Christoph Röllig, Prof. Dr.

Manja Reimann, Dr.

Veit Bücklein, Dr.

Maher Hanoun, PD Dr.

Edgar Jost, Prof.

Christoph Schmid, Prof.

Mathias Hänel, Prof.

Christoph Röllig, Prof.

Björn Steffen, Dr.

Christine Dierks, Prof.

Tim Sauer, Dr.

Sebastian Scholl, Prof. Dr.

Lars Fransecky, Dr.

Dirk Niemann, Dr.

Madlen Jentzsch, PD Dr.

Nadine Müller, Dr.

Kristina Sohlbach, Dr.

Alexander Höllein, Prof. Dr.

Christoph Schliemann, Prof.

Kerstin Schäfer-Eckart, Dr.

Nadia Maguire

Martin Kaufmann, Dr.

Markus Schaich, Prof. Dr.

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).

The phase I dose escalation trial (MODULE) will be conducted according to the 3+3 design.

The phase II trial in CBF AML (MAGNOLIA) will be conducted in a open label and randomized manner.

The phase II trial in FLT3 mutated AML (MAGMA) will be conducted in a open label and randomized manner.

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

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

as measured by the number of dose limiting toxicities related to midostaurin or GO exposure.

Time interval from date of randomization until either primary treatment failure or relapse or death, whichever occurs first.

CR/CRi rate is defined as the proportion of patients, who achieved a morphologic complete remission or a complete remission with incomplete hematologic recovery (CR or CRi) during study participation.

Duration of remission is defined as time interval from date of CR/CRi until morphologic relapse.

Cumulative incidence of relapse is defined as the time interval from date of first CR/CRi until relapse.

Relapse-free survival is defined as the time interval from date of first CR/CRi until either morphologic relapse or death in remission.

Overall survival is defined as time interval from date of randomization until death from any cause.

Early mortality is defined as death from any reason within 30 days and 60 days from start of induction.

Spots Global Cancer Trial Database for module: conventional chemotherapy (cytarabine+daunorubicin) in combination with midostaurin+go