Gemtuzumab Ozogamicin Plus Midostaurin in Combination with Standard Intensive Induction Therapy in Newly Diagnosed AML: Results from a Phase-I Study
Authors: Röllig Christoph , Schliemann Christoph , Mikesch Jan-Henrik , Fransecky Lars , Baldus Claudia D. , Heydrich Björn-Niklas , Hanoun Maher , Noppeney Richard , Scholl Sebastian , Schnetzke Ulf , Schäfer-Eckart Kerstin , Wendelin Knut , Wermke Martin , Reimann Manja , Fiebig Frank , Kretschmann Theresa , Stoelzel Friedrich , Alakel Nael , Bornhäuser Martin 
Published: November 2021

Abstract
Background
In newly diagnosed acute myeloid leukemia (AML) with FLT3 mutations (FLT3-mut), the tyrosine kinase inhibitor midostaurin (MIDO) in combination with intensive chemotherapy (IC) is considered standard of care (SoC). Subgroup analyses from the ALFA 0701 trial indicate that the addition of the conjugated CD33 antibody gemtuzumab ozogamicin (GO) to IC increases efficacy in the FLT3-ITD subgroup of patients (pts), providing a rationale for the combined use of MIDO plus GO with IC in newly diagnosed FLT3-mut AML. On the other hand, there is evidence that the subgroup of core-binding factor (CBF) AML benefits from the inhibition of the tyrosine kinase KIT with respect to survival end points. In this respect, MIDO is a more powerful KIT inhibitor as compared to dasatinib which has been applied in previous studies. While the combination of IC plus GO in induction treatment is considered SoC in patients with CBF AML the addition of MIDO to SoC seems promising to further improve treatment outcomes in the CBF subgroup. We therefore set up the clinical trial MOSAIC composed of a phase-I part to prospectively assess the feasibility of combining MIDO plus GO with IC (MODULE), followed by a randomized phase-II part evaluating the benefit of adding GO to SoC in FLT3-mut AML (MAGMA) and of adding MIDO to SoC in CBF AML (MAGNOLIA). Here, we report the results of the phase-I part (MODULE).
Methods
MODULE is a dose escalation phase-I trial following a 3+3 design. Eligibility criteria include newly diagnosed AML harboring either FLT3 or CBF mutations, and fitness for IC. Standard 7+3 IC using cytarabine 200 mg/m 2 continuous infusion over 7 days plus daunorubicin 60 mg/m 2 on 3 days was combined with increasing doses of MIDO and GO in three dose levels: 1 st dose level (GO 3 mg/m 2 i.v. QD on day 1+4 plus 25 mg MIDO p.o. BID days 8-21); 2 nd dose level (GO 3 mg/m 2 i.v. QD on day 1+4 plus 50 mg MIDO p.o. BID days 8-21); 3 rd dose level (GO 3 mg/m 2 i.v. QD on day 1+4+7 plus 50 mg MIDO p.o. BID days 8-21). Based on the 3+3 design, each dose cohort consisted of three but maximal six pts. The protocol predefined the maximal tolerable dose (MTD) as reached if ≤2 dose-limiting toxicity events (DLTs) would occur in maximum six evaluable pts who received ≥80% of the planned study therapy.

Results
From September 2020 to July 2021, 11 pts were enrolled. In the 1 st dose level, three pts completed the regular study period without DLT, whereas treatment had to be discontinued in one patient on day 6 before commencement of MIDO due to infusion related reaction CTC grade 4. This patient was subsequently replaced. In the 2 nd dose level, one of three enrolled pts experienced neutropenic colitis CTC grade 3 on day 14 of treatment, which was classified as DLT. The colitis fully recovered by day 27 after commencement of treatment. As a result of the DLT, the dose cohort was subsequently extended by three additional pts. Of those, one patient developed signs of sinusoidal obstruction syndrome (SOS) CTC grade 3 starting on day 13 of treatment. SOS was classified as DLT. The patient was treated with defibrotide and supportive care until recovery on day 28. Another patient had to discontinue treatment on day 14 due to inability of swallowing MIDO. This patient was replaced as the target dose of MIDO was not reached. As predefined in the study protocol, the occurrence of 2 DLTs in six evaluable pts precluded further dose escalation to the 3 rd dose level and defined the 2 nd dose level as safe and feasible.
A total number of 5 serious adverse events (SAEs) were observed among all 11 pts who completed the DLT evaluation period: infusion related reaction, colitis, parvo-B19 infection, prolonged neutropenia CTC grade 4, and SOS. An unexpected increase in frequency of common AML adverse events was not observed. The 30-day mortality among all enrolled pts was 0%.
After blood count recovery, remission assessment showed complete remission (CR) in 7 pts, CR with incomplete hematologic/platelet recovery (CRi/CRp) in 3 pts and primary refractory disease in one patient.
Conclusion
GO standard dose on days 1 + 4 and MIDO standard dose on days 8-21 of induction treatment is defined as MTD which can be safely combined with standard IC in newly diagnosed AML. In the phase-I cohort of the MOSAIC trial, CR/CRi/CRp rates of 91% were reached. Based on the results of this dose finding trial the MTD of combined MIDO and GO will be defined as phase-II dose for the randomized phase-II studies in CBF and FLT-mut AML.
Figure 1 Figure 1.

Disclosures
Röllig: Jazz: Honoraria; Amgen: Honoraria; Bristol-Meyer-Squibb: Honoraria, Research Funding; Janssen: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Roche: Honoraria, Research Funding. Schliemann: Philogen S.p.A.: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Other: travel grants; Astellas: Consultancy; AstraZeneca: Consultancy; Boehringer-Ingelheim: Research Funding; BMS: Consultancy, Other: travel grants; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy; Roche: Consultancy; Pfizer: Consultancy. Fransecky: Novartis: Honoraria; Abbvie: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Honoraria; Medac: Honoraria. Baldus: Novartis: Honoraria; Amgen: Honoraria; Celgene/BMS: Honoraria; Jazz: Honoraria. Wermke: Novartis, Roche, Pfizer, BMS: Consultancy, Honoraria, Research Funding.