Midostaurin + Gemtuzumab Ozogamicin combination in first-line standard therapy for acute myeloid leukemia (MOSAIC)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Technische Universitaet Dresden

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

2 Sep 2020 → ongoing

Decision date (initial)

2024-11-08

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

External identifiers

EU CT number

2024-514014-13-00

EudraCT number

2019-003863-23

ClinicalTrials.gov

NCT04385290

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Safety

To evaluate the tolerability and efficacy of midostaurin plus gemtuzumab ozogamicin (GO) in combination with standard AML induction
chemotherapy

Conditions and MedDRA coding

female and male adult patients with acute myeloid leukemia

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Written informed consent
2. Newly diagnosed AML according to the criteria of the World Health Organisation plus the following molecular or cytogenetic specifications: Phase I Trial - MODULE: o ITD or TKD activating mutation at codons D835 and I836 in the FLT3 gene or o t(8;21)/RUNX1-RUNX1T1 or o inv(16) or o t(16;16)/CBFB-MYH11; Phase II Trial - MAGNOLIA: o t(8;21)/RUNX1-RUNX1T1 or o inv(16) or o t(16;16)/CBFB-MYH11; Phase II Trial - MAGMA: o ITD or TKD activating mutation at codons D835 and I836 in the FLT3 gene (FLT3- ITD or FLT3-TKD), o Absence of mutations in the core-binding factor genes (i.e. t(8;21)/RUNX1-RUNX1T1 or inv(16) or t(16;16)/CBFB-MYH11)
3. Male and female patients aged: • 18 - ≤ 75 years in Phase I Trial - MODULE • 18 - ≤ 70 years in Phase II Trials - MAGMA and MAGNOLIA
4. Eastern Cooperative Oncology Group (ECOG) Score of 0-2
5. Life expectancy > 14 days
6. Adequate hepatic and renal function: o ALAT/ASAT ≤ 2.5 x ULN o Bilirubin < 2 x ULN unless in case of hyperbilirubinemia due to an isolated Gilbert syndrome o Creatinine < 1.5 x ULN or Creatinine clearance > 40 ml/min,
7. White blood cell count < 30 × 109/L. Note: Hydroxyurea and/or a dose of 100-200 mg/m2 cytarabine per day for up to 3 days (for emergency use for clinical stabilization) is permitted to meet this criterion

Exclusion criteria 19

1. Exclusion Criteria (all study parts): Previous antineoplastic treatment for AML other than hydroxyurea and/or cytarabine for emergency use (100-200 mg/m2 per day on maximal 3 days)
2. Previous treatment with anthracyclines
3. CNS involvement
4. Isolated extramedullary AML
5. Uncontrolled infection
6. AML after antecedent myelodysplasia (MDS) with prior cytotoxic treatment (e.g., azacytidine or decitabine)
7. 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
8. Prior treatment with a FLT3 inhibitor (e.g., midostaurin, quizartinib, sorafenib)
9. Strong CYP3A4/5 enzyme inducing drugs (see 6.4) unless they can be discontinued or replaced prior to enrollment
10. 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
11. Impairment of gastrointestinal (GI) function or GI disease that might alter significantly the absorption of midostaurin
12. Confirmed diagnosis of HIV infection
13. 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
14. Cardiovascular abnormalities, including any of the following: o History of myocardial infarction, angina pectoris, Coronary Artery Bypass Grafting within 6 months prior to starting study treatment, o Clinically uncontrolled cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block), o Uncontrolled congestive heart failure, o Left ventricular ejection fraction of < 50%, o Poorly controlled arterial hypertension
15. Pregnant or nursing (lactating) women
16. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they fulfill at least one of the following criteria: o Post-menopausal (12 months of natural amenorrhea or 6 months of amenorrhea with Serum FSH > 40 U/ml), o Postoperative (i.e. 6 weeks) after bilateral ovariectomy with or without hysterectomy o Women of childbearing potential must have a negative serum pregnancy test performed within 7 days before the first dose of study drug, o 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) o Sexual abstinence, o Vasectomy of the sexual partner
17. 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
18. Unwillingness or inability to comply with the protocol
19. Known hypersensitivity to midostaurin, GO, cytarabine or daunorubicin or to any of the excipients of midostaurin, GO, cytarabine or daunorubicin

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Primary endpoint dose escalation part (phase I, MODULE): Maximum tolerated dose (MTD) of midostaurin and GO in combination
2. Primary endpoint expansion part (phase II in CBF AML, MAGNOLIA): Event-free survival; event is being defined as either primary treatment failure or relapse or death, whichever occurs first
3. Primary endpoint expansion part (phase II in FLT3mut AML, MAGMA): Event-free survival; event is being defined as either primary treatment failure or relapse or death, whichever occurs first

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Technische Universitaet Dresden

Sponsor organisation

Technische Universitaet Dresden

Address

Mommsenstrasse 11, Raecknitz/zschertnitz Raecknitz/zschertnitz

City

Dresden

Postcode

01069

Country

Germany

Scientific contact point

Organisation

Technische Universitaet Dresden

Contact name

Prof. Dr. med. Christoph Röllig

Public contact point

Organisation

Technische Universitaet Dresden

Contact name

Prof. Dr. med. Christoph Röllig

Locations

1 EU/EEA country · 26 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 12 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications