JOURNAL ONKOLOGIE – STUDIE

MOSAIC

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

Studien-Informationen Einschlusskriterien Studien-Rationale Studien-Arme Geprüfte Regime

Rekrutierend

Studienbeginn:
September 2020

Letztes Update:
09.08.2023

Wirkstoff:
MODULE: conventional chemotherapy (Cytarabine+Daunorubicin) in combination with midostaurin+GO, MAGNOLIA-trial: Midostaurin associated with conventional chemotherapy (AraC+DNR)+GO, MAGNOLIA-trial: conventional chemotherapy (AraC+DNR)+GO, MAGMA-trial:GO associated with conventional chemotherapy (AraC+DNR)+Midostaurin, MAGMA-trial: conventional chemotherapy (AraC+DNR)+Midostaurin

Indikation (Clinical Trials):
Leukemia, Leukemia, Myeloid, Leukemia, Myeloid, Acute

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
-

Sponsor:
Technische Universität Dresden

Collaborator:
Novartis Pharmaceuticals, Pfizer,

Studienleiter

Christoph Röllig, Prof. Dr.
Principal Investigator
Technische Universität Dresden, Medical Faculty Carl Gustav Carus

Kontakt

Christoph Röllig, Prof. Dr.
Kontakt:
Phone: +49 351 458
Phone (ext.): 3775
E-Mail: MOSAIC@ukdd.de» Kontaktdaten anzeigen

Manja Reimann, Dr.
Kontakt:
Phone: +49 351 458
Phone (ext.): 3091
E-Mail: MOSAIC@ukdd.de» Kontaktdaten anzeigen

Studienlocations
(3 von 21)

LMU Klinikum, Campus Großhadern
81377 München
(Bayern)
GermanyRekrutierend» Google-Maps

Kinderonkologisches Zentrum Universitätsklinikum Essen
Hufelandstraße 55
45147 Essen
DeutschlandRekrutierend» Google-Maps

Universitätsklinikum Aachen
52074 Aachen
GermanyRekrutierend» Google-Maps

Universitätsklinikum Augsburg
86156 Augsburg
(Bayern)
GermanyNoch nicht rekrutierend» Google-Maps

Klinikum Chemnitz gGmbH
09116 Chemnitz
(Sachsen)
GermanyRekrutierend» Google-Maps

Universitätsklinikum Dresden
01307 Dresden
(Sachsen)
GermanyRekrutierend» Google-Maps

Johann Wolfgang Goethe-Universität
60590 Frankfurt am Main
(Hessen)
GermanyRekrutierend» Google-Maps

Hauttumorzentrum am Universitätsklinikum Halle
Ernst-Grube-Straße 40
06120 Halle (Saale)
(Sachsen-Anhalt)
DeutschlandRekrutierend» Google-Maps

Universitätsklinikum Heidelberg
69120 Heidelberg
(Baden-Württemberg)
GermanyRekrutierend» Google-Maps

Universitätsklinikum Jena
07740 Jena
(Thüringen)
GermanyRekrutierend» Google-Maps

Darmkrebszentrum am Universitätsklinikum Schleswig-Holstein, Campus Lübeck
Ratzeburger Allee 160
23562 Lübeck
DeutschlandRekrutierend» Google-Maps

Gemeinschaftsklinikum Mittelrhein gGmbH
56068 Koblenz
(Rheinland-Pfalz)
GermanyRekrutierend» Google-Maps

Gynäkologisches Tumorzentrum am Universitätsklinikum Leipzig
4103 Leipzig
DeutschlandRekrutierend» Google-Maps

Klinikum Mannheim gGmbH
68167 Mannheim
(Baden-Württemberg)
GermanyRekrutierend» Google-Maps

Philipps-Universität Marburg Fachbereich Medizin
35043 Marburg
(Hessen)
GermanyRekrutierend» Google-Maps

Rotkreuzklinikum München gGmbH
80634 München
(Bayern)
GermanyRekrutierend» Google-Maps

Kinderonkologisches Zentrum am Universitätsklinikum Münster
Albert-Schweitzer-Campus 1
48149 Münster
DeutschlandRekrutierend» Google-Maps

Klinikum Nürnberg-Nord
90419 Nürnberg
(Bayern)
GermanyNoch nicht rekrutierend» Google-Maps

Onkologisches Zentrum - Krankenhaus Barmherzige Brüder Regensburg
Prüfeninger Straße 86
93049 Regensburg
(Bayern)
DeutschlandRekrutierend» Google-Maps

Brustzentrum Robert-Bosch-Krankenhaus
Auerbachstraße 110
70376 Stuttgart
DeutschlandRekrutierend» Google-Maps

Onkologisches Zentrum Rems-Murr-Klinikum Winnenden
Am Jakobsweg 1
71364 Winnenden
DeutschlandRekrutierend» Google-Maps

Alle anzeigen

Studien-Informationen

Detailed Description:

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).

Ein-/Ausschlusskriterien

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.

Studien-Rationale

Primary outcome:

1. Maximum tolerated dose (MTD) of midostaurin and GO combination (Time Frame - treatment day 8 until day 42 at the latest):
as measured by the number of dose limiting toxicities related to midostaurin or GO exposure.

2. Event Free Survival (EFS) (Time Frame - up to 3 years from enrolment):
Time interval from date of randomization until either primary treatment failure or relapse or death, whichever occurs first.

Secondary outcome:

1. CR/CRi rate (Time Frame - after induction treatment, approx. 2 months):
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.

2. Duration of remission (Time Frame - up to 3 years from enrolment):
Duration of remission is defined as time interval from date of CR/CRi until morphologic relapse.

3. Cumulative incidence of relapse (Time Frame - up to 3 years from enrolment):
Cumulative incidence of relapse is defined as the time interval from date of first CR/CRi until relapse.

4. Relapse-free survival (Time Frame - up to 3 years from enrolment):
Relapse-free survival is defined as the time interval from date of first CR/CRi until either morphologic relapse or death in remission.

5. Overall survival (Time Frame - up to 3 years from enrolment):
Overall survival is defined as time interval from date of randomization until death from any cause.

6. Early mortality rate (Time Frame - 30 and 60 days after commencement of therapy):
Early mortality is defined as death from any reason within 30 days and 60 days from start of induction.

Studien-Arme

Experimental: MODULE trial: dose escalation
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).
Experimental: MAGNOLIA-trial: conventional chemotherapy+GO and midostaurin
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
Active Comparator: MAGNOLIA-trial: conventional chemotherapy+GO
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.
Experimental: MAGMA-trial: conventional chemotherapy+midostaurin and GO
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
Active Comparator: MAGMA-trial: conventional chemotherapy+midostaurin
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.

Geprüfte Regime

MODULE: conventional chemotherapy (Cytarabine+Daunorubicin) in combination with midostaurin+GO (Rydapt / Mylotarg / ):
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
MAGNOLIA-trial: Midostaurin associated with conventional chemotherapy (AraC+DNR)+GO (Rydapt / Mylotarg / ):
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: conventional chemotherapy (AraC+DNR)+GO (Mylotarg):
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
MAGMA-trial:GO associated with conventional chemotherapy (AraC+DNR)+Midostaurin (Mylotarg / Rydapt / ):
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: conventional chemotherapy (AraC+DNR)+Midostaurin (Rydapt):
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

Quelle: ClinicalTrials.gov

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