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

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ClinicalTrials.gov Identifier: NCT04385290
Recruitment Status : Recruiting
First Posted : May 12, 2020
Last Update Posted : September 30, 2020
Sponsor:
Collaborators:
Novartis Pharmaceuticals
Pfizer
Information provided by (Responsible Party):
Technische Universität Dresden

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Drug: MODULE: conventional chemotherapy (Cytarabine+Daunorubicin) in combination with midostaurin+GO Drug: MAGNOLIA-trial: Midostaurin associated with conventional chemotherapy (AraC+DNR)+GO Drug: MAGNOLIA-trial: Placebo associated with conventional chemotherapy (AraC+DNR)+GO Drug: MAGMA-trial:GO associated with conventional chemotherapy (AraC+DNR)+Midostaurin Drug: MAGMA-trial: conventional chemotherapy (AraC+DNR)+Midostaurin Phase 1 Phase 2

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 placebo 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).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 214 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

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 double-blinded and randomized manner.

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

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Since the trial part MAGNOLIA is designed to be double-blinded, patients, investigators, site personnel, study team members, and anyone involved in the study conduct will remain blinded to the identity of the study drug midostaurin / placebo from the time of randomization until database lock for the primary endpoint analysis.
Primary Purpose: Treatment
Official Title: MidOStaurin + Gemtuzumab OzogAmIcin Combination in First-line Standard Therapy for Acute Myeloid Leukemia (MOSAIC)
Actual Study Start Date : September 4, 2020
Estimated Primary Completion Date : May 2021
Estimated Study Completion Date : April 2028


Arm Intervention/treatment
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).
Drug: MODULE: conventional chemotherapy (Cytarabine+Daunorubicin) in combination with midostaurin+GO

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

Other Names:
  • Rydapt
  • Mylotarg

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
Drug: MAGNOLIA-trial: Midostaurin associated with 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 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

Other Names:
  • Rydapt
  • Mylotarg

Placebo Comparator: MAGNOLIA-trial: conventional chemotherapy+GO and placebo
Phase II (Trial part MAGNOLIA): placebo 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
Drug: MAGNOLIA-trial: Placebo associated with conventional chemotherapy (AraC+DNR)+GO

Placebo:

peroral, days 8 to 21, 1-2 induction cycles; peroral BID, days 8 to 21, 3 consolidation cycles; 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 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

Other Name: Mylotarg

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
Drug: 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;

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

Other Names:
  • Mylotarg
  • Rydapt

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.
Drug: MAGMA-trial: 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

Other Name: Rydapt




Primary Outcome Measures :
  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 5 years from enrolment ]
    Time interval from date of randomization until either primary treatment failure or relapse or death, whichever occurs first.


Secondary Outcome Measures :
  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. Depth of remission [ Time Frame: after induction treatment, approx. 2 months ]
    Quantification of measurable residual disease (MRD)

  3. Duration of remission [ Time Frame: up to 5 years from enrolment ]
    Duration of remission is defined as time interval from date of CR/CRi until morphologic relapse.

  4. Cumulative incidence of relapse [ Time Frame: up to 5 years from enrolment ]
    Cumulative incidence of relapse is defined as the time interval from date of first CR/CRi until relapse.

  5. Relapse-free survival [ Time Frame: up to 5 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.

  6. Overall survival [ Time Frame: up to 5 years from enrolment ]
    Overall survival is defined as time interval from date of randomization until death from any cause.

  7. 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.

  8. Incidence and severity of adverse events (tolerability) [ Time Frame: until 2 months after commencement of therapy; up to app. 1,5 years after commencement of therapy ]
    Number and grade of adverse events assessed by CTCAE v5.0

  9. CD33 expression of AML blasts [ Time Frame: after 18 months of study treatment ]
    Proportion of AML blasts positive for CD33 antigen

  10. Proportion of allogeneic stem cell transplantation [ Time Frame: up to 5 years from enrolment ]
    Number of patients with allogeneic stem cell transplantations following response to induction.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
      • FLT3 wild-type
    • Phase II Trial - MAGMA

      • FLT3-ITD or
      • FLT3-TKD
  • Male and female patients with age

    • 18 - ≤ 75 years in Phase I Trial - MODULE or Phase II Trial - MAGNOLIA
    • 18 - ≤ 60 years in Phase II Trial - MAGMA
  • 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 is permitted to meet this criterion.

Exclusion Criteria (all study parts):

  • Previous antineoplastic treatment for AML other than hydroxyurea
  • 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 or active viral hepatitis
  • 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/placebo, GO, cytarabine or daunorubicin.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04385290


Contacts
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Contact: Christoph Röllig, Prof. Dr. +49 351 458 ext 3775 MOSAIC@ukdd.de
Contact: Manja Reimann, Dr. +49 351 458 ext 3091 MOSAIC@ukdd.de

Locations
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Germany
Universitätsklinikum Dresden Recruiting
Dresden, Germany, 01307
Johann Wolfgang Goethe-Universität Not yet recruiting
Frankfurt am Main, Germany, 60590
Contact: Björn Steffen, Dr.         
Universitätsklinikum Heidelberg Not yet recruiting
Heidelberg, Germany, 69120
Contact: Richard Schlenk, Prof. Dr.         
Universitätsklinikum Jena Not yet recruiting
Jena, Germany, 07740
Contact: Sebastian Scholl, Dr.         
Universitätsklinikum Schleswig-Holstein Not yet recruiting
Kiel, Germany, 24105
Contact: Lars Fransecky, Dr.         
Universitätsklinikum Leipzig Not yet recruiting
Leipzig, Germany, 04103
Contact: Sabine Kayser, Dr.         
Klinikum Mannheim gGmbH Not yet recruiting
Mannheim, Germany, 68167
Contact: Stefan Klein, Dr.         
Universitätsklinikum Münster Not yet recruiting
Münster, Germany, 48149
Contact: Christoph Schliemann, Prof. Dr.         
Klinikum Nürnberg-Nord Not yet recruiting
Nürnberg, Germany, 90419
Contact: Kerstin Schäfer-Eckart, Dr.         
Sponsors and Collaborators
Technische Universität Dresden
Novartis Pharmaceuticals
Pfizer
Investigators
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Principal Investigator: Christoph Röllig, Prof. Dr. Technische Universität Dresden, Medical Faculty Carl Gustav Carus
Additional Information:
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Responsible Party: Technische Universität Dresden
ClinicalTrials.gov Identifier: NCT04385290    
Other Study ID Numbers: TUD-MOSAIC-075
First Posted: May 12, 2020    Key Record Dates
Last Update Posted: September 30, 2020
Last Verified: September 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Technische Universität Dresden:
AML
FLT3 mutation
CBF
midostaurin
gemtuzumab ozogamicin
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Cytarabine
Daunorubicin
Gemtuzumab
Midostaurin
Staurosporine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Antineoplastic Agents, Immunological
Protein Kinase Inhibitors