Clinical Trials /

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

NCT04385290

Description:

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.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Combination of Midostaurin and Gemtuzumab Ozogamicin in First-line Standard Therapy for Acute Myeloid Leukemia (MOSAIC)
  • Official Title: MidOStaurin + Gemtuzumab OzogAmIcin Combination in First-line Standard Therapy for Acute Myeloid Leukemia (MOSAIC)

Clinical Trial IDs

  • ORG STUDY ID: TUD-MOSAIC-075
  • NCT ID: NCT04385290

Conditions

  • Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
MODULE: conventional chemotherapy (Cytarabine+Daunorubicin) in combination with midostaurin+GORydapt, MylotargMODULE trial: dose escalation
MAGNOLIA-trial: Midostaurin associated with conventional chemotherapy (AraC+DNR)+GORydapt, MylotargMAGNOLIA-trial: conventional chemotherapy+GO and midostaurin
MAGNOLIA-trial: Placebo associated with conventional chemotherapy (AraC+DNR)+GOMylotargMAGNOLIA-trial: conventional chemotherapy+GO and placebo
MAGMA-trial:GO associated with conventional chemotherapy (AraC+DNR)+MidostaurinMylotarg, RydaptMAGMA-trial: conventional chemotherapy+midostaurin and GO
MAGMA-trial: conventional chemotherapy (AraC+DNR)+MidostaurinRydaptMAGMA-trial: conventional chemotherapy+midostaurin

Purpose

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.

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).
    

Trial Arms

NameTypeDescriptionInterventions
MODULE trial: dose escalationExperimentalPhase 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).
  • MODULE: conventional chemotherapy (Cytarabine+Daunorubicin) in combination with midostaurin+GO
MAGNOLIA-trial: conventional chemotherapy+GO and midostaurinExperimentalPhase 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
  • MAGNOLIA-trial: Midostaurin associated with conventional chemotherapy (AraC+DNR)+GO
MAGNOLIA-trial: conventional chemotherapy+GO and placeboPlacebo ComparatorPhase 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
  • MAGNOLIA-trial: Placebo associated with conventional chemotherapy (AraC+DNR)+GO
MAGMA-trial: conventional chemotherapy+midostaurin and GOExperimentalPhase 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
  • MAGMA-trial:GO associated with conventional chemotherapy (AraC+DNR)+Midostaurin
MAGMA-trial: conventional chemotherapy+midostaurinActive ComparatorPhase 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.
  • MAGMA-trial: conventional chemotherapy (AraC+DNR)+Midostaurin

Eligibility 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.
      
Maximum Eligible Age:75 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

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

Secondary Outcome Measures

Measure:CR/CRi rate
Time Frame:after induction treatment, approx. 2 months
Safety Issue:
Description: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.
Measure:Depth of remission
Time Frame:after induction treatment, approx. 2 months
Safety Issue:
Description:Quantification of measurable residual disease (MRD)
Measure:Duration of remission
Time Frame:up to 5 years from enrolment
Safety Issue:
Description:Duration of remission is defined as time interval from date of CR/CRi until morphologic relapse.
Measure:Cumulative incidence of relapse
Time Frame:up to 5 years from enrolment
Safety Issue:
Description:Cumulative incidence of relapse is defined as the time interval from date of first CR/CRi until relapse.
Measure:Relapse-free survival
Time Frame:up to 5 years from enrolment
Safety Issue:
Description:Relapse-free survival is defined as the time interval from date of first CR/CRi until either morphologic relapse or death in remission.
Measure:Overall survival
Time Frame:up to 5 years from enrolment
Safety Issue:
Description:Overall survival is defined as time interval from date of randomization until death from any cause.
Measure:Early mortality rate
Time Frame:30 and 60 days after commencement of therapy
Safety Issue:
Description:Early mortality is defined as death from any reason within 30 days and 60 days from start of induction.
Measure: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
Safety Issue:
Description:Number and grade of adverse events assessed by CTCAE v5.0
Measure:CD33 expression of AML blasts
Time Frame:after 18 months of study treatment
Safety Issue:
Description:Proportion of AML blasts positive for CD33 antigen
Measure:Proportion of allogeneic stem cell transplantation
Time Frame:up to 5 years from enrolment
Safety Issue:
Description:Number of patients with allogeneic stem cell transplantations following response to induction.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Technische Universität Dresden

Trial Keywords

  • AML
  • FLT3 mutation
  • CBF
  • midostaurin
  • gemtuzumab ozogamicin

Last Updated

May 12, 2020