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Study to Improve OS in 18 to 60 Year-old Patients, Comparing Daunorubicin Versus High Dose Idarubicin Induction Regimens, High Dose Versus Intermediate Dose Cytarabine Consolidation Regimens, and Standard Versus MMF Prophylaxis of GvHD in Allografted Patients in First CR

NCT02416388

Description:

This open label, multicenter phase II/III study with multiple randomization phases at differents stages of AML treatment (induction, consolidation and HSCT where applicable) is designed to improve OS in younger (18 to 60 year-old) patients, with AML risk-adapted patient strategies. Within the intermediate risk AML group, optimal GvHD prophylaxis following allogeneic SCT in first CR, after either myeloablative (MAC) or reduced intensity (RIC) conditioning, will also be evaluated. With an adaptative design, this clinical trial could test up to 3 novel AML agents of interest.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 2/Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Study to Improve OS in 18 to 60 Year-old Patients, Comparing Daunorubicin Versus High Dose Idarubicin Induction Regimens, High Dose Versus Intermediate Dose Cytarabine Consolidation Regimens, and Standard Versus MMF Prophylaxis of GvHD in Allografted Patients in First CR
  • Official Title: Phase II/III Randomized Study to Improve Overall Survival in 18 to 60 Year-old Patients, Comparing Daunorubicin Versus High Dose Idarubicin Induction Regimens, High Dose Versus Intermediate Dose Cytarabine Consolidation Regimens, and Standard Versus Mycophenolate Mofetil Prophylaxis of Graft Versus Host Disease in Allografted Patients in First CR : a Backbone InterGroup-1 Trial

Clinical Trial IDs

  • ORG STUDY ID: PHRC-2010-03
  • NCT ID: NCT02416388

Conditions

  • Acute Myeloid Leukemia (AML)

Interventions

DrugSynonymsArms
IdarubicinR1-IDA
DaunorubicinR1-DAUNO
HD CytarabineR2-HDAC
CyclosporineR3-MAC-MPA
MethotrexateR3-MAC-MTX
Mycophenolic acid (MPA)R3-MAC-MPA
vosaroxinR4-VOS-IDAC
ID cytarabineR2-IDAC
DexamethasoneR4-DEX-HDAC
VenetoclaxR4-VEN-IDAC

Purpose

This open label, multicenter phase II/III study with multiple randomization phases at differents stages of AML treatment (induction, consolidation and HSCT where applicable) is designed to improve OS in younger (18 to 60 year-old) patients, with AML risk-adapted patient strategies. Within the intermediate risk AML group, optimal GvHD prophylaxis following allogeneic SCT in first CR, after either myeloablative (MAC) or reduced intensity (RIC) conditioning, will also be evaluated. With an adaptative design, this clinical trial could test up to 3 novel AML agents of interest.

Trial Arms

NameTypeDescriptionInterventions
R1-IDAExperimentalIdarubicin
  • Idarubicin
R1-DAUNOActive ComparatorDaunorubicin
  • Daunorubicin
R2-HDACActive ComparatorHigh dose cytarabine
  • HD Cytarabine
R2-IDACExperimentalIntermediate dose cytarabine
  • ID cytarabine
R3-MAC-MTXActive ComparatorMethotrexate and mycophenolic acid
  • Methotrexate
  • Mycophenolic acid (MPA)
R3-MAC-MPAExperimentalCyclosporine and mycophenolic acid
  • Cyclosporine
  • Mycophenolic acid (MPA)
R3-RIC-CICLOActive ComparatorCyclosporine
  • Cyclosporine
R3-RIC-MPAExperimentalCyclosporine and mycophenolic acid
  • Cyclosporine
  • Mycophenolic acid (MPA)
R4-VOS-IDACExperimentalIntermediate dose cytarabine and vosaroxin
  • vosaroxin
  • ID cytarabine
R4-IDAC (without VOS)Active ComparatorIntermediate dose cytarabine alone
  • ID cytarabine
R4-DEX-HDACExperimentalHigh dose cytarabine and dexamethasone
  • HD Cytarabine
  • Dexamethasone
R4-HDAC (without DEX)Active ComparatorHigh dose cytarabine alone
  • HD Cytarabine
R4-VEN-IDACExperimentalIntermediate dose cytarabine and venetoclax
  • ID cytarabine
  • Venetoclax
R4-IDAC (without VEN)Active ComparatorIntermediate dose cytarabine alone
  • ID cytarabine

Eligibility Criteria

        Inclusion Criteria (at diagnosis) :

          1. Age ≥ 18 years and < 61 years

          2. With a newly diagnosed de novo or secondary type AML (post myelodysplastic syndrome
             MDS or therapy-related AML)

          3. No prior treatment for neither AML (with the exception of hydroxyurea), nor MDS (with
             the exception of EPO)

          4. ECOG performance status ≤ 3

          5. Absence of severe uncontrolled infection

          6. No cardiac contraindications for the use of anthracyclines : decompensated or
             uncontrolled heart failure, recent myocardial infarction, current signs of cardiac
             impairment, uncontrolled arrhythmias, LVEF (left ventricular ejection fraction) < 50%

          7. Total bilirubin ≤ 2 x upper limit of normal (UNL), ASAT(SGOT) and ALAT (SGPT) ≤ 2.5 X
             UNL, creatinine < 150 µmol/l, unless AML-related out of range values

          8. Genetic mutation testing of the FLT3 (FLT3-ITD ou FLT3-TKD) gene, performed in local
             or central laboratory

          9. Use of appropriate methods of contraception:

               -  for patients treated with Midostaurin:

                    -  women of childbearing potential should use appropriate methods of
                       contaception throughout treatment, and for 5 months post cessation of
                       treatment

                    -  men will need to use condoms during intercourse throughout treatment, and
                       for 5 months post cessation of treatment with Midostaurin

         10. Patients who are covered by or beneficiaries of a social security system (Social
             Security or Universal Medical Coverage)

         11. Patients who have read and understood the information sheet and signed the informed
             consent form

        Exclusion criteria (at diagnosis) :

        1.Patients with acute promyelocytic leukemia (APL), as confirmed either by t(15;17) or by
        the presence of PML-RARA fusion transcripts 2.Patients with core binding factor (CBF) AML,
        as confirmed either by t(8;21), t(16,16) or inv(16), or by fusion transcripts resulting
        from these cytogenetic abnormalities (RUNX1-RUNX1T1, CBFB-MYH11).

        3.Patients with secondary AML arising from myeloproliferative disorders previously known
        according to the 2008 WHO classification 4.Patients with Ph1+ AML or previous Ph1+ disorder
        (chronic myelogenous leukemia) 5.Severe psychiatric or organic disorder, supposed to be
        independent from AML, that would contraindicate treatment, including allogeneic HSCT 6.No
        psychological, familial, social, or geographic reason that would compromise clinical follow
        up 7.History of uncontrolled cancer for the last 2 years, with the exception of basal cell
        carcinoma or carcinoma in situ of the cervix 8.Uncontrolled severe infection 9.Patients
        with positive serology for HIV-1 and -2, or HTLV -1 and -2, or active hepatitis virus B or
        C infection 10.Pregnant or lactating women 11.Legal incapacity (patients under tutorship,
        curatorship or judicial protection)

        ------------------------------------------

        For randomization R4-VOS (post-induction/salvage) :

        Inclusion criteria

          1. Patients enrolled in the BIG-1 trial at diagnosis

          2. Patient presenting with AML in first CR or CRp/CRi after induction or one cycle of
             salvage therapy (confirmed in the 15 days preceding R4-VOS)

          3. Favorable or intermediate risk AML patients, as stratified with BIG-1 prognostic
             classification

          4. Patients randomized to R2-IDAC arm (intermediate dose cytarabine)

          5. ECOG performance status ≤ 2

          6. Left ventricular ejection fraction (LVEF) at least 40% by multiple gated acquisition
             (MUGA) scan or echocardiogram (ECHO)

          7. Local clinical laboratory values as follows:

             o Serum creatinine ≤ 2.0 mg/dL

             o Total bilirubin ≤ 1.5 X the upper limit of normal (ULN)

               -  Aspartate aminotransferase (AST) ≤ 2.5 X ULN

               -  Alanine aminotransferase (ALT) ≤ 2.5 X ULN

          8. Signed written informed consent for vosaroxin study (R4-VOS)

          9. Women of childbearing potential must have a negative pregnancy test within 8 days
             before randomization R4-VOS and commit to the use of effective contraception during
             the period of treatment and up to 36 days after vosaroxin has been stopped. Men must
             use effective contraception during the treatment period and up to 96 days after
             vosaroxin has been stopped.

        Exclusion criteria

        1.Patients classified in the unfavorable risk group according to the BIG-1 protocol
        classification 2.Complete remission is not attained (CR, CRp/CRi) after induction and/or
        salvage therapy 3.Positive pregnancy test 4.Severe uncontrolled infection such as sepsis,
        or multiple organ dysfunction syndrome, uncontrolled fever 5.Documented uncontrolled fungal
        infection (positive blood test and cultures) 6.History of myocardial infarction, unstable
        angina, cerebrovascular accident (CVA) or transient ischemic attack (TIA) in the 3 months
        before randomization 7.Patient under hemodialysis (HD) or peritoneal dialysis (PD)

        ------------------------------------------

        For randomization R4-DEX (post-induction/salvage) :

        Inclusion criteria

          1. Patients enrolled in the BIG-1 trial at diagnosis

          2. Patient presenting with AML in first CR or CRp/CRi after induction or one cycle of
             salvage therapy (confirmed in the 15 days preceding R4-DEX)

          3. Favorable or intermediate risk AML patients, as stratified with BIG-1 prognostic
             classification

          4. ECOG performance status ≤ 2

          5. Local clinical laboratory values as follows:

               -  Serum creatinine ≤ 150 µmol/L

               -  Total bilirubin ≤ 1.5 X the upper limit of normal (ULN)

               -  Aspartate aminotransferase (AST) ≤ 2.5 X ULN

               -  Alanine aminotransferase (ALT) ≤ 2.5 X ULN

          6. Signed written informed consent for dexamethasone study (R4-DEX)

        Exclusion criteria

        1.Severe uncontrolled infection such as sepsis, or multiple organ dysfunction syndrome,
        uncontrolled fever 2.Documented uncontrolled fungal infection (positive blood test and
        cultures 3.History of myocardial infarction, unstable angina, cerebrovascular accident
        (CVA) or transient ischemic attack (TIA) in the 3 months before randomization 4.Patient
        under hemodialysis (HD) or peritoneal dialysis (PD)

        --------------------------------------

        For randomization R4-VEN (post-induction/salvage) :

        Inclusion criteria

          1. Age 18 - 60 years at inclusion in BIG-1 protocol

          2. diagnosis of AML according to WHO classification de novo or secondary to
             myelodysplastic syndrome (myelodysplastic syndrome must not have been treated except
             by ESA, Lenalidomide or non-chemotherapy) or therapy-related AML

          3. Patients included in the BIG-1 protocol

          4. Patients in first CR or CRp/CRi following 1 or 2 courses of induction chemotherapy
             according to BIG-1 protocol and who are planned to receive consolidation.

          5. Patients stratified within the favorable and intermediate risk groups as defined by
             BIG-1 protocol

          6. ECOG performance status ≤ 2

          7. Left ventricular ejection fraction (LVEF) at least 40% by multiple gated acquisition
             (MUGA) scan or echocardiogram (ECHO)

          8. Creatinine clearance ≥ 30 ml/min (calculated by the usual method of each institution),
             total bilirubin ≤ 1.5 times the ULN; ASAT and ALAT ≤ times the upper limit of normal
             (ULN)

          9. Absence of uncontrolled infection

         10. Women of childbearing potential must agree to use effective contraception without
             interruption throughout the study and for a further 3 months after the end of
             treatment

         11. Written signed informed consent

        Exclusion criteria

        1.AML stratified in the unfavorable BIG-1 risk-group. 2.Diagnosis of Acute Promyelocytic
        Leukemia or CBF AML (ie. AML with t(8;21), t(16,16) or inv(16), or their molecular
        equivalents RUNX1-RUNX1T1 and CBFB-MYH11) 3.AML secondary to prior myeloproliferative
        disorder according to WHO classification (2008) and Philadelphia chromosome-positive AML
        (Ph1+) 4.Absence of CR/CRp/CRi after a maximum of two chemotherapy cycles 5.Severe medical
        or mental condition precluding the administration of protocol treatments 6.Prior history of
        cancer unless controlled for at least 2 years and except for basocellular cutaneous cancers
        and in situ cervix cancers 7.Positive pregnancy test 8.Breast feeding 9.Uncontrolled
        infection such as sepsis, or multiple organ dysfunction syndrome, uncontrolled fever
        10.Documented uncontrolled fungal infection (positive blood test and cultures) 11.Prior
        venetoclax exposure 12.Known HBV with detectable viral load 13.Known HIV positive patients
        14.Known hypersensitivity to any of the study medication 15.History of myocardial
        infarction, unstable angina, cerebrovascular accident (CVA) or transient ischemic attack
        (TIA) in the 3 months before randomization 16.Patient under hemodialysis (HD) or peritoneal
        dialysis (PD) 17.Concomitant treatment with cytochrome CYP3A4 inhibitor which cannot be
        stopped during venetoclax administration ONLY FOR PHASE 1 18.During the phase 2, for
        patients randomized in the IDAC + Venetoclax arm, if concomitant treatment with cytochrome
        CYP3A4 inhibitor cannot be stopped, a dose reduction of 70% of venetoclax must be apply

        --------------------------------------

        For randomization R3 (before AlloHSCT):

        Inclusion criteria

          1. Patients enrolled in the BIG-1 trial at diagnosis

          2. Patient presenting with AML in first CR or CRp/CRi treated in the BIG-1 trial and
             classified in the intermediate risk group, namely:

               -  either initially favorable but poor molecular responders for NPM1 MRD: NPM1
                  mutation, without FLT3-ITD mutation or with an FLT3-ITD ratio < 0.50 and MRD2
                  positive blood (decrease of less than 4 log from baseline at diagnosis)).

               -  Or initially favorable but requiring two cycles of chemotherapy (a salvage
                  therapy) to obtain the first CR/CRp/CRi

               -  Or other immediate intermediaries

          3. No metastatic or progressive cancer, with the exception of basal cell skin carcinoma
             and cervical carcinoma in situ

          4. Patients with general condition preserved (ECOG ≤ 3) and with no uncontrolled severe
             infection

          5. Women of childbearing age must make use of effective contraception

          6. Patients who are covered by or beneficiaries of a social security system (Social
             Security or Universal Medical Coverage).

          7. Patients who have read and understood the information sheet and signed the informed
             consent form

        Exclusion criteria

          1. Complete remission is not obtained (CR, CRp/CRi) after induction and/or salvage
             therapy

          2. Patient presenting with AML in first CR or CRp/CRi treated in the BIG-1 trial and
             classified either in the favorable risk group or the unfavorable risk group

          3. Patients with a severe organ or psychiatric pathology, presumed to be independent of
             AML and contraindicating the allograft

          4. Patients who, for family, social or geographic reasons, do not wish to be regularly
             monitored via consultation

          5. Uncontrolled severe infection at the time of inclusion

          6. Serology positive for HIV 1 or 2 or HTLV 1 or 2, or active HBV or HCV viral infection

          7. Pregnant women (beta-HCG positive) or currently breastfeeding

          8. Adult patient who is incapacitated, under wardship, legal guardianship, or under the
             protection of the courts

          9. Patients under State Medical Assistance (AME)
      
Maximum Eligible Age:61 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall survival
Time Frame:3 years
Safety Issue:
Description:For randomizations R1 (idarubicine vs daunorubicine) and R2 (HDAC vs IDAC)

Details

Phase:Phase 2/Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University Hospital, Angers

Last Updated

October 20, 2020