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A Randomized Trial of a Combination of Nintedanib/Placebo in Combination With Induction Chemotherapy for Patients With Refractory or First Relapse Acute Myeloid Leukemia

NCT02665143

Description:

The purpose of this study is to determine if a combination of nintedanib+ induction chemotherapy can be an effective strategy for patients where outcome of relapse/refractory acute myeloid leukemia (AML) is poor.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Randomized Trial of a Combination of Nintedanib/Placebo in Combination With Induction Chemotherapy for Patients With Refractory or First Relapse Acute Myeloid Leukemia
  • Official Title: A Phase I-II Randomized Trial of a Combination of Nintedanib/Placebo in Combination With Induction Chemotherapy for Patients With Refractory or First Relapse Acute Myeloid Leukemia

Clinical Trial IDs

  • ORG STUDY ID: 1507016193
  • NCT ID: NCT02665143

Conditions

  • Relapsed/Refractory Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
nintedanib and AML inductionPhase INintedanib and AML induction
AML induction (placebo)Phase IIPlacebo and AML induction

Purpose

The purpose of this study is to determine if a combination of nintedanib+ induction chemotherapy can be an effective strategy for patients where outcome of relapse/refractory acute myeloid leukemia (AML) is poor.

Detailed Description

      This study will conducted as a Phase 1/Phase 2 trial.

      The primary objective of Phase 1 is to determine the safety and tolerability of a combination
      of Nintedanib + induction chemotherapy in patients with acute myeloid leukemia.

      The primary objective of Phase 2 is to determine the efficacy (rate of CR/CRp/CRi) of
      Nintedanib+ induction vs Placebo+ induction.

      The secondary objectives of this study include: determining the overall response rate
      according to IWG AML 2003 criteria, the toxicity profile and safety of the combination, the
      percentage of patients bridging to transplantation, the overall survival, leukemia free
      survival including analysis with censoring at HSCT and rates of haematological improvement
      according to IWG MDS 2006 criteria. In addition, exploratory correlative studies will be
      conducted.
    

Trial Arms

NameTypeDescriptionInterventions
Nintedanib and AML inductionExperimentalThe AML induction regimen combines Idarubicin 12mg/m2/d day 1 to 3 and Cytarabine 0.667g/m2/d CIV day 1 to 3. Based on the phase I dose, in the randomized phase II, the combination will be compared with chemotherapy+placebo. Nintedanib or placebo will be added at day 8 and continued until end of cycle .
  • nintedanib and AML induction
Placebo and AML inductionActive ComparatorThe AML induction regimen combines Idarubicin 12mg/m2/d day 1 to 3 and Cytarabine 0.667g/m2/d CIV day 1 to 3. Nintedanib or placebo will be added at day 8 and continued until end of cycle.
  • AML induction (placebo)

Eligibility Criteria

        Inclusion Criteria:

          -  Diagnosis of AML according to WHO 2008 criteria. Therapy related AML may be included
             if off treatment for their prior malignancy for more than 2 years and in complete
             remission. AML arising after documented MPD is excluded.

          -  Patient must meet one of the following criteria: a/ patient refractory to one or two
             standard induction regimens b/ patients with a first untreated relapse within 2 years
             of documentation of complete remission. Patients relapsing after allogeneic stem cell
             transplantation are eligible if more than 6 months after transplantation and without
             signs of active GVHD.

          -  Patient may have been pre treated with intermediate to high dose cytarabine if the day
             of the last infusion was at least 90 days before the inclusion.

          -  ECOG performance status of 2 or less

          -  Patient is willing to participate to the study, has the ability to adhere to the study
             visit schedule and other protocol procedures, and has the ability to understand and
             sign an inform consent form.

          -  Women of childbearing potential must agree to use effective contraception without
             interruption throughout the study and for 3 months after the end of treatment;

          -  Men must agree to not conceive during the treatment and to use effective contraception
             during the treatment period (including periods of dose reduction or temporary
             suspension) and for 3 months after the end of treatment if their partner is of
             childbearing potential.

        Exclusion Criteria:

          -  Patient with documented acute promyelocytic leukemia and/or PML-RAR transcript.

          -  Patient relapsing more than 2 years after initial remission.

          -  Use of any active treatment for relapse including but not restricted to chemotherapy,
             targeted agents, hypomethylating agents or investigational drugs. Use of hydroxyurea
             up to 6g per day for cytoreduction is allowed for a maximum of 30 days prior
             treatment.

          -  Patients with clinical evidence of active CNS disease at enrollment

          -  LVEF below 45% or lifetime exposure to anthracyclines over 350mg/m2 of daunorubicin
             equivalent

          -  Liver function tests: ASAT ALAT above 2.5 ULN, total bilirubin above 2.5 ULN in the
             absence of Hemolysis or diagnosis of Gilbert's syndrome

          -  Serum creatinine above 2.0mg/dl

          -  Any sign of active uncontrolled disease including but not restricted to cardiac
             disease, infections, hepatitis. Any severe chronic disease potentially interfering
             with the protocol including HIV infection, active hepatitis B or C. It includes major
             injuries and/or surgery within the past 4 weeks prior to start of study treatment with
             incomplete wound healing and/or planned surgery during the on-treatment study period.

          -  Documented platelet refractoriness

          -  Patient has a history of GI surgery, procedures or conditions that might interfere
             with the absorption or swallowing of the study drugs .

          -  Women who are or pregnant, or who are currently breastfeeding

          -  Prior treatment with nintedanib or any other VEGFR inhibitor

          -  Known hypersensitivity to nintedanib, any other trial drug, or their excipients

          -  Persistence of any clinically relevant (CTCAE grade 2 or above) toxicities from
             previous AML therapy

          -  Active alcohol or drug abuse

          -  Any other condition that, according to the investigator, may forbid the administration
             of the idarubicin+cytarabine regimen

          -  Therapeutic anticoagulation with INR modifying drug of or use of antiplatelet therapy
             (with the exception of low dose aspirin<325mg/d)

          -  Any other malignancies requiring an active treatment within the past year other than
             basal cell skin cancer or carcinoma in situ of the cervix. Patients actively treated
             with hormonotherapy for prostate cancer or breast cancer are eligible.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of Treatment-Emergent Adverse Events (Phase 1)
Time Frame:60 days
Safety Issue:
Description:In the Phase 1 portion of the study, safety will be assessed after the inclusion of the first 6 patients, to analyze tolerance and adverse events occurring during this trial and will decide on any action to be taken. Safety will be evaluated according to NCI CTCAE V4 criteria.

Secondary Outcome Measures

Measure:Incidence of Hematological Improvement (Phase 2)
Time Frame:Up to 2 years
Safety Issue:
Description:Evaluation of hematological improvement will be assessed based on IWG MDS 2006 criteria. Due to differing pretreatment conditions of participants, response to treatment in this construct will be assessed in the following manner: Erythroid response (pretreatment <11 g/dL) : Hgb increase at least by 1.5 g/dL. Relevant reduction of units of RBC transfusions by an absolute number of at least 4 RBC transfusions/8 wk compared with the pretreatment transfusion number in the previous 8 wk. Only RBC transfusions given for a Hgb of below or equal to 9.0 g/dL pretreatment will count in the RBC transfusion response evaluation. Platelet response (pretreatment 100x109/L): Absolute increase of at least 30x109/L for patients starting with more than 20x109/L platelets. Increase from less than 20x109/L to more than 20x109/L and by at least 100%. Neutrophil response (pretreatment, <1.0x109/L) At least 100% increase and an absolute increase of at least 0.5x109/L.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Yale University

Trial Keywords

  • acute myeloid leukemia

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