A Randomized Trial of a Combination of Nintedanib/Placebo in Combination With Induction Chemotherapy for Patients With Refractory or First Relapse Acute Myeloid Leukemia
Condition: Relapsed/Refractory Acute Myeloid Leukemia
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
Intervention: Nintedanib and AML induction
Intervention description: The AML induction regimen combines Idarubicin 12mg/m2/d day 1 to 3 and Cytarabine 0.667g/m2/d CIV day 1 to 3. In the phase I part, all patients will receive the combination with Nintedanib 200mg bid begun at day 8 and continued until end of cycle. If a significant incidence of dose limiting toxicities is demonstrated, Nintedanib will be given at a lower dose level (150mg bid).
Intervention MeSH terms: Nintedanib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 25.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: acute myeloid leukemia

Summary:

      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.
    

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) non-hematological
             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.