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

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.

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.

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.