Nintedanib, Idarubicin Hydrochloride, and Cytarabine in Treating Patients with Relapsed or Refractory Acute Myeloid Leukemia

Inclusion Criteria

• Patient aged 18y or older
• Diagnosis of AML according to World Health Organization (WHO) 2008 criteria; therapy related AML may be included if in complete response and off treatment for their prior malignancy for more than 2 years; AML arising after documented myeloproliferative disease (MPD) are excluded
• Patient must meet one of the following criteria: * Patient refractory to one or two standard induction regimen * Patients with a first untreated relapse within 2 years of documentation of clinical remission; patients relapsing after allogeneic stem cell transplantation are eligible if more than 6 months after transplantation and without sign of active graft versus host disease (GVHD)
• Patient may have been pretreated with intermediate to high dose cytarabine (more than 1000mg/m2/d over 5d) if the day of the last infusion was at least 90 days before inclusion in the study
• Eastern Cooperative Oncology Group (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 signs an informed consent form
• 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
• 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 a further 3 months after the end of treatment if their partner is of childbearing potential

Exclusion Criteria

• Patient with documented acute promyelocytic leukemia and/or promyelocytic leukemia (PML)- retinoic acid receptor (RAR) transcript
• Patient relapsing more than 2 years after initial remission
• Use of any active treatment for relapse/refractory AML including but not restricted to chemotherapy, targeted agents, hypomethylating agents or investigational drugs; use of hydroxyurea up to 6 g per day for cytoreduction is allowed for a maximum of 30 days prior treatment
• Patients with clinical evidences of active central nervous system (CNS) disease at inclusion
• Left ventricular ejection fraction (LVEF) below 45% or lifetime exposure to anthracyclines over 350mg/m2 of daunorubicin equivalent
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT) above 2.5 upper limit of normal (ULN)
• Total bilirubin above 2.5 ULN in the absence of hemolysis or diagnosis of Gilbert’s syndrome
• Serum creatinine above 2.0 mg/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 human immunodeficiency virus (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 gastrointestinal (GI) surgical procedures, non-surgical procedures or conditions that might interfere with the absorption or swallowing of the study drugs
• Women who are pregnant, or who are currently breastfeeding
• Prior treatment with nintedanib or any other vascular endothelial growth factor receptor (VEGFR) inhibitor, with the exception of treatment of prior malignancies with a VEGFR inhibitor
• Known hypersensitivity to nintedanib, any other trial drug, or their excipients
• Persistence of any clinically relevant (Common Terminology Criteria for Adverse Events [CTCAE] grade 2 or above) non-haematological 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 international normalized ratio (INR) modifying drug of or use of antiplatelet therapy (with the exception of low dose aspirin < 325 mg/d)
• Any malignancies requiring 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