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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Relapsed/Refractory Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Nintedanib and AML induction


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nintedanib and AML induction<br>The 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 . | Drug: Nintedanib and AML induction<br>* 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).<br>* Other names: Phase II Open Label;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Count of Patients With Treatment-Emergent Adverse Events (Phase 1) | 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. TEAE's were considered adverse events that occurred within 60 days of treatment initiation. The title of this outcome measure was adjusted when results were entered. | 60 days | 
| Complete Remission Rate (Phase 2) | In Phase 2, the primary endpoint of complete remission rate will be based on IWG 2003 AML response criteria. This construct is an overall response composite and it will be assessed using the following metrics: Morphologic complete remission (CR): ANC ≥ 1,000/mcl, platelet count ≥ 100,000/mcl, < 5% bone marrow blasts, no Auer rods, no evidence of extramedullary disease. (No requirements for marrow cellularity, hemoglobin concentration). Morphologic complete remission with incomplete blood count recovery (CRi): Same as CR but ANC may be < 1,000/mcl but >500 mcl and/or platelet count < 100,000/mcl but >20,000/mcl Partial remission (PR): ANC ≥ 1,000/mcl, platelet count > 100,000/mcl, and at least a 50% decrease in the percentage of marrow aspirate blasts to 5-25%, or marrow blasts < 5% with persistent Auer rods. Marrow Leukemia Free State: < 5% bone marrow blasts, no Auer rods, no extra medullary disease. No requirement on cytopenias. | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Hematological Improvement (Phase 2) | 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. | Up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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acute myeloid leukemia