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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

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ClinicalTrials.gov Identifier: NCT02665143
Recruitment Status : Recruiting
First Posted : January 27, 2016
Last Update Posted : March 29, 2018
Sponsor:
Collaborator:
Vanderbilt University
Information provided by (Responsible Party):
Yale University

Brief 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.

Condition or disease Intervention/treatment Phase
Relapsed/Refractory Acute Myeloid Leukemia Drug: nintedanib and AML induction Drug: AML induction (placebo) Phase 1 Phase 2

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
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
Study Start Date : June 2016
Estimated Primary Completion Date : July 2018
Estimated Study Completion Date : December 2018


Arm Intervention/treatment
Experimental: Nintedanib and AML induction
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
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).
Other Name: Phase I
Active Comparator: Placebo and AML induction
The 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.
Drug: AML induction (placebo)
The 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.
Other Name: Phase II



Primary Outcome Measures :
  1. Incidence of Treatment-Emergent Adverse Events (Phase 1) [ Time Frame: 60 days ]
    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.

  2. Complete Remission Rate (Phase 2) [ Time Frame: Up to 2 years ]

    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.



Secondary Outcome Measures :
  1. Incidence of Hematological Improvement (Phase 2) [ Time Frame: Up to 2 years ]

    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.




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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02665143


Contacts
Contact: Tara McPartland, MSW, MPH 203-737-7173 tara.mcpartland@yale.edu
Contact: Julie Holub, CCRP 203-737-8358 julie.holub@yale.edu

Locations
United States, Connecticut
Yale University Recruiting
New Haven, Connecticut, United States, 06520
Contact: Rebecca Lilian    203-737-8358    rebecca.lilian@yale.edu   
United States, Tennessee
Vanderbilt Ingram Cancer Center Recruiting
Nashville, Tennessee, United States, 37232
Contact: Channing V Dudley, RN, MSN    615-875-5503    channing.v.dudley@vanderbilt.edu   
Principal Investigator: Stephen Strickland, MD         
Sponsors and Collaborators
Yale University
Vanderbilt University
Investigators
Principal Investigator: Thomas Prebet, MD,PhD Internal medicine Department (Hematology), Yale Comprehensive Cancer Center, Yale University

Responsible Party: Yale University
ClinicalTrials.gov Identifier: NCT02665143     History of Changes
Other Study ID Numbers: 1507016193
First Posted: January 27, 2016    Key Record Dates
Last Update Posted: March 29, 2018
Last Verified: March 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Yale University:
acute myeloid leukemia

Additional relevant MeSH terms:
Leukemia, Myeloid, Acute
Leukemia
Leukemia, Myeloid
Neoplasms by Histologic Type
Neoplasms
Cytarabine
Nintedanib
Idarubicin
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors