An Open-label Phase II Study of Lirilumab (BMS-986015) in Combination with 5-azacytidine (vidaza) for the Treatment of Patients with Refractory/Relapsed Acute Myeloid Leukemia
The goal of this clinical research study is to find the highest tolerated dose of the combination of lirilumab and 5-azacytidine that can be given to patients with AML or high-risk MDS. Researchers also want to learn if the drug combination can help to control the disease. The safety of the drug combination will also be studied.
Disease Group: Leukemia
Treatment Agent: 5-Azacytidine
Treatment Location: Only at MDACC
Sponsor: BMS pharmaceuticals
Primary Objectives Part a. Lead-in phase: 1. To determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of lirilumab in combination with 5-azacytidine in patients with refractory/ relapsed acute myeloid leukemia (AML). Part b. Phase II: 1. To determine the overall response rate (ORR) of lirilumab in combination with 5-azacytidine in patients with refractory/ relapsed AML. Secondary Objectives: 1. To determine the duration of response, disease-free survival (DFS), and overall survival (OS) of patients with refractory/ relapsed AML treated with this combination. 2. To determine the safety of lirilumab in combination with 5-azacytidine in patients with refractory/ relapsed AML. Exploratory Objectives: 1. To study immunological and molecular changes in the peripheral blood and bone marrow in response to lirilumab and 5-azacytidine therapy. 2. To determine induction of hypomethylation and DNA damage during therapy with this combination and its correlation with response.
IRB Review and Approval Date: 04/20/2015
Recruitment Status: Open
Projected Accrual: N/A
1) Patients with AML or biphenotypic or bilineage leukemia who have
failed at least one prior therapy. Patients with AML should have failed
prior therapy or have relapsed after prior therapy.
2) Patients should not be eligible or able to receive approved therapy of confirmed clinical benefit in this patient population.
3) Patients with MDS or CMML who received therapy for the MDS or CMML and progress to AML are eligible at the time of diagnosis of AML regardless any prior therapy for AML. The WHO classification will be used for AML.
4) Prior therapy with hydroxyurea, chemotherapy, biological or targeted therapy (e.g. FLT3 inhibitors, other kinase inhibitors), or hematopoietic growth factors is allowed
5) Age >/=18 years
6) Eastern Cooperative Oncology Group (ECOG) Performance Status </= 2
7) Adequate organ function: total bilirubin </= 2 times upper limit of normal (x ULN) (</= 3 x ULN if considered to be due to leukemic involvement or Gilbert’s syndrome); aspartate aminotransferase or alanine aminotransferase </= 2.5 x ULN (</= 5.0 x ULN if considered to be due to leukemic involvement); serum creatinine </= 2 x ULN or GFR>/=50
8) Patients must provide written informed consent
9) 9) In the absence of rapidly progressing disease, the interval from prior treatment to time of initiation of 5-azacytidine and lirilumab will be at least 2 weeks OR at least 5 half-lives for cytotoxic/noncytotoxic agents. Use of one dose of cytarabine (up to 2 g/m2) is allowed prior to the start of study therapy or hydroxyurea for patients with rapidly proliferative disease is allowed before the start of study therapy and while the patient is on active study treatment, as needed, for clinical benefit and after discussion with the PI. Concurrent therapy for CNS prophylaxis or continuation of therapy for controlled CNS disease is permitted
10) Females must be surgically or biologically sterile or postmenopausal (amenorrheic for at least 12 months) or if of childbearing potential, must have a negative serum or urine pregnancy test within 72 hours before the start of the treatment
11) Women of childbearing potential must agree to use an adequate method of contraception during the study and until 30 days after the last treatment. Males must be surgically or biologically sterile or agree to use an adequate method of contraception during the study until 30 days after the last treatment. The details of adequate method of contraception are shown in the protocol section 4.1.10;Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.
1) Patients with known allergy or hypersensitivity to lirilumab,
5-azacytidine, or any of their components. Patients who have previously
been treated with lirilumab in combination with 5-azacytidine will be excluded.
2) Patients with a known history of severe interstitial lung disease or severe pneumonitis or active pneumonitis that is uncontrolled in the opinion of the treating physician.
3) Patients with a known history of any of the following autoimmune diseases are excluded: (a) patients with a history of inflammatory bowel disease (including Crohn’s disease and ulcerative colitis) (b) patients with a history of rheumatoid arthritis, systemic progressive sclerosis [scleroderma], Systemic Lupus Erythematosus, autoimmune vasculitis [e.g., Wegener’s Granulomatosis]).
4) Patients with organ allografts (such as renal transplant) are excluded
5) Patients with allogeneic stem cell transplantation within the last 6 months or patients with active GVHD will be excluded.
6) Ongoing immunosuppressive therapy, including cyclosporine and tacrolimus. Patients who are on high dose steroid. Note: Subjects may be using systemic corticosteroids (daily doses </= 10 mg of prednisone or equivalent) or topical or inhaled corticosteroids.
7) Patients with symptomatic CNS leukemia or patients with poorly controlled CNS leukemia.
8) Active and uncontrolled disease/(active uncontrolled infection, uncontrolled hypertension despite adequate medical therapy, active and uncontrolled congestive heart failure NYHA class III/IV, clinically significant and uncontrolled arrhythmia) as judged by the treating physician.
9) Patients with active and uncontrolled Human Immunodeficiency Virus (HIV) infection will be excluded. However, patients with well controlled HIV infection will be considered.
10) Patients known to be positive for hepatitis B by surface antigen expression. Known to have active hepatitis C infection (positive by polymerase chain reaction or on antiviral therapy for hepatitis C within the last 6 months)
11) Any other medical, psychological, or social condition that may interfere with study participation or compliance, or compromise patient safety in the opinion of the investigator
12) Patients unwilling or unable to comply with the protocol.
13) Pregnant or breastfeeding
14) Acute promyelocytic leukemia (APL).
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