Lirilumab and Azacitidine in Treating Patients With Refractory or Relapsed Acute Myeloid Leukemia

Phase 2

Terminated

Conditions: Recurrent Acute Myeloid Leukemia
Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome
Refractory Acute Myeloid Leukemia
Acute Biphenotypic Leukemia

Interventions: Drug: Azacitidine
Biological: Lirilumab

Registration Number: NCT02399917

Lead Sponsor: M.D. Anderson Cancer Center

Brief Summary: This phase II trial studies the side effects lirilumab and azacitidine and to see how well they work in treating patients with acute myeloid leukemia that has not responded to treatment or has returned after a period of improvement. Monoclonal antibodies, such as lirilumab, may interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving lirilumab with azacitidine may be an effective treatment for relapsed or refractory acute myeloid leukemia.

Detailed Description: PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of lirilumab in combination with 5-azacytidine (azacitidine) in patients with refractory/relapsed acute myeloid leukemia (AML). (Part A, Lead-In Phase) II. To determine the overall response rate (ORR) of lirilumab in combination with 5-azacytidine in patients with refractory/relapsed AML. (Part B, Phase II)

SECONDARY OBJECTIVES:

I. To determine the duration of response, disease-free survival (DFS), and overall survival (OS) of patients with refractory/relapsed AML treated with this combination.

II. To determine the safety of lirilumab in combination with 5-azacytidine in patients with refractory/relapsed AML.

OUTLINE:

Patients receive azacitidine subcutaneously (SC) or intravenously (IV) over 1 hour as determined by the treating physician on days 1-7 and lirilumab IV over 60 minutes on day 8. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and up to 90 days.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 36

Inclusion Criteria

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
Patients should not be eligible or able to receive approved therapy of confirmed clinical benefit in this patient population
Patients with myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (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 World Health Organization (WHO) classification will be used for AML
Prior therapy with hydroxyurea, chemotherapy, biological or targeted therapy (e.g. FLT3 inhibitors, other kinase inhibitors), or hematopoietic growth factors is allowed
Eastern Cooperative Oncology Group (ECOG) performance status =< 2
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 glomerular filtration rate (GFR) >= 50
Patients must provide written informed consent
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/m^2) 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 principal investigator (PI); concurrent therapy for central nervous system (CNS) prophylaxis or continuation of therapy for controlled CNS disease is permitted
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
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; 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

Exclusion Criteria

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
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
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])
Patients with organ allografts (such as renal transplant) are excluded
Patients with allogeneic stem cell transplantation within the last 6 months or patients with active graft-versus-host disease (GVHD) will be excluded
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
Patients with symptomatic CNS leukemia or patients with poorly controlled CNS leukemia
Active and uncontrolled disease/(active uncontrolled infection, uncontrolled hypertension despite adequate medical therapy, active and uncontrolled congestive heart failure New York Heart Association [NYHA] class III/IV, clinically significant and uncontrolled arrhythmia) as judged by the treating physician
Patients with active and uncontrolled human immunodeficiency virus (HIV) infection will be excluded; however, patients with well controlled HIV infection will be considered
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)
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
Patients unwilling or unable to comply with the protocol
Pregnant or breastfeeding
Acute promyelocytic leukemia (APL)

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Phase 1b Lead-in Cohort 2	Lirilumab	Patients receive azacitidine SC or IV over 1 hour as determined by the treating physician on days 1-7 and lirilumab IV over 60 minutes on day 8. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. 5-Azacitidine 75mg/m\^2 Lirilumab 3.0 mg/kg
Phase 1b Lead-in Cohort 1	Lirilumab	Patients receive azacitidine SC or IV over 1 hour as determined by the treating physician on days 1-7 and lirilumab IV over 60 minutes on day 8. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. 5-Azacitidine 75mg/m\^2 Lirilumab 1.0 mg/kg
Phase 2	Lirilumab	Patients receive azacitidine SC or IV over 1 hour as determined by the treating physician on days 1-7 and lirilumab IV over 60 minutes on day 8. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. 5-Azacitidine 75mg/m\^2 Lirilumab 3.0 mg/kg
Phase 1b Lead-in Cohort 1	Azacitidine	Patients receive azacitidine SC or IV over 1 hour as determined by the treating physician on days 1-7 and lirilumab IV over 60 minutes on day 8. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. 5-Azacitidine 75mg/m\^2 Lirilumab 1.0 mg/kg
Phase 1b Lead-in Cohort 2	Azacitidine	Patients receive azacitidine SC or IV over 1 hour as determined by the treating physician on days 1-7 and lirilumab IV over 60 minutes on day 8. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. 5-Azacitidine 75mg/m\^2 Lirilumab 3.0 mg/kg
Phase 2	Azacitidine	Patients receive azacitidine SC or IV over 1 hour as determined by the treating physician on days 1-7 and lirilumab IV over 60 minutes on day 8. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. 5-Azacitidine 75mg/m\^2 Lirilumab 3.0 mg/kg

Primary Outcome Measures

Name	Time	Method
Maximum Tolerated Dose of Iirilumab in Combination With 5-azacitidine	Up to 28 days	To identify the dose at which \<2/6 participants experience Dose Limiting Toxicities (DLT). The dose level at which 0-1/6 participants experience a DLT in the first 28 days of treatment will be the maximum tolerated dose (MTD) and would be used to treat an additional 34 participants in the phase II potion of the study. (Part A, Lead-In Phase)
Participants With an Objective Response	Up to 3 months	Objective Response Rate (ORR) will be monitored using the Bayesian approach of Thall, Simon, Estey and the extension by Thall and Sung. Overall response rate (ORR), defined as complete remission (CR) + CR with incomplete platelet recovery (CRp) + CR with incomplete count recovery (CRi) + partial response (PR) + marrow clearance of blasts + hematological improvement within 3 months of treatment initiation among adult patients with refractory/relapsed Acute Myelogenous Leukemia (AML) (Phase II)

Secondary Outcome Measures

Name	Time	Method
Duration of Response	Up to 2.5 years	The date of Objective Response to the date of loss of response or last follow-up.
Overall Survival	Up to 2 years	Overall Survival (OS) is defined: Time of presentation to date of death or censored at last follow-up date.
Disease Free Survival	Up to 2.5 years	Disease Free Survival (DFS) is defined: Time from date of treatment start until the date of first objective documentation of disease-relapse