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

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ClinicalTrials.gov Identifier: NCT02399917
Recruitment Status : Completed
First Posted : March 26, 2015
Last Update Posted : November 30, 2018
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Acute Biphenotypic Leukemia Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome Recurrent Acute Myeloid Leukemia Refractory Acute Myeloid Leukemia Drug: Azacitidine Other: Laboratory Biomarker Analysis Biological: Lirilumab Phase 2

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.

TERTIARY OBJECTIVES:

I. To study immunological and molecular changes in the peripheral blood and bone marrow in response to lirilumab and 5-azacytidine therapy.

II. To determine induction of hypomethylation and deoxyribonucleic acid (DNA) damage during therapy with this combination and its correlation with response.

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.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 37 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : April 20, 2015
Actual Primary Completion Date : July 12, 2018
Actual Study Completion Date : July 12, 2018


Arm Intervention/treatment
Experimental: Treatment (azacitidine, 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.
Drug: Azacitidine
Given SC or IV
Other Names:
  • 5 AZC
  • 5-AC
  • 5-Azacytidine
  • 5-AZC
  • Azacytidine
  • Azacytidine, 5-
  • Ladakamycin
  • Mylosar
  • U-18496
  • Vidaza

Other: Laboratory Biomarker Analysis
Correlative studies

Biological: Lirilumab
Given IV
Other Names:
  • BMS-986015
  • IPH2102




Primary Outcome Measures :
  1. Maximum tolerated dose of azacitidine, defined as the dose at which =< 1/6 patients experience dose limiting toxicity (Part A, Lead-In Phase) [ Time Frame: Up to 28 days ]
  2. Objective response rate (ORR), defined as complete remission (CR) + CR with incomplete platelet recovery + CR with incomplete count recovery + partial response + marrow clearance of blasts + hematological improvement (Part B, Phase II) [ Time Frame: Up to 3 months ]
    ORR will be monitored using the Bayesian approach of Thall, Simon, Estey and the extension by Thall and Sung. The target ORR with the experimental treatment is 30%. This regimen of the combination treatment will be considered worthy of further investigation if it elicits an increase in ORR to 30% with acceptable toxicity.


Secondary Outcome Measures :
  1. Toxicity rate [ Time Frame: Up to 30 days after completion of study treatment ]
    Toxicity will be monitored simultaneously using the Bayesian approach of Thall, Simon, Estey and the extension by Thall and Sung. A > 30% therapy related grade 3/4 toxicity rate is considered unacceptable.



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

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)

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): NCT02399917


Locations
United States, Texas
M D Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
National Cancer Institute (NCI)
Investigators
Principal Investigator: Naval Daver M.D. Anderson Cancer Center

Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT02399917     History of Changes
Other Study ID Numbers: 2014-0862
NCI-2015-00678 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2014-0862 ( Other Identifier: M D Anderson Cancer Center )
P30CA016672 ( U.S. NIH Grant/Contract )
First Posted: March 26, 2015    Key Record Dates
Last Update Posted: November 30, 2018
Last Verified: November 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Preleukemia
Leukemia, Biphenotypic, Acute
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Leukemia, Lymphoid
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Azacitidine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors