Nivolumab and Azacitidine With or Without Ipilimumab in Treating Patients With Refractory/Relapsed or Newly Diagnosed Acute Myeloid Leukemia

An Open-Label Phase II Study of Nivolumab (BMS-936558) in Combination With 5-Azacytidine (Vidaza) or Nivolumab With Ipilimumab in Combination With 5-Azacytidine for the Treatment of Patients With Refractory/ Relapsed Acute Myeloid Leukemia and Newly Diagnosed Older AML (> 65 Years) Patients

This will be a phase II, open-label, non-randomized study with a safety lead-in phase. There are 3 Arms in this study each with 2 parts. If you are eligible, you will be assigned to an Arm and a part when you join the study. In each arm, you will receive a different combination of study drugs: Arm 1: nivolumab and azacitidine, Ih Arm 2: nivolumab, azacitidine, and ipilimumab, Arm 3: nivolumab, azacitidine, and venetoclax.

There are 2 parts in each arm: Part A (dose escalation) and Part B (dose expansion).

The goal of Part A of this clinical research study is to find the highest tolerable dose of the study drugs (nivolumab, azacitidine, ipilimumab, and/or venetoclax) that can be given to patients with AML. The goal of Part B of this study is to learn if the dose found in Part A can help to control AML.

Study Overview

• Status: Completed
• Conditions: Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Chronic Myelomonocytic Leukemia; Secondary Acute Myeloid Leukemia; Myelodysplastic Syndrome; Recurrent Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia; Therapy-Related Acute Myeloid Leukemia; Acute Bilineal Leukemia; Acute Biphenotypic Leukemia
• Intervention / Treatment: Drug: Azacitidine; Drug: Ipilimumab; Drug: Nivolumab; Drug: Venetoclax

Detailed Description

Arm 1 Up to 5 groups of up to 6 participants will be enrolled in Part A of the study, and up to 110 participants will be enrolled in Part B of the study. If you are enrolled in Part A of the study, the dose of nivolumab and azacitidine you receive will depend on when you joined this study. The first group of participants will receive the starting dose levels of nivolumab and azacitidine. If intolerable side effects are seen, the next group may receive a lower dose level of nivolumab and/or azacitidine. This will continue until the highest tolerable combination dose is found.

If you are enrolled in Part B, you will receive nivolumab and azacitidine at the highest dose that was tolerated in Part A.

Arm 2 Up to 4 groups of up to 6 participants will be enrolled in Part A of the study, and up to 84 participants will be enrolled in Part B of the study. If you are enrolled in Part A of the study, the dose of nivolumab, azacitidine, and ipilimumab you receive will depend on when you joined this study. The first group of participants will receive the starting dose levels of nivolumab, azacitidine and ipilimumab. If intolerable side effects are seen, the next group may receive a lower dose level of nivolumab, azacitidine and/or ipilimumab. This will continue until the highest tolerable combination dose is found. If you are enrolled in Part B, you will receive nivolumab, azacitidine, and ipilimumab at the highest dose that was tolerated in Part A.

Arm 3 About 6-18 participants will be enrolled in Part A and up to 60 participants will be enrolled in Part B. If you are enrolled in Part A of the study, the dose of nivolumab, azacitidine, and venetoclax you receive will depend on when you joined this study. The first group of participants will receive the starting dose levels of nivolumab, azacitidine and venetoclax. If intolerable side effects are seen, the next group may receive a lower dose level of nivolumab, azacitidine and/or venetoclax. This will continue until the highest tolerable combination dose is found. If you are enrolled in Part B, you will receive nivolumab, azacitidine, and venetoclax at the highest dose that was tolerated in Part A.

• Study Type: Interventional
• Enrollment (Actual): 150
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• ARM 1 SALVAGE COHORT: Patients with AML or biphenotypic or bilineage leukemia who have failed prior therapy; patients with AML should have failed prior therapy or have relapsed after prior therapy will be eligible for Arm 1;
• ARM 2 SALVAGE COHORT: Patients with AML who have failed up to one prior salvage therapy (i.e. salvage 1 or 2 status) will be eligible for Arm 2 relapse cohort; allogeneic stem cell transplant for patients in remission at the time of stem cell transplant will not be considered a salvage regimen; similarly, hydroxyurea if used alone will not be considered a salvage regimen
• ARM 1 AND 2 FRONT LINE OLDER COHORT: Patients age 65 years and above with previously untreated AML who are unfit for or decline standard induction therapy; prior therapy with hydroxyurea, biological or targeted therapy (e.g. FLT3 inhibitors, other kinase inhibitors), or hematopoietic growth factors is allowed, however prior therapy with chemotherapy agents for the disease under study is not allowed; patients may have received one dose of cytarabine (up to 2 g/m2 administered at presentation for control) of hyperleucocytosis
• 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 MDS or CMML; the World Health Organization (WHO) classification will be used for AML; prior therapy for MDS or CMML will not be considered as a prior therapy for AML, hence such patients will be considered as frontline AML and eligible for the frontline elderly cohort
• 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 nivolumab will be at least 2 weeks OR at least 5 half-lives for cytotoxic/noncytotoxic agents; the half-life for the therapy in question will be based on published pharmacokinetic literature (abstracts, manuscripts, investigator brochure's, or drug-administration manuals) and will be documented in the protocol eligibility document; since the effect of both nivolumab and 5-azacytidine may be delayed; use of one dose of cytarabine (up to 2 g/m2) or hydroxyurea for patients with rapidly proliferative disease is allowed before the start of study therapy and during the study treatment; 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 3 months after the last treatment; males must be surgically or biologically sterile or agree to use an adequate method of contraception during the study until 3 months after the last treatment; adequate methods of contraception include: total abstinence when this is in line with the preferred and usual lifestyle of the patient; periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception; female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment; in case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment; male sterilization (at least 6 months prior to screening); for female patients on the study, the vasectomized male partner should be the sole partner for that patient

• Combination of any of the two following

  • Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate < 1%), for example hormone vaginal ring or transdermal hormone contraception
  • Placement of an intrauterine device (IUD) or intrauterine system (IUS)
  • Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository; in case of use of oral contraception, women should have been stable on the same pill before taking study treatment; note: oral contraceptives are allowed but should be used in conjunction with a barrier method of contraception
• 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
• Patients with graft versus host disease (GVHD) active < grade 2 who are on a stable dose of immunosuppressive therapy (tacrolimus, cyclosporine, or other) for > 2 weeks will be included; Note: subjects may be using systemic corticosteroids or topical or inhaled corticosteroids

Exclusion Criteria:

• Patients with known allergy or hypersensitivity to nivolumab, ipilimumab, 5-azacytidine, or any of their components
• 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 who have previously been treated with nivolumab and/or ipilimumab in combination with 5-azacytidine will be excluded

• Patients with a known history of any of the following autoimmune diseases are excluded:

  • Patients with a history of inflammatory bowel disease (including Crohn's disease and ulcerative colitis)
  • 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 active GVHD > grade 2 will be excluded; patients with recent increase in the immunosuppressive medication dose within last 2 weeks to control GVHD will not be included; patients with grade 1 or lower GVHD on =< 10 mg prednisone without any additional immunosuppressive therapies (tacrolimus, prograf, etc) will be eligible
• 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 known human immunodeficiency virus seropositivity will be excluded
• 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1 A Lead-In (azacitidine, nivolumab); Patients receive azacitidine IV over 1 hour or SC on days 1-7 or days 1-4 and 7-9. Patients also receive nivolumab IV over 60 minutes on days 1 and 14 (courses 1-4) or on day 1 (course 5 and all subsequent courses). 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; Drug: Nivolumab; Given IV; Other Names: BMS-936558; MDX-1106; NIVO; ONO-4538; Opdivo
Experimental: Arm 2 A Lead-In (azacitidine, nivolumab, ipilimumab); Patients receive azacitidine and nivolumab as Arm I. Patients also receive ipilimumab IV over 90 minutes on day 1 and then every 6 or 12 weeks. Treatment continues 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; Drug: Ipilimumab; Other Names: Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody; BMS-734016; MDX-010; MDX-CTLA4; Yervoy; Drug: Nivolumab; Given IV; Other Names: BMS-936558; MDX-1106; NIVO; ONO-4538; Opdivo
Experimental: Arm 1 B (azacitidine, nivolumab); Patients receive azacitidine IV over 1 hour or SC on days 1-7 or days 1-4 and 7-9. Patients also receive nivolumab IV over 60 minutes on days 1 and 14 (courses 1-4) or on day 1 (course 5 and all subsequent courses). 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; Drug: Nivolumab; Given IV; Other Names: BMS-936558; MDX-1106; NIVO; ONO-4538; Opdivo
Experimental: Arm 3 Lead-In (azacitidine, nivolumab, Venetoclax); Patients will receive therapy with nivolumab IV infusion on Day 8 and Day 22 (+/-3 days) of each 5-azacyidine cycle for first 4 cycles or until CR (whichever occurs earlier) followed by a maintenance regimen (one dose of nivolumab on Day 8 of each cycle of 5-azacytdine). Venetoclax will be administered orally daily on Days 1-21 of the first cycle; and Days 1-14 or Days 1-21 for subsequent cycles.	Drug: Azacitidine; Given SC or IV; Other Names: 5 AZC; 5-AC; 5-Azacytidine; 5-AZC; Azacytidine; Azacytidine, 5-; Ladakamycin; Mylosar; U-18496; Vidaza; Drug: Nivolumab; Given IV; Other Names: BMS-936558; MDX-1106; NIVO; ONO-4538; Opdivo; Drug: Venetoclax; Given Orally; Other Names: ABT-199; GDC-0199
Experimental: Arm 2 B (azacitidine, nivolumab, ipilimumab); Patients receive azacitidine and nivolumab as Arm I. Patients also receive ipilimumab IV over 90 minutes on day 1 and then every 6 or 12 weeks. Treatment continues 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; Drug: Ipilimumab; Other Names: Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody; BMS-734016; MDX-010; MDX-CTLA4; Yervoy; Drug: Nivolumab; Given IV; Other Names: BMS-936558; MDX-1106; NIVO; ONO-4538; Opdivo
Experimental: Arm 3 (azacitidine, nivolumab, Venetoclax); Patients will receive therapy with nivolumab IV infusion on Day 8 and Day 22 (+/-3 days) of each 5-azacyidine cycle for first 4 cycles or until CR (whichever occurs earlier) followed by a maintenance regimen (one dose of nivolumab on Day 8 of each cycle of 5-azacytdine). Venetoclax will be administered orally daily on Days 1-21 of the first cycle; and Days 1-14 or Days 1-21 for subsequent cycles.	Drug: Azacitidine; Given SC or IV; Other Names: 5 AZC; 5-AC; 5-Azacytidine; 5-AZC; Azacytidine; Azacytidine, 5-; Ladakamycin; Mylosar; U-18496; Vidaza; Drug: Nivolumab; Given IV; Other Names: BMS-936558; MDX-1106; NIVO; ONO-4538; Opdivo; Drug: Venetoclax; Given Orally; Other Names: ABT-199; GDC-0199

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Tolerated Dose of 5-azacytidine in the Combination of Nivolumab With Dihydro-5-azacytidine	The maximum tolerated dose is defined as the highest dose level of 5-azacitidine with < 2 out of 6 patients experiencing a dose limiting toxicity during the first 28 days of treatment. The starting dose level for Azacitidine is 75 mg/m^2 and the starting dose level for Nivolumab is 3.0 mg/kg.	Up to 28 days
Participants With a Response	Responders are patients who obtain a Complete Remission (CR), Complete Remission with Incomplete blood count recovery CRi, Complete Remission with Incomplete Platelet Recovery (CRp) or Partial Remission (PR), with or without cytogenetic response, hematologic improvements (HI), and morphologic leukemia-free state. CR is counts of 0 circulating blasts, Neutrophil count of >/= 1.0 x 10^9/L, Platelet count >/= 100 x 10 ^9/L. Bone marrow </= 5% blasts, No auer rods, No extramedullary disease. CRp is patients who have achieved a CR except for incomplete platelet recovery (<100 x 10^9/L). CRi is counts of 0 circulating blasts, Neutrophil count of >/= 1.0 x 10^9/L OR Platelet count >/= 100 x 10 ^9/L. PR is All CR criteria if abnormal before treatment except >/= 50% reduction in bone marrow blast but still >5%. morphologic leukemia-free state is Bone marrow: </=5% myeloblasts. HI is Hematologic response must be described by the number of positively affected cell lines.	Up to 7 years, 6 months
Maximum Tolerated Dose of Nivolumab in the Combination of Nivolumab With Dihydro-5-azacytidine	The maximum tolerated dose is defined as the highest dose level of nivolumab with < 2 out of 6 patients experiencing a dose limiting toxicity during the first 28 days of treatment. The starting dose level for Azacitidine is 75 mg/m^2 and the starting dose level for Nivolumab is 3.0 mg/kg.	Up to 28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease-free Survival	Time from date of treatment start until the date of first objective documentation of disease-relapse.	Up to 7 years, 6 months
Overall Survival	Time from date of treatment start until date of death due to any cause or last Follow-up.	Up to 7 years, 6 months
Progression-free Survival	Time from date of treatment start until the date of progression or death from leukemia.	Up to 7 years, 6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immunological changes in peripheral blood and bone marrow	Determined using paired t-tests. Descriptive statistics including plots, mean, median and standard deviations will be used to summarize data. For continuous outcomes, t-tests and analysis of variance will be used to compare outcome measures across patient characteristics. Dunnett's and Tukey's test that properly adjust for multiplicity in multiple test will be implemented. Pair-wise comparison's will be performed using pre- and post-therapy samples from each patient. The chi-square test or Fisher's exact test will be used to test the association between categorical variables such as disease state and performance status. Both univariate and multivariate logistic regressions will be performed to model prognostic factors.	Baseline up to 5 years
Molecular changes in the peripheral blood and bone marrow	Determined using paired t-tests. Descriptive statistics including plots, mean, median and standard deviations will be used to summarize data. For continuous outcomes, t-tests and analysis of variance will be used to compare outcome measures across patient characteristics. Dunnett's and Tukey's test that properly adjust for multiplicity in multiple test will be implemented. Pair-wise comparison's will be performed using pre- and post-therapy samples from each patient. The chi-square test or Fisher's exact test will be used to test the association between categorical variables such as disease state and performance status. Both univariate and multivariate logistic regressions will be performed to model prognostic factors.	Baseline up to 5 years
Induction of hypomethylation and deoxyribonucleic acid damage during therapy	Correlation analysis (such as logistic regression analysis) will be conducted to determine the relationship between induction of hypomethylation/deoxyribonucleic acid damage and clinical response.	Up to 5 years

Collaborators and Investigators

• Sponsor: M.D. Anderson Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Naval Daver, M.D. Anderson Cancer Center

Publications and helpful links

General Publications

• El Hussein S, Daver N, Liu JL, Kornblau S, Fang H, Konoplev S, Kantarjian H, Khoury JD. Microsatellite Instability Assessment by Immunohistochemistry in Acute Myeloid Leukemia: A Reappraisal and Review of the Literature. Clin Lymphoma Myeloma Leuk. 2022 Jun;22(6):e386-e391. doi: 10.1016/j.clml.2021.12.004. Epub 2021 Dec 9.

Helpful Links

• MD Anderson Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): April 7, 2015
• Primary Completion (Actual): October 9, 2023
• Study Completion (Actual): October 9, 2023

Study Registration Dates

• First Submitted: March 19, 2015
• First Submitted That Met QC Criteria: March 24, 2015
• First Posted (Estimated): March 25, 2015

Study Record Updates

• Last Update Posted (Actual): June 8, 2025
• Last Update Submitted That Met QC Criteria: May 28, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Chronic Disease; Disease Attributes; Immune System Diseases; Neoplasms by Histologic Type; Disease; Hematologic Diseases; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Precancerous Conditions; Myelodysplastic-Myeloproliferative Diseases; Bone Marrow Diseases; Leukemia, Lymphoid; Syndrome; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Preleukemia; Myelodysplastic Syndromes; Leukemia, Biphenotypic, Acute; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Nivolumab; Ipilimumab; Venetoclax; Azacitidine
• Other Study ID Numbers: 2014-0861 (Other Identifier: M D Anderson Cancer Center); NCI-2015-00593 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No