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

NCT02397720 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 2014-0861NCI-2015-00593
• Study Type: interventional
• Target: 150
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Acute Bilineal Leukemia; Acute Biphenotypic Leukemia; Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Chronic Myelomonocytic Leukemia; Myelodysplastic Syndrome; Recurrent Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Therapy-Related Acute Myeloid Leukemia

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (3)

• Disease-free Survival

  Up to 7 years, 6 months

• Overall Survival

  Up to 7 years, 6 months

• Progression-free Survival

  Up to 7 years, 6 months

Study Arms (6)

Arm 1 A Lead-In (azacitidine, nivolumab)

EXPERIMENTAL

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; Drug: Nivolumab

Arm 2 A Lead-In (azacitidine, nivolumab, ipilimumab)

EXPERIMENTAL

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; Drug: Ipilimumab; Drug: Nivolumab

Arm 1 B (azacitidine, nivolumab)

EXPERIMENTAL

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; Drug: Nivolumab

Arm 3 Lead-In (azacitidine, nivolumab, Venetoclax)

EXPERIMENTAL

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; Drug: Venetoclax; Drug: Nivolumab

Arm 2 B (azacitidine, nivolumab, ipilimumab)

EXPERIMENTAL

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; Drug: Ipilimumab; Drug: Nivolumab

Arm 3 (azacitidine, nivolumab, Venetoclax)

EXPERIMENTAL

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; Drug: Venetoclax; Drug: Nivolumab

Interventions

Azacitidine DRUG

Given SC or IV

Also known as: 5 AZC, 5-AC, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, U-18496, Vidaza

Arm 1 A Lead-In (azacitidine, nivolumab); Arm 1 B (azacitidine, nivolumab); Arm 2 A Lead-In (azacitidine, nivolumab, ipilimumab); Arm 2 B (azacitidine, nivolumab, ipilimumab); Arm 3 (azacitidine, nivolumab, Venetoclax); Arm 3 Lead-In (azacitidine, nivolumab, Venetoclax)

Ipilimumab DRUG

Also known as: Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, MDX-010, MDX-CTLA4, Yervoy

Arm 2 A Lead-In (azacitidine, nivolumab, ipilimumab); Arm 2 B (azacitidine, nivolumab, ipilimumab)

Venetoclax DRUG

Given Orally

Also known as: ABT-199, GDC-0199

Arm 3 (azacitidine, nivolumab, Venetoclax); Arm 3 Lead-In (azacitidine, nivolumab, Venetoclax)

Nivolumab DRUG

Given IV

Also known as: BMS-936558, MDX-1106, NIVO, ONO-4538, Opdivo

Arm 1 A Lead-In (azacitidine, nivolumab); Arm 1 B (azacitidine, nivolumab); Arm 2 A Lead-In (azacitidine, nivolumab, ipilimumab); Arm 2 B (azacitidine, nivolumab, ipilimumab); Arm 3 (azacitidine, nivolumab, Venetoclax); Arm 3 Lead-In (azacitidine, nivolumab, Venetoclax)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Publications (2)

• Root JL, Desai PN, Ly C, Wang B, Jelloul FZ, Zhou J, Mackay S, Alfayez M, Matthews J, Pierce S, Reville PK, Daver N, Abbas HA. Single-Cell CD4 and CD8 T-Cell Secretome Profiling Reveals Temporal and Niche Differences in Acute Myeloid Leukemia Following Immune Checkpoint Blockade Therapy. Cancer Res Commun. 2024 Mar 6;4(3):671-681. doi: 10.1158/2767-9764.CRC-23-0402.

  PMID: 38391202 DERIVED

• 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.

  PMID: 34980577 DERIVED

Related Links

• MD Anderson Cancer Center

MeSH Terms

Conditions

Leukemia, Biphenotypic, Acute; Leukemia, Myelomonocytic, Chronic; Myelodysplastic Syndromes; Leukemia, Myeloid, Acute

Interventions

Azacitidine; Ipilimumab; CTLA-4 Antigen; venetoclax; Nivolumab

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, Myeloid; Myelodysplastic-Myeloproliferative Diseases; Bone Marrow Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Immune Checkpoint Proteins; Costimulatory and Inhibitory T-Cell Receptors; Receptors, Immunologic; Receptors, Cell Surface; Membrane Proteins; Antigens, Differentiation, T-Lymphocyte; Antigens, Differentiation; Antigens, Surface; Antigens; Biological Factors; Biomarkers

Results Point of Contact

• Title: Naval Daver MD./Professor
• Organization: The University of Texas MD Anderson Cancer Center

NDaver@mdanderson.org

713-794-4392

Study Officials

• Naval Daver

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 19, 2015
• First Posted: March 25, 2015
• Study Start: April 7, 2015
• Primary Completion: October 9, 2023
• Study Completion: October 9, 2023
• Last Updated: June 8, 2025
• Results First Posted: November 4, 2024

Record last verified: 2025-05

Locations

US (1)