Houston, Texas 77030


Purpose:

There are 2 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. Arm 1: There are 2 parts : 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 nivolumab and azacitidine 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. The safety of this drug combination will also be studied. Arm 2: There are 2 parts: 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 nivolumab, azacitidine, and ipilimumab 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. The safety of this drug combination will also be studied. This is an investigational study. Azacitidine is FDA approved and commercially available for the treatment of myelodysplastic syndrome (MDS) and it is approved as frontline therapy for AML in elderly participants. Nivolumab is commercially available and approved for the treatment of certain types of melanoma and lung cancers. Their use in this study is considered investigational. The study doctor can explain how the study drugs are designed to work. Up to 182 participants will take part in this study. All will be enrolled at MD Anderson.


Study summary:

Study Groups: If you are found to be eligible to take part in this study, you will be assigned to a study group based on when you join this study. 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. There are 2 groups in Part B: Part 1B and Part 2B. Up to 70 participants with AML who are younger than 65 years old will be enrolled in Part 1B and up to 40 participants with AML who are 65 years or older will be enrolled in Part 2B. Arm 2: Up to 4 groups of up to 6 participants will be enrolled in Part A of the study, and up to 60 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. There are 2 groups in Part B: Part 1B and Part 2B. Up to 30 participants with AML who are younger than 65 years old will be enrolled in Part 1B and up to 30 participants with AML who are 65 years or older will be enrolled in Part 2B. Study Treatment: Each cycle will be about 28 days long. However, cycles may be longer or shorter depending on how the disease responds to the treatment and what the doctor thinks is in your best interest. The study doctor will tell you if your study cycles are longer or shorter than 28 days. Arm 1: You will receive azacitidine by vein over about 1 hour or as an injection under the skin. You will receive this drug either on Days 1-7 of each cycle, or on Days 1-5 and then 8 and 9 of each cycle. The study doctor will tell you how and when you will receive the drug, and may change the method or schedule if it is in your best interest. You will also receive nivolumab by vein over about 1 hour on Days 1 and 14 (+/- 3 days) of Cycles 1-4 and then on Day 1 only of Cycles 5 and beyond. Arm 2: You will receive azacitidine by vein over about 1 hour or as an injection under the skin. You will receive this drug either on Days 1-7 of each cycle, or on Days 1-5 and then 8 and 9 of each cycle. The study doctor will tell you how and when you will receive the drug, and may change the method or schedule if it is in your best interest. You will also receive nivolumab by vein over about 1 hour on Days 1 and 14 (+/- 3 days) of Cycles 1-4 and then on Day 1 only of Cycles 5 and beyond. You will receive ipilimumab by vein over 90 minutes starting on Day 1 and every 6 (or 12) weeks (+/-3 days) after that. You will receive a total of 4 doses of ipilimumab every 6 (or 12) weeks and then stop therapy. If you have evidence of relapse or seem to be benefitting you may continue the ipilimumab every 6 (or 12) weeks. Depending on how the disease responds to the study drugs, the number of days you receive the study drugs may change. Your doctor will discuss this with you. If the study doctor thinks it is in your best interest, your dose of azacitidine and/or nivolumab may be changed and/or delayed. Study Visits: On Day 1 of each cycle (+/- 4 days): - You will have a physical exam. - You will have an EKG. One (1) time each week during Cycles 1-3 and then 1 time every 2-4 weeks after Cycle 3, blood (about 1 tablespoon) will be drawn for routine tests. If the doctor thinks it is needed, you may have this blood draw more often. If the doctor thinks it is acceptable, you may have these blood draws at a local lab or clinic. The results will be sent to the study doctor at MD Anderson. On Day 28 of Cycle 1 (+/- 7 days) and then every 1-3 cycles after that, you will have a bone marrow aspiration/biopsy to check the status of the disease. Any time that the doctor thinks it is needed while you are on study: - Blood (about 1-2 tablespoons) may be drawn for routine tests. - You may have a bone marrow aspiration/biopsy to check the status of the disease. Length of Study: You will receive nivolumab and azacitidine for as long as the doctor thinks it is in your best interest. You will no longer be able to take the study drugs if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions. Your participation on the study will be over after the follow-up visits. End-of-Study Visit: Within 14 days after your last dose of study drugs: - You will have a physical exam. - Blood (about 2-3 tablespoons) will be drawn for routine tests. - If the doctor thinks it is needed, you will have a bone marrow aspirate/biopsy to check the status of the disease. Follow-Up: You will be called about 30 days after your end-of-study visit and asked if you have had any side effects and/or started any new treatment(s). This call should last about 5 minutes. You may also be asked to come into the clinic for a physical exam, if the study staff thinks it is needed. Long-Term Follow-Up: If the disease appears to be getting better while you are taking the study drugs, you will be called every 3-6 months for up to 5 years. Each call should last about 5 minutes. You may also be asked to come into the clinic for a physical exam, if the study staff thinks it is needed.


Criteria:

Inclusion Criteria: 1. 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 Frontline older cohort:. Patients age 65 years and above with previously untreated AML (>/= 20% blasts) who are unfit for or decline standard induction therapy. 2. (continued from Inclusion #1) 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. The frontline cohort of vidaza+nivolumab+ipilimumab and vidaza+nivolumab will be open simultaneously and we will enroll alternately to these two frontline protocols with close monitoring for futility and as specified in the predefined statistical futility and toxicity stopping rules in Statistics Section 11.0. 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. Prior therapy for MDS or CMML will not be considered as a prior therapy 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 as long as within restrictions outlined in inclusion 4.2.1. 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. 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 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 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 12. (continued from Inclusion #10.) (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 (a+b or a+c or b+c). 13. (continued). 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 b. Placement of an intrauterine device (IUD) or intrauterine system (IUS) c. 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 due to unknown effect of drug-drug interaction. 14. (continued). 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. 15. Patients with 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: 1. Patients with known allergy or hypersensitivity to nivolumab, ipilimumab, 5-azacytidine, or any of their components. 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 who have previously been treated with nivolumab and/or ipilimumab in combination with 5-azacytidine will be excluded. 4. 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]). 5. Patients with organ allografts (such as renal transplant) are excluded 6. 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. 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 known Human Immunodeficiency Virus seropositivity will be excluded. 10. 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).


NCT ID:

NCT02397720


Primary Contact:

Principal Investigator
Naval Daver, MD
M.D. Anderson Cancer Center

Naval Daver, MD
Phone: 713-794-4392


Backup Contact:

N/A


Location Contact:

Houston, Texas 77030
United States



There is no listed contact information for this specific location.

Site Status: Recruiting


Data Source: ClinicalTrials.gov

Date Processed: November 17, 2017

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