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

Trial Status: Active

This phase II trial studies the side effects and best dose of nivolumab and azacitidine with or without ipilimumab when given together and to see how well they work in treating patients with acute myeloid leukemia that has not responded to previous treatment (refractory) or has returned after a period of improvement (relapsed) or is newly diagnosed. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor 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 nivolumab, azacitidine and ipilimumab may kill more cancer cells.

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 AND 3 SALVAGE COHORT: Patients with AML who have failed up to two prior therapeutic regimens (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, 2, AND 3 FRONT LINE COHORTS: Not considered candidates for intensive remission induction chemotherapy at time of enrollment based on EITHER: * >= 75 years of age OR * < 75 years of age with at least 1 of the following: ** Poor performance status (Eastern Cooperative Oncology Group (ECOG) [ECOG]) score of 2-3 ** Clinically significant heart or lung comorbidities, as reflected by at least 1 of: *** Left ventricular ejection fraction (LVEF) =< 50% *** Lung diffusing capacity for carbon monoxide (DLCO) =< 65% of expected *** Forced expiratory volume in 1 second (FEV1) =< 65% of expected *** Chronic stable angina or congestive heart failure controlled with medication ** Liver transaminases > 3 x upper limit of normal (ULN) ** Other contraindication(s) to anthracycline therapy (must be documented) ** Other comorbidity the investigator judges incompatible with intensive remission induction chemotherapy, which must be documented and approved by the principal investigator (PI) Patients with newly diagnosed AML with poor risk karyotype or complex karyotype and/or TP53 deletions/mutations equal or younger than 60 year old will be eligible for the Frontline cohort as well
  • 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 as long as within restrictions
  • 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 protocol therapy 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 immune checkpoint therapy and hypomethylating agents may be delayed, use of one dose of cytarabine (up to 2 g/m^2) 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 1 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
  • Subjects may be receiving systemic corticosteroids (daily doses =< 10 mg of prednisone or equivalent if indicated for adrenal replacement or antiemetic therapy), topical, or inhaled corticosteroids at study enrollment; patients receiving prednisone > 10 mg of prednisone or equivalent will not be eligible
  • 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)

Texas

Houston
M D Anderson Cancer Center
Status: ACTIVE
Contact: Naval G. Daver
Phone: 713-794-4392

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of nivolumab in combination with azacitidine (5-azacytidine) in patients with refractory/relapsed acute myeloid leukemia (AML). (Lead-in phase)

II. To determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of nivolumab with ipilimumab in combination with 5-azacytidine in patients with refractory/relapsed acute myeloid leukemia (AML). (Lead-in phase)

III. To determine the overall response rate (ORR) of nivolumab in combination with 5-azacytidine in patients with refractory/ relapsed AML. (Phase II)

IV. To determine the overall response rate (ORR) of nivolumab in combination with 5-azacytidine in older patients (>= 65 years) with newly diagnosed AML. (Phase II)

V. To determine the overall response rate (ORR) of nivolumab with ipilimumab in combination with 5-azacytidine in patients with refractory/relapsed AML. (Phase II)

VI. To determine the overall response rate (ORR) of nivolumab with ipilimumab in combination with 5- azacytidine in older patients (>= 65 years) with newly diagnosed AML. (Phase II)

VII. To determine the overall response rate (ORR) of nivolumab in combination with 5-azacytidine and venetoclax in patients with refractory/ relapsed AML. (Phase II)

VIII. To determine the overall response rate (ORR) of nivolumab in combination with 5-azacytidine and venetoclax in older patients (>= 65 years) with newly diagnosed AML. (Phase II)

SECONDARY OBJECTIVES:

I. To determine the number of patients who achieve a > 50% reduction in blasts on therapy with either azacitidine (vidaza) + nivolumab or vidaza + nivolumab + ipilimumab.

II. To determine the duration of response, event-free survival (EFS), 4- and 8-week mortality, and overall survival (OS) OS of patients with refractory/ relapsed AML treated with either vidaza + nivolumab, vidaza + nivolumab + ipilimumab or vidaza + venetoclax + nivolumab.

III. To determine the duration of response, event-free survival (EFS), 4- and 8-week mortality, and OS in older patients with newly diagnosed AML treated with either vidaza + nivolumab, vidaza + nivolumab + ipilimumab or vidaza + venetoclax + nivolumab.

EXPLORATORY OBJECTIVES:

I. To study immunological and molecular changes in the peripheral blood and bone marrow in response to nivolumab and 5-azacytidine therapy or nivolumab with ipilimumab and 5-azacutidine therapy or nivolumab with azacytidine and venetoclax therapy, including:

Ia. To investigate possible relationships between response and non-response to the combination with pretherapy, on-therapy, and progression gene expression signatures.

Ib. To investigate the characterization of genetic heterogeneity in tumor cell populations, by performing targeted single-cell sequencing on longitudinally collected AML tumor populations from patients using a novel microfluidic approach that barcodes amplified genomic deoxyribonucleic acid (DNA) from thousands of individual leukemia cells confined to droplets (single cell sequencing).

Ic. To identify individual cell populations (AML blasts, T-cells - both bulk and T-cell subsets and coreceptor/ligand expression, macrophages and their coreceptor/ligands) and how their signaling state in disease relates to clinical outcomes.

Id. To store and/or analyze surplus blood or tissue including bone marrow, if available, for potential future exploratory research into factors that may influence development of AML and/or response to the combination (where response is defined broadly to include efficacy, tolerability or safety).

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

OUTLINE: This is a lead-in phase, dose-escalation study followed by a phase II study. Patients are assigned to 1 of 2 arms.

ARM I: Patients receive azacitidine intravenously (IV) over 1 hour or subcutaneously (SC) on days 1-7 or days 1-5 and 8-9 or days 1-4 and 7-9 per physician discretion. Patients also receive nivolumab IV over 60 minutes on days 1 and 14 of cycles 1-4 and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM II: 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.

ARM III: Patients receive azacitidine as in Arm I and nivolumab IV over 1 hour on days 8 and 22 of cycles 1-4 and on day 8 of subsequent cycles. Patients also receive venetoclax orally (PO) once daily (QD) on days 1-21 of cycle 1 and on days 1-14 of subsequent cycles. Cycles 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 then every 3-6 months for up to 5 years.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
M D Anderson Cancer Center

Principal Investigator
Naval G. Daver

  • Primary ID 2014-0861
  • Secondary IDs NCI-2015-00593
  • Clinicaltrials.gov ID NCT02397720