Single Agent and Combined Inhibition After Allogeneic Stem Cell Transplant

Study Overview
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Brief Summary
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The purpose of the study is to determine the safety and benefit of nivolumab, ipilimumab or the combination of nivolumab with ipilimumab given after bone marrow transplant for patients with acute myelogenous leukemia and myelodysplastic syndrome.

Detailed Description
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The primary objectives of this study are: To assess the safety of single-agent and combined checkpoint inhibition with nivolumab and ipilimumab in patients with acute myelogenous leukemia and myelodysplastic syndrome who have undergone hematopoietic stem cell transplantation and are at high risk for post-transplant recurrence. Safety endpoint: The composite endpoint consisting of the occurrence of at least one treatment-related limiting toxicity (after checkpoint inhibitor treatment is initiated) defined as a ≥ grade 4 non-hematologic toxicity as specified by the CTCAE. Exceptions listed in section 5.9 apply to this endpoint as well. If 3 of 7 patients in a single cohort experience a treatment-related limiting toxicity, that single cohort will be terminated.

Official Title
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Phase I Study of Single-agent and Combined Checkpoint Inhibition After Allogeneic Hematopoietic Stem Cell Transplantation in Patients at High Risk for Post-transplant Recurrence

Conditions
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Acute Myeloid Leukemia and Myelodysplastic Syndrome

Intervention / Treatment
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* Drug: Nivolumab
* Drug: Ipilimumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Voluntary signed and dated IRB/IEC approved written informed consent form in accordance with regulatory and local guidelines. Be 18 years or older and 70 years or younger on the day of signing consent Have a confirmed diagnosis of non-M3 acute myeloid leukemia (AML) (Intermediate-II is high risk. Our population will consist of Intermediate-II and high risk patients or any FLT3+ AML) or IPSS intermediate -2 or high risk myelodysplastic syndrome (MDS) (Appendices A and B). Have an available 6/6 related donor or an unrelated donor with a 10/10 match for HLA-A, B, C, DRB1 and DQ antigen who consents to provide a marrow or peripheral blood stem cell allograft. Typing is by DNA techniques: intermediate resolution for A, B and C, and high resolution for DRB1/DQ Be receiving one of the following conditioning regimen: fludarabine at a dose of 30 mg/m2 IV daily for 5 days, busulfan at a dose of 130 mg/m2 IV daily for 2 days, and rabbit antithymocyte globulin (ATG) at a dose of 2 mg/kg IV daily for 2 days OR fludarabine at a dose of 30 mg/m2 IV daily for 4 days, melphalan at a dose of 140 mg/m2 for one day with or without ATG at a dose of 2 mg/kg IV daily for 2 days Be deemed eligible for an allogenic stem cell transplantation as per institutional guidelines of the Blood and Marrow Transplantation Program at John Theurer Cancer Center at Hackensack University Medical Center Patients with adequate organ function as measured by: Cardiac: left ventricular ejection fraction at rest > 50% Hepatic: serum total bilirubin < 1.5x upper limit of normal for age as per local laboratory (with the exception of isolated hyperbilirubinemia due to Gilbert's syndrome); ALT and AST < 4x upper limit of normal for age as per local laboratory Renal: serum creatinine < 2x upper limit of normal for age (as per local laboratory). For patients with serum creatinine above the normal range, a glomerular filtration rate (measured as per institutional practice, typically creatinine clearance) equal to or greater than 60 mL/min (corrected to 1.73m2 body surface area) is required. Pulmonary: FEVl, FVC and DLCO (corrected for Hb) >50% predicted. Have a performance status of 2 or lower on ECOG performance scale. Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug. Version 1.0 23Mar2017 Page 4 of 73 Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of nivolumab. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Female subjects of childbearing potential should agree to ongoing pregnancy testing, to be performed prior to each dosing of ipilimumab and nivolumab. See Note below for definition of WOCBP. Women must not be breastfeeding. Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving nivolumab, and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product, even if they have had a vasectomy. Women who are not of childbearing potential (ie, who are postmenopausal or surgically sterile as well as azoospermic men do not require contraception). See Note below for definition of WOCBP. Females of childbearing potential must be willing to use two methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 2 years. See Note below for definition of WOCBP. Exclusion Criteria: Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 20 mg/day prednisone equivalents) for at least 4 weeks prior to study drug administration. This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability. Note: Subjects are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic corticosteroids are permitted, even if > 20 mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions (eg, delayed-type hypersensitivity reaction caused by contact allergen) is permitted. Is unable or unwilling to sign informed consent. Has an active, known, or suspected autoimmune disease. Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger Patients should be excluded if they have a condition such as GVHD requiring systemic treatment with either corticosteroids (> 20 mg daily prednisone equivalents) or other immunosuppressive medications within 4 weeks of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 20 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. Note: Subjects are permitted to use topical, ocular, intra-articular, intranasal, and inhalation corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic corticosteroids are permitted, even if > 20 mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions (eg, delayed-type hypersensitivity reaction caused by contact allergen) is permitted. As there is potential for hepatictoxicity with nivolumab or nivolumab/ipilimumab combinations, drugs with a predisposition to hepatoxicity should be used with caution in patients treated with nivolumab-containing regimen. Has received a prior allogeneic stem cell transplant. Has a history of hypersensitivity to nivolumab, ipilimumab, or any of its excipients, or severe hypersensitivity reaction to any previous monoclonal antibody. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to Day 1 of checkpoint inhibitor treatment administration or who has not recovered (i.e., t administration mAb) within 4 weeks prior to t dose of trial treatment. Rituximab within that time frame is allowed. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Note: Subjects are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic corticosteroids are permitted, even if > 20 mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions (eg, delayed-type hypersensitivity reaction caused by contact allergen) is permitted. Has known history of, or any evidence of active, non-infectious pneumonitis. Has an active infection requiring intravenous systemic therapy. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 agent, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies) or known acquired immunodeficiency syndrome (AIDS). Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected). Has the presence of a large accumulation of ascites or pleural effusions, which would be a contraindication to the administration of methotrexate for GVHD prophylaxis. Has known history of grade 3 or 4 GVHD.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients will be assigned to Groups A, and B in a 1:1 fashion. If the safety endpoint is met for each of these groups, enrollment to Group C will open. Each patient will be monitored for toxicities for at least 28 days before the next patient is added to the same cohort.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A - Nivolumab<br>Nivolumab for 12 doses, on day 1 of weeks 1, 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34 Dose level 1: 1 mg/kg Dose level 2: 3 mg/kg | Drug: Nivolumab<br>* Nivolumab is a fully humanized immunoglobulin 4 (IgG4) monoclonal antibody (mAb) which binds to PD-1 (CD279) with nanomolar affinity and shows a high degree of specificity for PD-1; blocking binding of PD-1 to PD-L1 and PD-L2. Nivolumab binds selectively to human PD-1 and does not bind to other members of the cluster of differentiation protein 28 (CD28) family.<br>* Other names: Bristol-Myers Squibb (BMS-936558);|
| Experimental: Group B - Ipilimumab<br>Ipilimumab for 6 doses on day 1 of weeks 1, 4, 7, 10, 13, 16 Dose level 1: 0.3 mg/kg Dose level 2: 1.0 mg/kg Dose level 3: 3.0 mg/kg | Drug: Ipilimumab<br>* Ipilimumab is a recombinant, human mAb that binds to the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). Ipilimumab is an immunoglobulin 1 (IgG1) kappa immunoglobulin with an approximate molecular weight of 148 kilo-Daltons (kDa). Ipilimumab is produced in mammalian (Chinese hamster ovary) cell culture.<br>* Other names: BMS-734016;|
| Experimental: Group C - Nivolumab + Ipilimumab<br>Nivolumab 3 mg/kg for 12 doses, on day 1 of weeks 1, 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34 Ipilimumab for 6 doses on day 1 of weeks 1, 4, 7, 10, 13, 16 Dose level 1: 0.3 mg/kg Dose level 2: 0.6 mg/kg Dose level 3: 1.0 mg/kg | Drug: Nivolumab<br>* Nivolumab is a fully humanized immunoglobulin 4 (IgG4) monoclonal antibody (mAb) which binds to PD-1 (CD279) with nanomolar affinity and shows a high degree of specificity for PD-1; blocking binding of PD-1 to PD-L1 and PD-L2. Nivolumab binds selectively to human PD-1 and does not bind to other members of the cluster of differentiation protein 28 (CD28) family.<br>* Other names: Bristol-Myers Squibb (BMS-936558);Drug: Ipilimumab<br>* Ipilimumab is a recombinant, human mAb that binds to the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). Ipilimumab is an immunoglobulin 1 (IgG1) kappa immunoglobulin with an approximate molecular weight of 148 kilo-Daltons (kDa). Ipilimumab is produced in mammalian (Chinese hamster ovary) cell culture.<br>* Other names: BMS-734016;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety: The occurrence of at least one treatment-related limiting toxicity defined as a ≥ grade 4 non-hematologic toxicity as specified by the CTCAE 4.0. | Exceptions are: Isolated Grade 4 amylase or lipase values that are not associated with symptoms or clinical manifestations of pancreatitis and decrease to < Grade 4 within 1 week of onset and isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical sequelae and are corrected with supplementation/appropriate management within 72 hours of their onset. If 3 of 7 patients in a single cohort experience a treatment-related limiting toxicity, that single cohort will be terminated. | After treatment is initiated through 100 days of discontinuation of dosing. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicities: Common Terminology Criteria for Adverse Events (CTCAE) will be used for the assessment and grading of all toxicities experienced by patients enrolled into this study. | Patients will be assigned to Groups A, B, and C in a 1:1:1 fashion. Each patient will be monitored for toxicities for at least 14 days before the next patient is added to the same cohort. The toxicity will be evaluated for all adverse events with grade 3 or grade 4 observed in each cohort and presented as counts (proportion). | Through 100 days of discontinuation of dosing. | 
| Assessment of blood immune reconstitution by sequencing to determine diversity and highest frequency clonal specificities |  | At consent for subjects and within 30 days pre allo transplant conditioning for donors, at apheresis, and day 1 of week 1 of protocol treatment (tx) and then weeks 4,7,12,18,26, and at 9,12,15,18 mos post-transplant and at relapse if within 18 mos of tx. | 
| Tumor site immune phenotyping | Absolute number of PD-L1/L2-bearing activated helper T cell subpopulations from bone marrow biopsy will be examined for two time points prior to conditioning and time of progression (within 18 months post-checkpoint inhibitor initiation) using Poisson regression analysis with GEE described in analysis of blood phenotype above. | If bone marrow biopsy is available prior to allogeneic transplantation conditioning and then at time of relapse within 18 months following initiation of therapy. | 
| Assessment of complete response (CR) rate | The estimates of the CR will be presented as count (proportion) and corresponding exact binomial 95% confidence intervals for proportion at each time point. | Assess at 3, 6 and 12 months after transplant | 
| Assessment of blood phenotype | Phenotype analysis of for T cells, Dendritic cells, Macrophages, Myeloid derived suppressor cells, B cells, natural killer (NK) cells, natural killer T (NKT) cells, Plasma Cytokine levels: Multiplex 25 Cytokine - Luminex via Flow Cytometric Phenotype Analysis | At consent for subjects and within 30 days pre allogeneic transplant conditioning for donors, at apheresis, and day 1 of week 1 of protocol tx and weeks 4,7,12,18,26, and at 9,12,15,18 months post-transplant and at relapse if within 18 months of tx. | 
| Assessment of blood TCR repertoire via TCR Immunoseq Assay Profiling | Via TCR Immunoseq for T cell receptor Vbeta complementarity determining region CDR3 highest frequency specificities. | At consent for subjects and within 30 days pre allogeneic transplant conditioning for donors, at apheresis, and day 1 of week 1 of protocol tx and weeks 4,7,12,18,26, and at 9,12,15,18 months post-transplant and at relapse if within 18 months of tx. | 
| Assess tumor site TCR repertoire using Poisson regression analysis with generalized estimating equations (GEE) | GEE method will be performed by utilizing the Statistical Analysis Software (SAS 9.4) procedure (PROC) generalized linear product analysis (GENMOD) with Poisson distribution, log link function and independent covariance structure. | When bone marrow biopsy is available prior to allogeneic transplantation conditioning and then at time of relapse within 18 months following initiation of therapy. | 
| Assess tumor site PD-L1/2 expression | If viable biopsy material is unavailable for research purposes, Dr. Korngold's lab will access fixed archival tumor materials for preparing tumor lysates and possibly for retrieving T cell DNA for repertoire analysis. | When bone marrow biopsy is available prior to allogeneic transplantation conditioning and then at time of relapse within 18 months following initiation of therapy. | 
| Efficacy as assessed by progression free survival (PFS) | PFS is defined as time interval from date of protocol treatment initiation to pathologic disease progression or death from any cause. PFS will be estimated using Kaplan-Meier method and probabilities will be calculated for 12 months. | At 12 months after treatment is initiated | 
| Efficacy as assessed by progression free survival (PFS) | PFS is defined as time interval from date of protocol treatment initiation to pathologic disease progression or death from any cause. PFS will be estimated using Kaplan-Meier method and probabilities will be calculated for 18 months. | At 18 months after treatment is initiated |