Phase I dose escalation study of nivolumab (Anti-PD-1; BMS-936558; ONO-4538) in patients (pts) with advanced hepatocellular carcinoma (HCC) with or without chronic viral hepatitis.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS3111-TPS3111 ◽  
Author(s):  
Bruno Sangro ◽  
Todd S. Crocenzi ◽  
Theodore Hobart Welling ◽  
Mercedes Iñarrairaegui ◽  
Jesús Prieto ◽  
...  
Keyword(s):  
T Cell ◽  
Phase I ◽  
Viral Hepatitis ◽  
T Cell Activation ◽  
Dose Escalation ◽  
Cell Activation ◽  
Hcv Infection ◽  
Advanced Hepatocellular Carcinoma ◽  
Dose Escalation Study ◽  
Advanced Hcc

TPS3111 Background: Pts with advanced HCC have limited treatment options. Sorafenib, the current standard of care, achieves only modest overall survival improvements. There is a clear etiologic association between HCC and prior/concurrent hepatitis B (HBV) or C (HCV) infection. Programmed death-1 (PD-1) is an immune checkpoint receptor that inhibits T-cell activation when bound by ligands including PD-L1/L2. PD-L1 overexpression has been noted on HCC tumors, and PD-1/PD-L1 interaction may contribute to viral hepatitis induced T-cell exhaustion. Nivolumab, a PD-1 receptor blocking antibody, has shown efficacy against various solid tumor types in Ph 1 trials. We hypothesized that blockade of PD-1/PD-L1 interaction could enhance T-cell activation and mediate antitumor and/or antiviral activity in HCC pts. We describe a phase I, dose-escalation study of nivolumab in advanced HCC pts. Methods: Successive pt cohorts with histologically confirmed advanced HCC with/without HBV or HCV infection (N=72 max) will be treated on 3 distinct arms with IV nivolumab at 0.3, 1 and 3.0 mg/kg (uninfected or HCV-infected pts) or 0.1, 0.3, 1 and 3.0 mg/kg (HBV-infected pts) every 2 weeks using a 3+3 escalation scheme. Pts must have progressive disease or intolerance after ≥1 line of therapy or have refused sorafenib treatment, and a Child-Pugh class A. HBV-infected pts must be receiving antiviral therapy (viral DNA <100 IU/mL) for ≥3 months. Pts with brain metastasis, encephalopathy, prior/current ascites requiring paracentesis, history of recent variceal bleeding, active coinfection with HIV, or both HBV and HCV, or concurrent hepatitis D and HBV infection will be excluded. Primary endpoints include characterization of safety, tolerability, dose-limiting toxicities and maximum tolerated dose of nivolumab. Secondary endpoints include assessment of the preliminary antitumor activity (per modified RECIST for HCC), PK and immunogenicity. Exploratory endpoints include evaluation of the relationship between tumor PD-L1 expression and clinical outcome, and nivolumab’s antiviral and immunoregulatory activity in peripheral blood and/or tumor specimens. Clinical trial information: NCT01658878.

Phase I dose escalation study of recombinant interleukin-21 (rIL-21, BMS-982470) in combination with ipilimumab (Ipi) in patients (pts) with advanced or metastatic melanoma (MM).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS3109-TPS3109 ◽  
Author(s):  
Shailender Bhatia ◽  
Brendan D. Curti ◽  
Michael S. Gordon ◽  
Jason Chesney ◽  
Theodore Logan ◽  
...  
Keyword(s):  
T Cell ◽  
Antitumor Activity ◽  
Phase I ◽  
T Cell Activation ◽  
Dose Escalation ◽  
Cell Activation ◽  
Cell Function ◽  
Nk Cell ◽  
Combined Treatment ◽  
Clinical Activity

TPS3109 Background: Ipilimumab is a monoclonal anti-CTLA-4 antibody that promotes T-cell activation and has been approved for the treatment of pts with advanced melanoma. The cytokine rIL-21 is a T-cell and NK-cell growth factor that has also demonstrated antitumor activity in selected solid tumors including MM. We hypothesize that coordinated stimulation of T and/or NK cell function with rIL-21 in conjunction with T-cell checkpoint inhibitor blockade with Ipi will achieve enhanced biologic and clinical activity compared to either agent alone. Here we describe an ongoing phase Ib study to investigate the clinical and biologic effects of combined treatment with rIL-21 and Ipi in pts with MM. Methods: The phase I study includes dose escalation (Part 1) using a 6 + 6 design and cohort expansion (Part 2). In Part 1 (n=48), successive cohorts of pts with melanoma will be treated with rIL-21 in combination with Ipi as follows: Arm A, rIL-21 (10, 30, or 50 μg/kg daily x 5) + Ipi (3 or 10 mg/kg Q3W) in a 3 week cycle; or Arm B, rIL-21 (30, 100, or 150 μg/kg weekly) + Ipi (3 or 10 mg/kg Q3W) in a 3 week cycle. In Part 1, all subjects will receive an initial cycle with rIL-21 monotherapy (lead-in) for biomarker and PK assessment that will be the same as the dose of rIL-21 specified for the cohort. Four cycles of combination treatment will follow the lead-in with restaging evaluation after 4 combination cycles. Subjects with initial benefit are eligible for retreatment at progression. In Part 2, pts (n=25/arm) will be randomly assigned to one of 3 cohorts: Ipi monotherapy at 3 mg/kg Q3W or Ipi + weekly rIL-21 or Ipi + daily rIL-21 at the MTD determined for each schedule in Part 1. The primary objectives of this study are to evaluate the safety of rIL-21 + Ipi and to define the MTD of the respective rIL-21 + Ipi regimens. Secondary objectives include assessment of the preliminary antitumor activity, pharmacokinetics, and immunogenicity. Exploratory objectives include investigation of the immunologic effects of this combination in peripheral blood and paired tumor biopsy specimens, and the association of these effects with clinical outcome. Clinical trial information: NCT01489059.

Phase Ib study of mapatumumab in combination with sorafenib in patients with advanced hepatocellular carcinoma (HCC) and chronic viral hepatitis.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 261-261 ◽  
Author(s):  
W. Sun ◽  
D. Nelson ◽  
S. R. Alberts ◽  
F. Poordad ◽  
S. Leong ◽  
...  
Keyword(s):  
Viral Hepatitis ◽  
Dose Escalation ◽  
Hepatitis B Surface Antigen ◽  
Maximum Tolerated Dose ◽  
Chronic Viral Hepatitis ◽  
Advanced Hepatocellular Carcinoma ◽  
Dose Escalation Study ◽  
Advanced Hcc ◽  
Tumor Measurements ◽  
Apoptotic Activity

261 Background: Mapatumumab is a fully human agonist monoclonal antibody to the tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1). Sorafenib targets Mcl-1, a key TRAIL resistance protein, and accordingly could enhance mapatumumab's pro-apoptotic activity. Based on this and on preclinical data on mapatumumab in HCC cell lines, the current dose-escalation study is evaluating mapatumumab in combination with sorafenib in patients with advanced HCC. Methods: Eligible patients had advanced HCC, Child-Pugh A or Model for End-Stage Liver Disease score < 15, and were positive for hepatitis B surface antigen or hepatitis C antibody. Intravenous mapatumumab was administered at 3, 10 or 30 mg/kg every 21 days with sorafenib (400 mg twice daily) until disease progression or unacceptable toxicity. Dose-limiting toxicities (DLTs) included events considered at least possibly related to mapatumumab and/or its interaction with sorafenib. Tumor measurements were performed every 2 cycles. Dose escalation required at least 3 patients in a cohort to receive >= 50% of full-dose sorafenib in the first 2 cycles. Results: To date, 19 patients have been enrolled in the 3 mg/kg (n=6), 10 mg/kg (n=9) and 30 mg/kg (n=4) cohorts and have received a median of 4 cycles (range 1 to 24 cycles); 4 patients have received >= 11 cycles. The maximum tolerated dose has not been reached. DLTs that prompted expansion of the 3 mg/kg and 10 mg/kg cohorts were elevations of amylase and/or lipase (1 at 3 mg/kg, 1 at 10 mg/kg). Other Grade 3-4 events considered at least possibly related to mapatumumab and/or its interaction with sorafenib included hepatic pain (1/17), thrombocytopenia (1/17), increased aspartate aminotransferase (1/17), increased lipase (1/17), and increased gamma-glutamyltransferase (1/17). Two patients have had a partial response and 4 patients have had stable disease lasting > 12 weeks, based on investigator assessment. Conclusions: Mapatumumab was well-tolerated at doses up to 30 mg/kg in combination with sorafenib in patients with HCC and viral hepatitis. A randomized phase II study of this combination in patients with advanced HCC is planned. [Table: see text]

406 CDX527–01, a phase 1 dose-escalation and expansion study of the PD-L1xCD27 bispecific antibody CDX-527 in patients with advanced malignancies

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A431-A431
Author(s):  
Michael Yellin ◽  
Tracey Rawls ◽  
Diane Young ◽  
Philip Golden ◽  
Laura Vitale ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Dose Escalation ◽  
Clinical Studies ◽  
Cell Activation ◽  
Bispecific Antibody ◽  
Phase 1 ◽  
Clinical Activity ◽  
Tumor Types ◽  
Anti Tumor Activity

BackgroundCD27 ligation and PD-1 blockade elicit complementary signals mediating T cell activation and effector function. CD27 is constitutively expressed on most mature T cells and the interaction with its ligand, CD70, plays key roles in T cell costimulation leading to activation, proliferation, enhanced survival, maturation of effector capacity, and memory. The PD-1/PD-L1 pathway plays key roles in inhibiting T cell responses. Pre-clinical studies demonstrate synergy in T cell activation and anti-tumor activity when combining a CD27 agonist antibody with PD-(L)1 blockade, and clinical studies have confirmed the feasibility of this combination by demonstrating safety and biological and clinical activity. CDX-527 is a novel human bispecific antibody containing a neutralizing, high affinity IgG1k PD-L1 mAb (9H9) and the single chain Fv fragment (scFv) of an agonist anti-CD27 mAb (2B3) genetically attached to the C-terminus of each heavy chain, thereby making CDX-527 bivalent for each target. Pre-clinical studies have demonstrated enhanced T cell activation by CDX-527 and anti-tumor activity of a surrogate bispecific compared to individual mAb combinations, and together with the IND-enabling studies support the advancement of CDX-527 into the clinic.MethodsA Phase 1 first-in-human, open-label, non-randomized, multi-center, dose-escalation and expansion study evaluating safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of CDX-527 is ongoing. Eligible patients have advanced solid tumor malignancies and have progressed on standard-of-care therapy. Patients must have no more than one prior anti-PD-1/L1 for tumor types which have anti-PD-1/L1 approved for that indication and no prior anti-PD-1/L1 for tumor types that do not have anti-PD-1/L1 approved for that indication. CDX-527 is administered intravenously once every two weeks with doses ranging from 0.03 mg/kg up to 10.0 mg/kg or until the maximum tolerated dose. The dose-escalation phase initiates with a single patient enrolled in cohort 1. In the absence of a dose limiting toxicity or any ≥ grade 2 treatment related AE, cohort 2 will enroll in a similar manner as cohort 1. Subsequent dose-escalation cohorts will be conducted in 3+3 manner. In the tumor-specific expansion phase, up to 4 individual expansion cohort(s) of patients with specific solid tumors of interest may be enrolled to further characterize the safety, PK, PD, and efficacy of CDX 527. Tumor assessments will be performed every 8-weeks by the investigator in accordance with iRECIST. Biomarker assessments will include characterizing the effects on peripheral blood immune cells and cytokines, and for the expansion cohorts, the impact of CDX-527 on the tumor microenvironment.ResultsN/AConclusionsN/ATrial RegistrationNCT04440943Ethics ApprovalThe study was approved by WIRB for Northside Hospital, approval number 20201542

scholarly journals 480 A first-in-human phase I dose-escalation trial of the B7-H6/CD3 T-cell engager BI 765049 ± ezabenlimab (BI 754091) in patients with advanced solid tumors expressing B7-H6

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A510-A510
Author(s):  
Gerald Falchook ◽  
David Spigel ◽  
Manish Patel ◽  
Babar Bashir ◽  
Susanna Ulahannan ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Dose Escalation ◽  
Cell Activation ◽  
Primary Objective ◽  
List Type ◽  
Open Label ◽  
Eu Directive ◽  
Dosing Regimens

BackgroundB7-H6 is a member of the B7 family of immune receptors, which is expressed in several solid tumor types but very little expression can be detected in normal tissues.1 2 BI 765049 is a novel IgG-like bispecific T-cell engager designed to bind simultaneously to B7-H6 on tumor cells and CD3 on T cells, resulting in cytolytic synapse formation and tumor lysis. Preclinical studies have demonstrated that BI 765049 monotherapy induced dose-dependent anti-tumor activity in humanized in vivo CRC tumor models. Consistent with the mode of action, the treatment with BI 765049 led to target cell apoptosis, local T-cell activation/proliferation and cytokine production in the tumor tissue, with PD-(L)1 upregulation.3 Activation of the PD-(L)1 provides the rationale for combining BI 765049 with a PD1 inhibitor.MethodsNCT04752215 is a first-in-human, open-label, dose-escalation trial of BI 765049 ± the PD-1 inhibitor, ezabenlimab. Adults with advanced, unresectable and/or metastatic CRC, NSCLC, HNSCC, hepatocellular, gastric or pancreatic carcinoma are eligible. Patients must have failed on, or be ineligible, for standard therapies. B7-H6 positivity must be confirmed at screening by central review (immunohistochemistry assay) in archived tissues/in-study fresh biopsies (except CRC). Patients must have ≥1 evaluable lesion (modified RECIST 1.1) outside of the central nervous system and adequate organ function. The primary objective is to determine the maximum tolerated dose (MTD) or recommended dose for expansion of BI 765049 ± ezabenlimab, based on dose-limiting toxicities during the MTD evaluation period. Further objectives are to evaluate safety, tolerability, PK/PD and preliminary efficacy of BI 765049 ± ezabenlimab. The trial may assess up to 4 dosing regimens: A (BI 765049 once every 3 weeks [q3w]); B1 (BI 765049 qw); B2 (BI 765049 qw with step-in doses); C (BI 765049 + ezabenlimab [q3w]). Dose escalation will be guided by a Bayesian Logistic Regression Model with overdose control that will be fitted to binary toxicity outcomes using a hierarchical modelling approach to jointly model all dosing regimens. Treatment will be allowed to continue until confirmed progressive disease, unacceptable toxicity, other withdrawal criteria or for a maximum duration of 36 months, whichever occurs first. Approximately 150–175 patients will be screened and ~120 patients enrolled. As of July 2021, patients are being recruited in early dose-escalation cohorts.AcknowledgementsMedical writing support for the development of this abstract, under the direction of the authors, was provided by Becky O’Connor, of Ashfield MedComms, an Ashfield Health company, and funded by Boehringer Ingelheim.Trial RegistrationNCT04752215ReferencesBrandt et al. J Exp Med 2009;206:1495–503.Boehringer Ingelheim. Data on file.Hipp et al. AACR Annual Meeting 2021.Ethics ApprovalThe trial will be carried out in compliance with the protocol, the ethical principles laid down in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good Clinical Practice (GCP) and the EU directive 2001/20/EC/EU regulation 536/2014.

A Phase I Open Label Dose Escalation Study To Evaluate MEDI-507 in Patients with CD2-Positive T-Cell Lymphoma/Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2727-2727 ◽  
Author(s):  
Deborah A. Casale ◽  
Nancy L. Bartlett ◽  
David D. Hurd ◽  
Francine Foss ◽  
Barbara Pro ◽  
...  
Keyword(s):  
T Cell ◽  
Phase I ◽  
Dose Escalation ◽  
Cell Lymphoma ◽  
Tumor Lysis Syndrome ◽  
Lymphocytic Leukemia ◽  
T Cell Lymphoma ◽  
Cell Recovery ◽  
Open Label ◽  
Dose Escalation Study

Abstract This ongoing multicenter study is a Phase I trial with MEDI-507 (Siplizumab) [a humanized IgG1k class monoclonal antibody that binds to the CD2 receptor on human T- and NK-cells] to determine the maximum tolerated dose (MTD) or the optimum biologic dose (OBD) in patients with relapsed/refractory CD2-positive T-cell lymphoma/leukemia [CD2-positive adult T-cell leukemia (ATL), cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL), and large granular lymphocytic leukemia (LGL).] Open label 3+3 dose escalation was conducted in which patients receive bi-weekly infusions of MEDI-507 over 3 consecutive days at total doses of 0.7 mg/kg, 3.4 mg/kg or 4.8 mg/kg. Predose and serial MEDI-507 pharmacokinetics (ELISA) at Visit 2 and anti MEDI-507 antibodies (ELISA), peripheral blood total T-Cell and CD2-positive T-cells (flow cytometry), and C3 and C4 complement are obtained for each patient. Patients are followed for one year after their last dose of MEDI-507 for tumor assessment and CD2-positive T-cell recovery. 16 patients have been enrolled: 3 (0.7 mg/kg); 9 (3.4); 4 (4.8). Three additional patients were added to the 3.4 mg/kg cohort to replace patients who progressed early and one patient with tumor lysis syndrome. Diagnoses of the 16 patients: PTCL (9), CTCL (6) and NK-LGL (1). Frequent adverse events reported, to date, are infusion reaction (7/16) patients; hypertension (4/16); lymphopenia (4/16); fatigue (4/16) and leukopenia (3/16). Two DLT’s have been observed. The first, erythematous confluent dermatitis, occurred in one patient at 3.4 mg/kg and the cohort was expanded with eventual dose escalation. The second, pulmonary edema, occurred in one patient at 4.8 mg/kg and the cohort is currently being expanded without further DLT identified to date. Two responses have been observed, one PR in an NK-LGL patient at 3.4 mg/kg and one CR in a PTCL patient at 3.4 mg/kg. MEDI-507 has been well tolerated and shown anti-tumor activity. Dosing will change to weekly dosing with dose escalation (3+3) starting at 1.2 mg/kg as 0.8 mg/kg was seen to be safe in the single center study. MTD and/or OBD have not been determined.

T Cell Responses during Long-Term Continuous Infusion of MT103 (MEDI-538; Anti-CD19 BiTE) in Patients with Relapsed B-NHL: Data from Dose-Escalation Study MT103-104.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2725-2725 ◽  
Author(s):  
Matthias Klinger ◽  
Peter Kufer ◽  
Petra Kirchinger ◽  
Ralf Lutterbüse ◽  
Eugen Leo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Dose Escalation ◽  
Cell Expansion ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
Cell Counts ◽  
T Cell Expansion

Abstract MT103 (MEDI-538) is a bispecific single-chain antibody construct directed at CD3 on human T cells and CD19 on human B lymphoma and normal B cells. Transient linkage of B and T cells by MT103 provides T cells with a T cell receptor (TCR)-like signal leading to redirected lysis of B cell targets without apparent need of costimulation and inducing T cells to proliferate, secrete cytokines and upregulate surface activation markers. TCR-like signalling by MT103 is strictly dependent on the presence of target cells. Redirected lysis of CD19-positive cells by MT103 is seen at low picomolar concentrations and at low effector-to-target ratios. The in-vivo half-life of MT103 is approximately two hours. In the ongoing dose escalation study MT103-104, patients with relapsed B-NHL have so far received continuous infusion of MT103 at maintenance flow-rates of 0.5, 1.5, 5 and 15 μg/m2/24h for 4 or 8 weeks following a 3+3 dose escalation design. Serum concentrations of MT103 remained constant over the entire treatment period at a level depending on the respective maintenance flow-rate. Depletion of circulating B (lymphoma) cells could be observed more frequently with increasing dose levels (DL) from DL1 to DL3, and in all evaluable patients at DL4. Three of six evaluable patients at DL4 showed clinical responses (2 PR, 1 CR) according to standardized Cheson criteria, but no patient of DL1-3. The time courses of absolute CD4 and CD8 T cell counts in peripheral blood were determined by flow cytometry. CD8 T lymphocytes were further subdivided for analysis into naïve T cells, TCM (central memory T cells), TEM (effector memory T cells) and TEMRA (non-proliferating terminally differentiated CTL), and CD4 T lymphocytes into naïve T cells, TCM and TEM. Activation of CD4 and CD8 T cell subsets was determined by measuring upregulation of CD69, CD25 and HLA-DR. Serum levels of cytokines were determined as additional biomarkers for T cell activation. In 50% of patients at DL1 to DL3, CD4 and CD8 T cell counts increased during the course of treatment - over pre-treatment levels. The TEM subset from both CD4 and CD8 T cells accounted for most of the observed increases, while the naïve T cell subsets showed no increase but also no signs of apoptosis. The non-proliferative TEMRA subset of CD8 T cells also remained unchanged in most patients. This indicated that the selective increase of proliferation-competent TEM subsets was attributed to MT103-induced T cell proliferation. At DL4, all evaluable patients showed signs of T cell expansion after 2 weeks of MT103 infusion, which was most pronounced in those who developed a partial or complete remission. The increase of CD8 T cell counts was more pronounced than that of CD4 T cells. T cell expansion was accompanied by upregulation of T cell activation markers as well as by increases in serum concentrations of cytokines like IFN-γ. T cell expansion and activation reverted in all cases when the infusion of MT103 was stopped. In summary, MT103 induced a reversible secondary T cell response involving T cell activation and proliferation as well as T cell cytotoxicity against circulating B cells and lymphoma tissue. The dose-dependent T cell expansion observed during long-term infusion of MT103, particularly within the cytotoxic TEM subset of CD8 T cells, appears to play a key role for clinical activity.

Clinical Trial of Therapeutic Blockade of CTLA4 with Ipilimumab in Patients with Relapse of Malignancy Following Allogeneic Hematopoietic Transplantation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1646-1646
Author(s):  
Asad Bashey ◽  
Bridget Medina ◽  
Sue Corringham ◽  
Mildred Pasek ◽  
Ewa Carrier ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Human Monoclonal Antibody ◽  
Negative Regulator ◽  
Dose Escalation Study ◽  
Hematopoietic Stem ◽  
Objective Evidence ◽  
Anti Cancer ◽  
Grade 3

Abstract Relapse/progression of malignancy (RM) is an important cause of treatment failure and death following allogeneic hematopoietic stem cell transplantation (allo-HCT). CTLA-4 is an important negative regulator of effector T-cell activation. CTLA-4 inhibition has demonstrated potent anti-cancer effects in animal models, and in patients with some solid tumors. CTLA-4 blockade following allo-HCT may potentially augment graft-versus-malignancy but GVHD may also possibly be increased. We report the safety and preliminary efficacy of a dose-escalation study of a neutralizing human monoclonal antibody targeting CTLA-4 (ipilimumab) in patients with RM following allo-HCT. Eligibility criteria included allo-HCT ≥90 days previously, &gt; 50% donor T-cell chimerism, no prior grade 3/4 GVHD, no prophylaxis/therapy for GVHD for ≥ 6 weeks. Patients received a single dose of ipilimumab over 90 min. DLI at a dose of 5 × 10e6 CD3 cells/kg was allowed 8 weeks following ipilimumab if no GVHD occurred and RM was present. A total of 29 patients were treated at four centers (23M, 6F; median age 43 (21–65); Hodgkins disease [HD] =14 Myeloma [MM]=6, CML=2, CLL=2, AML=2, NHL=1, Renal Ca =1, Breast Ca=1; 19 related donors, 10 unrelated; 6 myeloablative, 23 RICT).(4 at dose-level 1 [DL1] 0.1 mg/kg, 3 at 0.33 mg/kg [DL2], 4 at 0.66 mg/kg [DL3], 3 at 1.0 mg/kg [DL4] and 15 at 3.0 mg/kg [DL5]). Eight patients had failed prior DLI. Median time between BMT and ipilimumab was 366 d (125–2368). Dose-limiting toxicity was not encountered. No patient developed clinically significant GVHD within 90 days following ipilimumab alone. Three possible immune adverse events were documented: grade 3 polyarthropathy 14 weeks following ipilimumab, and 6 weeks post DLI, which resolved with corticosteroid therapy, (AML, DL1); grade 1 hyperthyroidism with thyroid-stimulating antibody 6 weeks post ipilimumab (CLL, DL3). Grade 2 pneumonitis responsive to corticosteroids (HD, DL5). Ten patients received DLI after ipilimumab. Three patients developed objective evidence of disease response after ipilimumab alone: PR in a patient with mantle cell NHL lasting 3m [DL4]; ongoing CR in a two patients with HD [DL5]. Two of these patients had failed prior DLI. Three additional patients demonstrated possible anti-cancer effects (MR in a HD patient, reduction of PB and BM blasts in AML, DL1; maintenance of molecular remission in a CML patient given ipilimumab alone for 3.5 yrs despite stopping imatinib, DL1). This study shows that doses of ipilimumab (up to 3.0 mg/kg) can safely be administered to patients with RM following allo-HCT without inducing/exacerbating GVHD while inducing regressions of malignancy including durable CR in some patients.

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