Pidilizumab in Treating Patients With Stage III-IV Diffuse Large B-Cell Lymphoma Following First Remission

Study Overview
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Brief Summary
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The purpose of this study is to evaluate pidilizumab and its effect, bad and/or good, on the immune system in relation to its ability to fight cancer cells. Many cancers can be brought to a phase called complete remission (no cancer is found) but have a chance that they may come back. Researchers are working to improve therapy and to find new drugs that lower the chance of disease coming back. This study uses a drug called pidilizumab. The drug targets our immune system. It can change how our immune system finds cancer cells. The drug may kill any remaining cancer cells that we cannot see with computed tomography (CT) scans. The drug, pidilizumab, is being studied in other cancers.

Detailed Description
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PRIMARY OBJECTIVES: I. To estimate the rate of response, whereby either cluster of differentiation (CD)4+CD25+programmed death 1 ligand 1 (PD-L1)+ T lymphocytes or CD4+CD62L+CD127+ T lymphocytes has an increase following administration of pidilizumab in patients with diffuse large B-cell lymphoma (DLBCL) that have completed induction chemotherapy. SECONDARY OBJECTIVES: I. To determine the toxicity and tolerability of pidilizumab therapy following induction chemotherapy. II. To estimate the progression free survival (PFS) at 2 years. III. To estimate the overall survival (OS) at 2 years. IV. To estimate time to second line chemotherapy (TSLC) at 2 years. TERTIARY OBJECTIVES: I. To characterize programmed death 1 (PD-1) pathway specific expression markers from the diagnostic biopsy specimens. II. To characterize serum biomarkers of immune and inflammatory response during treatment with pidilizumab. III. To characterize levels of soluble PD-L1 related to treatment with pidilizumab. OUTLINE: Patients receive pidilizumab intravenously (IV) over approximately 5 hours on day 1. Treatment repeats every 42 days for 3 courses in the absence of disease progression or unacceptable toxicity. After completion of treatment, patients are followed up at 30 days and then every 3 months for 2 years.

Official Title
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Phase II Study of Pidilizumab (MDV9300) in Patients With Diffuse Large B-Cell Lymphoma Following First Remission

Conditions
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Stage III Diffuse Large B-Cell Lymphoma, Stage IV Diffuse Large B-Cell Lymphoma

Intervention / Treatment
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* Other: Laboratory Biomarker Analysis
* Biological: Pidilizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed de novo DLBCL by the 4th edition of the World Health Organization (WHO) Classification of Tumors of Hematopoietic and Lymphoid Tissues published in 2008; patients with transform lymphoma are excluded; patients with known primary mediastinal large B-cell lymphoma (PMLBCL) are excluded; patients with known c-v-myc avian myelocytomatosis viral oncogene homolog (c-myc) translocation (by fluorescence in situ hybridization) positive DLBCL are eligible for enrollment; c-myc testing prior to study enrollment is not required; availability of diagnostic biopsy samples in encouraged for the exploratory analysis but not required for enrollment; patients with double-hit or triple-hit lymphoma are eligible for enrollment Previously completed anthracycline-based induction chemotherapy with standard regimens including rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (R-CHOP), dose adjusted (DA)-etoposide, prednisone, vincristine sulfate, doxorubicin hydrochloride, cyclophosphamide (EPOCH), and rituximab (R), and R-hyper cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, dexamethasone, methotrexate, and cytarabine (CVAD); patients need a minimum of 6 cycles of treatment; initial treatment with pidilizumab must be administered between 30-90 days from last dose of induction chemotherapy Complete remission (CR) according to the Revised Response Criteria for Malignant Lymphoma after first-line treatment Diagnostic CT scans with contrast of chest, abdomen, and pelvis must have been performed within 8 weeks from the first day of the last cycle of R-chemotherapy; a neck CT will be required if the patient had involvement of the neck region at initial diagnosis A negative fludeoxyglucose F 18 (FDG)-positron emission tomography (PET)/CT scan performed within 8 weeks from the first day of the last cycle of R-chemotherapy and confirming CR, with negative defined as a score of 1-3 on the Deauville 5-point scale used to quantify radionucleotide density in PET scans as determined locally; PET positive/indeterminate lesions which are confirmed on biopsy to harbor no active lymphoma will be considered negative for determination of CR status If positive bone marrow involvement at initial diagnosis the patient must have a negative bone marrow biopsy following R-chemotherapy to confirm the CR Stage III/IV disease by Ann Arbor Staging Eastern Cooperative Oncology Group (ECOG) performance status =< 2 Any National Comprehensive Cancer Network (NCCN)-International Prognostic Index (IPI) score; a calculated score required for enrollment Absolute neutrophil count (ANC) >= 1000 Platelet count >= 50,000 Total bilirubin =< 2 x upper limit of normal (ULN) or if total bilirubin is > 2 x ULN, the direct bilirubin must be normal Alkaline (Alk.) phosphatase =< 3 x ULN Aspartate aminotransferase (AST) =< 3 x ULN Creatinine =< 2 x ULN or creatinine clearance (CrCl) > 30 ml/min Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test at enrollment; FCBP must either commit to abstinence from heterosexual intercourse or commit to the use of 2 acceptable methods of birth control; a FCBP is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months) Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy All subjects must have given signed, informed consent prior to registration on study Exclusion Criteria: Active malignancy requiring therapy such as radiation, chemotherapy, or immunotherapy; exceptions to this are as follows: localized nonmelanotic skin cancer and any cancer that in the judgment of the investigator has been treated with curative intent and will not interfere with the study treatment plan and response assessment Known central nervous system (CNS) involvement Prior stem cell transplantation (autologous or allogeneic) Persistent diarrhea or malabsorption > National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade 2, despite medical management Subjects with known immunodeficiency, known autoimmune disease, or concurrent use of immunomodulatory agents Any cancer directed therapies between completion of induction chemotherapy and treatment on protocol Known hypersensitivity to murine or chimeric antibodies or proteins Presence of co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens; this includes, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Subjects with known human immunodeficiency virus (HIV) infection Subjects with known active hepatitis B virus (HBV) and hepatitis C virus (HCV) infection Women must not be pregnant or breast-feeding Unwillingness or inability to comply with the protocol

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (pidilizumab)<br>Patients receive pidilizumab IV over approximately 5 hours on day 1. Treatment repeats every 42 days for 3 courses in the absence of disease progression or unacceptable toxicity. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Biological: Pidilizumab<br>* Given IV<br>* Other names: CT-011;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response to Pidilizumab | Response will be defined as the proportion of CD4+CD25+PD-L1+ T lymphocytes and CD4+CD62L+CD127+ T lymphocytes responders. Responders are defined as either a) a 50% increase or b) a half standard deviation increase in lymphocyte subsets. Lymphocyte subsets will be evaluated by flow cytometry on peripheral blood obtained at specified time points through the treatment period. | Baseline to up to 127 days. Study terminated before this timeframe. As a result insufficient data was collected to be analyzed. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Frequency and Severity of Toxicity - Number of Grade 1, 2, 3, 4, and 5, Adverse Events Experienced During Treatment of Pidilizumab Defined by NCI CTCAE v 4.03. | Adverse events (AEs) were graded according to the National Cancer Institute's Common Toxicity Criteria for Adverse Events (CTCAE) version 3.0. In general, AEs are graded according to the following: Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE | Start of treatment, and at days 22, 43, 85, 127 and every 3 months for up to 2 years. Due to early termination of the study, AEs for all patients were collected throughout treatment and up to the point of termination of the study. | 
| Overall Survival (OS) | To estimate the overall survival (OS) at 2 years | From study enrollment until death, or until last contact, assessed up to 2 years. Study terminated before this timeframe. As a result insufficient data was collected to be analyzed. | 
| Progression Free Survival (PFS) | To estimate the progression free survival (PFS) at 2 years. PFS will be defined as time from study enrollment until the first occurrence of disease relapse, progression, re-initiation of cytotoxic chemotherapy, or death due to disease, or until last contact if the patient did not experience any of these. | Up to 2 years. Study terminated before this timeframe. As a result insufficient data was collected to be analyzed. | 
| Relapsed Disease |  | Up to 2 years. Study terminated before this timeframe. As a result insufficient data was collected to be analyzed. | 
| Time to Second Line Chemotherapy (TSLC) | To estimate time to second line chemotherapy (TSLC) at 2 years | Up to 2 years |