A Phase II Study of Pembrolizumab (MK-3475) in Subjects with Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL) or Relapsed or Refractory Richter Syndrome (rrRS)
The goal of this optional sub-study is to collect new blood samples and leftover blood and/or tissue samples for use in future research related to cancer. This research may include genetic research and biomarker testing (which may include genetic biomarkers), and pharmacogenetic (PGt) testing. Biomarkers are found in the blood and tissue and may be related to your reaction to the study drugs. PGt testing looks at how someone's genes may influence how they respond to chemotherapy drugs. This testing is different from genetic testing done to diagnose you with a genetic disease or find out your risk of having a genetic disease.
Disease Group: Malignant neoplasms stated as primary lymphoid haematopoietic
Treatment Agent: Pembrolizumab
Treatment Location: Both at MDACC & and Other Sites
Sponsor: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
This clinical research phase II study will only enroll patients with relapsed or refractory Richter Syndrome. A separate study (2015-0916) will enroll patients with relapsed or refractory primary mediastinal large B-cell lymphoma. Primary Objective: In subjects with Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL) or Refractory Richter Syndrome (rrRS) : 1) To evaluate the Overall Response Rate (ORR) of pembrolizumab by independent central review according to the International Working Group (IWG) response criteria with special considerations for Richter Syndrome (RS). Secondary Objective: 1) To evaluate the Overall Response Rate (ORR) of pembrolizumab by investigator assessment according to the International Working Group (IWG) response criteria or IWG with special considerations for RS. 2) To evaluate Progression Free Survival (PFS), Duration of Response (DOR) and Disease Control Rate (DCR) of pembrolizumab by independent central review and investigator assessment according to the IWG response criteria or IWG with special considerations for RS. 3) To evaluate the Overall Survival (OS) of patients treated with pembrolizumab. 4) To determine the safety and tolerability of pembrolizumab. Exploratory Objectives: 1) To evaluate efficacy (ORR, PFS, DOR, and DCR), incorporating response assessments for subjects continuing pembrolizumab treatment after initial progression. 2) To evaluate the Overall Response Rate (ORR) of pembrolizumab by independent central review and investigator assessment, the 5-point scale according to the Lugano Classification will be used in appropriate patients. 3)To compare the extent of pre-pembrolizumab PD-L1 expression in tumor biopsies for pembrolizumab responders versus non-responders. 4) To investigate the relationship between candidate efficacy biomarkers and anti-tumor activity of pembrolizumab utilizing pre- and post-treatment lymph node biopsies and blood sampling. 5) To evaluate pharmacokinetic parameters, and the presence of anti -drug antibodies, following intravenous (IV) administration of 200 mg pembrolizumab Q3W, as monotherapy. 6) To explore the relationship between genetic variation and response to the treatment(s) administered. Variation across the human genome will be analyzed for association with clinical data collected in this study.
IRB Review and Approval Date: 06/29/2017
Recruitment Status: Not Accepting
Projected Accrual: 53
1) Be willing and able to provide written informed consent for the
trial. The subject may also provide consent for Future Biomedical
Research. However, the subject may participate in the main trial without
participating in Future Biomedical Research.
2) Be >/= 18 years of age on day of signing informed consent.
3) Diagnosis of Primary Mediastinal Large B-cell lymphoma, according to the WHO classification of neoplasms of the hematopoietic and lymphoid tissues. Subject must be able to provide an evaluable core or excisional lymph node biopsy for evaluation of PMBCL diagnosis from an archival or newly obtained lymph node biopsy at Screening. (Central review is not required before enrollment. Enrollment can be done on local pathologic review for diagnosis.)
4) Have relapsed or refractory Richters syndrome and has received at least 1 previous treatment for RS.
5) Must have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
6) Life expectancy >/= 3 months
7) Must demonstrate adequate organ function as defined in Table 1; all screening labs should be performed within 7 days of treatment initiation. (Subjects may be enrolled based on local laboratory results pending central laboratory results.)
8) Female subjects of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
9) Female subjects of childbearing potential must be willing to use an adequate method of contraception as outlined in the protocol. Contraception, for the course of the study through 120 days after the last dose of study medication.
10) Male subjects of childbearing potential must agree to use an adequate method of contraception as outlined in the protocol . Contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy.
11) Have radiographically measureable disease by independent central review, defined as at least one lesion that can be accurately measured in at least two dimensions with appropriate anatomic imaging (CT scan or MRI). Minimum measurement must be >/= 15 mm in the longest diameter.
1) Is currently participating and receiving study therapy or has
participated in a study of an investigational agent and received study
therapy or used an investigation al device within 4 weeks of the first
dose of treatment.
2) Is receiving systemic steroid therapy < 3 days before the first dose of trial treatment or receiving any other form of immunosuppressive medication. Note: (a) Corticosteroid use on study after Cycle 1 for management of adverse events, serious adverse events, and events of clinical interest, as a premedication for IV contrast allergies/reactions, or if considered necessary for a subject’s welfare is allowed. (b) Subjects who receive daily steroid replacement therapy are an exception. Daily prednisone at doses of 5 to 7.5 mg is an example of replacement therapy. (c) Equivalent hydrocortisone doses are also permitted if administered as replacement therapy.
3) Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered (i.e. </= Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
4) Has had prior chemotherapy or targeted small molecule therapy within 2 weeks prior to study Day 1 or has had prior radiation therapy within 4 weeks prior to study Day 1 or who has not recovered (i.e. </= Grade 1 or at baseline) from adverse events due to a previously administered agent. Exception: Subjects with RS with CLL may receive ibrutinib (or similar for CLL) up to 7 days before study Day 1. Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy. Note: Toxicity that has not recovered to </= Grade 1 is allowed if it meets the inclusion requirements for laboratory parameters defined in the protocol.
5) Has undergone prior allogeneic hematopoetic stem cell transplantation within the last 5 years. (Subjects who have had a transplant greater than 5 years ago are eligible as long as there are no symptoms of Graft versus Host Disease (GVHD).
6) Has a known additional malignancy (except underlying CLL for RS) that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.
7) Has known active CNS involvement. Subjects with prior CNS involvement are eligible if their CNS disease is in radiographic, cytological (for CSF disease) and clinical remission.
8) Has active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
9) Has a history of (non-infectious) pneumonitis that required steroids, or current pneumonitis.
10) Has an active infection requiring intravenous systemic therapy.
11) Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
12) 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.
13) Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
14) Has a known history of Human Immunodeficiency Virus (HIV)(HIV ½ antibodies).
15) Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
16) Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
Information and next steps
Malignant neoplasms stated as primary lymphoid haematopoietic
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