Pembrolizumab in Relapsed and Refractory Gray-Zone Lymphoma (GZL), Primary Central Nervous System Lymphoma (PCNSL), and Other Extranodal Diffuse Large B-cell Lymphomas

Phase 2

Completed

Conditions: Diffuse Large B-Cell Lymphoma
Gray-zone Lymphoma
Non-Hodgkin Lymphoma
Lymphoma
Primary Central Nervous System Lymphoma

Interventions: Biological: Pembrolizumab

Registration Number: NCT03255018

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: Background:

B-cell lymphoma is a cancer of white blood cells that are found in lymph nodes. Some kinds of these cancers, such as gray-zone and extra-nodal, are rare and often aggressive. They are usually resistant to current treatments. Researchers want to see if a drug called pembrolizumab may treat these types of lymphoma.

Objective:

To collect data to see if it may be effective to give pembrolizumab to people with certain types of rare, aggressive B-cell lymphomas.

Eligibility:

People ages 18 and older who have a B-cell lymphoma, including gray-zone lymphoma or extra-nodal lymphoma

Design:

Participants will be screened with:

Medical history

Physical exam

Blood and urine tests

Scans. They will lie in a machine that takes images.

A tissue sample from a previous procedure will be tested.

The study will be done in 21-day cycles. During the study, participants:

Will repeat the screening tests.

Will get the study drug as an infusion into a vein over about 30 minutes.

Will have a cheek swab and/or saliva sample collected.

May have a bone marrow aspiration. A needle will be put into the hipbone, and a small amount of bone marrow will be taken out.

May have a lumbar puncture. If cerebrospinal fluid is collected, researchers will study it.

May have an eye exam.

May provide tissue samples.

May have tumor samples taken.

Participants will have a visit about 30 days after the last dose of the study drug. They will then have 4 visits in year 1, 2 visits a year in years 2-5, and once each year thereafter. They will also be contacted by phone.

Detailed Description: Background:

* Gray-zone lymphomas (GZL) are rare, aggressive lymphomas that share clinical and biological features of diffuse large B-cell lymphoma (DLBCL) and Hodgkin lymphoma

* Standard upfront therapy for GZL is dose-intensive chemotherapy, though disease is often resistant; consolidative radiation therapy reserved for patients who are relapsed or refractory, and patients who fail radiation therapy have a poor prognosis

* Primary central nervous system lymphoma (PCNSL), primary testicular lymphoma (PTL), primary breast lymphoma (PBL), primary cutaneous DLBCL, leg-type, and intravascular B-cell lymphoma (IVBCL) are rare, aggressive extranodal subsets of DLBCL that usually have gene expression signatures of activated B-cell (ABC) DLBCL

* ABC-DLBCL has cure rates below 40% after standard therapy, and is associated with late recurrences, often involving the central nervous system (CNS) where treatment options are limited by chemotherapy resistance and an inability of many agents to cross the blood-brain barrier

* Molecular biology studies of GZL and extranodal DLBCL have identified potentially targetable genetic features involving the programmed death-1 (PD-1) signaling pathway

* A high proportion of GZL, PCNSL, and PTL cases have copy number alterations or chromosomal rearrangements involving the PD-1 ligands, programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2)

* Pembrolizumab, a humanized immunoglobulin G4 (IgG4) monoclonal antibody that targets the PD-1 receptor, is a rational therapeutic target for patients with relapsed and refractory GZL, PCNSL, PTL, and other extranodal DLBCL

Objectives:

-To determine the best overall response rate of pembrolizumab in patients with relapsed and refractory GZL and extranodal DLBCL

Eligibility:

* Confirmed diagnosis of B-cell lymphoma, relapsed from or refractory to prior:

* Cohort 1: B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma (i.e., Gray-zone lymphoma or GZL)

* Cohort 2: Extranodal diffuse large B-cell lymphoma involving one or more of the specified extranodal sites (i.e., extranodal DLBCL)

* Adequate bone marrow and organ function defined

* Age greater than or equal to 18 years

Design:

* Phase 2 study of patients with relapsed and refractory GZL and extranodal DLBCL

* Patients will be treated with pembrolizumab 200 mg (flat dose) intravenous (IV) every 3 weeks provided they have clinical benefit and no unacceptable toxicity; patients who achieve a complete response (CR) will have the option stop after 1 year of therapy.

* All responding patients (CR, partial response (PR), or stable disease (SD) with clinical benefit) who subsequently relapse or progress within 1 year after discontinuation of study drug are eligible for re-treatment.

* At least 20 evaluable patients each with GZL and DLBCL will be evaluated on this protocol for the primary endpoint (overall accrual ceiling of 52 patients)

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 12

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Participants with Gray-zone Lymphoma (GZL) or Extranodal Diffuse Large B-cell Lymphomas (DLBCL)	Pembrolizumab	Participants with gray-zone lymphoma (GZL) or extranodal DLBCL relapsed from or refractory to prior therapy with an anthracycline-based regimen

Primary Outcome Measures

Name	Time	Method
Best Overall Response Rate of Pembrolizumab in Participants With Relapsed/Refractory Gray-zone Lymphomas (GZL) and Extra-nodal Diffuse Large B-cell Lymphomas (DLBCL)	Up to 24 months	Response was assessed by the International Working Group (IWG) response criteria which utilizes computed tomography (CT) scan to measure lymph node masses to assess response, bone marrow biopsies and aspirates done only if positive at the time of diagnosis or if clinically indicated. Response is calculated by measuring the sum of the products of all target lesions and then calculating the percent change from baseline or nadir. Products are calculated by multiplying the longest length by the perpendicular width of each target lesion. Confirmed complete response is \<1 cm lymph nodes/lymph node masses; unconfirmed complete response is \>1 cm lymph nodes and \>75% decrease in size of lymph node masses; partial response is ≥50% decrease in size of lymph nodes/lymph node masses; and progression is \>50% new or increased lymph node masses/lymph nodes. Complete response (confirmed) followed by complete response(unconfirmed) and partial response are associated with better outcomes in that order.

Secondary Outcome Measures

Name	Time	Method
Number of Grades 1-5 Adverse Events in Participant With Gray-zone Lymphomas (GZL) and Extra-nodal Diffuse Large B-cell Lymphomas (DLBCL)	Adverse events are collected from the first dose of therapy through 30 days past the last dose of study drug or start of new anti-cancer therapy, approximately 5 months and 7 days for cohort 1, and 44 months and 25 days for cohort 2.	Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Grade 1 is mild. Grade 2 is moderate. Grade 3 is serious. Grade 4 is life-threatening. Grade 5 is death related to adverse event.
Event-free Survival (EFS)	up to 2 months	EFS is defined as the duration of time from the date of study enrollment until time of disease relapse, disease progression, alternative therapy for lymphoma given (such as radiation), or death, whichever occurs first. EFS will be estimated for each of the two types of lymphoma individually using Kaplan-Meier curves with appropriate confidence intervals reported. Response was assessed by the International Working Group response criteria (Cheson et al.). Disease relapse is decline in prognosis and progression \>50% increase in lymph node masses/lymph nodes, enlarging liver/spleen, new sites and reappearance in bone marrow.
Duration of Response for Participants Who Respond to Pembrolizumab	every 3-6 months for 24 months	DOR is beginning at the date clinical response is first identified; measured from the time measurement criteria are met for complete response or partial response (whichever is first recorded) until the first date that recurrent or progressive disease is documented and will be estimated for each of the two types of lymphoma individually using Kaplan-Meier curves with appropriate confidence intervals reported. Response was assessed by the International Working Group response criteria (Cheson et al.). Complete response is \<1 cm lymph nodes/lymph node masses, and normal bone marrow/physical exam (PE); unconfirmed complete response is \>1 cm lymph nodes and \>75% decrease lymph node masses, normal PE and indeterminate in bone marrow; partial response is ≥50% decrease in lymph nodes/lymph node masses, decrease in liver/spleen and irrelevant in bone marrow; and progression is \>50% new or increased lymph node masses/lymph nodes, enlarging liver/spleen, and reappearance in bone marrow.
Best Overall Response Rate According to the 5-point Lugano Classification for Interpreting 18 F-fluorodeoxyglucose (FDG)-Positron Emission Tomography (PET) Scans	every 3-6 months for 24 months	The response rate is calculated by dividing the number of participants that had a complete response (CR) or partial response (PR) to therapy measured on positron emission tomography (PET) scan in accordance with the 5-point Lugano classification. Best overall response is the best response (complete or partial response) recorded from the start of the treatment until disease progression/recurrence. The 5-Point Scale Deauville criteria scores the most intense uptake in a site of initial disease: no uptake or no residual uptake, slight uptake, but above blood pool, uptake above mediastinal but below or =to uptake in liver, uptake slightly to moderately higher than liver, \& markedly increased uptake. 5Point Scale ranges:1 to 5, 1=best; 5=worst: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake \> mediastinum but ≤ liver; 4, uptake moderately \> liver; 5, uptake markedly higher than liver; X. CR=scores 1-3 on \& PR is calculated by measured change from baseline (score 4 or 5).
Progression-free Survival (PFS)	up to 2 months	PFS is defined as the duration of time from the date of study enrollment until time of disease relapse, disease progression, or death, whichever occurs first. PFS will be estimated for each of the two types of lymphoma individually using Kaplan-Meier curves with appropriate confidence intervals reported. Response was assessed by the International Working Group response criteria (Cheson et al.). Disease relapse is decline in prognosis and progression \>50% increase in lymph node masses/lymph nodes, enlarging liver/spleen, new sites and reappearance in bone marrow.
Overall Survival (OS)	every 3-6 months, up to 2.5 years	OS is the time from treatment start date until date of death from any cause, date last known alive or last follow up. OS will be estimated for each of the two types of lymphoma individually using Kaplan-Meier curves with appropriate confidence intervals reported.