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

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ClinicalTrials.gov Identifier: NCT03255018
Recruitment Status : Recruiting
First Posted : August 21, 2017
Last Update Posted : March 27, 2018
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( 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 14 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.


Condition or disease Intervention/treatment Phase
Non-Hodgkin Lymphoma Lymphoma Diffuse Large B-Cell Lymphoma Gray Zone Lymphoma Primary Central Nervious System Lymphoma Drug: Pembrolizumab Phase 2

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 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, PD-L1 and PD-L2
  • Pembrolizumab, a humanized 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 14 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) 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, PR, or 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)

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 52 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 2 Trial of Pembrolizumab in Relapsed and Refractory Gray-Zone Lymphoma (GZL), Primary Central Nervous System Lymphoma(PCNSL), and Other Extranodal Diffuse Large B-cell Lymphomas
Actual Study Start Date : February 15, 2018
Estimated Primary Completion Date : July 1, 2020
Estimated Study Completion Date : July 1, 2022


Arm Intervention/treatment
Experimental: 1
Subjects with gray-zone lymphoma (GZL) or extranodal DLBCL relapsed from or refractory to prior therapy with an anthracycline-based regimen
Drug: Pembrolizumab
Administered intravenously (IV) at a fixed dose of 200 mg every 3 weeks until disease progression or unacceptable toxicity; treatment may continue indefinitely if clinical benefit with options for treatment interruption if responding disease and re-treatment upon relapse.



Primary Outcome Measures :
  1. Best overall response rate of pembrolizumab in patients with relapsed/refractory gray- zone lymphomas (GZL) and extra-nodal diffuse large B-cell lymphomas (DLBCL) [ Time Frame: 24 months ]
    The response rate will be determined and reported along with a 95% confidence interval.


Secondary Outcome Measures :
  1. toxicity profile of pembrolizumab in patients with GZL and extra-nodal DLBCL [ Time Frame: every 3 weeks ]
    The type, grade and frequency of toxicities will be reported.

  2. best overall response rate according to the 5-point Lugano classification for interpreting FOG-PET scans [ Time Frame: every 3-6 months for 24 months ]
    The response rate will be will be estimated for each of the two types of lymphoma individually using Kaplan- Meier curves with appropriate confidence intervals reported.

  3. duration of response for patients who respond to pembrolizumab [ Time Frame: every 3-6 months for 24 months ]
    The duration of response (DOR; beginning at the date clinical response is first identified) will be estimated for each of the two types of lymphoma individually using Kaplan-Meier curves with appropriate confidence intervals reported.

  4. progression-free survival (PFS) [ Time Frame: every 3-6 months for 24 months ]
    The progression free survival (PFS) will be estimated for each of the two types of lymphoma individually using Kaplan-Meier curves with appropriate confidence intervals reported.

  5. event-free survival (EFS) [ Time Frame: every 3-6 months for 5 years ]
  6. overall survival (OS) [ Time Frame: every 3-6 months for 5 years ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   14 Years to 99 Years   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:
  • Patients must have a diagnosis of B-cell lymphoma confirmed by Laboratory of Pathology, NCI, that is relapsed from or refractory to prior therapy as follows:

    • 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). The following subtypes are included (they do not have to be confirmed as non-GCB subtype for study entry):

      • Primary CNS lymphoma (PCNSL)
      • Primary testicular lymphoma (PTL)
      • Primary breast lymphoma (PBL)
      • Primary cutaneous DLBCL, leg-type
      • Intravascular large B-cell lymphoma (IVBCL)
      • Diffuse large B-cell, NOS, activated B-cell type, involving 1 or more extranodal site

NOTE: For GZL, diagnosis will be in accordance with the 2016 World Health Organization classification of lymphoid malignancies. Patients diagnosed with other extranodal DLBCL subtypes or that are not otherwise specified (NOS) must involved at least 1 extranodal site and must be considered non-GCB by local immunohistochemistry algorithms. Cases that are non-GCB by the Hans criteria are considered eligible as well as cases of DLBCL that are both CD10+ and MUM1+.

  • Evaluable disease by clinical exam (i.e., palpable lymphadenopathy, measurable skin lesions, etc.), laboratory assessment (i.e., lymphoma involvement of bone marrow or peripheral blood by morphology, cytology or flow cytometry), and/or imaging (measurable lymph nodes or masses on CT or MRI and/or evaluable FDG-avid lesions on PET)
  • Adequate tumor tissue (archival or fresh) must be available for correlative studies. NOTE: Tumor tissue may be from any previously collected tissue and adequacy is at the discretion of the Principal Investigator. If prior tissue is not available, patient must be willing to undergo baseline tumor biopsy.
  • Be 14 years of age or older on day of signing informed consent
  • Adequate performance status (PS) as follows:

    • Patients greater than or equal to 16 years must have ECOG 0-1 (and Karnofsky greater than or equal to 60%)
    • Pediatric patients < 16 years must have Lansky play-performance of equal to or less than 60.

NOTE: Patients greater than or equal to 16 years with an ECOG PS of 2 and Karnofsky greater than or equal to 60 will be considered eligible at the discretion of the Principal Investigator if decreased ECOG performance status is felt to be related to residual neurologic deficits caused by CNS disease involvement that are not progressive or anticipated to cause clinical managemnt problems during study participation.

- Adequate organ function as evidenced by the following laboratory parameters (unless related to lymphoma infiltration at the discretion of the investigator):

  • Absolute neutrophil count (ANC) greater than or equal to 750 /mcL
  • Platelets greater than or equal to 50,000 / mcL (transfusions not permitted)
  • Hemoglobin greater than or equal to 9 g/dL (transfusions permitted)
  • Serum creatinine: Adults: less than or equal to 1.5 times upper limit of normal (ULN). Children: age greater than or equal to 14: less than or equal to 1.5 mg/dL OR Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl):

Greater than or equal to 30 mL/min/1.73 m(2) for subject with creatinine levels > 1.5 times institutional ULN (CrCl should be calculated per institutional standard)

--Serum total bilirubin less than or equal to 1.5 times ULN

OR

Direct bilirubin less than or equal to ULN for patients with total bilirubin levels > 1.5 ULN

  • AST (SGOT) and ALT (SGPT) less than or equal to 3 times ULN (less than or equal to 5 X ULN if liver involvement)

    - The effects of pembrolizumab on the developing human fetus are unknown. For this reason, the following measures apply:

  • Women of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to the first dose of pembrolizumab.
  • Men and women of childbearing potential (WOCBP) who are sexually active must agree to adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for at least 120 days after the last dose of pembrolizumab. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
  • Participants must not be planning to conceive or father children within the projected duration of the trial, starting with the pre-screening/screening visit through 120 days after the last dose of pembrolizumab.
  • WOCBP is defined as any female who has experienced menarche and who has not undergone successful surgical sterilization or who is not postmenopausal.

    • Ability of patient or Legally Authorized Representative (LAR) to understand and the willingness to sign a written informed consent document

EXCLUSION CRITERIA:

  • Patients with DLBCL who best fit the criteria of EBV+ DLBCL, NOS are not eligible
  • Current or prior anti-cancer treatment prior to the first dose of pembrolizumab as defined below:

    • Chemotherapy, targeted small molecule therapy, or other anti-cancer treatment not otherwise specified below within 2 weeks
    • Radiation therapy within 2 weeks
    • Anti-cancer monoclonal antibody (mAb) treatment within 4 weeks
    • Use of an investigational agent (e.g., biologic, drug, or other) within 4 weeks
    • Allogeneic stem cell transplant within 100 days
    • Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent at any time
  • Uncontrolled intercurrent illness including, but not limited to the following that may limit interpretation of results or that could increase risk to the patient at the discretion of the investigator:

    • 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). NOTE: 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.
    • History of (non-infectious) pneumonitis that required steroids, evidence of interstitial lung disease or active, non-infectious pneumonitis.
    • Hepatitis B virus surface antigen or Hepatitis B core antibody positive
    • Active hepatitis C infection. NOTE: Subjects who are hepatitis C antibody positive will need to have a negative PCR result before enrollment. Those with a positive PCR for hepatitis C are excluded.
    • Uncontrolled and/or symptomatic thyroid disease
    • Active graft-vs-host disease (GVHD) requiring treatment or any history of >= grade II acute GVHD
    • Seizure activity within the past 4 weeks
    • Known mental or physical illness that would interfere with cooperation with the requirements of the trial or confound the results or interpretation of the results of the trial and, in the opinion of the treating investigator, would make the patient inappropriate for entry into the study.
  • Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with pembrolizumab, breastfeeding must be discontinued if the mother is treated with pembrolizumab
  • Received a live vaccine within 30 days of planned start of study therapy. NOTE: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist ) are live attenuated vaccines, and are not allowed.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to pembrolizumab unless felt to be in the best interests of the patient in the opinion of the investigator
  • Known additional malignancy that requires active systemic treatment

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03255018


Contacts
Contact: Maureen E Edgerly, R.N. (240) 760-6013 edgerlym@pbmac.nci.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Mark J Roschewski, M.D. National Cancer Institute (NCI)

Additional Information:
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03255018     History of Changes
Other Study ID Numbers: 170149
17-C-0149
First Posted: August 21, 2017    Key Record Dates
Last Update Posted: March 27, 2018
Last Verified: March 23, 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
Monoclonal Antibody
PD-1 Receptor

Additional relevant MeSH terms:
Lymphoma
Lymphoma, Non-Hodgkin
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Pembrolizumab
Antineoplastic Agents