PRIMARY OBJECTIVES:
I. Overall response rate (ORR) of rituximab and pembrolizumab in relapsed/refractory
follicular lymphoma (FL).
II. Overall response rate (ORR) of rituximab and pembrolizumab in relapsed/refractory diffuse
large B cell lymphoma (DLBCL).
SECONDARY OBJECTIVES:
I. To evaluate the safety and tolerability of the combination of rituximab and pembrolizumab,
and of extended pembrolizumab administered for up to 1 year.
II. To evaluate progression-free survival (PFS), and overall survival (OS) with this
combination, in relapsed/refractory FL, and relapsed/refractory DLBCL.
III. To explore treatment outcomes with this combination in patients with rituximab
refractory FL.
OUTLINE:
INDUCTION: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1.
Patients also receive rituximab IV on days 1, 8, and 15 of course 1 and on day 1 of course 2.
Courses repeat every 3 weeks for 4 courses in the absence of disease progression or
unacceptable toxicity.
EXTENDED THERAPY: Patients with at least a partial response receive pembrolizumab IV over 30
minutes on day 1. Courses repeat every 3 weeks for up to 2 years (35 doses) in the absence of
disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 90 days.
Inclusion Criteria:
- Subjects must have relapsed/refractory DLBCL or relapsed/refractory FL
- For DLBCL, patients must have relapsed after, declined, or considered ineligible
for high-dose chemotherapy and autologous stem cell transplantation
- For FL, in addition to relapsed/refractory disease status, patients must have
received therapy with CD20 antibody-directed therapy, and must have an indication
for treatment; FL eligibility also requires patients have no standard options
with curative potential, nor options with more favorable risk/benefit ratio in
the judgment of the investigator
- Be willing and able to provide written informed consent/assent for the trial
- Have measurable disease (1.5 cm or greater in the longest diameter of nodal or
extranodal disease)
- Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
performance scale
- Within 28 days of cycle 1 day 1: Absolute neutrophil count (ANC) >= 1,000/mcL
- Within 28 days of cycle 1 day 1: Platelets >= 75,000/mcL
- Within 28 days of cycle 1 day 1: Hemoglobin >= 8 g/dL
- Within 28 days of cycle 1 day 1: Serum creatinine =< 1.5 X upper limit of normal (ULN)
OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can
also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min for
subject with creatinine levels > 1.5 X institutional ULN
- Within 28 days of cycle 1 day 1: Serum total bilirubin =< 1.5 X ULN OR direct
bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN
- Within 28 days of cycle 1 day 1: Aspartate aminotransferase (AST) (serum
glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum
glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for subjects with
liver involvement by lymphoma
- Within 28 days of cycle 1 day 1: Albumin >= 2.5 mg/dL
- Within 28 days of cycle 1 day 1: International normalized ratio (INR) or prothrombin
time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT
or partial thromboplastin time (PTT) is within therapeutic range of intended use of
anticoagulants
- Within 28 days of cycle 1 day 1: Activated (a)PTT =< 1.5 X ULN unless subject is
receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of
intended use of anticoagulants
- Female subject of childbearing potential should have a negative urine or serum
pregnancy 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
- Female subjects of childbearing potential must be willing to use an adequate method of
contraception; contraception, for the course of the study through 120 days after the
last dose of study medication
- Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject
- Male subjects of childbearing potential must agree to use an adequate method of
contraception starting with the first dose of study therapy through 120 days after the
last dose of study therapy
- Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject
Exclusion Criteria:
- Is currently participating and receiving study therapy or has participated in a study
of an investigational agent and received study therapy or used an investigational
device within 4 weeks of the first dose of treatment
- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to the first dose of trial
treatment, except for physiologic corticosteroid replacement therapy for adrenal or
pituitary insufficiency which is permitted
- Has a known history of active TB (Bacillus tuberculosis)
- Hypersensitivity to pembrolizumab or any of its excipients
- Has had a prior anti-cancer monoclonal antibody (mAb) 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
- Prior allogeneic transplant, within the last 5 years
- Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
within 2 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
- Note: Subjects with =< grade 2 neuropathy are an exception to this criterion and
may qualify for the study
- Note: If subject received major surgery, they must have recovered adequately from
the toxicity and/or complications from the intervention prior to starting therapy
- Has a known additional malignancy that is progressing or requires active treatment;
exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
skin that has undergone potentially curative therapy or in situ cervical cancer
- Has known active central nervous system (CNS) metastases and/or lymphomatous
meningitis; subjects with previously treated brain metastases or lymphomatous
meningitis may participate provided they are stable (without evidence of progression
by imaging for at least four weeks prior to the first dose of trial treatment and any
neurologic symptoms have returned to baseline), have no evidence of new or enlarging
brain metastases, and are not using steroids for at least 7 days prior to trial
treatment
- Has 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); 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
- Has known history of, or any evidence of active, non-infectious pneumonitis
- Has an active infection requiring systemic therapy
- Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject's
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator
- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial
- 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
- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
- Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
- Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or
hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is
detected)
- Has 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
