Pembrolizumab and Vorinostat in Treating Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma, Follicular Lymphoma, or Hodgkin Lymphoma

PRIMARY OBJECTIVES:

I. To assess the safety and tolerability of vorinostat plus pembrolizumab therapy by
evaluation of toxicities including: type, frequency, severity, attribution, time course and
duration.

II. To determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D) of
vorinostat when given in combination with pembrolizumab.

SECONDARY OBJECTIVES:

I. To obtain preliminary estimates of the anti-tumor activity of pembrolizumab plus
vorinostat therapy by assessing the overall response rate (ORR), complete response (CR) rate,
duration of response (DOR), overall survival (OS) and progression-free survival (PFS).

TERTIARY OBJECTIVES:

I. Evaluate responses and disease progression according to the Lymphoma Response to
Immunomodulatory Therapy Criteria (LYRIC).

II. Explore genomic biomarkers of response and resistance to pembrolizumab plus vorinostat
therapy in patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), or
Hodgkin lymphoma (HL).

III. Explore immunologic biomarkers of response and resistance to pembrolizumab plus
vorinostat therapy in patients with DLBCL, FL, or HL.

IV. Explore the value of circulating DNA (ctDNA) as a biomarker of response to pembrolizumab
plus vorinostat therapy.

OUTLINE: This is a dose-escalation study of vorinostat.

Patients receive vorinostat orally (PO) twice a day (BID) on days 1-5 and 8-12 and
pembrolizumab intravenously (IV) over 30 minutes on day 1. Courses repeat every 21 days for
24 months in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, and then every 12
weeks.

Inclusion Criteria:

- Have a histologically confirmed diagnosis of follicular lymphoma, diffuse large B-cell
lymphoma, or classical Hodgkin lymphoma according to the World Health Organization
(WHO) classification, with hematopathology review at the participating institution

- FL: grade 1, 2, 3A, or 3B are eligible

- DBLCL: transformed indolent lymphomas (TIL), primary mediastinal large B-cell
lymphoma (PMBCL), and aggressive B-cell lymphoma unclassified (BCL-U) are
eligible

- HL: all classical HL subtypes are eligible except for nodular lymphocyte
predominant Hodgkin lymphoma, which is excluded

- Patients with HL or DLBCL must refuse or not be candidates for curative autologous
stem cell transplantation

- Have relapsed or refractory disease after at least 1 prior regimen, including:

- Recurrence of disease after a documented complete response (CR)

- Progression of disease after a partial response (PR) to the prior regimen

- Partial response (PR), stable disease (SD) or progressive disease (PD) at the
completion of the prior treatment regimen; if a patient has PR to prior regimen
without PD, there must be biopsy-proven residual disease that is measurable

- Documented informed consent of the participant or legally authorized representative

- Have measurable disease by computed tomography (CT) or positron emission tomography
(PET) scan, with one or more sites of disease >= 1.5 cm in longest dimension

- Be willing to provide tissue from a fresh core or excisional biopsy of a tumor lesion
prior to starting study therapy or from archival tissue of a biopsy that was performed
after the most recent systemic therapy

- Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
performance scale

- Absolute neutrophil count (ANC) >= 1,000/mcL

- Platelets >= 75,000/mcL

- Hemoglobin >= 8g/dL without transfusion or erythropoietin (EPO) dependency (within 7
days of assessment)

- Serum creatinine OR measured or calculated a creatinine clearance (GFR can also be
used in place of creatinine or creatinine clearance [CrCl]) =< 1.5 x upper limit of
normal (ULN) OR >= 60 mL/min for subject with creatinine levels > 1.5 x institutional
ULN

- Serum total bilirubin =< 1.5 x ULN or =< 3 x ULN if patient has Gilberts disease OR
direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN

- 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 as the etiology of
transaminase elevation

- Albumin >= 2.5 mg/dL

- International Normalized Ratio or prothrombin time (PT) (INR) =<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

- Activated partial thromboplastin time (aPTT) =< 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; 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 3 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

- Has received a prior allogeneic hematopoietic stem cell transplant within the past 5
years, requires immunosuppression, or has evidence of active graft-versus-host-disease

- Has received prior autologous hematopoietic stem cell transplant within the last 60
days

- Has a known history of active TB (Bacillus tuberculosis)

- Severe hypersensitivity to pembrolizumab or any of its excipients

- Has had a prior anti-cancer monoclonal antibody (mAb) within 3 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 3 weeks earlier; if a patient has progressive or
stable disease to prior regimen, rituximab is allowed up to 2 weeks prior to the
initiation of study therapy

- 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 taken valproic acid, or another histone deacetylase inhibitor, within 2 weeks
prior to study day 1

- 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) involvement by lymphoma, including
leptomeningeal involvement; subjects with prior CNS involvement by lymphoma must have
remission of the CNS component of the lymphoma; these subjects must have a baseline
magnetic resonance imaging (MRI) during screening without evidence of new or enlarging
brain lesions and must not have any new or progressive neurologic symptoms

- 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 (eg., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment; a history of hemolytic anemia associated with the lymphoma
does not exclude a patient from the study

- Has a history of (non-infectious) pneumonitis that required steroids or current
pneumonitis

- Has an active infection requiring systemic therapy

- Has a QT interval corrected for heart rate (QTc) > 470 ms using the Fridericia
formula; if the screening electrocardiogram (ECG) has a QTc > 470ms, the mean QTc of 3
electrocardiograms (ECGs) can be utilized, but must be < 470 ms

- Is unable to swallow capsules, has a partial or small bowel obstruction, or has a
gastrointestinal condition resulting in a malabsorptive syndrome (e.g. small bowel
resection with malabsorption)

- 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

- Patients who received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
without having had evidence of objective response

- 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 aid [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