PET-Directed Therapy With Pembrolizumab and Combination Chemotherapy in Treating Patients With Previously Untreated Classical Hodgkin Lymphoma

PRIMARY OBJECTIVES:

I. Assess the percent of patients who achieve a complete response (CR) to single-agent
pembrolizumab induction, among patients with classical Hodgkin lymphoma (cHL) using Lugano
2014 criteria., as measured at PET #2.

SECONDARY OBJECTIVES:

I. Assess the safety and tolerability of pembrolizumab in combination with chemotherapy in
the frontline setting.

II. Determine the three-year progression free survival (PFS) and overall survival (OS) for
patients < 60 with early non-bulky disease, and elderly patients (all stages) treated with
pembrolizumab with doxorubicin hydrochloride (Adriamycin), (bleomycin), vinblastine sulfate,
dacarbazine (A[B]VD) in the frontline treatment of patients with cHL.

III. Determine the extent of fludeoxyglucose F-18 (FDG) uptake, using a semi-quantitative
approach (e.g., Deauville score), after pembrolizumab induction, and after subsequent
chemotherapy.

TERTIARY OBJECTIVES:

I. To characterize PD-1 pathway specific expression and correlate with response.

II. To characterize serum biomarkers of immune and inflammatory response during treatment.

III. To characterize levels of soluble PD-L1 related to treatment with pembrolizumab.

IV. To characterize T-lymphocyte subset changes to treatment with pembrolizumab.

V. To investigate the prevalence and clinical correlation of chromosome 9p24.1 alterations
for this population.

OUTLINE:

INITIATION: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1.
Treatment repeats every 21 days for up to 3 courses in the absence of disease progression or
unacceptable toxicity. Patients also undergo FDG-PET/computed tomography (CT) scans before
the start of pembrolizumab and after 3 courses.

AVD: Within 21 days after final dose of pembrolizumab, patients receive doxorubicin
hydrochloride IV, vinblastine sulfate IV, and dacarbazine IV over 30 minutes on days 1 and
15. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression
or unacceptable toxicity. Patients then undergo a final FDG-PET/CT scan on day 117-120 or
26-29 of course 2. Patients with stage I/II disease with a CR continue treatment for up to 2
courses. Patients with stage III/IV disease with a CR or age >= 60 with stage III/IV disease
with any response continue treatment for up to 4 courses.

CONSOLIDATION: Patients age >= 60 with stage III/IV disease who received < 6 courses of AVD
or patients age >= 60 with DV 4-5 on FDG-PECT/CT scan receive pembrolizumab IV over 30
minutes on day 1. Treatment repeats every 21 days for up to 17 cycles in the absence of
disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years.

Inclusion Criteria:

- Patients must have a histologically confirmed diagnosis of classical Hodgkin lymphoma
including nodular sclerosis, mixed cellularity, lymphocytic-rich, and lymphocyte
depleted subtypes by the 4th edition of the World Health Organization (WHO)
Classification of Tumors of Hematopoietic and Lymphoid Tissues published in 2008
(nodular lymphocyte-predominant Hodgkin lymphoma [NLPHL] excluded)

- Patients must have measurable disease by the Lugano criteria

- Patients must have previously untreated disease (except for one week or less of
corticosteroids)

- Patients must exhibit a/an Eastern Cooperative Oncology Group (ECOG) performance
status of 0-1

- Patients may have any stage and any International Prognostic Score (IPS)

- Patients must have adequate organ and bone marrow function within 14 days prior to
registration, as defined below:

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcl

- Total bilirubin within normal institutional limits

- Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT])
=< 2.5 X institutional upper limit of normal (ULN)

- Creatinine within normal institutional limits

- Platelet transfusions are acceptable prior to treatment to achieve the above numbers,
however growth factors are not allowed within 14 days of registration

- Females of child-bearing potential (FOCBP) and males must agree to avoid becoming
pregnant, or impregnating a partner, respectively, by complying with any of the
approved contraception techniques prior to registration, for the duration of study
participation, and for 120 days following completion of therapy; abstinence is
acceptable if this is the usual lifestyle and preferred contraception for the subject;
should a female patient become pregnant or suspect she is pregnant while participating
in this study, she should inform her treating physician immediately

NOTE: A FOCBP is any woman (regardless of sexual orientation, having undergone a tubal
ligation, or remaining celibate by choice) who meets the following criteria:

- Has not undergone a hysterectomy or bilateral oophorectomy

- Has had menses at any time in the preceding 12 consecutive months (and therefore has
not been naturally postmenopausal for > 12 months)

- FOCBP must have a negative pregnancy test within 7 days prior to registration on
study; NOTE: a negative pregnancy test is also required within 3 days prior to
first dose of pembrolizumab and therefore may need to be repeated if screening
test is more than 3 days prior to first dose

- Patients must have the ability to understand and the willingness to sign a
written informed consent prior to registration on study

Exclusion Criteria:

- Patients are not eligible who have had prior chemotherapy, targeted small molecule
therapy, or radiation therapy within 2 weeks prior to registration or who have 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

- Patients who have a diagnosis of immunodeficiency or are receiving systemic steroid
therapy or any other form of immunosuppressive therapy within 7 days prior to
registration are not eligible

- Patients who have a known history of active TB (bacillus tuberculosis) are not
eligible

- Patients must not have a history of allergic reactions attributed to compounds of
similar chemical or biologic composition to pembrolizumab

- Patients who have an uncontrolled intercurrent illness including, but not limited to
any of the following, are not eligible:

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Cardiac arrhythmia

- Patients who have a known additional malignancy that is progressing or requires active
treatment are not eligible

- NOTE: 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

- Patients who have known active central nervous system (CNS) metastases and/or
carcinomatous meningitis are not eligible

- NOTE: Subjects with previously treated brain metastases 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 registration; this exception
does not include carcinomatous meningitis which is excluded regardless of
clinical stability

- Patients who have active autoimmune disease that has required systemic treatment in
the past 2 years are not eligible (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

- Patients who have known history of, or any evidence of active, non-infectious
pneumonitis are not eligible

- Patients who have an active infection requiring systemic therapy are not eligible,
except for uncomplicated urinary tract infections

- Patients are not eligible who have 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

- Patients who have known psychiatric or substance abuse disorders that would interfere
with cooperation with the requirements of the trial are not eligible

- Patients may not be pregnant or breastfeeding, or expecting to conceive or father
children within the projected duration of the trial, from registration through 120
days after the last dose of trial treatment

- Patients who have received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2
agent are not eligible

- Patients who have a known history of human immunodeficiency virus (HIV) (HIV 1/2
antibodies) are not eligible

- Patients who have active hepatitis B (e.g., hepatitis B virus surface antigen [HBsAg]
reactive) or hepatitis C (e.g., hepatitis c virus [HCV] ribonucleic acid [RNA]
[qualitative] is detected) are not eligible

- Patients who received a live vaccine within 30 days of planned start of study therapy
are not eligible; examples of live vaccines include, but are not limited to, the
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, bacillus
Calmette-Guerin (BCG), and typhoid vaccine

- 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