Mogamulizumab and Pembrolizumab in Treating Patients With Relapsed or Refractory Lymphomas

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of
mogamulizumab when administered in combination with pembrolizumab in patients with relapsed,
refractory lymphomas. (Phase I) II. To assess the safety and tolerability of mogamulizumab
when administered in combination with pembrolizumab in patients with relapsed, refractory
lymphomas. (Phase I) III. To assess the progression-free survival of mogamulizumab when
administered in combination with pembrolizumab compared to pembrolizumab alone in patients
with relapsed and refractory diffuse large B-cell lymphomas. (Phase II)

SECONDARY OBJECTIVES:

I. To observe and record anti-tumor activity. (Phase I) II. To assess the overall response
rate, complete response rate, partial response rate, duration of response of mogamulizumab
and pembrolizumab compared to pembrolizumab alone in patients with relapsed and refractory
diffuse large B-cell lymphomas. (Phase II)

EXPLORATORY OBJECTIVES:

I. To determine whether the progression-free survival of mogamulizumab and pembrolizumab when
administered to patients with relapsed and refractory diffuse large B-cell lymphomas differs
based on the presence or absence of mutations in B2M or CD58 or amplifications in PD-L1.

II. To determine whether the progression-free survival of mogamulizumab and pembrolizumab
when administered to patients with relapsed and refractory diffuse large B-cell lymphomas
differs based on changes in CD8 T-cell, natural killer (NK) cell, and FoxP3+ regulatory T
cell (Treg) prevalence in response to therapy as measured by immunohistochemistry.

III. To determine whether mogamulizumab and pembrolizumab alters the prevalence of peripheral
blood CCR4+/FoxP3+ regulatory T-cells as well as effector CD4 and CD8 T-cells by
multi-parametric flow cytometry.

OUTLINE: This is a phase I, dose-escalation study of mogamulizumab followed by a phase II
study. Patients are randomized to 1 of 2 arms.

ARM I: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1 and
mogamulizumab IV over 60 minutes on days 1, 8 and 15 of course 1, then day 1 of subsequent
courses.

ARM II: Patients receive pembrolizumab IV over 30 minutes on day 1.

In both arms, courses repeat every 21 days for up to 2 years in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 4 weeks.

Inclusion Criteria:

- For phase 1 dose-escalation: patients must have histologically confirmed relapsed or
refractory lymphoma for which standard curative or palliative measures do not exist or
are no longer effective; this includes non-Hodgkin and Hodgkin lymphomas

- For phase 2: patients must have histologically confirmed diffuse large B-cell
lymphoma; all subtypes of diffuse large B-cell lymphoma are eligible, including
high-grade B-cell lymphoma and diffuse large B-cell lymphoma (DLBCL) that has
transformed from a prior indolent B-cell non-Hodgkin lymphoma

- Patients must have measurable disease per 2014 Lugano Classification Criteria which is
defined as at least one nodal lesion measuring > 1.5 cm in greatest diameter or at
least one extranodal lesion measuring > 1.0 cm in greatest diameter

- For phase 2: patients and received at least 2 prior lines of therapy and must have
previously received or been deemed ineligible for autologous stem cell transplantation

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

- Absolute neutrophil count >= 1,500/mcL (if neutropenia is related to bone marrow
involvement with lymphoma, the absolute neutrophil count must be >= 1,000/mcL)

- Platelets >= 75,000/mcL (if thrombocytopenia is related to bone marrow involvement
with lymphoma, the platelet count must be >= 50,000/mcL)

- Hemoglobin >= 9 g/dL (if anemia is related to bone marrow involvement with lymphoma,
the hemoglobin must be >= 8 g/dL)

- Total bilirubin within normal institutional limits of < 3X the upper limit of normal
in patients with Gilbert's disease

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5x
institutional upper limit of normal

- Creatinine =< 1.5x institutional upper limit of normal OR measured or calculated
creatinine clearance if creatinine > 1.5x upper limit of normal (ULN) then creatinine
clearance >= 40 mL/min/1.73 m^2 as calculated by Cockcroft and Gault equation

- Life expectancy of greater than 3 months

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and for
the duration of study participation; 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; men treated or enrolled on this protocol must also
agree to use adequate contraception prior to the study, for the duration of study
participation, and 4 months after completion of MK-3475 (pembrolizumab) in combination
with KW-0761 (mogamulizumab) administration

- Submit adequate archival tissue specimen from a biopsy performed after progression of
disease on most recent therapy OR subject is willing to undergo a new core or
excisional biopsy to obtain evaluable tumor tissue sample for immunohistochemical
assessment and sequencing for B2M loss; repeat samples may be required if adequate
tissue is not provided

- Ability to understand and the willingness to sign a written informed consent document

- Subjects with prior history of chemotherapy-induced or radiation-induced pulmonary
toxicity require confirmation of diffuse capacity of the lung for carbon monoxide
(DLCO) over 60% (adjusted for hemoglobin) by a pulmonary function test prior to study
enrollment

Exclusion Criteria:

- Patients who have had previous systemic anti-cancer therapy within 3 weeks of
registration or those who have not recovered from adverse events due to agents
administered previously

- Note: Patients are considered enrolled on the study after protocol registration
and not after signing consent

- Patients who are receiving any other concurrent investigational agents

- Patient is receiving systemic steroid therapy or any other form of immunosuppressive
therapy within 7 days prior to the first dose of trial treatment; the use of
physiologic doses of corticosteroids may be approved after consultation with the study
principal investigator (PI); topical or inhaled corticosteroids are allowed

- Has a known additional malignancy that is progressing or requires active treatment;
exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
skin that has undergone potentially curative therapy, or in situ cervical cancer

- Patients with known cerebral or meningeal involvement by lymphoma should be excluded
from this clinical trial

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to MK-3475 (pembrolizumab) or KW-0761 (mogamulizumab)

- Subject with active autoimmune disease; subjects with vitiligo, eczema, alopecia, type
I diabetes mellitus, psoriasis not requiring systemic treatment, or endocrine
deficiencies (such as hypothyroidism) managed with replacement hormones, including
physiologic corticosteroid replacement therapy are eligible

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

- Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the patient's
participation for the full duration of the trial, or is not in the best interest of
the patient to participate, in the opinion of the treating investigator

- Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4
antibody (including ipilimumab or any other antibody or drug specifically targeting
T-cell co-stimulation or checkpoint pathways)

- Prior allogeneic stem cell transplant (SCT)

- Patients who are planning to receive allogeneic SCT in the future

- Autologous SCT =< 90 days prior to first dose of study drug

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, interstitial lung disease or active, non-infectious pneumonitis,
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or
psychiatric illness/social situations that would limit compliance with study
requirements

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with MK-3475

- Patients are excluded from this study if pregnant or breastfeeding, or expecting to
conceive or father children within the projected duration of the trial, starting with
the screening visit through 180 days after the last dose of trial treatment

- Patients with human immunodeficiency virus (HIV) are excluded if they have a
detectable viral load, are not on a stable antiretroviral regimen, have a decreased
CD4+ T-cell count (< 500), or require prophylactic antibiotics for the prevention of
opportunistic infections

- Has known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg]
reactive) or known active hepatitis C virus (defined as HCV ribonucleic acid [RNA]
[qualitative] is detected) infection

- Note: No testing for hepatitis B and hepatitis C is required unless mandated by
local health authority

- Has a known history of active tuberculosis (TB)

- Patients with significant cardiac disease (e.g., New York Heart Association [NYHA]
class III-IV congestive heart failure, unstable angina, recent myocardial infarction
within the last 6 months, etc.)