Lenvatinib Mesylate and Pembrolizumab in Treating Patients With Metastatic or Recurrent Gastric or Gastroesophageal Cancer

PRIMARY OBJECTIVES:

I. To determine the overall response rate as measured by Response Evaluation Criteria in
Solid Tumors (RECIST) 1.1 for the combination of lenvatinib mesylate (lenvatinib) and
pembrolizumab in patients with metastatic gastroesophageal cancer who have progressed on
first or subsequent line(s) therapies.

SECONDARY OBJECTIVES:

I. To determine the progression free survival (PFS), overall survival (OS), and toxicity
rates in advanced gastroesophageal patients treated with lenvatinib and pembrolizumab.

TERTIARY OBJECTIVES:

I. To characterize changes in the immune cell phenotype, immune pathway activity, and immune
response following lenvatinib only, and then with the addition of pembrolizumab.

OUTLINE:

Patients receive lenvatinib mesylate orally (PO) on days 1-7 of course 1, then on days 1-21
of subsequent courses. Patients also receive pembrolizumab intravenously (IV) over 30 minutes
on day 8 of course 1, then on day 1 of subsequent courses. Courses repeat every 21 days in
the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 9 and
12 weeks.

Inclusion Criteria:

- Be willing and able to provide written informed consent/assent for the trial

- Have histologically or cytologically confirmed metastatic or recurrent gastric or
gastroesophageal junction (GEJ) adenocarcinoma

- Have measurable disease based on RECIST 1.1

- Must have received and have progressed, or are intolerant to at least one systemic
regimen (platinum- or fluoropyrimidine-based chemotherapy regimen for metastatic or
recurrent disease or progressed within 6 month of completion of adjuvant therapy with
a platinum- or fluoropyrimidine-based regimen)

- If Her2 positive, must have received and have progressed or are intolerant to
treatment with trastuzumab for metastatic or recurrent disease

- Subjects must consent to provide archival tumor tissue (initial and subsequent tumor
biopsy samples, if possible) for correlative biomarker studies

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

- Adequately controlled blood pressure with or without antihypertensive medications
defined as blood pressure (BP) < 140/90 mmHg at screening and no change in
antihypertensive mediation within 1 week prior to the screening visit

- Performed within 10 days of treatment initiation: absolute neutrophil count (ANC) >=
1,500 /mcL

- Performed within 10 days of treatment initiation: platelets >= 100,000 / mcL

- Performed within 10 days of treatment initiation: hemoglobin >= 9 g/dL or >= 5.6
mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of
assessment)

- Performed within 10 days of treatment initiation: 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

- Performed within 10 days of treatment initiation: serum total bilirubin =< 1.5 X ULN
OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN

- Performed within 10 days of treatment initiation: aspartate aminotransferase (AST)
(serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT)
(serum glutamate pyruvate transaminase [SGPT]) =< 3 X ULN

- Performed within 10 days of treatment initiation: 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

- Performed within 10 days of treatment initiation: 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 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 (in
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within 7 days prior to the first dose of trial treatment

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

- Hypersensitivity to pembrolizumab or lenvatinib 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

- 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, a minimum of four weeks must have passed
and 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

- Subjects having > 1+ proteinuria on urine dipstick testing will undergo 24 hours (h)
urine collection for quantitative assessment of proteinuria; subjects with urine
protein >= 1 g/24h will be ineligible

- Gastrointestinal malabsorption or any other condition in the opinion of the
investigator that might affect the absorption of lenvatinib

- Prolongation of corrected QT using Fridericia's formula (QTcF) interval to > 480 ms

- Significant cardiovascular impairment: history of congestive heart failure greater
than New York Heart Association (NYHA) class II, unstable angina, myocardial
infarction or stroke within 6 months of the first dose of study drug

- Arrhythmias requiring class Ia and III antiarrhythmics and/or grade >= 2 bradycardia

- Bleeding disorders or active significant bleeding (i.e. hemoptysis, hematochezia,
hematemesis) within 3 weeks

- Thrombotic disorders or use of anticoagulants, such as warfarin, requiring therapeutic
international normalized ratio (INR) monitoring; (treatment with low molecular weight
heparin (LMWH) or direct acting oral anti-coagulants is allowed)

- History of prior gastrointestinal fistula and/or perforation

- Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis; 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 trial treatment; this exception does not include
carcinomatous meningitis which is excluded regardless of clinical stability

- 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 and is allowed

- Has known history of, or any evidence of active, non-infectious pneumonitis

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
angina pectoris

- 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 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