Pembrolizumab and Ziv-aflibercept in Treating Patients With Advanced Solid Tumors

PRIMARY OBJECTIVES:

I. To determine the safety, tolerability and recommended phase II dosing for the combination
of ziv-aflibercept plus MK-3475 (pembrolizumab) in patients with unresectable stage III or
stage IV melanoma, renal cell cancer, ovarian cancer, colorectal cancer, or sarcoma.

SECONDARY OBJECTIVES:

I. To obtain preliminary estimates of progression-free survival at 6 months. II. To obtain
preliminary estimates of the rate of 1-year overall survival. III. To obtain preliminary
estimates of the response rate. IV. To obtain preliminary estimates of time to progression.
V. To perform correlative sciences that provide information regarding the mechanisms of
action for this combination treatment.

OUTLINE: This is a dose-escalation and dose expansion study of ziv-aflibercept.

Patients receive pembrolizumab intravenously (IV) over approximately 30 minutes and
ziv-aflibercept IV over 1-2 hours on day 1. Courses repeat every 2 weeks for up to 2 years in
the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for at least 12 weeks.

Inclusion Criteria:

- In dose escalation, patients must have histologically or cytologically confirmed
metastatic disease from any solid tumor; in dose expansion part 1, patients must have
histologically or cytologically confirmed metastatic melanoma, renal cell carcinoma,
ovarian cancer, or colorectal cancer. In dose expansion part 2, patients must have
PD-1 resistant melanoma, PD-1 resistant renal cancer, or sarcoma

- Renal cell patients must have had at least one prior vascular endothelial growth
factor (VEGF) tyrosine kinase inhibitor (TKI)

- Ovarian cancer patients must be resistant to platinum therapy; therapy (i.e. within 6
months of last platinum therapy); patients who received greater than two prior
platinum containing regimens will not be eligible

- Patients with colorectal cancer should have failed at least one oxaliplatin-containing
regimen

- No more than two prior therapies for metastatic disease

- Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)

- Estimated life expectancy of greater than 6 months

- Leukocytes >= 2,000/mcL (within 10 days of treatment initiation)

- Absolute neutrophil count >= 1,500/mcL (within 10 days of treatment initiation)

- Platelets >= 100,000/mcL (within 10 days of treatment initiation)

- Hemoglobin >= 9 g/dL OR >= 5.6 mmol/L (within 10 days of treatment initiation)

- Serum total bilirubin =< 1.5 X upper limit of normal (ULN) or direct bilirubin =< ULN
for patients with total bilirubin levels > 1.5 ULN (within 10 days of treatment
initiation)

- Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT])
=< 2.5 × institutional ULN OR =< 5 X ULN for patients with liver metastases (within 10
days of treatment initiation)

- Serum creatinine =< 1.5 X ULN or measured or calculated creatinine clearance (CrCl) >=
60 mL/min for subject with creatinine levels > 1.5 X institutional ULN (glomerular
filtration rate [GFR] can also be used in place of creatinine or CrCl); creatinine
clearance should be calculated per institutional standard (within 10 days of treatment
initiation)

- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless
subject is receiving anticoagulant therapy not requiring laboratory monitoring as long
as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use
of anticoagulants; therapeutic Coumadin is not acceptable (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 (within 10 days of treatment initiation)

- Urine protein-creatinine ratio (UPCR) =< 1 on spot urinalysis or protein =< 500 mg/24
hour urine

- Archival tissue must be available or newly obtained core or excisional biopsy of a
tumor lesion

- Patients must have measurable disease based on Response Evaluation Criteria in Solid
Tumors (RECIST) 1.1

- 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; patients should continue contraceptive measures
for 6 months from the last dose of all study medications

- Female patients of childbearing potential should have a negative urine or serum
pregnancy test within 24 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 patients of childbearing potential should be willing to use 2 methods of birth
control or be surgically sterile, or abstain from heterosexual activity for the course
of the study through 120 days after the last dose of study medication; patients of
childbearing potential are those who have not been surgically sterilized or have not
been free from menses for > 1 year

- Should a woman become pregnant or suspect she is pregnant while she 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 and ziv-aflibercept administrations

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

- Dose expansion part 2 PD-1/PD-L1 resistant or refractory melanoma and renal cell
cancer only: subjects must have received prior immunotherapy with an anti-PD-1 or
anti-PD-L1 containing regimen and must have progressive or recurrent disease after
prior PD-1/PD-L1 directed therapy; primary resistance is determined at the time of
initial restaging from initiation of treatment, as evidenced by progression by RECIST
1.1; acquired resistance would be a subject who had a best overall RECIST response of
stable disease, partial response, or complete response confirmed radiographically by a
second scan who subsequently developed progressive disease by RECIST 1.1 at any time
thereafter

- Dose expansion part 2 sarcoma only: subjects must have received standard of care
treatment

Exclusion Criteria:

- Patients who have had chemotherapy, targeted small molecule therapy, or radiotherapy
within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study
or those who have not recovered from adverse events due to agents administered more
than 4 weeks earlier

- Note: patients with =< grade 2 neuropathy are an exception to this criterion and
may qualify for the study

- Note: if patients received major surgery, they must have recovered adequately
from the toxicity and/or complications from the intervention prior to starting
therapy

- Patients who are currently participating in or have participated in a study of an
investigational agent or using 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

- Has had a prior monoclonal antibody within 4 weeks prior to study day 1 or who has not
recovered (i.e., =< grade 1 or at baseline) from adverse events (AEs) due to agents
administered more than 4 weeks earlier

- 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, or in situ cervical cancer that has undergone potentially curative therapy

- Lesions suspected to be at higher-risk for bleeding such as bowel involvement with
tumor that invades into the bowel wall or involves the intraluminal component of bowel
by imaging or direct visualization or central pulmonary lesions

- Ulcerated skin lesions

- Full anti-coagulant therapy Coumadin; patients may be receiving therapeutic Lovenox,
Fragmin, or other heparin product that does not require laboratory monitoring

- Poorly-controlled hypertension as defined blood pressure (BP) > 150/100 mmHg, or
systolic (S) BP > 180 mmHg when diastolic (D) BP < 90 mmHg, on at least 2 repeated
determinations on separate days within 3 months prior to study enrollment

- Pregnant or nursing women

- Patients with known brain metastases should be excluded from this clinical trial

- Patients with carcinomatous meningitis should also be excluded

- Patients with previously treated brain metastases may participate provided they are
stable (without evidence of progression by imaging for at least 3 months 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

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to MK-3475 and ziv-aflibercept

- Has an active autoimmune disease requiring systemic treatment within the past 3 months
or a documented history of clinically severe autoimmune disease, or a syndrome that
requires systemic steroids or immunosuppressive agents; patients with vitiligo or
resolved childhood asthma/atopy would be an exception to this rule; patients that
require intermittent use of bronchodilators or local steroid injections would not be
excluded from the study; patients with hypothyroidism stable on hormone replacement or
Sjogren's syndrome will not be excluded from the study

- 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 known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial

- Dose escalation and dose expansion part 1 only: Has received prior therapy with an
anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or ziv-aflibercept (prior treatment
with bevacizumab is not an exclusion criteria)

- 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

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

- Men and non-pregnant, non-breast-feeding women may be enrolled if they are willing to
use 2 methods of birth control or are considered highly unlikely to conceive; highly
unlikely to conceive is defined as 1) surgically sterilized, or 2) postmenopausal (a
woman who is >= 45 years of age and has not had menses for greater than 2 years will
be considered postmenopausal), or 3) not heterosexually active for the duration of the
study; the two birth control methods can be barrier method or a barrier method plus a
hormonal method to prevent pregnancy; patients should start using birth control from
study visit 1 throughout the study period up to 120 days after the last dose of study
therapy; the following are considered adequate barrier methods of contraception:
diaphragm, condom (by the partner), copper intrauterine device, sponge, or spermicide;
appropriate hormonal contraceptives will include any registered and marketed
contraceptive agent that contains an estrogen and/or a progestational agent (including
oral, subcutaneous, intrauterine, or intramuscular agents); patients should continue
contraceptive measures for 6 months from the last dose of all study medications

- Patients who are human immunodeficiency virus (HIV) positive may participate IF they
meet the following eligibility requirements:

- They must be stable on their anti-retroviral regimen, and they must be healthy
from an HIV perspective

- They must have a cluster of differentiation (CD)4 count of greater than 250
cells/mcL

- They must not be receiving prophylactic therapy for an opportunistic infection

- 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 prior to the first dose of trial treatment

- History within 6 months prior to treatment of myocardial infarction, severe/unstable
angina pectoris, coronary artery bypass graft (CABG), New York Heart Association
(NYHA) class III or IV congestive heart failure (CHF), stroke or transient ischemic
attack (TIA)

- History within 3 months prior to treatment of grade 3-4 gastrointestinal (GI)
bleeding/hemorrhage, treatment resistant peptic ulcer disease, erosive esophagitis or
gastritis, infectious or inflammatory bowel disease, diverticulitis, pulmonary
embolus, or other uncontrolled thromboembolic event

- Patients who are less than 4 weeks post-operative (op) after major surgery