Phase II Nivolumab and Ramucirumab for Patients With Previously-Treated Mesothelioma

The programmed death ligand 1 (PD-L1) [16] and VEGFR2 [34] are highly-expressed on
mesothelioma cells, and are therefore attractive options for this cancer. We chose to study
the combination of ramucirumab with nivolumab because of the potential efficacy of these two
agents in mesothelioma and because of the potential synergistic activity between them [30].
As previously discussed, immunotherapies such as anti-PD-1 inhibitors must contend with a
hostile, immunosuppressive tumor microenvironment due to angiogenesis that results in
hypoxia. This hypoxia decreases the ability of antibodies to infiltrate the tumor. We
hypothesize that the normalization of tumor vasculature (by reducing the area of the tumor
that is hypoxic) with an anti-VEGF strategy (i.e., ramucirumab) used in synergy with a PD-1
inhibitor will facilitate the infiltration of T-lymphocytes into tumor parenchyma. We will
conduct a phase II study based on this premise using nivolumab and ramucirumab as second-line
therapy in patients with malignant mesothelioma who have failed standard doublet platinum and
anti-folate therapy.

Inclusion Criteria:

- Histologically-confirmed malignant mesothelioma not amenable to curative surgery and
who have received at least one pemetrexed-containing chemotherapy regimen.

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

- total bilirubin < 1.5 mg/dL (25.65 μmol/L) OR direct bilirubin ≤ ULN for subjects with
total bilirubin levels > 1.5 mg/dL (except subject with Gilbert's Syndrome, who can
have total bilirubin < 3.0 mg/dl)

- aspartate aminotransferase (AST) ≤ 3 × ULN or ≤ 5 × ULN for subjects with known
hepatic metastases

- alanine aminotransferase (ALT) ≤ 3 × ULN or ≤ 5 × ULN for subjects with known hepatic
metastases

- hemoglobin ≥ 9 g/dL, subjects requiring transfusion will not be eligible to start
study

- absolute neutrophil count (ANC) ≥ 1.5 × 109/L

- platelet count ≥ 100 × 109/L

- serum creatinine ≤1.5 times the ULN, or creatinine clearance (measured via 24-hour
urine collection) ≥40 mL/minute (that is, if serum creatinine is >1.5 times the ULN, a
24-hour urine collection to calculate creatinine clearance must be performed)

- subject's urinary protein is ≤1+ on dipstick or routine urinalysis (UA; if urine
dipstick or routine analysis is ≥2+, a 24-hour urine collection for protein must
demonstrate <1000 mg of protein in 24 hours to allow participation in this protocol)

- INR < 1.5 × ULN, and a partial thromboplastin time (PTT) (PTT/aPTT) < 1.5 x ULN
(unless receiving anticoagulant therapy)

- Subjects on full-dose anticoagulation must be on a stable dose (minimum duration 14
days) of oral anticoagulant or low molecular weight heparin (LMWH). Patients receiving
warfarin must be switched to low molecular weight heparin and have achieved stable
coagulation profile prior to first dose of protocol therapy. For heparin and LMWH
there should be no active bleeding (that is, no bleeding within 14 days prior to first
dose of protocol therapy) or pathological condition present that carries a high risk
of bleeding (for example, tumor involving major vessels or known varices).

- Women of childbearing potential (WOCP) must be willing to use two methods of birth
control. The two birth control methods can be either two barrier methods or a barrier
method plus a hormonal method to prevent pregnancy. WOCP should begin using birth
control from the screening visit, throughout the study period, and up to 161 days
(about 5 months) following the last dose of study drugs.

- Men who are not surgically or medically sterile must agree to use an acceptable method
of contraception. Male subjects with female sexual partners who are pregnant, possibly
pregnant, or who could become pregnant during the study must agree to use condoms with
spermicide from the date of the first dose of study drug, throughout the study period,
and through at least 217 days (about 7 months) after the last dose of study drug.
Total abstinence for the same study period is an acceptable alternative.

- Measurable disease, defined as at least 1 tumor that fulfills the criteria for a
target lesion according to modified RECIST 1.1 criteria, and obtained by imaging
within 28 days prior to study registration.

- Prior intracavity cytotoxic or sclerosing agents (including bleomycin) is acceptable.

- Radiation therapy must be completed > 28 days before study registration, and the
measurable disease must be outside of the radiation port.

- Pemetrexed-containing chemotherapy must be completed > 28 days before study
registration.

- Must provide written informed consent and HIPAA authorization approved by an
Institutional Review Board (IRB). NOTE: HIPAA authorization may be included in the
informed consent or obtained separately.

- All previous toxicity resolved to Grade 1 or less.

Exclusion Criteria:

- Any Grade 3-4 GI bleeding within 3 months prior to study registration.

- History of deep vein thrombosis, pulmonary embolism, or any other significant
thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis
are not considered "significant") during the 3 months prior to study registration.

- Any arterial thromboembolic events, including but not limited to myocardial
infarction, transient ischemic attack, cerebrovascular accident, or unstable angina,
within 6 months prior to study registration.

- Cirrhosis at a level of Child-Pugh B (or worse), or cirrhosis (any degree) with a
history of hepatic encephalopathy, or clinically meaningful ascites resulting from
cirrhosis. Clinically meaningful ascites is defined as ascites from cirrhosis
requiring diuretics or paracentesis.

- Uncontrolled or poorly-controlled hypertension (>160 mmHg systolic or > 100 mmHg
diastolic for >4 weeks) despite standard medical management.

- Prior history of GI perforation/fistula (within 6 months of study registration) or
risk factors for perforation.

- Serious or nonhealing wound, ulcer, or bone fracture within 28 days prior to study
registration.

- Active brain metastases or carcinomatous meningitis. Subjects with neurological
symptoms must undergo a head CT scan or brain MRI to exclude brain metastasis.
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 study drugs 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 14 days prior to study registration. This exception does not include
carcinomatous meningitis, which is excluded regardless of clinical stability.

- Major surgery within 28 days prior to study registration

- Subcutaneous venous access device placement within 7 days prior to study registration.

- Elective or planned major surgery to be performed during the course of the clinical
trial.

- Is receiving chronic antiplatelet therapy, including aspirin, nonsteroidal
anti-inflammatory drugs (NSAIDs, including ibuprofen, naproxen, and others),
dipyridamole or clopidogrel, or similar agents. Once-daily aspirin use (maximum dose
325 mg/day) is permitted.

- Known history of testing positive for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome (AIDS). NOTE: HIV testing is not required.

- Known history of testing positive for hepatitis B virus surface antigen (HBV sAg) or
hepatitis C virus ribonucleic acid (HCV antibody), indicating acute or chronic
infection. NOTE: Hepatitis B and Hepatitis C testing is not required.

- Condition requiring systemic treatment with either corticosteroids (> 10 mg daily
prednisone equivalents) or other immunosuppressive medications within 14 days of study
drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg
daily prednisone equivalents are permitted in the absence of active autoimmune
disease.

- 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). Subjects are permitted to enroll if they have vitiligo, type I diabetes
mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone
replacement, psoriasis not requiring systemic treatment, or conditions not expected to
recur in the absence of an external trigger.

o 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.

- Received a live vaccine within 30 days prior to the first dose of trial treatment.
Examples of live vaccines include, but are not limited to: measles, mumps, rubella,
chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza
vaccines for injection are generally killed virus vaccines and are allowed; however,
intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines and are
not allowed.

- History of interstitial lung disease or active, non-infectious pneumonitis.

- Female subject is pregnant or breast-feeding.

- NOTE: Women of childbearing potential (WOCP) must have a negative pregnancy test
(either serum β-HCG with a sensitivity of 50 mIU/ml or urine dipstick within 24
hours of study registration).

- NOTE: Women are not considered to be of childbearing potential if they meet at
least one of the following: 1) surgically sterilized, or 2) postmenopausal (a
woman who is ≥45 years of age and has not had menses for greater than 1 year), or
3) not heterosexually active for the duration of the study. See section 5.6.2.

- Major blood vessel invasion or significant intratumor cavitation.

- If they experience hemoptysis (defined as bright red blood or ≥ ½ teaspoon) within 2
months prior to first dose of protocol therapy or with radiographic evidence of
intratumor cavitation or has radiologically documented evidence of major blood vessel
invasion or encasement by cancer.

- Any condition that, in the opinion of the investigator, might jeopardize the safety of
the subject or interfere with protocol compliance.

- Any mental or medical condition that prevents the subject from giving informed consent
or participating in the trial.

- Any pathological condition that carries a high risk of bleeding (for example, tumor
involving major vessels or known varices.)

- Known hypersensitivity to nivolumab or ramucirumab or any of their components.

- Known history of active tuberculosis.

- Received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or
anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including
ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation
or checkpoint pathways).

- No prior malignancy is allowed except for adequately treated basal cell or squamous
cell skin cancer, in situ cervical cancer, Gleason ≤ grade 7 prostate cancers, or
other cancer for which the subject has been disease-free for at least 5 years.

- Treatment with any investigational agent within 28 days prior to study registration.
The subject must have recovered from the acute toxic effects of the regimen.