Anti-Mesothelin Antibody Drug Conjugate Anetumab Ravtansine for Mesothelin Expressing Lung Adenocarcinoma

Background:

- Lung cancer is the leading cause of cancer-related death worldwide, accounting for more
than one million deaths every year.

- Non-small-cell lung cancer (NSCLC) constitutes approximately 85% of lung cancers and
about 40% of patients with newly diagnosed NSCLC have advanced disease. The median year
overall survival for advanced NSCLC is at least 1 year.

- In recent years, identification of oncogenic alterations such as mutations in EGFR and
ALK translocations and therapies targeting tumor immune escape mechanisms have led to a
substantial improvement in the prognosis of patients with advanced lung cancer;

however, such alterations have been detected in less than half of all advanced NSCLC patients
in only a small subset of patients respond to immunotherapeutic interventions available
today.

- Anetumab ravtansine (BAY 94-9343) is an antibody-drug conjugate targeting mesothelin, a
protein normally present on mesothelial cells. A Phase I trial showed the overall
acceptable and manageable safety profile. It is being developed for patients with
mesothelin expressing cancers; clinical development is furthest along in mesothelioma
where it is in a registration phase II clinical trial.

- NCI researchers have demonstrated that mesothelin mRNA and protein are present in a
substantial number of lung adenocarcinoma cell lines; mesothelin expression has been
observed in over 50% of advanced lung adenocarcinomas by immunohistochemical

assessment

Objectives:

Safety Run-in

-To evaluate safety and tolerability of anetumab ravtansine in patients with previously
treated unresectable mesothelin expressing advanced lung adenocarcinoma (stage IIIB or IV).

Phase 2

-To determine the efficacy (objective response rate) of anetumab ravtansine in patients with
advanced (Stage IIIb) or metastatic (Stage IV) mesothelin expressing lung adenocarcinoma.

Eligibility:

- Age >18 years.

- Histologically or cytologically confirmed previously treated unresectable mesothelin
expressing advanced lung adenocarcinoma (stage IIIB or IV)

- Positive mesothelin expression in the archival tumor tissue, defined as the mesothelin
membrane intensity score of 2+ or 3+ (on the 0-3 scale) expressed on the membrane of
greater than or equal to 10% of tumor cells.

- Should have received at least one prior platinum based chemotherapy and an immune
checkpoint targeted agent. In addition, subjects with epidermal growth factor receptor
[EGFR]-mutated and anaplastic lymphoma kinase [ALK]-translocated NSCLC should have
received FDA-approved targeted therapies as appropriate.

- Normal organ function

Design:

- This is an open label, single center, phase I/II study of anetumab ravtansine in
subjects with mesothelin positive lung adenocarcinoma.

- During the safety run-in portion of the study, de-escalating doses will be assessed to
determine a recommended phase 2 dose (RP2D).

- During the phase 2 portion of the study, the (RP2D) will be assessed for objective
response rate.

- During both portions of the study, anetumab ravtansine will be administered
intravenously every 3 weeks until disease progression in the absence of clinical
benefit, patient withdrawal or the occurrence of intolerable toxicities.

- Response assessments (imaging) will occur every 6 weeks for the first 6 months, then
every 9 weeks until the end of year 2, then every 12 weeks thereafter.

- Up to 12 evaluable patients will be enrolled in the safety run-in portion of the study.
Approximately twenty patients, including 6 from the safety run-in portion of the study,
will be evaluated in the phase 2 portion of the study. The accrual ceiling will be set
at 55 to accommodate screen failures (a 50% failure rate with regard to mesothelin
expression) and inevaluable subjects.

- INCLUISION CRITERIA:

Subjects must have histologically or cytologically confirmed previously treated
unresectable mesothelin expressing advanced lung adenocarcinoma (stage IIIB or IV) as
confirmed by the Laboratory of Pathology, NCI

Subjects must have positive mesothelin expression in the archival tumor tissue, defined as
the mesothelin membrane intensity score of 2+ or 3+ (on the 0-3 scale) expressed on the
membrane of greater than or equal to 10% of tumor cells.

Subjects must provide sample of archival tumor tissue (tissue block preferred, at least 5
formalin-fixated, paraffin-embedded [FFPE] slides acceptable) collected any time before the
general screening. A fresh biopsy will be collected if archival sample is

unavailable or insufficient.

Subjects must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded for nonnodal
lesions and short axis for nodal lesions) as >20 mm with conventional techniques or as >10
mm with spiral CT scan. See Section 6.3 for the evaluation of measurable disease.

Subjects with resected primary tumors who have documented metastases are eligible.

Subjects should have received at least one prior platinum based chemotherapy and an immune
checkpoint targeted agent. Subjects with epidermal growth factor receptor [EGFR]-mutated
and anaplastic lymphoma kinase [ALK]-translocated NSCLC

should have received FDA-approved targeted therapies as appropriate.

Age >18 years. Because no dosing or adverse event data are currently available on the use
of anetumab ravtansine in subjects <18 years of age, children are excluded from this study.

ECOG performance status < or equal to 2

Subjects must have adequate bone marrow function as assessed by the following laboratory
test results:

- Hemoglobin greater than or equal to 9.0 g/dL or greater than or equal to 5.6 mmol/L

- Absolute neutrophil count (ANC) greater than or equal to 1,500/mm3 or greater than or
equal to 1.5 x 109/L

- Platelet count greater than or equal to 100,000/mm3 or greater than or equal to 100 x
109/L

Subjects must have adequate kidney function, with serum creatinine <1.5 x ULN or calculated
glomerular filtration rate (GFR) of > 45/mL/min/1.73 m2

Subjects must have adequate liver function as assessed by the following laboratory test
results:

- Total bilirubin less than or equal to 1.5 times the upper limit of normal (ULN)

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 3.0 times ULN in
subjects without liver metastases or 5.0 times ULN in subjects with liver metastases

Subjects must have adequate coagulation, as assessed by the following laboratory test
results:

- INR or PT less than or equal to 1.5 x ULN

- PTT less than or equal to 1.5 x ULN

Due to the lack of adequate reproductive toxicity data on anetumab ravtansine, subjects
must use 2 forms of highly effective contraception concomitantly from the initiation of
study therapy until 6 months after the last dose of study therapy. Additionally, the use

of condoms is required. It should also be noted that, where 2 forms of effective
contraception are required, a subject may choose to use a double-barrier method consisting
of condom and cervical occlusive cap / diaphragm with spermicide

Ability of subject to understand and the willingness to sign a written informed consent
document.

Subjects must provide a signed informed consent before any screening procedures.

EXCLUSION CRITERIA:

Subjects who have a previous or concurrent cancer that is distinct in primary site or
histology from lung adenocarcinoma, except cervical carcinoma in situ, treated basal cell
carcinoma, superficial noninvasive bladder tumors or any previous cancer curatively treated
<2 years before the start of study treatment.

Subjects who have a history or current evidence of bleeding disorder, i.e. any
hemorrhage/bleeding event of CTCAE Grade greater than or equal to 2 within 4 weeks before
the start of study treatment.

History of symptomatic metastatic brain or meningeal tumors unless the subject is > 3
months from definitive therapy and has no evidence of tumor growth on an imaging study
within 2 weeks prior to study entry. Subjects with brain metastases must not be

undergoing acute corticosteroid therapy or steroid taper. Chronic steroid therapy is
acceptable provided that the dose is stable for one month prior to screening.

Subjects who have a history or current evidence of uncontrolled cardiovascular disease
including but not limited to the following conditions:

- Congestive heart failure of New York Heart Association (NYHA) Class III or IV

- Unstable angina (symptoms of angina at rest) or new-onset angina within <3 months
before the start of study treatment.

- Arterial thrombosis, deep vein thrombosis, or pulmonary embolism within <3 months
before the start of study treatment.

- Myocardial infarction or stroke within <3 months before the start of study treatment.

- Pericarditis (any CTCAE grade), pericardial effusion (CTCAE Grade greater than or
equal to 2) or pleural effusion (CTCAE Grade greater than or equal to 2)

- Cardiac arrhythmia requiring anti-arrhythmic therapy. Subjects receiving digoxin,
calcium channel blockers except verapamil, or beta-adrenergic blockers except
propranolol are eligible at the investigator s discretion if the dose has been stable
for at least 2 weeks before the start of study treatment. Subjects with sinus
arrhythmia and infrequent premature ventricular contractions are eligible at the
investigator s discretion.

Subjects who have a left ventricular ejection fraction (LVEF) <50%, as assessed by
echocardiogram performed at screening.

Subjects who have a corrected QT (QTcF) interval >480 ms (CTCAE Grade >1) determined by the
electrocardiogram (ECG) recorder s algorithm on the screening ECG.

Subjects who have a history or current evidence of uncontrolled hypertension defined as
systolic blood pressure >150 mmHg or diastolic blood pressure >95 mmHg at screening despite
optimal medical management. Subjects with a history of mild to moderate

hypertension are eligible at the investigator s discretion if the hypertension is
adequately controlled by antihypertensive treatment used at a stable dose for at least 2
weeks before the start of study treatment.

Subjects who have a heart rate greater than or equal to 100 beats per minute (bpm) or less
than or equal to 45 bpm determined by the ECG recorder s algorithm on the screening ECG.

Women who are pregnant or breast-feeding. Women of reproductive potential must have a
negative serum beta human chorionic gonadotropin (beta-HCG) pregnancy test obtained within
7 days before the start of study treatment.

Subjects who have had a major surgery or significant trauma within 4 weeks before the start
of study treatment.

Subjects who have had solid organ or bone marrow transplantation.

Subjects who have a history of hypersensitivity to any of the study drugs or their
excipients, or a history of severe hypersensitivity to any other antigen.

Subjects who have a history of human immunodeficiency virus (HIV) infection or subjects who
have an active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection requiring
treatment due to a theoretical concern that the degree of immune suppression associated
with the treatment may result in progression of HIV infection. Subjects with chronic HBV or
HCV infection are eligible at the investigator s discretion if the subject is considered
non-infectious based on serological markers.

Subjects who have an active clinically serious infection of CTCAE Grade greater than or
equal to 2.

Subjects with a non-healing serious wound, ulcer, or bone fracture unrelated to the primary
tumor.

Subjects with corneal epitheliopathy or any eye disorder that may predispose the subjects
to drug-induced corneal epitheliopathy, or may interfere with diagnosis of
treatment-emergent corneal epitheliopathy at the discretion of the investigator in

consultation with the ophthalmologist/optometrist. Low grades of superficial punctate
keratitis, within the range seen in the normal population, should not lead to the exclusion
of the patient

Subjects experiencing unresolved toxicity of previous antitumor therapy which is CTCAE
Grade >1 before the start of study treatment, except for alopecia or hemoglobin greater
than or equal to 9.0 g/dL or greater than or equal to 5.6 mmol/L.

Subjects with any clinical condition that is considered unstable or might jeopardize the
safety of the subject and/or influence the subject s compliance in the study.

Subjects who have received systemic anticancer therapy within 3 weeks before the start of
study treatment. Mitomycin C or nitrosoureas must be excluded within 6 weeks before the
start of study treatment.

Subjects who have received radiotherapy to tumor lesions that would be chosen as target
lesions (measurable disease) within 4 weeks before the start of treatment, except if there
is objective evidence of progression of the lesion by RECIST 1.1 between the

prior radiotherapy and the screening CT or MRI scan. Palliative radiotherapy to nontarget
lesions is allowed at the investigator s discretion..

Use of drugs that inhibit renal tubular secretion (e.g. probenecid and cimetidine) within 2
weeks before the start of study treatment.

Use of strong cytochrome P450 3A4 (CYP3A4) inhibitors or strong CYP3A4 inducers within 2
weeks before the start of study treatment.

Subjects who have previously received anetumab ravtansine.

Subjects who are concurrently receiving any other investigational agents.