A Phase 2 Study of the MET Kinase Inhibitor INC280 in Papillary Renal Cell Cancer

Background:

- Papillary RCC is the second most common histologic subtype of kidney cancer, accounting
for approximately 10-15% of cases

- Type 1 papillary RCC occurs in both sporadic and hereditary forms, which are
histologically identical. Non familial type 1 papillary RCC can present as both solitary
renal tumors and as bilateral, multifocal disease

- There are no standard agents of proven efficacy for patients with advanced papillary

RCC.

- Patients with disease localized to the kidney are managed surgically while patients with
advanced/unresectable disease are usually managed in the community with VEGF pathway
antagonists or mTOR inhibitors.

- Activating mutations of MET were identified in the germline of affected HPRC patients,
who have a predilection for the development of bilateral, multifocal type 1 papillary
RCC. Somatic MET mutations have been found in a subset of patients with non-inherited,
sporadic papillary renal carcinoma

- The investigational agent INC280 is a selective MET inhibitor lacking activity against
the VEGF pathway

- This is a proof-of-concept study using INC280 in patients with papillary RCC to test the
idea that effectively blocking the HGF/MET pathway will lead to clinical activity in
patients with papillary renal cell cancer

Objectives:

Primary Objective:

-To determine the overall response rate (RECIST 1.1) in patients with papillary renal cell
carcinoma treated with single agent INC280

Eligibility:

- Diagnosis of hereditary papillary renal carcinoma (HPRC) or sporadic papillary renal
cell carcinoma (RCC)

- Patients with bilateral multifocal disease can have tumors localized to the kidney
or have metastatic disease

- Patients with sporadic papillary RCC (but without multifocal disease) should have
advanced disease that is considered unresectable

- ECOG 0-2

- Measurable disease

- Adequate organ function

- No active brain metastases

- Prior therapy

- No more than 3 prior lines of systemic therapy

- Prior therapy with a MET inhibitor is allowed as long as the patient has not had
progressive disease while receiving the agent

Design:

- This is a phase 2 single center non-randomized trial.

- The study will be conducted using a Simon 2 stage minimax design. Initially 13 evaluable
subjects will be recruited. If there are no responses to therapy, the study will be
terminated. If there is at least 1 response an additional 7 evaluable subjects will be
accrued.

- The two-stage minimax design is based on assuming an ineffective response rate of 5% and
a targeted effective response rate of 25%. We also assume that the probability of
accepting an ineffective treatment and the probability of rejecting an effective
treatment are each 10%.

- Subjects will be dosed orally at a starting dose of 400 mg twice daily.

- The overall response rate (complete response + partial response) will be determined.

- INCLUSION CRITERIA

2.1.1.1 Patients must have histologically or cytologically confirmed papillary RCC.

1. Patients with bilateral multifocal disease can have tumors localized to the kidney or
have metastatic disease

2. Patients with sporadic papillary RCC (but without multifocal disease) should have
advanced disease that is considered unresectable

2.1.1.2 Patients 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). Nodal lesions must be (Bullet) 15mm by CT scan
or MRI. Non nodal lesions must be >10 mm with CT scan or MRI.

2.1.1.3 Patients must have normal organ and marrow function as defined below:

- Hemoglobin > 9 g/dL (SI Units: 90 g/L)

- Platelet count greater than or equal to 75 x 10 (9)/L

- Absolute neutrophil count (ANC) greater than or equal to 1.5 x 10(9)/L without growth
factor support

- Total bilirubin less than or equal to 2 x upper limit of normal (ULN)

- AST/SGOT and/or ALT/SGPT less than or equal to 2.5 x upper limit of normal (ULN)

- Serum creatinine less than or equal to 1.5 x ULN

- Asymptomatic serum amylase less than or equal to 2 x ULN; patients with > ULN but less
than or equal to 2 x ULN serum amylase at study start must be confirmed to have no
signs and/or symptoms suggestion pancreatitis or pancreatic injury ( e.g. elevated
P-amylase, abnormal imaging findings of pancreas, etc.)

- Serum lipase less than or equal to ULN

- Fasting serum triglyceride level less than or equal to 500 mg/dL

2.1.1.4 Patients may have had no more than 3 prior lines of systemic therapy. Prior therapy
with a MET inhibitor is allowed as long as the patient has not had progressive disease
while receiving the agent

2.1.1.5 Patient must be able to swallow and retain oral medication

2.1.1.6 Age greater than or equal to18 years.

2.1.1.7 ECOG performance status 0 - 2.

2.1.1.8 Patients must provide written informed consent prior to any study procedures.

2.1.1.9 Patients must be willing and able to comply with scheduled visits, treatment plan
and laboratory tests

EXCLUSION CRITERIA

2.1.2.1 Patients who are receiving any other investigational agents for treatment of their
kidney cancer.

2.1.2.2 History of allergic reactions attributed to compounds of similar chemical or
biologic composition to INC280. Excipients in the current formulation include
microcrystalline cellulose, mannitol, sodium starch glycolate, magnesium stearate and
colloidal silicon dioxide

2.1.2.3 Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection requiring intravenous antibiotics, symptomatic congestive heart failure, unstable
angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would
limit compliance with study requirements or potentially affect the interpretation of study
data.

2.1.2.4 Subjects with significant or uncontrolled cardiovascular disease (e.g.,
uncontrolled hypertension, peripheral vascular disease, congestive heart failure, cardiac
arrhythmia, or acute coronary syndrome) within 6 months prior to starting study treatment
or heart attack within 12 months prior to starting study treatment

2.1.2.5 Patients receiving any medications that are known to be strong inducers or
inhibitors of CYP3A4, or sensitive substrates of CYP3A4, CYP1A2, CYP2C9, CYP2C9, CYP2C19 or
P-gp with a narrow therapeutic index.

2.1.2.6 Symptomatic CNS metastases that are neurologically unstable or requiring > 5 mg/day
of dexamethasone (or equivalent) to control CNS disease.

Note: Patients with controlled CNS metastases are allowed. Radiotherapy or surgery for CNS
metastases must have been completed >2 weeks prior to study entry. Patients must be
neurologically stable, having no new neurologic deficits on clinical examination, and no
new findings on CNS imaging. Steroid use for management of CNS metastases must be at a
stable dose for two weeks preceding study entry.

2.1.2.7 Patients with greater than or equal to Grade 2 neuropathy.

2.1.2.8 Treatment with proton pump inhibitors within 3 days prior to study entry. If
continued use of GI prophylaxis is required, the patient will be switched to an appropriate
H2 antagonist with appropriate counsel and caution.

2.1.2.9 Currently receiving any prohibited medications including vitamins and herbal
Supplements.

2.1.2.10 Major surgery within 4 weeks prior to initiating treatment, excluding the
placement of vascular access.

2.1.2.11 The subject has not recovered to baseline, CTCAE less than or equal to Grade 1
from toxicity due to all prior therapies for RCC or to a level permitted under other
sections of the eligibility criteria except alopecia and other non-clinically significant
AEs.

2.1.2.12 Any other condition that would, in the Investigator s judgment, contraindicate
participation in the clinical study due to safety concerns or compliance with clinical
study procedures, e.g., infection/inflammation, intestinal obstruction, unable to swallow
medication, social/ psychological issues, etc.

2.1.2.13 Pregnant or nursing (lactating) women, where pregnancy is defined as the state of
a female after conception and until the termination of gestation, confirmed by a positive
hCG laboratory test (> 30 mIU/mL). Laboratory values >5 mIU/mL, but <30 mIU/mL should be
repeated in 48 hours.

2.1.2.14 Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using highly effective methods of contraception during
dosing and for 3 month days after stopping study drug. Highly effective contraception
methods include:

- Total abstinence or

- Male or female sterilization or

- Combination of any two of the following (a+b or a+c or b+c):

1. Use of oral, injected or implanted hormonal methods of contraception

2. Placement of an intrauterine device (IUD) or intrauterine system (IUS)

3. Barrier methods of contraception: condom or occlusive cap (diaphragm or
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository
Women are considered post-menopausal and not of child bearing potential if they
have had 12 months of natural (spontaneous) amenorrhea with an appropriate
clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have
had surgical bilateral oophorectomy (with or without hysterectomy) or tubal
ligation at least six weeks ago. In the case of oophorectomy alone, only when the
reproductive status of the woman has been confirmed by follow up hormone level
assessment is she considered not of child bearing potential.

2.1.2.15 Sexually active males must use a condom during intercourse while taking the drug
and for 3 months after stopping study drug and should not father a child in this period. A
condom is required to be used also by vasectomized men in order to prevent delivery of the
drug via seminal fluid.

2.1.2.16 HIV-positive patients on combination antiretroviral therapy are ineligible because
of the potential for pharmacokinetic interactions with INC280.

2.1.2.17 Prior invasive malignancy of other histology currently requiring treatment.