Tivantinib With or Without Erlotinib Hydrochloride in Treating Patients With Metastatic or Locally Advanced Kidney Cancer That Cannot Be Removed by Surgery

PRIMARY OBJECTIVES:

I. To assess the response rate (confirmed complete and partial response) of patients with
locally advanced or metastatic papillary renal cell carcinoma treated with either ARQ 197
(tivantinib) or ARQ 197 combined with erlotinib (erlotinib hydrochloride).

SECONDARY OBJECTIVES:

I. To assess the progression free survival (PFS) of patients with locally advanced or
metastatic papillary renal cell carcinoma treated with either ARQ 197 or ARQ 197 combined
with erlotinib.

II. To assess the safety and tolerability of ARQ 197 therapy and ARQ 197 combined with
erlotinib.

III. To descriptively assess the role of prior treatment on outcome.

TERTIARY OBJECTIVES:

I. To bank tissue specimens for future use and once funding is obtained to evaluate the
expression of tissue correlative biomarkers such as hepatocyte growth factor receptor (c-MET)
and epidermal growth factor receptor (EGFR), and to perform exploratory correlation with
clinical outcomes.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive tivantinib orally (PO) twice daily (BID) on days 1-28.

ARM II: Patients receive tivantinib PO BID and erlotinib hydrochloride PO once daily (QD) on
days 1-28.

In both arms, courses repeat every 28 days in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year and
then every 6 months for up to 2 years.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed papillary histology renal
cell carcinoma which is metastatic, or locally advanced and unresectable; mixed
histologies will be allowed provided that they contain >= 50% of the papillary
component

- Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension; x-rays, scans or physical examinations
used for tumor measurement must have been completed within 28 days prior to
registration; x-rays, scans or physical examinations for non-measurable disease must
have been completed within 42 days prior to registration; all disease must be assessed
and documented on the Baseline Tumor Assessment form

- Patients with metastatic disease who have a resectable primary tumor and are deemed a
surgical candidate may have undergone resection; at least 28 days must have elapsed
since surgery and patient must have recovered from any adverse effects of surgery

- Patients with a history of brain metastases who are asymptomatic and have not received
steroid therapy in the 14 days prior to registration are eligible; anti-seizure
medications are allowed provided they are non-enzyme inducing (e.g. topiramate,
levetiracetam, gabapentin)

- Patients may have received up to one prior systemic therapy for advanced or metastatic
renal cell carcinoma; patients must not have received a MET inhibitor or erlotinib as
prior therapy; at least 21 days must have elapsed since completion of prior systemic
therapy, 42 days for nitrosoureas or mitomycin C; patients must have recovered from
all associated toxicities at the time of registration

- Patients may have received prior radiation therapy, but must have measurable disease
outside the radiation port; at least 21 days must have elapsed since completion of
prior radiation therapy; patients must have recovered from all associated toxicities
at the time of registration

- Patients must not be receiving or planning to receive any other investigational agents

- Patients must have a complete physical examination and medical history within 28 days
prior to registration

- Patients must have a Zubrod performance status of 0-2

- White blood cell (WBC) >= 2,000/mcL

- Absolute neutrophil count (ANC) >= 1,000/mcL

- Platelet count >= 75,000/mcL

- Serum bilirubin =< 1.5 x institutional upper limits of normal (ULN)

- Serum glutamic oxaloacetic transaminase (SGOT)/aspartate aminotransferase (AST) and
serum glutamic pyruvate transaminase (SGPT)/alanine aminotransferase (ALT) must be =<
1.5 x the institutional ULN unless the liver is involved with the tumor, in which case
serum transaminase (SGOT/SGPT) must be =< 5 x the institutional ULN

- Serum creatinine must be =< 2 x the institutional ULN

- Sodium, potassium and calcium must be obtained within 14 days prior to registration

- Patients with a known history of the following corneal diseases are not eligible: dry
eye syndrome, Sjogren's syndrome, keratoconjunctivitis sicca, exposure keratopathy,
Fuchs' dystrophy or other active disorders of cornea

- Patients known to be human immunodeficiency virus (HIV)-positive and receiving
combination anti-retroviral therapy are not eligible

- Patients must be able to take oral medications; patients must not have
gastrointestinal tract disease resulting in an inability to take oral medication or a
requirement for intravenous (IV) alimentation, prior surgical procedures affecting
absorption, or active peptic ulcer disease; patients with intractable nausea or
vomiting are not eligible

- Patients must not be pregnant or nursing; women/men of reproductive potential must
have agreed to use an effective contraceptive method; a woman is considered to be of
"reproductive potential" if she has had menses at any time in the preceding 12
consecutive months; in addition to routine contraceptive methods, "effective
contraception" also includes heterosexual celibacy and surgery intended to prevent
pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy,
bilateral oophorectomy or bilateral tubal ligation; however, if at any point a
previously celibate patient chooses to become heterosexually active during the time
period for use of contraceptive measures outlined in the protocol, he/she is
responsible for beginning contraceptive measures

- No other prior malignancy is allowed except for the following: adequately treated
basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated
stage I or II cancer from which the patient is currently in complete remission, or any
other cancer from which the patient has been disease-free for 5 years

- Patients must be offered the opportunity to participate in specimen banking for future
translational medicine studies

- All patients must be informed of the investigational nature of this study and must
sign and give written informed consent

- As a part of the Oncology Patient Enrollment Network (OPEN) registration process the
treating institution's identity is provided in order to ensure that the current
(within 365 days) date of institutional review board approval for this study has been
entered in the system