A Phase II Study of Bevacizumab and Erlotinib in Subjects With Advanced Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) or Sporadic Papillary Renal Cell Cancer

Background:

- Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is a familial cancer syndrome
characterized by a propensity for developing renal cancer, uterine and cutaneous
leiomyomas.The kidney cancer associated with HLRCC is associated with HLRCC is
clinically aggressive and is characterized by unique histopathologic features that are
sometimes described as type2 papillary RCC.

- Germline mutations in fumarate hydratase (FH) are the genetic hallmark of HLRCC.
Mutational inactivation of FH has been shown to result in VHL-independent upregulation
of hypoxia inducible factor (HIF) and its downstream transcriptional targets.

- The recognition that HIF upregulation may play an important role in the formation and
propagation of renal cancer associated with HLRCC suggests that interventions directed
against components of this pathway, such as VEGF and TGF-alpha/EGFR, may be of benefit
in this patient population.

- We propose to test the hypothesis that dual VEGF/EGFR blockade with
bevacizumab/erlotinib is likely to be clinically active in patients with HLRCC
associated RCC as well as those with sporadic papillary sporadic RCC.

Objective:

Primary Objective

-To determine the overall response rate (RECIST) in patients with 1) metastatic RCC
associated with HLRCC and 2) metastatic sporadic/non-HLRCC papillary renal cancer treated
with a combination of bevacizumab and erlotinib

Eligibility:

- Diagnosis of advanced RCC associated with HLRCC (cohort1) or sporadic/non-HLRCC
papillary RCC (cohort2)

- ECOG PS 0-2

- Measurable disease as outlined in RECIST 1.1

- No history of major bleeding, recent or active myocardial ischemia, GI perforation,
cerebrovascular accidents or other significant intercurrent illness

- No coagulopathy or bleeding diathesis

- No recent surgery (< 4 weeks or inadequately healed surgical scars)

- Adequate organ function:

- Adequate liver function (total bilirubin less than or equal to 1.5 mg/dL or < 3
times the upper limit of normal (ULN) in subjects with Gilbert s disease, and AST/
ALT less than or equal to 2.5 times the ULN)

- Adequate renal function (creatinine less than or equal to 2.0 times the ULN or
creatinine clearance > 30 mL/min)

- Neutrophils >1500/microL and platelets >100,000

- No brain metastases

- No more than 2 prior regimens containing a VEGF-pathway inhibitor; no prior bevacizumab

- Ability to understand and sign informed consent

Design:

- Patients will receive a fixed dose of bevacizumab (10mg/kg IV every 2 weeks) and
erlotinib (150mg/day po). Dose reductions and drug interruptions for unacceptable
toxicity will be allowed.

- Patients will be evaluated for response every 8 weeks using RECIST criteria

- The study is based on an open label Simon two-stage minmax design in two cohorts, 1)
cohort 1- patients with HLRCC, and 2) cohort 2-patients with sporadic papillary RCC. In
each cohort, 13 patients will be accrued in the first stage and will accrue a maximum of
20 patients. Accrual into and analysis of the two cohorts will be independent.

- Following completion of accrual to cohorts 1 and 2, the study was expanded to include
two additional cohorts- Cohort 3 (HLRCC patients and Cohort 4 (patients with
sporadic/non HLRCC papillary RCC) to better estimate the overall response rate and to
perform additional exploratory biomarker analyses. Up to 20 additional evaluable
patients will be included in each of these cohorts.

- INCLUSION CRITERIA:

Patients must meet all the following criteria to be eligible for study enrolment:

- Diagnosis of advanced RCC associated with HLRCC (cohort 1) or sporadic/non-HLRCC
papillary RCC (cohort 2)

- Measurable disease outlined in RECIST 1.1

- No more than two prior regimens targeting the VEGF pathway; no prior bevacizumab
therapy

- Age greater than or equal to 18 years.

- Performance status ECOG 0-2

- Patients must have normal organ and marrow function as defined below: WBC count
greater than or equal to 3,000/microL, absolute neutrophil count greater than or equal
to 1,500/microL, platelet count greater than or equal to 100,000/microL, serum
creatinine greater than or equal to 2 times the upper limit of reference range or
creatinine clearance greater than or equal to 30 ml/min, AST and ALT less than 2.5
times the upper limit of reference range, total bilirubin less than 1.5 times the
upper limit of reference range ( less than 3 x upper limit of reference range in
patients with Gilbert s disease), alkaline phosphatase less than or equal to 2.5 times
the upper limit of reference range (or less than than or equal to 5 times the upper
limit of reference range if considered to be related to liver or bone metastases by
the PI)

- Recovery from acute toxicity of prior treatment for RCC (to less than or equal to
grade 1 the active version of CTCAE or to a level permitted under other sections of
Inclusion/ Exclusion criteria).

- At least 4 weeks from completion of major surgery and a healed surgical incision

- Negative pregnancy test (within 7 days of enrolment) in women of childbearing
potential

- No myocardial infarction, GI perforation/fistula, intraabdominal abscess,
cerebrovascular accidents within six months prior to study entry

- No coagulopathy or bleeding diathesis

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

- Archival tissue block or unstained tumor tissue available for correlative studies

EXCLUSION CRITERIA:

- Prior invasive malignancy of other histology, with the exception of adequately treated
basal or squamous cell carcinoma of the skin, or any other malignancy for which the
patient does not currently require treatment and/or has no evidence of disease for
greater than or equal to 2 years.

- Patients with known brain metastases unless treated with an appropriate modality with
no evidence of progression/recurrence for greater than 3 months

- Hypertension not controlled by medical therapy (resting systolic blood pressure
greater than 140 mmHg or diastolic blood pressure greater than 90 mmHg on at least two
occasions over a 24 hour period despite optimal medical management).

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection requiring intravenous antibiotics, symptomatic congestive heart failure (New
York Heart Association grade III or greater), unstable angina pectoris, or psychiatric
illness/social situations that would limit compliance with study requirements.

- Serious, non-healing wound or ulcer; bone fracture within 3 months prior to study
entry

- Patient known to be HIV-positive and requiring antiretroviral therapy (due to the risk
of potential drug interactions)

- Concomitant therapy with potent inhibitors of CYP450 3A4 (e.g. ketoconazole, verapamil
etc) or with potent CYP450 1A2 inhibitors (fluoroquinolone antibiotics including
ciprofloxacin, levofloxacin, and norfloxacin; ticlodipine, cimetidine, amiodarone,etc.
see Appendix C)

- Pregnant women are excluded from this study because bevacizumab and erlotinib are
anti-cancer agents with the potential for teratogenic or abortifacient effects.
Because there is an unknown but potential risk for adverse events in nursing infants
secondary to treatment of the mother with these agents, breastfeeding should be
discontinued if the mother is treated on this study

- All men and women of childbearing potential must be willing to use effective
contraception as determined by the principal investigator (including but not limited
to abstinence, hormonal contraceptives (birth control pills, injections, or implants),
intrauterine device (IUD), tubal ligation, vasectomy) from the time of enrolment to at
least six months following the last dose of drug

- Any known hypersensitivity to bevacizumab, erlotinib or other excipients of these
drugs

- Documented baseline proteinuria greater than 1000mg/day on 24 hour urine collection.
Only patients with 1+ or greater proteinuria on UA and a spot urine protein:creatinine
ratio of greater than 0.5 will undergo a 24 hour urine collection for quantitation of
proteinuria.

- Left ventricular ejection fraction less than 40% as measured on transthoracic
echocardiogram.

INCLUSION OF WOMEN AND MINORITIES:

Both men and women and members of all races and ethnic groups are eligible for this trial.