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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


Phase 2
18 Years
N/A
Open (Enrolling)
Both
HLRCC, Metastatic Papillary RCC

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Trial Information

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:

- 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

Secondary Objectives

- To assess progression-free survival, duration of response, and overall survival

- To investigate the effect of bevacizumab/erlotinib on circulating endothelial cells and
endothelial progenitor cells and to explore the utility of these markers as surrogates
of angiogenesis inhibition

- To investigate the effect of bevacizumab/erlotinib on potential biomarkers of
angiogenesis in plasma such as VEGF and soluble VEGFR2

- To evaluate the prevalence of somatic FH mutations/inactivation in patients with
sporadic papillary RCC

- To determine the extent of TGF-alpha upregulation and/or EGFR expression or pathway
activation in leiomyomas/ RCC tumor tissue (when available)

- To evaluate modulation of HIF, VEGF and EGFR pathways in leiomyomas (in patients with
HLRCC) and in renal tumors (when tumors are accesible for biopsy) following therapy

- To assess the effect of therapy on HLRCC-associated leiomyomas

Eligibility:

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

- ECOG PS 0-2

- Measurable disease

- 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 stratified into 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.

Inclusion Criteria


- INCLUSION CRITERIA:

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

- Measurable disease, defined as at least one lesion that can be accurately measured in
at least one dimension (longest diameter to be recorded) as greater than or equal to
20 mm with conventional techniques or as greater than or equal to 10 mm with spiral
CT scan.

- 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.

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 has not required treatment for three 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.

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

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

Principal Investigator

Ramaprasad Srinivasan, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Federal Government

Study ID:

100114

NCT ID:

NCT01130519

Start Date:

May 2010

Completion Date:

March 2017

Related Keywords:

  • HLRCC
  • Metastatic Papillary RCC
  • Advanced HLRCC
  • Sporadic Papillary Renal Cell Cancer
  • Papillary Kidney Cancer
  • Bevacizumab
  • Erlotinib
  • Kidney Cancer
  • Renal Cell Cancer
  • Hereditary Leiomyomatosis and Renal Cell Cancer
  • HLRCC
  • Carcinoma, Renal Cell
  • Leiomyomatosis
  • Kidney Neoplasms
  • Neoplastic Syndromes, Hereditary

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892