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

Completed

Conditions: HLRCC
Sporadic Papillary Renal Cell Cancer

Interventions: Drug: Bevacizumab
Drug: Erlotinib

Registration Number: NCT01130519

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: Background:

* At the present time, there are no drugs that have been proven to work in patients with papillary kidney cancer that has spread (metastasized) beyond the kidneys. Researchers are interested in determining whether the combination of the drugs bevacizumab and erlotinib can be used to treat metastatic papillary kidney cancer.

* Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC) is an inherited type of papillary kidney cancer (it runs in families). Papillary kidney cancer can also occur sporadically, or without a family connection. More research is needed to determine whether treatments for papillary kidney cancer, such as bevacizumab and erlotinib, work in inherited or sporadic types of kidney cancer, and if so, whether there are any differences.

Objectives:

-To determine the effectiveness of the combination of bevacizumab and erlotinib as a treatment for patients with (1) metastatic HLRCC kidney cancer and (2) metastatic kidney cancer not associated with HLRCC (or sporadic papillary RCC).

Eligibility:

* Individuals 18 years of age or older who have been diagnosed with papillary kidney cancer that has spread beyond the kidneys.

* Participants may have either HLRCC or sporadic papillary kidney cancer.

Design:

* Participants will be screened with a full medical history, physical examination, blood and urine tests, and computed tomography (CT) and other scans to evaluate tumor size and treatment options.

* Participants will receive 28-day treatment cycles of bevacizumab (given intravenously every 2 weeks) and erlotinib (a tablet taken by mouth daily).

* Every cycle, participants will return for regular blood and urine tests. Every other cycle, participants will have imaging scans to assess tumor size and response to treatment. Female participants who have uterine fibroid tumors related to their kidney cancer may have additional scans to assess tumor size and response to treatment.

* Participants will continue to receive treatment on the study until their tumors grow or spread to new areas (disease progression), intolerable side effects develop, a better treatment option becomes available, the study closes, it is unsafe to continue treatment, or the participant decides not to remain in the study.

Detailed Description: Background

* Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is a familial cancer syndrome characterized by a propensity for developing renal cancer, and uterine and cutaneous leiomyomas. The kidney cancer associated with HLRCC is clinically aggressive and is characterized by unique histopathologic features that are sometimes described as type 2 papillary RCC.

* Germline mutations in the fumarate hydratase (FH) gene are the genetic hallmark of HLRCC. Mutational inactivation of FH has been shown to result in Von Hippel-Lindau (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 vascular endothelial growth factor (VEGF) and transforming growth factor-alpha/epidermal growth factor receptor (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 (Response Evaluation Criteria in Solid Tumors (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 (cohorts 1 and 3) or sporadic/non-HLRCC papillary RCC (cohorts 2 and 4)

* Eastern Cooperative Oncology Group (ECOG) PS 0-2

* Measurable disease, consistent with RECIST 1.1

* No history of major bleeding, recent or active myocardial ischemia, gastrointestinal (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 \<= 1.5 mg/dL or \< 3 x upper limit of normal (ULN) in subjects with Gilbert's disease, and aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT) serum glutamic pyruvic transferase (SGPT) 2.5 x ULN

* Adequate renal function (creatinine \<= 2.0 x 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 therapy with bevacizumab

* Ability to understand and sign informed consent

Design

* Patients will receive a fixed starting dose of bevacizumab (10mg/kg intravenous (IV) every 2 weeks) and erlotinib (150mg/day by mouth (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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 83

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
1 - Bevacizumab and Erlotinib	Bevacizumab	All patients will be receiving fixed starting dose of bevacizumab (10 mg/kg intravenous (IV) every 2 weeks) and erlotinib (150 mg/day by mouth (PO)
1 - Bevacizumab and Erlotinib	Erlotinib	All patients will be receiving fixed starting dose of bevacizumab (10 mg/kg intravenous (IV) every 2 weeks) and erlotinib (150 mg/day by mouth (PO)

Primary Outcome Measures

Name	Time	Method
Overall Response Rate	Every 8 weeks during the first 32 weeks and every 12 weeks thereafter, a median of 64.3 months	Participants whose tumors regressed (Complete Response (CR) plus Partial Response (PR)) after therapy as measured by the Response Evaluation Criteria in Solid Tumors (RECIST). CR is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR is at least a 30% decrease in the sum of the longest diameters of target lesions. Progressive Disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progressions. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Data shown with 95% confidence intervals.

Secondary Outcome Measures

Name	Time	Method
Progression-free Survival	Amount of time subject survives without disease progression after treatment; a median of 15 months.	Median amount of time subject survives without disease progression after treatment. Progression was measured by the Response Evaluation Criteria in Solid Tumors (RECIST) and is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progressions.
Duration of Response	Time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented; a median of 19 months.	Duration of overall response is measured from the time measurement criteria are met for Complete Response (CR) or Partial Response (PR) (whichever is first recorded) until the first date that recurrent or progressive disease (PD) is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started), measured by the Response Evaluation Criteria in Solid Tumors (RECIST). CR is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR is at least a 30% decrease in the sum of the diameters of target lesions. PD is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progressions.
Overall Survival (OS)	Time from the date of study enrolment until time of death; a median of 29.3 months.	Overall survival is defined as the duration of time from the date of study enrolment until time of death estimated using a Kaplan Meier analysis. Participants without a death event will be censored at the date survival assessment was last evaluated (e.g., clinic visit, phone call).