HLRCC, Sporadic Papillary Renal Cell Cancer
Conditions
Keywords
Immunotherapy, Biomarker, Kidney Cancer, Renal Cell Cancer, Hereditary Leiomyomatosis and Renal Cell Cancer, HLRCC
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.
Interventions
DRUGBevacizumab
Commercially available. Administered by intravenous infusion.
DRUGErlotinib
Commercially available. Administered orally.
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* INCLUSION CRITERIA: Patients must meet all the following criteria to be eligible for study enrolment: * Diagnosis of advanced renal cell cancer (RCC) associated with hereditary leiomyomatosis and renal cell cancer (HLRCC) (cohorts 1 & 3) or sporadic/non-HLRCC papillary RCC (cohort 2 & 4) * Measurable disease outlined in Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 * No more than two prior regimens targeting the vascular endothelial growth factor (VEGF) pathway; no prior bevacizumab therapy * Age greater than or equal to 18 years. * Performance status Eastern Cooperative Oncology Group (ECOG) 0-2 * Patients must have normal organ and marrow function as defined below: white blood cell (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, aspartate aminotransferase (AST) and alanine aminotransferase (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 or equal to 5 times the upper limit of reference range if considered to be related to liver or bone metastases by the principal investigator (PI) * Recovery from acute toxicity of prior treatment for RCC (to less than or equal to grade 1 the active version of Common Terminology Criteria for Adverse Events (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, gastrointestinal (GI) perforation/fistula, intra-abdominal 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0) | Date treatment consent signed to date off study, approximately 133 months and 13 days; and 119 months and 2 days for the first and second group respectively. | Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| COHORT 1-Advanced Renal Cell Cancer Associated With Hereditary Leiomyomatosis and Renal Cell Cancer All participants will be receiving fixed starting dose of bevacizumab (10 mg/kg intravenous (IV) every 2 weeks) and erlotinib (150 mg/day by mouth (PO).
Participants with metastatic Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC), diagnosed by either germline mutation of the fumarate hydratase (FH) gene, or based upon evidence of the clinical syndrome of HLRCC (characteristic renal cancer histology, cutaneous leiomyomas, uterine fibroids, and a family history). | 20 |
| COHORT 2 - Sporadic Papillary Renal Cell Cancer All participants will be receiving fixed starting dose of bevacizumab (10 mg/kg intravenous (IV) every 2 weeks) and erlotinib (150 mg/day by mouth (PO).
Participants with sporadic papillary renal cancer. | 21 |
| COHORT 3 - Hereditary Leiomyomatosis and Renal Cell Cancer Associated Kidney Cancer All participants will be receiving fixed starting dose of bevacizumab (10 mg/kg intravenous (IV) every 2 weeks) and erlotinib (150 mg/day by mouth (PO).
Participants with metastatic Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC), diagnosed by either germline mutation of the fumarate hydratase (FH) gene, or based upon evidence of the clinical syndrome of HLRCC (characteristic renal cancer histology, cutaneous leiomyomas, uterine fibroids, and a family history). | 23 |
| COHORT 4-Sporadic/NonHereditary Leiomyomatosis and Renal Cell Cancer Papillary Kidney Cancer All participants will be receiving fixed starting dose of bevacizumab (10 mg/kg intravenous (IV) every 2 weeks) and erlotinib (150 mg/day by mouth (PO).
Participants with sporadic papillary renal cancer. | 19 |
| Total | 83 |
Baseline characteristics
| Characteristic | COHORT 1-Advanced Renal Cell Cancer Associated With Hereditary Leiomyomatosis and Renal Cell Cancer | COHORT 2 - Sporadic Papillary Renal Cell Cancer | COHORT 3 - Hereditary Leiomyomatosis and Renal Cell Cancer Associated Kidney Cancer | COHORT 4-Sporadic/NonHereditary Leiomyomatosis and Renal Cell Cancer Papillary Kidney Cancer | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 5 Participants | 1 Participants | 3 Participants | 9 Participants |
| Age, Categorical Between 18 and 65 years | 20 Participants | 16 Participants | 22 Participants | 16 Participants | 74 Participants |
| Age, Continuous | 43.43 years STANDARD_DEVIATION 12.15 | 56.99 years STANDARD_DEVIATION 9.61 | 44.53 years STANDARD_DEVIATION 12.98 | 52.37 years STANDARD_DEVIATION 13.98 | 49.21 years STANDARD_DEVIATION 13.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants | 20 Participants | 22 Participants | 19 Participants | 80 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 2 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 0 Participants | 1 Participants | 3 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 15 Participants | 21 Participants | 20 Participants | 15 Participants | 71 Participants |
| Region of Enrollment United States | 20 participants | 21 participants | 23 participants | 19 participants | 83 participants |
| Sex: Female, Male Female | 10 Participants | 6 Participants | 3 Participants | 8 Participants | 27 Participants |
| Sex: Female, Male Male | 10 Participants | 15 Participants | 20 Participants | 11 Participants | 56 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 28 / 43 | 36 / 40 |
| other Total, other adverse events | 43 / 43 | 40 / 40 |
| serious Total, serious adverse events | 9 / 43 | 9 / 40 |
Outcome results
Primary
Overall Response Rate
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.
Time frame: Every 8 weeks during the first 32 weeks and every 12 weeks thereafter, a median of 64.3 months
Population: As pre-specified by the protocol for reporting purposes, our expansion cohorts were combined with the original cohorts (i.e., cohort 1, cohort 2, cohort 3, and cohort 4). Therefore, we reported on two groups: all Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) participants (Cohorts 1 \& 3) and all sporadic participants (Cohort 2 \& 4).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| COHORT 1&3 Advanced Renal Cell Cancer Associated With Hereditary Leiomyomatosis & Renal Cell Cancer | Overall Response Rate | 72 Percentage of participants |
| COHORT 2 and 4 - Sporadic Papillary Renal Cell Cancer | Overall Response Rate | 35 Percentage of participants |
Secondary
Duration of Response
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.
Time frame: 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.
Population: As pre-specified by the protocol for reporting purposes, our expansion cohorts were combined with the original cohorts (i.e., cohort 1, cohort 2, cohort 3, and cohort 4). Therefore, we reported on two groups: all Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) participants (Cohorts 1 \& 3) and all sporadic participants (Cohort 2 \& 4).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| COHORT 1&3 Advanced Renal Cell Cancer Associated With Hereditary Leiomyomatosis & Renal Cell Cancer | Duration of Response | 19.3 Months |
| COHORT 2 and 4 - Sporadic Papillary Renal Cell Cancer | Duration of Response | 18.4 Months |
Secondary
Overall Survival (OS)
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).
Time frame: Time from the date of study enrolment until time of death; a median of 29.3 months.
Population: As pre-specified by the protocol for reporting purposes, our expansion cohorts were combined with the original cohorts (i.e., cohort 1, cohort 2, cohort 3, and cohort 4). Therefore, we reported on two groups: all Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) participants (Cohorts 1 \& 3) and all sporadic participants (Cohort 2 \& 4).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| COHORT 1&3 Advanced Renal Cell Cancer Associated With Hereditary Leiomyomatosis & Renal Cell Cancer | Overall Survival (OS) | 44.6 Months |
| COHORT 2 and 4 - Sporadic Papillary Renal Cell Cancer | Overall Survival (OS) | 18.2 Months |
Secondary
Progression-free Survival
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.
Time frame: Amount of time subject survives without disease progression after treatment; a median of 15 months.
Population: As pre-specified by the protocol for reporting purposes, our expansion cohorts were combined with the original cohorts (i.e., cohort 1, cohort 2, cohort 3, and cohort 4). Therefore, we reported on two groups: all Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) participants (Cohorts 1 \& 3) and all sporadic participants (Cohort 2 \& 4).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| COHORT 1&3 Advanced Renal Cell Cancer Associated With Hereditary Leiomyomatosis & Renal Cell Cancer | Progression-free Survival | 21.1 Months |
| COHORT 2 and 4 - Sporadic Papillary Renal Cell Cancer | Progression-free Survival | 8.9 Months |
Other Pre-specified
Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)
Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
Time frame: Date treatment consent signed to date off study, approximately 133 months and 13 days; and 119 months and 2 days for the first and second group respectively.
Population: As pre-specified by the protocol for reporting purposes, our expansion cohorts were combined with the original cohorts (i.e., cohort 1, cohort 2, cohort 3, and cohort 4). Therefore, we reported on two groups: all Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) participants (Cohorts 1 \& 3) and all sporadic participants (Cohort 2 \& 4).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| COHORT 1&3 Advanced Renal Cell Cancer Associated With Hereditary Leiomyomatosis & Renal Cell Cancer | Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0) | 43 Participants |
| COHORT 2 and 4 - Sporadic Papillary Renal Cell Cancer | Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0) | 40 Participants |