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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

NCT01130519

Description:

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 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.

Related Conditions:
  • Renal Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: 100114
  • SECONDARY ID: 10-C-0114
  • NCT ID: NCT01130519

Conditions

  • HLRCC
  • Sporadic Papillary Renal Cell Cancer

Interventions

DrugSynonymsArms
Bevacizumab1
Erlotinib1

Purpose

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 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, 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.
    

Trial Arms

NameTypeDescriptionInterventions
1ExperimentalAll patient will be receiving fixed starting dose of bevacizumab (10 mg /kg IV every 2 weeks) and erlotinib (150 mg/day PO)
  • Bevacizumab
  • Erlotinib

Eligibility Criteria

        -  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.
      
Maximum Eligible Age:100 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate
Time Frame:4-5 years
Safety Issue:
Description:Proportion of patients whose tumors shrunk after therapy

Secondary Outcome Measures

Measure:Progression-free survival, duration of response, and overall survival.
Time Frame:4-5 years
Safety Issue:
Description:Median amount of time subject survives without disease progression after treatment
Measure:Effect on potential biomarkers of angiogenesis in plasma such as VEGF and soluble VEGFR2.
Time Frame:4-5 years
Safety Issue:
Description:Correlation between treatment and potential biomarkers such as VEGF and soluble VEGFR2
Measure:Determine the extent of TGF upregulation and/or EGFR expression/ pathway activation in leiomyomas/ RCC tumor tissue.
Time Frame:4-5 years
Safety Issue:
Description:EGFR expression/ pathway activation in leiomyomas/ RCC tumor tissue
Measure:Prevalence of somatic FH mutations/inactivation in patients with sporadic papillary RCC.
Time Frame:4-5 years
Safety Issue:
Description:Correlation between treatment and prevalence of somatic FH mutations
Measure:Effect on circulating endothelial cells and endothelial progenitor cells.
Time Frame:4-5 years
Safety Issue:
Description:Correlation between circulating endothelial cells and endothelial progenitor cells after treatment
Measure:Evaluate modulation of HIF, VEGF and EGFR pathways in cutaneous leiomyomas (in patients with HLRCC) and in renal tumors following therapy.
Time Frame:4-5 years
Safety Issue:
Description:Modulation of HIF, VEGF and EGFR pathways in cutaneous leiomyomas and in renal tumors after therapy
Measure:Effect on HLRCC associated uterine and skin leiomyomas.
Time Frame:4-5 years
Safety Issue:
Description:Correlation between therapy and skin leiomyomas

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • Immunotherapy
  • Biomarker
  • Kidney Cancer
  • Renal Cell Cancer
  • Hereditary Leiomyomatosis and Renal Cell Cancer
  • HLRCC

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