Clinical Trials /

Pharmacokinetically Guided Everolimus in Patients With Breast Cancer, Pancreatic Neuroendocrine Tumors, or Kidney Cancer

NCT02273752

Description:

This phase II trial studies how well real-time pharmacokinetic therapeutic drug monitoring works in preventing stomatitis from developing in patients with hormone receptor positive breast cancer, pancreatic neuroendocrine tumors, or kidney cancer that are receiving a type of cancer drug called everolimus. Stomatitis is a common side effect of everolimus that causes inflammation of the mouth, with or without oral ulcers, and frequently leads to patients discontinuing the medication. Monitoring the blood levels of everolimus and making adjustments in a patient's dose may be able to decrease the incidence of stomatitis, while maintaining the effectiveness of everolimus to treat the cancer.

Related Conditions:
  • Breast Carcinoma
  • Pancreatic Neuroendocrine Neoplasm
  • Renal Cell Carcinoma
Recruiting Status:

Terminated

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pharmacokinetically Guided Everolimus in Patients With Breast Cancer, Pancreatic Neuroendocrine Tumors, or Kidney Cancer
  • Official Title: Phase II Evaluation of Real-Time, Pharmacokinetically Guided Everolimus in Patients With Hormone Receptor Positive Breast Cancer, Pancreatic Neuroendocrine Tumors (PNET), and Renal Cell Carcinoma

Clinical Trial IDs

  • ORG STUDY ID: IRB00072091
  • SECONDARY ID: NCI-2014-02112
  • SECONDARY ID: WINSHIP2645-14
  • NCT ID: NCT02273752

Conditions

  • Estrogen Receptor-positive Breast Cancer
  • Gastrinoma
  • Glucagonoma
  • HER2-negative Breast Cancer
  • Insulinoma
  • Mucositis
  • Oral Complications
  • Pancreatic Polypeptide Tumor
  • Progesterone Receptor-positive Breast Cancer
  • Recurrent Breast Cancer
  • Recurrent Islet Cell Carcinoma
  • Recurrent Renal Cell Cancer
  • Somatostatinoma
  • Stage III Renal Cell Cancer
  • Stage IIIA Breast Cancer
  • Stage IIIB Breast Cancer
  • Stage IIIC Breast Cancer
  • Stage IV Breast Cancer
  • Stage IV Renal Cell Cancer

Interventions

DrugSynonymsArms
Everolimus42-O-(2-hydroxy)ethyl rapamycin, Afinitor, RAD001Supportive care (real-time pharmacokinetic TDM of everolimus)

Purpose

This phase II trial studies how well real-time pharmacokinetic therapeutic drug monitoring works in preventing stomatitis from developing in patients with hormone receptor positive breast cancer, pancreatic neuroendocrine tumors, or kidney cancer that are receiving a type of cancer drug called everolimus. Stomatitis is a common side effect of everolimus that causes inflammation of the mouth, with or without oral ulcers, and frequently leads to patients discontinuing the medication. Monitoring the blood levels of everolimus and making adjustments in a patient's dose may be able to decrease the incidence of stomatitis, while maintaining the effectiveness of everolimus to treat the cancer.

Detailed Description

      PRIMARY OBJECTIVE:

      To determine frequency of any grade of stomatitis at day 29 (cycle 2, day 1) in patients
      receiving dose-adjusted everolimus.

      SECONDARY OBJECTIVES:

        1. Progression-free survival rates at 6 months.

        2. Pharmacodynamic (PD)-inhibition of downstream mammalian target of rapamycin (mTOR)
           effectors in peripheral blood.

        3. Number of dose adjustments required.

        4. Percentage of days on therapy.

        5. Average minimum concentration (Cmin) values.

        6. Frequency and type of treatments for stomatitis.

        7. Genetic predictors of stomatitis development in selected outlier patients.

      OUTLINE:

      Patients receive everolimus orally (PO) daily on days 1-28. Treatment repeats every 28 days
      for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients
      also undergo real-time pharmacokinetic therapeutic drug monitoring (TDM) on days 4, 8, and 15
      of course 1. Dosing adjustments of everolimus will be performed on day 8, if necessary. If
      the everolimus dose is adjusted, patients will continue to undergo real-time pharmacokinetic
      TDM weekly until goal concentrations are achieved on 2 consecutive measures. Patients whose
      everolimus dose is not adjusted undergo real-time pharmacokinetic TDM on day 1 of courses
      2-6.

      After completion of study treatment, patients are followed up every 12 weeks.
    

Trial Arms

NameTypeDescriptionInterventions
Supportive care (real-time pharmacokinetic TDM of everolimus)ExperimentalPatients receive everolimus PO daily on days 1-28. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients also undergo real-time pharmacokinetic TDM on days 4, 8, and 15 of course 1. Dosing adjustments of everolimus will be performed on day 8, if necessary. If the everolimus dose is adjusted, patients will continue to undergo real-time pharmacokinetic TDM weekly until goal concentrations are achieved on 2 consecutive measures. Patients whose everolimus dose is not adjusted undergo real-time pharmacokinetic TDM on day 1 of courses 2-6.
  • Everolimus

Eligibility Criteria

        Inclusion Criteria:

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-2

          -  Confirmed diagnosis of:

               -  Postmenopausal advanced hormone receptor-positive, human epidermal growth factor
                  receptor 2 (HER2)-negative breast cancer after failure of treatment with
                  letrozole or anastrozole

               -  Progressive neuroendocrine tumors of pancreatic origin (PNET) that is
                  unresectable, locally advanced or metastatic

               -  Advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or
                  sorafenib

          -  Histologically confirmed, measurable or evaluable disease. Patients should have at
             least one measurable lesion.

          -  Adequate bone marrow function as indicated by the following:

               -  Absolute neutrophil count (ANC) > 1,500/μL

               -  Platelets ≥ 100,000/μL

               -  Hemoglobin > 10 g/dL

          -  Adequate renal function, as indicated by creatinine clearance > 30 mL/min

          -  Adequate liver function, as indicated by:

               -  Bilirubin ≤ 1.5 x upper limit of normal (ULN)

               -  International normalized ratio (INR) ≤ 2

               -  Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 2 x ULN
                  unless related to primary disease

          -  Signed informed consent

          -  Adequate birth control when appropriate

          -  Fasting serum cholesterol ≤ 300 mg/dL OR ≤ 7.75 mmol/L AND fasting triglycerides ≤ 2.5
             x ULN. NOTE: in case one or both of these thresholds are exceeded, the patient can
             only be included after initiation of appropriate lipid lowering medication.

        Exclusion Criteria:

          -  Patients currently receiving anticancer therapies or who have received anticancer
             therapies within 4 weeks of the start of everolimus (including chemotherapy, radiation
             therapy, antibody based therapy, etc., but not including somatostatin analogues, e.g.,
             octreotide)

          -  Known intolerance or hypersensitivity to everolimus or other rapamycin analogs (e.g.
             sirolimus, temsirolimus)

          -  Known impairment of gastrointestinal (GI) function or GI disease that may
             significantly alter the absorption of oral everolimus

          -  Uncontrolled diabetes mellitus as defined by HbA1c >8% despite adequate therapy.
             Patients with a known history of impaired fasting glucose or diabetes mellitus (DM)
             may be included, however blood glucose and antidiabetic treatment must be monitored
             closely throughout the trial and adjusted as necessary.

          -  Patients who have any severe and/or uncontrolled medical conditions such as:

               -  Unstable angina pectoris, symptomatic congestive heart failure, myocardial
                  infarction ≤ 6 months prior to start of everolimus, serious uncontrolled cardiac
                  arrhythmia, or any other clinically significant cardiac disease

               -  Symptomatic congestive heart failure of New York Heart Association Class III or
                  IV

               -  Active (acute or chronic) or uncontrolled severe infection, liver disease such as
                  cirrhosis, decompensated liver disease, and active and chronic hepatitis (i.e.
                  quantifiable hepatitis B virus [HBV]-DNA and/or positive HbsAg, quantifiable
                  hepatitis C virus [HCV]-RNA)

               -  Known severely impaired lung function (spirometry and diffusing capacity of the
                  lung for carbon monoxide [DLCO] 50% or less of normal and O2 saturation 88% or
                  less at rest on room air)

               -  Active, bleeding diathesis

          -  Chronic treatment with corticosteroids or other immunosuppressive agents. Topical or
             inhaled corticosteroids are allowed.

          -  Known history of HIV seropositivity

          -  Patients who have received live attenuated vaccines within 1 week of start of
             everolimus and during the study. Patient should also avoid close contact with others
             who have received live attenuated vaccines. Examples of live attenuated vaccines
             include intranasal influenza, measles, mumps, rubella, oral polio, Bacillus
             Calmette-Guérin (BCG), yellow fever, varicella and TY21a typhoid vaccines.

          -  Patients who have a history of another primary malignancy, with the exceptions of:
             nonmelanoma skin cancer, and carcinoma in situ of the cervix, uteri, or breast from
             which the patient has been disease free for ≥3 years

          -  Patients with a history of non-compliance to medical regimens or who are considered
             potentially unreliable or will not be able to complete the entire study

          -  Patients who are currently part of or have participated in any clinical investigation
             with an investigational drug within 1 month prior to dosing

          -  Pregnant or nursing (lactating) women

          -  Women of child-bearing potential (WOCBP), defined as all women physiologically capable
             of becoming pregnant, must use highly effective methods of contraception during the
             study and 8 weeks after. Highly effective contraception methods include combination of
             any two of the following:

               -  Use of oral, injected or implanted hormonal methods of contraception

               -  Placement of an intrauterine device (IUD) or intrauterine system (IUS)

               -  Barrier methods of contraception: condom or occlusive cap (diaphragm or
                  cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository

               -  Total abstinence

               -  Male/female sterilization

          -  Women are considered post-menopausal and not of child-bearing potential if they have
             had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile
             (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral
             oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks prior
             to randomization. In the case of oophorectomy alone, only when the reproductive status
             of the woman has been confirmed by follow up hormone level assessment is she
             considered not of child-bearing potential.

          -  Male patients whose sexual partner(s) are WOCBP who are not willing to use adequate
             contraception, during the study and for 8 weeks after the end of treatment
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of Stomatitis
Time Frame:Day 29
Safety Issue:
Description:Stomatitis graded rates and severity will be evaluated and recorded per World Health Organization and Common Terminology Criteria for Adverse Events criteria in the study population.

Secondary Outcome Measures

Measure:Progression Free Survival (PFS)
Time Frame:6 months
Safety Issue:
Description:PFS will be evaluated based on rates of cancer progression and time to progression in the population. Progression will be determined using standard RECIST criteria. The median PFS for this study will be estimated by Kaplan-Meier method along with 95% confidence interval.
Measure:Downstream Markers of Mammalian Target of Rapamycin (mTOR) Function Measured in Peripheral Blood Mononuclear Cells
Time Frame:Up to day 15 of course 1
Safety Issue:
Description:Pharmacodynamics will be evaluated for phosphorylated and non-phosphorylated ribosomal protein S6 kinase, protein kinase B, and eukaryotic translation initiation factor 4E-binding protein 1.
Measure:Percentage of Days on Therapy
Time Frame:Up to 6 months
Safety Issue:
Description:Percentage of days on therapy will be calculated using the formula: (expected - actual days)/expected x 100.
Measure:Dose Interruptions and Adjustments
Time Frame:Up to 6 months
Safety Issue:
Description:Dose interruptions and adjustments will be made on a per subject basis and total for the population.
Measure:Frequency of Treatments for Stomatitis
Time Frame:Up to 6 months
Safety Issue:
Description:Frequency of treatments for stomatitis will be collection of prescription and non-prescription interventions.
Measure:Type of Treatments for Stomatitis
Time Frame:Up to 6 months
Safety Issue:
Description:Type of treatments for stomatitis will be collection of prescription and non-prescription interventions.
Measure:Response Rate Assessed Using Response Evaluation Criteria in Solid Tumors (RECIST) Criteria
Time Frame:Up to 24 weeks
Safety Issue:
Description:Response rate will be measured at different time points, e.g. 8, 16, and 24 weeks, and will be summarized as percentage of stable disease, complete remission or partial remission along with 95% confidence interval.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Terminated
Lead Sponsor:Emory University

Last Updated

December 9, 2016