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

Primary Purpose

Estrogen Receptor-positive Breast Cancer, Gastrinoma, Glucagonoma

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Everolimus
Sponsored by
Emory University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Estrogen Receptor-positive Breast Cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Emory University Hospital Midtown
  • Emory University/Winship Cancer Institute

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Supportive care (real-time pharmacokinetic TDM of everolimus)

Arm Description

Patients 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.

Outcomes

Primary Outcome Measures

Incidence of Stomatitis
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

Progression Free Survival (PFS)
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.
Downstream Markers of Mammalian Target of Rapamycin (mTOR) Function Measured in Peripheral Blood Mononuclear Cells
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.
Percentage of Days on Therapy
Percentage of days on therapy will be calculated using the formula: (expected - actual days)/expected x 100.
Dose Interruptions and Adjustments
Dose interruptions and adjustments will be made on a per subject basis and total for the population.
Frequency of Treatments for Stomatitis
Frequency of treatments for stomatitis will be collection of prescription and non-prescription interventions.
Type of Treatments for Stomatitis
Type of treatments for stomatitis will be collection of prescription and non-prescription interventions.
Response Rate Assessed Using Response Evaluation Criteria in Solid Tumors (RECIST) Criteria
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.

Full Information

First Posted
October 22, 2014
Last Updated
December 9, 2016
Sponsor
Emory University
Collaborators
Novartis
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1. Study Identification

Unique Protocol Identification Number
NCT02273752
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
Study Type
Interventional

2. Study Status

Record Verification Date
December 2016
Overall Recruitment Status
Terminated
Why Stopped
Slow accrual
Study Start Date
November 2014 (undefined)
Primary Completion Date
December 2015 (Actual)
Study Completion Date
December 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Emory University
Collaborators
Novartis

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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: Progression-free survival rates at 6 months. Pharmacodynamic (PD)-inhibition of downstream mammalian target of rapamycin (mTOR) effectors in peripheral blood. Number of dose adjustments required. Percentage of days on therapy. Average minimum concentration (Cmin) values. Frequency and type of treatments for stomatitis. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
2 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Supportive care (real-time pharmacokinetic TDM of everolimus)
Arm Type
Experimental
Arm Description
Patients 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.
Intervention Type
Drug
Intervention Name(s)
Everolimus
Other Intervention Name(s)
42-O-(2-hydroxy)ethyl rapamycin, Afinitor, RAD001
Intervention Description
Given PO
Primary Outcome Measure Information:
Title
Incidence of Stomatitis
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.
Time Frame
Day 29
Secondary Outcome Measure Information:
Title
Progression Free Survival (PFS)
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.
Time Frame
6 months
Title
Downstream Markers of Mammalian Target of Rapamycin (mTOR) Function Measured in Peripheral Blood Mononuclear Cells
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.
Time Frame
Up to day 15 of course 1
Title
Percentage of Days on Therapy
Description
Percentage of days on therapy will be calculated using the formula: (expected - actual days)/expected x 100.
Time Frame
Up to 6 months
Title
Dose Interruptions and Adjustments
Description
Dose interruptions and adjustments will be made on a per subject basis and total for the population.
Time Frame
Up to 6 months
Title
Frequency of Treatments for Stomatitis
Description
Frequency of treatments for stomatitis will be collection of prescription and non-prescription interventions.
Time Frame
Up to 6 months
Title
Type of Treatments for Stomatitis
Description
Type of treatments for stomatitis will be collection of prescription and non-prescription interventions.
Time Frame
Up to 6 months
Title
Response Rate Assessed Using Response Evaluation Criteria in Solid Tumors (RECIST) Criteria
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.
Time Frame
Up to 24 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
R. Donald Harvey, PharmD
Organizational Affiliation
Emory University/Winship Cancer Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Emory University Hospital Midtown
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30308
Country
United States
Facility Name
Emory University/Winship Cancer Institute
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

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

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