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

NCT02273752 | Terminated Phase 2 Results DMC

• 3 other identifiers: IRB00072091NCI-2014-02112WINSHIP2645-14
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 2

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.

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

Outcome Measures

Primary Outcomes (1)

• 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.

  Day 29

Secondary Outcomes (7)

• Progression Free Survival (PFS)

  6 months

• Downstream Markers of Mammalian Target of Rapamycin (mTOR) Function Measured in Peripheral Blood Mononuclear Cells

  Up to day 15 of course 1

• Percentage of Days on Therapy

  Up to 6 months

• Dose Interruptions and Adjustments

  Up to 6 months

• Frequency of Treatments for Stomatitis

  Up to 6 months

Study Arms (1)

Supportive care (real-time pharmacokinetic TDM of everolimus)

EXPERIMENTAL

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.

Drug: Everolimus

Interventions

Everolimus DRUG

Given PO

Also known as: 42-O-(2-hydroxy)ethyl rapamycin, Afinitor, RAD001

Supportive care (real-time pharmacokinetic TDM of everolimus)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Emory University: lead
• Novartis: collaborator

Study Sites (2)

Emory University Hospital Midtown

Atlanta, Georgia, 30308, United States

Location

Emory University/Winship Cancer Institute

Atlanta, Georgia, 30322, United States

Location

MeSH Terms

Conditions

Gastrinoma; Glucagonoma; Insulinoma; Mucositis; Breast Neoplasms; Carcinoma, Islet Cell; Carcinoma, Renal Cell; Somatostatinoma

Interventions

Everolimus

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Pancreatic Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases; Adenoma, Islet Cell; Adenoma; Gastroenteritis; Gastrointestinal Diseases; Mouth Diseases; Stomatognathic Diseases; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases; Carcinoma, Neuroendocrine; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals

Limitations and Caveats

Trial closed early due to lack of timely accrual.

Results Point of Contact

• Title: R. Donald Harvey, PharmD
• Organization: Emory University

donald.harvey@emory.edu

404-778-1900

Study Officials

• R. Donald Harvey, PharmD

  Emory University/Winship Cancer Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: October 22, 2014
• First Posted: October 24, 2014
• Study Start: November 1, 2014
• Primary Completion: December 1, 2015
• Study Completion: December 1, 2015
• Last Updated: February 3, 2017
• Results First Posted: February 3, 2017

Record last verified: 2016-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)