Identifying Mechanisms of Resistance to mTOR Inhibitors in Cancer

mTOR kinase is part of the mTORC1 complex that promotes cap-dependent protein translation, and part of the mTORC2 complex that activates AKT. Everolimus (Afinitor) is an allosteric inhibitor of mTOR that suppresses mTORC1 activity. Everolimus is FDA-approved for the treatment of ER+/HER2- breast cancer (in combination with exemestane), renal cell carcinoma, subependymal giant cell astrocytoma (SEGA), and neuroendocrine tumors of pancreatic origin (PNET), and is currently being tested in ongoing clinical studies in other indications. While everolimus-based therapies elicit anti-cancer effects, most cancers ultimately progress and exhibit everolimus resistance. This study will evaluate genetic mechanisms of resistance to everolimus.

Study Overview

• Status: Terminated
• Conditions: Cancer
• Intervention / Treatment: Other: n/a- this is an observational study

• Study Type: Observational
• Enrollment (Actual): 2

Contacts and Locations

Study Locations

• United States
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth-Hitchcock Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Patients treated with everolimus for any cancer type.

Description

Inclusion Criteria:

1. Treatment with everolimus (as a single-agent or in combination) for any malignancy for ≥3 months.

2. A- Patients who are scheduled to undergo a clinically indicated tumor biopsy (as standard of care, or as part of another study) within 5 years following cancer progression on everolimus are eligible.

   B- Patients who already had such a biopsy procedure performed are eligible. Tumors biopsied shortly after progression on everolimus are strongly preferred.

3. Excess tumor tissue from biopsy must be available for molecular analysis. This will include tumor tissue sufficient to make ≥5 five-micron sections; more tumor tissue is preferred.
4. Patients currently seen at Dartmouth-Hitchcock Medical Center must be capable and willing to provide informed written consent for study participation. Patients who are no longer seen at DHMC will not be consented for use of archived tissues and data.
5. For patients currently seen at Dartmouth-Hitchcock Medical Center, patients must be willing to provide an extra 10-20 mL of blood during a routine, clinically indicated blood draw procedure.

Exclusion Criteria:

none

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Mutations in genes encoding components of the mTOR pathway that are detected in post-everolimus tumors but not pre-everolimus tumors.	1 year

Secondary Outcome Measures

Outcome Measure	Time Frame
Mutations detected in plasma DNA that are present in the post-everolimus tumor but not the pre-everolimus tumor.	1 year

Collaborators and Investigators

• Sponsor: Dartmouth-Hitchcock Medical Center
• Investigators: Principal Investigator: Todd W Miller, PhD, Dartmouth College

Study record dates

Study Major Dates

• Study Start: March 1, 2015
• Primary Completion (Actual): February 1, 2016
• Study Completion (Actual): March 1, 2016

Study Registration Dates

• First Submitted: December 1, 2014
• First Submitted That Met QC Criteria: December 1, 2014
• First Posted (Estimate): December 3, 2014

Study Record Updates

• Last Update Posted (Estimate): April 27, 2016
• Last Update Submitted That Met QC Criteria: April 25, 2016
• Last Verified: January 1, 2016

More Information

Terms related to this study

• Keywords: Cancer; Everolimus; Sirolimus; Rapamycin; Temsirolimus; mTOR; Tumor
• Other Study ID Numbers: D15036