Everolimus TDM to Predict Long Term Toxicity

NCT03033186 | Unknown

• 1 other identifier: NL58486.068.16
• Study Type: observational
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

Metastatic (HR-positive, HER2-negative) breast cancer (BC), advanced or unresectable neuroendocrine tumours of pancreatic (pNET), gastrointestinal or lung origin and metastatic renal cell carcinoma (mRCC) are diseases with poor outcome. Everolimus increases patients' median progression-free survival (PFS) with 4.6 months in metastatic BC (mBC), 7 months in (p)NET and 3 months in mRCC. However, serious adverse events (AEs) occur frequently. This reduces effectiveness of everolimus, because AEs are managed with dose reductions, treatment interruptions or even complete discontinuation of everolimus. Therapeutic-drug-monitoring (TDM) is used to adjust the prescribed daily dose, to maintain effective everolimus whole blood concentrations, with the lowest possible risk of AEs. While everolimus TDM has been common in transplantation medicine, it has not been implemented in oncology. The importance of TDM in oncology is supported by previous research which showed that a 2-fold increased everolimus whole blood trough concentration was associated with a short-term risk of grade ≥ 3 pneumonitis, stomatitis and metabolic events. Moreover, an exposure-toxicity relationship of everolimus in patients with thyroid cancer was observed, since initial everolimus concentrations could be associated with early toxicity (\< 12 weeks, e.g. stomatitis). However, the association between initial everolimus measurements and long-term AEs (≥12 weeks, e.g. pneumonitis, anorexia and anemia) of any grade and the need for everolimus dose reductions could not be made. Since levels ±\>18 µg/L were associated with toxicity, the investigators assume that the upper therapeutic window of everolimus in the oncologic setting will be ±18 µg/L. Similarly, a tendency to improved PFS and overall survival was observed when Cmin in steady state was above 14.1 μg/L. This seems to be the lower limit of the therapeutic window. Before consensus about the feasibility of everolimus TDM in the oncologic setting can be achieved, a number of questions (the knowledge gaps) need to be answered: 1. It is unknown whether everolimus whole blood trough levels (over time) predict long-term AEs. 2. The optimal concentration range for everolimus, with the treatment of mBC, mRCC, or (p)NET is unknown, especially the upper limit associated with toxicity. 3. It is unknown what everolimus concentration level is associated with the need for everolimus dose reductions.

Conditions

Breast Cancer; Renal Cell Carcinoma; Pancreatic Neuroendocrine Tumour; Gastrointestinal Neuroendocrine Tumour; Neuroendocrine Neoplasm of Lung

Keywords

Everolimus; Long term site effects; Dried Blood Spot; Therapeutic Drug Monitoring

Outcome Measures

Primary Outcomes (1)

• Everolimus TDM to predict long-term toxicity

  The difference in percentage of patients with a high everolimus trough level (i.e. \> 18 ng/mL) experiencing NCI-CTCAE v4.0 grade 2, 3 or 4 late AEs (i.e. toxicity reported from ≥ 12 weeks onward, e.g. pneumonitis, anorexia, anemia) compared to participants with lower trough concentrations.

  Up to 2 year

Secondary Outcomes (4)

• Everolimus TDM to predict short-term toxicity

  Up to 2 year

• Correlation everolimus concentration DBS from fingerprick with whole blood from venipuncture

  Up to 2 year

• Correlation everolimus concentration DBS from fingerprick with DBS spiked with whole blood from venipuncture

  Up to 2 year

• Everolimus TDM to predict dose reductions

  Up to 2 year

Study Arms (1)

Everolimus (afinitor)

Patients using everolimus as therapy for cancer: Advanced (Hormone-Receptor \[HR\]-positive, HER2-negative) breast cancer (BC), advanced or unresectable neuroendocrine tumours of pancreatic (pNET), gastrointestinal or lung origin and metastatic renal cell carcinoma (mRCC)

Eligibility Criteria

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

Study Population

Patients currently treated with everolimus for any type of cancer, such as the EMA registered indications i.e. advanced (Hormone-Receptor \[HR\]-positive, HER2-negative) breast cancer, metastatic renal cell carcinoma (mRCC) or neuroendocrine tumours of pancreatic (pNET), gastrointestinal or lung origin.

You may qualify if:

• Patients currently treated with everolimus for any type of cancer, such as the EMA registered indications i.e. advanced (Hormone-Receptor \[HR\]-positive, HER2-negative) breast cancer, metastatic renal cell carcinoma (mRCC) or neuroendocrine tumour (NET) of pancreatic, gastrointestinal or lung origin.
• Aged 18 or above
• Able and willing to sign the informed consent

You may not qualify if:

• No informed consent
• Alactasia

Sponsors & Collaborators

• Maastricht University Medical Center: lead

Study Sites (1)

Maastricht University Medical Centre

Maastricht, Limburg, 6202 AZ, Netherlands

RECRUITING

Biospecimen

Retention: SAMPLES WITHOUT DNA

Whole blood and drop of blood

MeSH Terms

Conditions

Breast Neoplasms; Carcinoma, Renal Cell; Adenoma, Islet Cell

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases; Adenoma; Pancreatic Neoplasms; Digestive System Neoplasms; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases

Study Officials

• S. Croes, PharmD, PhD

  Maastricht University Medical Centre+

  PRINCIPAL INVESTIGATOR

Central Study Contacts

S. Croes, PharmD PhD

CONTACT

(+31)43 3871431; s.croes@mumc.nl

L. Knapen, PharmD

CONTACT

(+31)43 3871881; lotte.knapen@mumc.nl

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 24, 2017
• First Posted: January 26, 2017
• Study Start: May 16, 2017
• Primary Completion: September 1, 2018
• Study Completion: December 31, 2018
• Last Updated: May 31, 2017

Record last verified: 2017-05

Data Sharing

• IPD Sharing: Will not share

Locations

NL (1)