Clinical Evaluation of the Underlying Mechanisms of Targeted Therapy Related Toxicities

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2014 by VU University Medical Center
Sponsor:
Information provided by (Responsible Party):
H.M.W. Verheul, VU University Medical Center
ClinicalTrials.gov Identifier:
NCT01758575
First received: December 11, 2012
Last updated: February 21, 2014
Last verified: February 2014
  Purpose

Single center, non-randomized, interventional pilot study with feasibility analysis after enrollment of 20 patients. Adult patients with advanced solid tumors, for whom standard palliative treatment with targeted agents as monotherapy is indicated, including antiangiogenic tyrosine kinase inhibitors, EGFR inhibitors, mTOR inhibitors, BRAF inhibitors and ipilimumab.After feasibility analysis in the first twenty patients, twenty more patients will be included in each of the five drug cohorts. Biopsies will be performed to determine possible immunohistochemical and histopathological changes in normal tissue, possible immunomodulatory changes as expressed by Tcell phenotyping and cytokine profiling and to compare tissue (phospho) proteomic and kinase activity profiles before and during therapy and also at the development of toxicity.The main objective of this pilot study is to determine the biological impact of treatment with targeted agents at the systemic and local tissue level in relation to toxicity.


Condition
Advanced or Metastatic Solid Malignancy

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: Clinical Evaluation of the Underlying Mechanisms of Targeted Therapy Related Toxicities

Resource links provided by NLM:


Further study details as provided by VU University Medical Center:

Primary Outcome Measures:
  • histopathological and immunomodulatory changes [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
    Biopsies of the areas most anticipated to be affected (skin, oral mucosa, colon mucosa) will be taken at the beginning and after 4 weeks of treatment. Specific attention will be directed in normal tissues at the percentage and types of inflammatory cells and cytokines. In addition, markers of proliferation and apoptosis will be evaluated.

  • Kinase activity profiles [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
    Kinase activity profiles will be measured according to standard methods as developed and modified in the laboratory of VUmc. PamChip will be applied to measure the signal intensity of both the pre- and on- treatment lysates, in the same experiment, to secure comparable conditions. The percentage inhibition is calculated by dividing the mean signal intensity of the on-treatment lysate by the mean signal intensity of the pre-treatment normal tissue lysates.

  • Kinome wide and quantitative (phospho)proteomic profiles [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
    Kinome wide and quantitative (phospho)proteomic profiles will be determined in normal tissue biopsies before and during treatment, for each patient. We anticipate that these profiles will reveal information on the effect of treatment on kinase abundances, phosphopeptide levels and on phosphorylation sites. Differences in levels of phosphopeptides and fold-change of phosphorylation sites will be quantified. We will try to correlate observed profile changes to toxicity development.


Secondary Outcome Measures:
  • Based on the results of the primary aim, potential novel markers predictive for toxicity will be evaluated using the measurements as described under the primary subaims 1-3 [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]

Biospecimen Retention:   Samples With DNA

Blood samples and blind biopsies of the oral mucosa, skin and colon mucosa will be taken pre-treatment and after 4 weeks of treatment.


Estimated Enrollment: 120
Study Start Date: November 2012
Estimated Study Completion Date: October 2014
Estimated Primary Completion Date: October 2014 (Final data collection date for primary outcome measure)
Groups/Cohorts
antiangiogenic tyrosine kinase inhibitors
Sunitinib: 50 mg orally once daily Sorafenib: 400 mg orally twice daily Pazopanib: 800 mg orally once daily
EGFR inhibitors
Cetuximab 250 mg/m2 intravenously, weekly Panitumumab 6 mg/Kg intravenously, every 2 weeks
mTOR inhibitors
Everolimus 10 mg orally once daily
BRAF inhibitor
Vemurafenib 960 mg orally twice daily
anti-CTL4 antibody
Ipilimumab 3 mg/kg intravenously, every 3 weeks

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population

Patients with advanced or metastatic solid malignancy, amenable to standard treatment with targeted agents will be included from the VUmc Medical Oncology outpatient clinic.

Criteria

Inclusion Criteria:

  1. Patients that will start palliative treatment with TKIs, mTOR inhibitors, ipilimumab, vemurafenib or EGFR inhibitors and therefore fulfill according to their attending physician all the usual criteria for receiving standard targeted therapy as monotherapy.
  2. PT-INR/PTT < 1.5 x ULN.
  3. Platelet count >/= 100 x 109/l

Exclusion Criteria:

  1. Concomitant use of anticoagulants
  2. Previous colonic surgery in the last 3 months
  3. History of inflammatory bowel disease, or other active gastrointestinal infection
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01758575

Contacts
Contact: Henk MW Verheul, MD, PhD +31-20-4444321

Locations
Netherlands
VU University Medical Center Recruiting
Amsterdam, Netherlands, 1081HV
Contact: Henk MW Verheul, MD, PhD    +31-20-4444321    h.verheul@vumc.nl   
Sponsors and Collaborators
VU University Medical Center
Investigators
Principal Investigator: Henk MW Verheul, MD, PhD VU University Medical Center
  More Information

No publications provided

Responsible Party: H.M.W. Verheul, Prof. dr., VU University Medical Center
ClinicalTrials.gov Identifier: NCT01758575     History of Changes
Other Study ID Numbers: 2012/76, 2011-005309-57
Study First Received: December 11, 2012
Last Updated: February 21, 2014
Health Authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Keywords provided by VU University Medical Center:
Patients

Additional relevant MeSH terms:
Neoplasms

ClinicalTrials.gov processed this record on July 29, 2014