Clinical Evaluation of the Underlying Mechanisms of Targeted Therapy Related Toxicities

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01758575
Recruitment Status : Terminated
First Posted : January 1, 2013
Last Update Posted : April 7, 2017
Information provided by (Responsible Party):
H.M.W. Verheul, VU University Medical Center

Brief Summary:
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 or disease
Advanced or Metastatic Solid Malignancy

  Show Detailed Description

Study Type : Observational
Actual Enrollment : 8 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Clinical Evaluation of the Underlying Mechanisms of Targeted Therapy Related Toxicities
Study Start Date : November 2012
Actual Primary Completion Date : April 2017
Actual Study Completion Date : April 2017

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

Primary Outcome Measures :
  1. histopathological and immunomodulatory changes [ Time Frame: 4 weeks ]
    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.

  2. Kinase activity profiles [ Time Frame: 4 weeks ]
    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.

  3. Kinome wide and quantitative (phospho)proteomic profiles [ Time Frame: 4 weeks ]
    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 :
  1. 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 ]

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.

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
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.

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01758575

VU University Medical Center
Amsterdam, Netherlands, 1081HV
Sponsors and Collaborators
VU University Medical Center
Principal Investigator: Henk MW Verheul, MD, PhD VU University Medical Center

Responsible Party: H.M.W. Verheul, Prof. dr., VU University Medical Center Identifier: NCT01758575     History of Changes
Other Study ID Numbers: 2012/76
2011-005309-57 ( EudraCT Number )
First Posted: January 1, 2013    Key Record Dates
Last Update Posted: April 7, 2017
Last Verified: April 2017

Keywords provided by H.M.W. Verheul, VU University Medical Center: