Clinical Evaluation of the Underlying Mechanisms of Targeted Therapy Related Toxicities
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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 |
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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 |
- 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.
- 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 |
|---|
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antiangiogenic tyrosine kinase inhibitors
Sunitinib: 50 mg orally once daily Sorafenib: 400 mg orally twice daily Pazopanib: 800 mg orally once daily
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EGFR inhibitors
Cetuximab 250 mg/m2 intravenously, weekly Panitumumab 6 mg/Kg intravenously, every 2 weeks
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mTOR inhibitors
Everolimus 10 mg orally once daily
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BRAF inhibitor
Vemurafenib 960 mg orally twice daily
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anti-CTL4 antibody
Ipilimumab 3 mg/kg intravenously, every 3 weeks
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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 |
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:
- 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.
- PT-INR/PTT < 1.5 x ULN.
- Platelet count >/= 100 x 109/l
Exclusion Criteria:
- Concomitant use of anticoagulants
- Previous colonic surgery in the last 3 months
- History of inflammatory bowel disease, or other active gastrointestinal infection
Contacts and Locations| Contact: Henk MW Verheul, MD, PhD | +31-20-4444321 |
| Netherlands | |
| VU University Medical Center | Recruiting |
| Amsterdam, Netherlands, 1081HV | |
| Contact: Henk MW Verheul, MD, PhD +31-20-4444321 h.verheul@vumc.nl | |
| 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: | December 31, 2012 |
| Health Authority: | Netherlands: The Central Committee on Research Involving Human Subjects (CCMO) |
Keywords provided by VU University Medical Center:
|
Patients |
Additional relevant MeSH terms:
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Neoplasms |
ClinicalTrials.gov processed this record on May 16, 2013