Ignite Creation Date:
2024-05-06 @ 1:11 AM
Last Modification Date:
2024-10-26 @ 11:01 AM
Study NCT ID:
NCT01758575
Status:
TERMINATED
Last Update Posted:
2017-04-07
First Post:
2012-12-11
Brief Title:
Clinical Evaluation of the Underlying Mechanisms of Targeted Therapy Related Toxicities
Sponsor:
Amsterdam UMC location VUmc
Organization:
Amsterdam UMC location VUmc
Study Overview
Official Title:
Clinical Evaluation of the Underlying Mechanisms of Targeted Therapy Related Toxicities
Status:
TERMINATED
Status Verified Date:
2017-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
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 ipilimumabAfter 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 toxicityThe 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
Detailed Description:
Rationale In the past decade multiple agents targeting specific signaling proteins important for tumor growth including tyrosine kinase inhibitors EGFR inhibitors mTOR inhibitors and BRAF inhibitors or agents that modulate the immune response such as ipilimumab have been developed and have reached clinical approval Initially it was anticipated that these agents would be active without causing major toxicities but recent clinical experiences have changed these expectations Diagnostic tools to predict whether a patient will develop toxicity to targeted agents are not yet available Our general hypothesis is that immunophenotyping studies combined with phospho proteomic and kinase activity profiling in normal tissue before and during treatment with targeted agents may provide more insight in underlying causative mechanisms of toxicity and provide potential biomarkers for clinical use to predict for toxicity
The investigators hypothesize that targeted therapy- induced toxicity is caused by interference with normal physiological homeostasis at the tissue level To date preclinical strategies to predict for clinical toxicities of targeting therapies are lacking
This study is intended to 1 explore the biological immunological mechanisms of targeted agents at the systemic and local tissue level in relation to toxicity 2 determine if off-target receptor kinase inhibition in normal cells and tissues is related to toxicity of the treatment and 3 try to identify novel biomarkers predictive of toxicity
Objective 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
Study design Single center non-randomized interventional pilot study with feasibility analysis after enrollment of 20 patients
Study population 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
Intervention Patients will be treated with targeted therapies according to the clinical standard guidelines At this point five targeted therapies with considerable skin and gastrointestinal toxicities have reached widespread clinical use and therefore antiangiogenic tyrosine kinase inhibitors EGFR inhibitors mTOR inhibitors BRAF inhibitors and ipilimumab will be investigated in this study 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
Main study parametersendpoints The main objective is to explore the biological impact of treatment with targeted agents at the systemic and local tissue level in relation to toxicity This objective will be assessed by studying in normal tissue whether treatment with targeted agents induces significant changes in normal tissue of 1 histopathology such as differences in the presence of infiltrating immune cells 2 phosphoproteomic profiles and 3 kinase activity profiles Secondary objectives are 1 to perform pharmacokinetics and to study whether serum peptide profiles and systemic circulating immune cells and cytokine profiles in patients during treatment with targeted agents are related to toxicity and 2 to identify novel biomarkers predictive of treatment induced toxicity based on pretreatment systemic or local tissue phenotypes
Nature and extent of the burden and risks associated with participation benefit and group relatedness Enrolment in this study is possible when the indication to receive standard targeted therapy has been determined Adverse events as a result of this standard treatment may occur Biopsies of skin oral mucosa colon mucosa once prior to and during treatment will be taken If toxicity develops a re-biopsy of the affected area will be taken These biopsies may cause physical discomfort During therapy follow-up will include laboratory analysis on a visit to the outpatient clinic Results of this study may provide new clues for prediction and treatment of targeted therapy induced toxicity
The investigators hypothesize that targeted therapy- induced toxicity is caused by interference with normal physiological homeostasis at the tissue level To date preclinical strategies to predict for clinical toxicities of targeting therapies are lacking
This study is intended to 1 explore the biological immunological mechanisms of targeted agents at the systemic and local tissue level in relation to toxicity 2 determine if off-target receptor kinase inhibition in normal cells and tissues is related to toxicity of the treatment and 3 try to identify novel biomarkers predictive of toxicity
Objective 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
Study design Single center non-randomized interventional pilot study with feasibility analysis after enrollment of 20 patients
Study population 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
Intervention Patients will be treated with targeted therapies according to the clinical standard guidelines At this point five targeted therapies with considerable skin and gastrointestinal toxicities have reached widespread clinical use and therefore antiangiogenic tyrosine kinase inhibitors EGFR inhibitors mTOR inhibitors BRAF inhibitors and ipilimumab will be investigated in this study 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
Main study parametersendpoints The main objective is to explore the biological impact of treatment with targeted agents at the systemic and local tissue level in relation to toxicity This objective will be assessed by studying in normal tissue whether treatment with targeted agents induces significant changes in normal tissue of 1 histopathology such as differences in the presence of infiltrating immune cells 2 phosphoproteomic profiles and 3 kinase activity profiles Secondary objectives are 1 to perform pharmacokinetics and to study whether serum peptide profiles and systemic circulating immune cells and cytokine profiles in patients during treatment with targeted agents are related to toxicity and 2 to identify novel biomarkers predictive of treatment induced toxicity based on pretreatment systemic or local tissue phenotypes
Nature and extent of the burden and risks associated with participation benefit and group relatedness Enrolment in this study is possible when the indication to receive standard targeted therapy has been determined Adverse events as a result of this standard treatment may occur Biopsies of skin oral mucosa colon mucosa once prior to and during treatment will be taken If toxicity develops a re-biopsy of the affected area will be taken These biopsies may cause physical discomfort During therapy follow-up will include laboratory analysis on a visit to the outpatient clinic Results of this study may provide new clues for prediction and treatment of targeted therapy induced toxicity
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 2011-005309-57 | EUDRACT_NUMBER | None | None |