Advanced or Metastatic Solid MalignancyNCT01758575
Clinical Evaluation of the Underlying Mechanisms of Targeted Therapy Related Toxicities
An observational study of Advanced or Metastatic Solid Malignancy, run by Amsterdam UMC, location VUmc at 1 site in Netherlands.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Advanced or Metastatic Solid Malignancy
- Type of treatment
- Pill or oral medicine, Injection or infusion
- How many people
- 8 participants
- Where
- 1 siteNetherlands
- Study dates
- Nov 2012to Apr 2017
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
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.
Who may be able to join
- 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
Who cannot join
- Concomitant use of anticoagulants
- Previous colonic surgery in the last 3 months
- History of inflammatory bowel disease, or other active gastrointestinal infection
Trial locations and contacts
1 site in 1 country.
About this study
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.
Read the 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 biomarker(s) 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 parameters/endpoints: 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) (phospho)proteomic 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
- Conditions
- Advanced or Metastatic Solid Malignancy
- Keywords
- Patients
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| 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 |
What is being measured
The primary outcome is the main question the study is designed to answer.
histopathological and immunomodulatory changes
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.
Measured: 4 weeks
Kinase activity profiles
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.
Measured: 4 weeks
Kinome wide and quantitative (phospho)proteomic profiles
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.
Measured: 4 weeks
Secondary outcomes (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
Measured: 4 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Jan 2013 (estimated)
- Study startNov 2012
- Primary completionApr 2017
- Study completionApr 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Advanced or Metastatic Solid MalignancyStudies of the same condition, open and under way.
- More trials run by Amsterdam UMC, location VUmcThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 8 participants (actual)
Sponsor and investigators
- Lead sponsor
- Amsterdam UMC, location VUmc
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, H.M.W. Verheul, Amsterdam UMC, location VUmc
- Investigators
- Henk MW Verheul, MD, PhD, Principal investigator, Amsterdam UMC, location VUmc
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01758575
- Sponsor's protocol ID
- 2012/76
- Other IDs
- 2011-005309-57
- Status last verified
- Apr 2017
- First submitted
- 11 Dec 2012
- Last updated
- 7 Apr 2017
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 7 Apr 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Clinical Evaluation of the Underlying Mechanisms of Targeted Therapy Related Toxicities
- ClinicalTrials.gov ID
- NCT01758575
- Acronym / sponsor ID
- 2012/76
- Conditions
- Advanced or Metastatic Solid Malignancy
- Keywords
- Patients
- Study type
- Observational
- Recruitment status
- Terminated
- Enrolment
- 8 participants (actual)
- Lead sponsor
- Amsterdam UMC, location VUmcUniversity, hospital or other
- Study start
- Nov 2012
- Primary completion
- Apr 2017 (actual)
- Study completion
- Apr 2017 (actual)
- First posted
- 1 Jan 2013 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 biomarker(s) 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 parameters/endpoints: 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) (phospho)proteomic 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 design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 5
| Arm | Type | Receives |
|---|---|---|
| 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 |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- 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.
Key inclusion criteria (3 listed)
- 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
Key exclusion criteria (3 listed)
- Concomitant use of anticoagulants
- Previous colonic surgery in the last 3 months
- History of inflammatory bowel disease, or other active gastrointestinal infection
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
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.
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.
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.
1 secondary outcome
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
Results and safety
The study was stopped early. Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Apr 2017.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Henk MW Verheul, MD, PhD principal investigator
Amsterdam UMC, location VUmc
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Advanced or Metastatic Solid Malignancy, run by Amsterdam UMC, location VUmc at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 7 Apr 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study was stopped early. Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
histopathological and immunomodulatory changes (time frame: 4 weeks). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Apr 2017.