Non Small Cell Lung Cancer (NSCLC)Phase 2NitroglycerinNCT01210378
Nitroglycerin in Non-small Cell Lung Cancer
A Phase 2 study testing Nitroglycerin patch in people with Non Small Cell Lung Cancer (NSCLC), run by Maastricht Radiation Oncology at 1 site in Netherlands.
Trial summary
Nitroglycerin is a nitric oxide donor which is mainly known as a vasodilating agent used in ischemic heart disease. It has also been shown to increase tumor blood flow in animal and human tumors. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Non Small Cell Lung Cancer (NSCLC)
- What is being tested?
- Nitroglycerin patch
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 47 participants
- Where
- 1 siteNetherlands
- Study dates
- Dec 2011to Mar 2017
- Phase
- Phase 2
- 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
Who may be able to join
- Non-small cell lung cancer stage IB-IV amenable for radiotherapy with curative intent.
- (Stage IV patients with oligometastic (1-4 metastases) NSCLC are regularly treated radically in the IKNL region).
- Patients not included in the PET-Boost or the Lucanix trial.
- WHO performance status 0-2.
- Willing and able to comply with the study prescriptions.
- 18 years or older.
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- Ability to give and having given written informed consent before patient registration.
- No recent (< 3 months) severe cardiac disease (NYHA class >1) (congestive heart failure, infarction).
- No radiotherapy in 4 weeks prior to this study.
- No treatment with investigational drugs in 4 weeks prior to or during this study.
- No known allergy to nitroglycerin or nitroglycerin patch.
- No known allergy to iodine based contrast agents
- No use of Levitra, Viagra or Cialis at the time of application of the nitroglycerin patch.
- No conditions necessitating the use of ergot alkaloids, alpha blockers (eg tamsulosine), betablockers or calcium channel blockers on the day of nitroglycerin patch application).
- No other active malignancy.
- No major surgery (excluding diagnostic procedures like eg mediastinoscopy) in previous 4 weeks.
- Adequate renal function: calculated creatinine clearance at least 60ml/min.
Who cannot join
None listed.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Nitroglycerin as a Sensitizer in the Treatment of Non Small Cell Lung Cancer: a Phase II Trial
Nitroglycerin is a nitric oxide donor which is mainly known as a vasodilating agent used in ischemic heart disease. It has also been shown to increase tumor blood flow in animal and human tumors.
The addition of nitroglycerin to chemotherapy in non small cell lung cancer has been shown to generate very favorable response rates with respect to standard treatment schedules[5]. Theoretically nitroglycerin might reduce resistance to chemotherapy via a plethora of different effects: better tumor perfusion, direct effects of NO on cancer cells, increase in activated p53 protein and via an increased blood flow in the tumour with as consequence a higher drug concentration in the tumor [6] .
Read more
In mice, nitric oxide donors such as isosorbide dinitrate have been shown to decrease tumor hypoxia by better tumor perfusion, which could enhance radiotherapy responses [7].
To date these combined effects have not been tested in humans. In this trial we would like to demonstrate the effect of nitroglycerin on tumor perfusion and hypoxia in non small cell lung cancer (using DCE and HX4 scanning), providing a rationale for further study and to test the effect of combining nitroglycerine to standard treatment of NSCLC (radiotherapy/chemotherapy).
Read the detailed description
Namely, the failure of many different tumor types to show a lasting response chemotherapy or radiotherapy might be attributable to a lack of oxygen supply (called "hypoxia" from hereon) in a large part of the cancer cells.
Tumor hypoxia is a well-known factor negatively influencing outcome in many solid tumors, including lung cancer, head and neck cancer, etc. Hypoxic cells are more radio-resistant, more chemo-resistant and more prone to develop distant metastases than normoxic cells.
Nitroglycerin, due to it's vasoactive effects, tends to redistribute the blood supply to the tumor, increasing tumor blood flow, hereby theoretically decreasing hypoxia.
It has been shown that NO donating drugs can alter tumor blood flow and oxygenation status in animal models [7]. In a randomized phase 2 trial by Yasuda nitroglycerin has been successfully combined at a dose of 25 mg daily for 5 days each chemo cycle with cisplatin and vinorelbine in non small cell lung cancer, enhancing chemotherapy response, possibly due to better delivery of the anti-cancer drugs in the tumor[5]. The toxicity profile between the 2 arms was not significantly different.
The effects of nitroglycerin or other donating drugs on cancer have been found to be numerous: not only is there an increase in tumor bloodflow, also direct effects on stabilization of p53 and degradation of Hif-1 alpha have been found[6]. Decreased hypoxic biomarkers (eg VEGF, P-glycoprotein) have been found in patients with NSCLC treated with nitroglycerin patches for 3 days prior to surgery when compared to non-treated individuals [8]. There might also be a supplementary effect on the MHC-molecules, rendering tumor cells more "visible" to the immune system [9].
Furthermore, hypoxia has been shown in vitro to increase the invasiveness of cancer cells in an NO-mediated manner, which can be blocked by NO-donors.[10] An interesting study in this respect is a non-randomized phase 2 trial by Siemens et al, in which a very low dose of nitroglycerin (Minitran 5 patch (18 mg) cut in 6 pieces, delivering 0.033 mg/h in stead of 0.2 mg/h normally) was given to patients with biochemical recurrence (PSA-failure) after primary therapy. After 24 months the PSA doubling time was more than 31 months versus 12.8 months before the start of therapy, demonstrating the inhibitory effect of nitroglycerin on prostate cancer cells. [11]
Due to these effects and the effect on tumor bloodflow and decrease of hypoxia nitroglycerin might also be interesting as a radiosensitizing agent.
Currently a Mexican phase 2 trial is recruiting 40 patients to evaluate the efficacy of nitroglycerin added to concurrent chemoradiotherapy in NSCLC stage III. (Clinical trials.gov identifier NCT00886405).
The aim of the present study is not only to demonstrate the effect of nitroglycerin on perfusion and hypoxia through (HX4-)scanning of patients, but also documenting the efficacy of the approach of giving nitroglycerin in an on/off (12h/12h) schedule to people receiving (chemo-)/radiotherapy, whilst monitoring toxicity.
The on-off schedule is chosen because of the existence of a tolerance effect on the vascular system, hence diminishing the effect of nitroglycerin already after the first 24 hours.
- Conditions
- Non Small Cell Lung Cancer (NSCLC)
- Being tested
- Nitroglycerin patch
- Keywords
- NSCLC, Nitroglycerin, Tumour perfusion, Hypoxia, Toxicity, Phase II, HX4
- Medical subject headings
- Carcinoma, Non-Small-Cell Lung, Hypoxia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Nitroglycerin patchDrug
Nitroglycerin patch
| Study group | Role | What they receive |
|---|---|---|
| Nitroglycerin | Experimental | Not described Receives: Drug: Nitroglycerin patch |
What is being measured
The primary outcome is the main question the study is designed to answer.
Increase of 2 year overall survival of 15% vs historical controls
Measured: 2 years
Secondary outcomes (4)
Demonstrate effect on enhancement on tumor perfusion
Measured: 3 days
Toxicity
Measured: 7 weeks
Demonstrate the effect on enhancement of tumor oxygenation
Measured: 3 days
Evaluating the possible value of Perfusion CT and hypoxia scans on treatment with nitroglycerin of NSCLC
Measured: 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Sep 2010 (estimated)
- Study startDec 2011
- Primary completionSep 2016
- Study completionMar 2017
Why it stopped: Accrual stopped
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Non Small Cell Lung Cancer (NSCLC)Studies of the same condition, open and under way.
- 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
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 47 participants (actual)
Sponsor and investigators
- Lead sponsor
- Maastricht Radiation Oncology
- Sponsor type
- University, hospital or other
- Collaborators
- Reliable Cancer Therapies, Anticancer Fund, Belgium
- Responsible party
- Sponsor
- Investigators
- Philippe Lambin, MD, PhD, Principal investigator, Maastro Clinic, The Netherlands
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01210378
- Sponsor's protocol ID
- Nitroglycerin in NSCLC
- Acronym
- Nitroglycerin
- Status last verified
- Feb 2019
- First submitted
- 27 Sep 2010
- Last updated
- 15 Feb 2019
- Results posted
- No
- Data monitoring committee
- No
Publications
van Elmpt W, Zegers CML, Reymen B, Even AJG, Dingemans AC, Oellers M, Wildberger JE, Mottaghy FM, Das M, Troost EGC, Lambin P. Multiparametric imaging of patient and tumour heterogeneity in non-small-cell lung cancer: quantification of tumour hypoxia, metabolism and perfusion. Eur J Nucl Med Mol Imaging. 2016 Feb;43(2):240-248. doi: 10.1007/s00259-015-3169-4. Epub 2015 Sep 4.
PubMed 26338178
Study at a glance
From the registry record, last updated by the sponsor on 15 Feb 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Nitroglycerin as a Sensitizer in the Treatment of Non Small Cell Lung Cancer: a Phase II Trial
- ClinicalTrials.gov ID
- NCT01210378
- Acronym / sponsor ID
- Nitroglycerin / Nitroglycerin in NSCLC
- Conditions
- Non Small Cell Lung Cancer (NSCLC)
- Keywords
- NSCLC, Nitroglycerin, Tumour perfusion, Hypoxia, Toxicity, Phase II, HX4
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Accrual stopped
- Enrolment
- 47 participants (actual)
- Lead sponsor
- Maastricht Radiation OncologyUniversity, hospital or other
- Collaborators
- Reliable Cancer Therapies, Anticancer Fund, Belgium
- Study start
- Dec 2011 (actual)
- Primary completion
- Sep 2016 (actual)
- Study completion
- Mar 2017 (actual)
- First posted
- 28 Sep 2010 (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.
Nitroglycerin is a nitric oxide donor which is mainly known as a vasodilating agent used in ischemic heart disease. It has also been shown to increase tumor blood flow in animal and human tumors.
The addition of nitroglycerin to chemotherapy in non small cell lung cancer has been shown to generate very favorable response rates with respect to standard treatment schedules[5]. Theoretically nitroglycerin might reduce resistance to chemotherapy via a plethora of different effects: better tumor perfusion, direct effects of NO on cancer cells, increase in activated p53 protein and via an increased blood flow in the tumour with as consequence a higher drug concentration in the tumor [6] .
In mice, nitric oxide donors such as isosorbide dinitrate have been shown to decrease tumor hypoxia by better tumor perfusion, which could enhance radiotherapy responses [7].
To date these combined effects have not been tested in humans. In this trial we would like to demonstrate the effect of nitroglycerin on tumor perfusion and hypoxia in non small cell lung cancer (using DCE and HX4 scanning), providing a rationale for further study and to test the effect of combining nitroglycerine to standard treatment of NSCLC (radiotherapy/chemotherapy).
Detailed description
Namely, the failure of many different tumor types to show a lasting response chemotherapy or radiotherapy might be attributable to a lack of oxygen supply (called "hypoxia" from hereon) in a large part of the cancer cells.
Tumor hypoxia is a well-known factor negatively influencing outcome in many solid tumors, including lung cancer, head and neck cancer, etc. Hypoxic cells are more radio-resistant, more chemo-resistant and more prone to develop distant metastases than normoxic cells.
Nitroglycerin, due to it's vasoactive effects, tends to redistribute the blood supply to the tumor, increasing tumor blood flow, hereby theoretically decreasing hypoxia.
It has been shown that NO donating drugs can alter tumor blood flow and oxygenation status in animal models [7]. In a randomized phase 2 trial by Yasuda nitroglycerin has been successfully combined at a dose of 25 mg daily for 5 days each chemo cycle with cisplatin and vinorelbine in non small cell lung cancer, enhancing chemotherapy response, possibly due to better delivery of the anti-cancer drugs in the tumor[5]. The toxicity profile between the 2 arms was not significantly different.
The effects of nitroglycerin or other donating drugs on cancer have been found to be numerous: not only is there an increase in tumor bloodflow, also direct effects on stabilization of p53 and degradation of Hif-1 alpha have been found[6]. Decreased hypoxic biomarkers (eg VEGF, P-glycoprotein) have been found in patients with NSCLC treated with nitroglycerin patches for 3 days prior to surgery when compared to non-treated individuals [8]. There might also be a supplementary effect on the MHC-molecules, rendering tumor cells more "visible" to the immune system [9].
Furthermore, hypoxia has been shown in vitro to increase the invasiveness of cancer cells in an NO-mediated manner, which can be blocked by NO-donors.[10] An interesting study in this respect is a non-randomized phase 2 trial by Siemens et al, in which a very low dose of nitroglycerin (Minitran 5 patch (18 mg) cut in 6 pieces, delivering 0.033 mg/h in stead of 0.2 mg/h normally) was given to patients with biochemical recurrence (PSA-failure) after primary therapy. After 24 months the PSA doubling time was more than 31 months versus 12.8 months before the start of therapy, demonstrating the inhibitory effect of nitroglycerin on prostate cancer cells. [11]
Due to these effects and the effect on tumor bloodflow and decrease of hypoxia nitroglycerin might also be interesting as a radiosensitizing agent.
Currently a Mexican phase 2 trial is recruiting 40 patients to evaluate the efficacy of nitroglycerin added to concurrent chemoradiotherapy in NSCLC stage III. (Clinical trials.gov identifier NCT00886405).
The aim of the present study is not only to demonstrate the effect of nitroglycerin on perfusion and hypoxia through (HX4-)scanning of patients, but also documenting the efficacy of the approach of giving nitroglycerin in an on/off (12h/12h) schedule to people receiving (chemo-)/radiotherapy, whilst monitoring toxicity.
The on-off schedule is chosen because of the existence of a tolerance effect on the vascular system, hence diminishing the effect of nitroglycerin already after the first 24 hours.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Nitroglycerin | Experimental | Drug: Nitroglycerin patch |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (17 listed)
- Non-small cell lung cancer stage IB-IV amenable for radiotherapy with curative intent.
- (Stage IV patients with oligometastic (1-4 metastases) NSCLC are regularly treated radically in the IKNL region).
- Patients not included in the PET-Boost or the Lucanix trial.
- WHO performance status 0-2.
- Willing and able to comply with the study prescriptions.
Key exclusion criteria (0 listed)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Nitroglycerin patchNitroglycerin patch | Drug | Nitroglycerin |
Primary outcome
Increase of 2 year overall survival of 15% vs historical controls
Time frame: 2 years
4 secondary outcomes
Demonstrate effect on enhancement on tumor perfusion
Time frame: 3 days
Toxicity
Time frame: 7 weeks
Demonstrate the effect on enhancement of tumor oxygenation
Time frame: 3 days
Evaluating the possible value of Perfusion CT and hypoxia scans on treatment with nitroglycerin of NSCLC
Time frame: 2 years
Results and safety
The study was stopped early (reason given: Accrual stopped). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Feb 2019.
- Derived from this study: PubMed 26338178van Elmpt W, Zegers CML, Reymen B, Even AJG, Dingemans AC, Oellers M, Wildberger JE, Mottaghy FM, Das M, Troost EGC, Lambin P. Multiparametric imaging of patient and tumour heterogeneity in non-small-cell lung cancer: quantification of tumour hypoxia, metabolism and perfusion. Eur J Nucl Med Mol Imaging. 2016 Feb;43(2):240-248. doi: 10.1007/s00259-015-3169-4. Epub 2015 Sep 4.
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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.
Philippe Lambin, MD, PhD principal investigator
Maastro Clinic, The Netherlands
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Nitroglycerin patch in people with Non Small Cell Lung Cancer (NSCLC), run by Maastricht Radiation Oncology 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 17 inclusion and 0 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 15 Feb 2019. 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.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: Accrual stopped). 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?
Increase of 2 year overall survival of 15% vs historical controls (time frame: 2 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01210378, which also lists 1 linked publication.
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 15 Feb 2019.