Neoplasms

Digestive System Diseases

All Conditions

Gland and Hormone Related Diseases

Symptoms and General Pathology

Rare Diseases

Esophageal Neoplasms

Pancreatic Neoplasms

Hypoxia

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Intestinal Diseases

Signs and Symptoms, Respiratory

Esophageal Cancer

Pancreatic Cancer

All Drugs and Chemicals

Anti-Obesity Agents

Vasoconstrictor Agents

Respiratory System Agents

Imidazole

Phenylpropanolamine

Guaifenesin

Chlorpheniramine, phenylpropanolamine drug combination

Enzyme Inhibitors

Patients undergo a \[F-18\]HX4 PET/CT scan 2,3 and 4h after \[F-18\]HX4 injection.

Patients undergo two \[F-18\]HX4 PET/CT scans 3.5h after \[F-18\]HX4 injection within a 10-day time frame.

400 MBq \[F-18\]HX4, is administered in a single intravenous bolus injection, followed by a saline flush.

[F-18]HX4

Several studies have shown that tumour hypoxia may have a negative impact on the outcome of anticancer treatment. Assessment of tumor hypoxia at baseline or shortly after start of treatment may serve as a predictive marker to determine treatment efficacy at an early stage. Preferably, such an assessment is performed in vivo and non-invasively.Non-invasive imaging with positron emission tomography (PET) using the 2-nitroimidazole nucleoside analogue, 3-18F-fluoro-2-(4-((2-nitro-1H-imidazol-1-yl)methyl)-1H-1,2,3-triazol-1- yl)propan-1-ol (18F-HX4), was tested as a new marker of tumor hypoxia. Before hypoxia-measurements can be clinically implemented for response prediction, the reproducibility of the technique should be assessed for each specific tumor type. Knowledge of reproducibility is needed to determine what change in parameters between two examinations can be considered relevant in an individual patient. Assessment of reproducibility becomes even more important in early response monitoring since the changes in the tumor induced by the treatment may be smaller during the treatment compared to response monitoring after completion of treatment. Also, as image quality of 18F-HX4-PET increases with increasing time intervals after injection, determination of the optimal time point for measurement of hypoxia is warranted.

Background of the study:

Several studies have shown that tumour hypoxia may have a negative impact on the outcome of anticancer treatment. Assessment of tumor hypoxia at baseline or shortly after start of treatment may serve as a predictive marker to determine treatment efficacy at an early stage. Preferably, such an assessment is performed in vivo and non-invasively.Non-invasive imaging with positron emission tomography (PET) using the 2-nitroimidazole nucleoside analogue, 3-18F-fluoro-2-(4-((2-nitro-1H-imidazol-1-yl)methyl)-1H-1,2,3-triazol-1- yl)propan-1-ol (18F-HX4), was tested as a new marker of tumor hypoxia. Before hypoxia-measurements can be clinically implemented for response prediction, the reproducibility of the technique should be assessed for each specific tumor type. Knowledge of reproducibility is needed to determine what change in parameters between two examinations can be considered relevant in an individual patient. Assessment of reproducibility becomes even more important in early response monitoring since the changes in the tumor induced by the treatment may be smaller during the treatment compared to response monitoring after completion of treatment. Also, as image quality of 18F-HX4-PET increases with increasing time intervals after injection, determination of the optimal time point for measurement of hypoxia is warranted.

Objective of the study:

In this study, we first intend to investigate the optimal time point for measurement of hypoxia in esophageal, pancreatic and rectal cancer using 18F-HX4-PET and then assess reproducibility of hypoxia measurements in these tumor types.

Study design:

In this study two steps will be taken. 1) First, as 18F-HX4-PET image quality may improve when allowing for relatively longer time intervals after injection, in three patients with esophageal, pancreatic or rectal cancer 18F-HX4-PET scans will be performed 90, 180 and 240 minutes after injection of 18F-HX4. The time-point with the best image quality (in terms of tumor-to-background-ratio) will be chosen for the reproducibility study. 2) In the second step, patients with proven esophageal, pancreatic or rectal cancer will undergo an 18F-HX4-PET twice within one week before start of treatment. 18F-HX4-PET will be performed at 90, 180 or 240 minutes after injection of 18F-HX4, depending on the results of the first part of the study. Reproducibility of hypoxia measured by 18F-HX4-PET will be assessed. In those patients for whom tumor tissue is available which has not been treated with radiation or chemotherapy, levels of hypoxia measured by 18F-HX4-PET will be compared with endogenous hypoxia markers (HIF1-alfa, CA9, GLUT1, PAI-1, VEGF) using immunohistochemistry. In those patients that underwent 18F-HX4-PET before start of neoadjuvant treatment, levels of hypoxia measured by 18F-HX4-PET will be compared to pathological response after neoadjuvant treatment.

In Vivo Assessment of Hypoxia in Gastro-intestinal Cancer Using 18F-HX4-PET: an Optimization and Reproducibility Study

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

M.D., Ph.D.

Respiratory Tract (Lung and Bronchial) Diseases

Carcinoma, Non-Small-Cell Lung

Lung Neoplasms

Carcinoma

Carcinoma, Bronchogenic

Bronchial Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Patients in this arm will receive radiotherapy (66Gy) in 24 fractions of 2.75 Gy with an integrated boost to the primary tumor as a whole

Patients in this arm receive radiotherapy (66Gy) in 24 fractions of 2.75Gy with an integrated boost to the 50% SUVmax area of the primary tumor (of the pre-treatment FDG-PET-CT scan)

Radiotherapy

José Belderbos, MD, PhD

Increasing ("boosting") the radiation dose for patients with non-small cell lung carcinoma to the individual maximal dose which can safely be given. The question is if patients should receive this boost on the whole tumor on part of the tumor. Therefore patients are randomized for one of these two treatment options. All patients will receive 24 radiations. Dose increasement will be enabled by a so called integrated boost.

Furthermore:

- PET imaging of hypoxia using \[18F\]HX4, single injection and then PET CT scanning two and four hours post injection.

A randomized phase II study will be conducted in patients with inoperable stage IB, II or III non-small cell lung cancer (NSCLC). The patients will be randomized to receive the standard 66 Gy given in 24 fractions of 2.75 Gy with an integrated boost to the primary tumor as a whole (Arm A) or with an integrated boost to the 50% SUVmax area of the primary tumor (of the pre-treatment FDG-PET scan) (Arm B). Both treatment arms may be combined with chemotherapy (concurrent or sequential). Patients fulfilling the eligibility criteria will be registered in the study, and an initial radiotherapy treatment planning will be performed. When an integrated boost to the primary tumor as a whole up to 72 Gy is not possible because of dose constraints, the patient will receive 66 Gy or lower according to the normal tissue tolerance (see below). They will not be randomized, but will be followed in the trial. As such, it will be clear which proportion of patients can receive an integrated boost and what the outcome is when dose-escalation is not possible.

Stage IB-II patients receive radiotherapy alone, and stage III patients combined chemotherapy and radiation. The patients may have received induction chemotherapy up to two cycles before registration in this trial. The statistical calculations have been performed to deal with this patient heterogeneity.

The primary objective of this study is to determine the local progression-free survival (LPFS)at 1 year.

Secondary objectives will be

* Toxicity as a function of radiotherapy dose and volume of the tissue irradiated.
* Overall survival.
* Quality of life

Furthermore:

* PET imaging of hypoxia using \[18F\]HX4, single injection and then PET CT scanning two and four hours post injection.
* Dynamic Contrast-Enhanced CT imaging

Dose Escalation by Boosting Radiation Dose Within the Primary Tumor Using FDG-PET-CT Scan in Stage IB, II and III NSCLC

Dose Escalation by Boosting Radiation Dose Within the Primary Tumor on the Basis of a Pre-treatment FDG-PET-CT Scan in Stage IB, II and III NSCLC: a Randomized Phase II Trial

European Union

The Netherlands Cancer Institute

Liver Neoplasms

Head and Neck Neoplasms

Patient will be injected with \[F-18\] FMISO

Patient will be injected with \[F-18\] HX4

10 mCi \[F18\] HX4 and 10 mCi \[F-18\] FMISO within 7 days of each other regardless of sequence

[F-18] FMISO

[F-18] HX4

Yi Hui Guan, MD

Positron Emission Tomography (PET) with fluorine-18 fluoromisonidazole (FMISO) has been used for several years as a non invasive imaging technique to study tumor hypoxia. Several experimental and clinical studies have indicated that FMISO uptake of tissues is correlated with tissue oxygen tension and that FMSO PET allows non-invasive differentiation between hypoxic and normoxic tumors. Currently, FMISO-PET represents the best characterized and validated noninvasive hypoxia imaging technique. Nevertheless, clinical studies have also shown the limitations of FMISO PET. Accumulation of FMISO in hypoxic tumors is relatively low, resulting in a low contrast between hypoxic tumors and surrounding normal tissues. In addition, imaging needs to be started relatively late after tracer injection (about 3 hours post-injection), when a significant percentage of the fluorine-18 label has already decayed and the count statistics of the PET images are relatively low. Because of these limitations, FMISO PET is still only used at a few research centers, despite high clinical interest in hypoxia imaging.

Objective of the study

The aim of this study is to:

* evaluate a hypoxia imaging agent, HX4, in patients with solitary tumors (i.e., locally advanced head and neck cancer)
* gain information on bio-distribution of \[F-18\]HX4
* compare the PET images of \[F-18\] FMISO to \[F-18\]HX4 for resolution, signal to background ratio, and tumor/blood ratio

Clinical Evaluation of the New Hypoxia Imaging Agent HX4

Fudan University

Siemens Molecular Imaging

PET Center, Huashan Hospital, Fudan University, Shanghai, China 200235

Vasodilator Agents

Nitroglycerin

Nitroglycerin patch

Philippe Lambin, MD, PhD

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).

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.

Nitroglycerin in Non-small Cell Lung Cancer

Nitroglycerin as a Sensitizer in the Treatment of Non Small Cell Lung Cancer: a Phase II Trial

Reliable Cancer Therapies

Anticancer Fund, Belgium

Maastricht Radiation Oncology

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
In Vivo Assessment of Hypoxia in Gastro-intestinal Cancer Using 18F-HX4-PET: an Optimization and Reproducibility Study	NCT01995084	Pancreatic Canc... Esophageal Canc... Rectal Cancer	[F-18]HX4	18 Years -	Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Dose Escalation by Boosting Radiation Dose Within the Primary Tumor Using FDG-PET-CT Scan in Stage IB, II and III NSCLC	NCT01024829	NSCLC	Radiotherapy	18 Years -	The Netherlands Cancer Institute
Clinical Evaluation of the New Hypoxia Imaging Agent HX4	NCT01213030	Head and Neck C... Lung Cancer Liver Cancer	[F-18] FMISO [F-18] HX4	18 Years -	Siemens Molecular Imaging
Nitroglycerin in Non-small Cell Lung Cancer	NCT01210378	Non Small Cell ...	Nitroglycerin p...	18 Years -	Maastricht Radiation Oncology
Dose Escalation by Boosting Radiation Dose Within the Primary Tumor Using FDG-PET-CT Scan in Stage IB, II and III NSCLC	NCT01024829	NSCLC	Radiotherapy	18 Years -	The Netherlands Cancer Institute
Dose Escalation by Boosting Radiation Dose Within the Primary Tumor Using FDG-PET-CT Scan in Stage IB, II and III NSCLC	NCT01024829	NSCLC	Radiotherapy	18 Years -	The Netherlands Cancer Institute

Spots Global Cancer Trial Database for hx4

Every month we try and update this database with for hx4 cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for hx4

Every month we try and update this database with for hx4 cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for hx4 cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.