Neoplasms

Symptoms and General Pathology

All Conditions

Nervous System Diseases

Neoplasm Metastasis

Brain Neoplasms

Neoplastic Processes

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Antineoplastic Agents

All Drugs and Chemicals

Bevacizumab

Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

Growth Inhibitors

first level dose : 5 mg/kg Second level dose : 10 mg/kg Third level dose : 15 mg/kg

5, 10 or 15 mg/kg, IV, on day 1, 15 and 29 plus radiation therapy of the whole brain.

For level 0,1 and 2, a total dose of 30 Gy will be administered in 15 fractions of 2 Gy, from D15 to D33 with 5 fractions a week.

For level 3,a total dose of 30 Gy will be administered in 10 fractions of 3 Gy, from D15 to D26 with 5 fractions a week.

Christelle LEVY, MD

This phase I pilot study aims to define the safety of a combined treatment of bevacizumab and whole brain radiation therapy for the treatment of patients with brain metastasis of solid tumors. If this therapeutic scheme confirms it's safety profile, the investigators can expect:

* first, to allow that all patients can receive bevacizumab for their advanced and/or metastatic cancer if necessary, even in case of brain metastasis.
* Secondly, if this trial confirm a synergic effect of the combination of angiogenesis inhibitors and brain radiotherapy for local control of brain metastasis, an improvement of the therapeutic results for these patients which have a poor hope of survival and for which none innovative approach is currently suggested.

Moreover, the investigators hope that the analysis of the different data of MRI evaluation - morphological and functional - will allow better definition of radiological evaluation of the therapeutic effect of angiogenesis inhibitors on brain metastasis.

Brain metastasis remain a common complication of many solid tumors, occurring from 10 to 20% of patients with cancer, and the incidence may arise up to 20-40% in autopsy series. Despite the treatment, the patient outcome is poor and brain metastasis become a major cause of death from cancer.

Some recent studies showed an increase incidence of brain metastasis; several explanations are evocated:

* The increased efficacy of brain imaging in screening of brain metastasis.
* The relative longer life expectancy of cancer patients in correlation with more efficient therapies (new chemotherapy drugs, targeted therapies) for visceral and bone metastasis, but without effect on the risk of brain metastasis (sanctuary effect),

Therapeutic management of brain metastasis: standards of care and improvement strategies

For patients with a poor survival hope, the treatment is limited to best supportive care with a palliative intent. At the opposite, a specific treatment of brain metastasis must be proposed when a real benefit may be expected.

Surgery or radiosurgery are indicated for limited brain involvement (1 to 3 metastasis).

In case of multiple localisations, whole brain radiation therapy (WBRT) is the most common approach; however this treatment is realized with a palliative intent: control of neurological symptoms and brain oedema.

In the literature, an objective response rate of 50-60 % is expected from WBRT, but the majority of these patients will relapse and died from brain metastasis, with a median survival time of 4 to 6 months.

Considering these poor results, it seems crucial to develop some innovative strategies, in order to improve the survival hope for these patients.

Different concomitant approaches were tested in association with WBRT (cytotoxics such as temozolomide, radio-sensitizers such as efaproxiral), and more recently combination of radiation therapy with therapy targeting different signalling pathway were developed, for example with lapatinib for HER2 pathway. Targeted therapies acting on neoangiogenesis seem also may be considered as an interesting axis of research.

Rationale utilisation of angiogenesis inhibitors for treatment of brain metastasis

Neo-angiogenesis plays an important role in the growth of brain metastasis, acting on different mechanisms such as tumor neo-angiogenesis (by development of new blood vessels), co-option with existing blood vessels and increased vascular permeability. Therefore, angiogenesis inhibitors, particularly agents targeting VEGF/VEGFR pathway, could be interesting in the treatment of brain metastasis.

In pre-clinical models, VEGF is the best characterized mediator of angiogenesis, and its role was pointed in the development of brain metastasis: increased transmigration of tumor cells through the blood-brain barrier by a VEGF-dependent disrupting effect, anti-apoptotic effect of VEGF by a paracrine action.

This data suggest a therapeutic effect of VEGF targeting agents on brain metastasis and a decrease of brain metastasis development has been observed in some anti-VEGF anti-sens therapy.

Moreover, VEGF involves vascular permeability and this mechanism is important in the development of peri-tumoral oedema.

Anti-angiogenic treatments are divided in two groups: on one hand, angiogenesis inhibitors (acting by normalization of the existing tumor vascularisation and through a decreased formation of new blood vessels) and on the other hand, vascular disrupting agents (which can destroy pathologic vessels).

For brain tumors, most of studies were focused on the role of angiogenesis inhibitors. Of special interest, anti-VEGF therapies, particularly the bevacizumab, were tested in clinical setting. Bevacizumab, a monoclonal recombinant antibody targeting VEGF, prevents the fixation of VEGF to VEGF receptors 1 and 2 on the endothelial cells, with a neutralizing effect on VEGF action.

In clinic, recent studies showed a significant benefit of bevacizumab (Avastin®) in the treatment of primary brain tumors, as shown by Vredenburgh et al. for patients with recurrent gliomas; these data confirm a synergic effect with chemotherapy. Similarly, a potential synergic action in a combined approach with radiation therapy seems to be an interesting therapeutic way.

Rationale for combining angiogenesis inhibitors with radiation therapy

In the tumor, the pathologic neo-angiogenesis reduces the diffusion of oxygen, and consequently promotes hypoxia. Hypoxia is one of the most causes of radio-resistance.

Ionizing radiations induce transient hypoxia in the central area of the tumor, increasing the production of VEGF and consequently the neo-angiogenesis. This "vicious circle" allows the development of optimal conditions for radio-resistance.

The normalization of pathologic vessels induced by angiogenesis inhibitors leads to a decrease of hypoxia and thus enhance the radio-sensitivity of tumor cells and endothelial cells.

In clinical setting, some studies were published about treatments combining radiation therapy and angiogenic inhibitors. The main study was conducted for rectal carcinoma (9), showing a safety profile of a combined scheme of bevacizumab and capecitabine in association with pre-operative pelvic irradiation. Efficacy data are encouraging (downstaging for 9 /11 patients, histological regression for 5 patients). Similar conclusions may be drawn from another study performed in patients with unresectable pancreatic carcinoma treated with a radio-chemotherapy including bevacizumab, leading to an objective response for 9 patients (20 %), 4 of them were operable at the end of radio-chemotherapy.

Interestingly, this combined approach seems interesting for brain tumors, as shown by a recent published trial conducted by Narayana in first-line treatment of gliomas. This phase 2 study combined temozolomide chemotherapy with bevacizumab administration for a dose of 10 m/kg at D14 and D28 during the course of radiotherapy (total dose of 59,40 Gy delivered to the tumor volume). An promising response rate was observed: 7% of complete response and 93% of partial response, the 1-year progression-free survival was 59,3%. The authors confirm the feasibility of this combined approach (13/15 patients completed their treatment). Three grade 3-4 haematological toxicities and 4 non-haematological toxicities (thrombo-embolism and HTA) are related. None intracerebral hemorrhage or death related to the treatment was reported.

These results indicate a possible way of innovative strategies in the therapeutic management of brain metastasis, by association of bevacizumab and whole brain radiation therapy. Furthermore, bevacizumab is now indicated for several advanced and/or metastatic cancer but its administration remains theorically contra-indicated for patients with brain metastasis, due to the fear of potential cerebral hemorrhage. However, this risk remains low, as shown by several studies.

Safety data were recorded with glioblastomas are reassuring, however, it is essential to determine the optimal dose level of bevacizumab when combined with irradiation of the entire brain at a dose of 30 Gy Thus for the phase 1 pilot study that we plan to carry, it is important to test several dose levels of bevacizumab in combination with irradiation of the brain: a precaution we have decided to use a conventional fractionation of 15 Gy in 2 fractions three weeks. Secondarily, given the good tolerability of this modality in combination with three levels of dose of bevacizumab used, we propose to continue the phase 1 according to the scheme commonly used in palliative situation (30 Gy in 10 fractions and 2 weeks) in combination with Avastin at a dose of 15 mg / kg, at which a maximum limiting toxicity has been observed.

Safety Evaluation of a Combination of Brain Radiation Therapy and Bevacizumab (Avastin®) for Treatment of Brain Metastasis

The primary objective is to determine the Maximal Tolerated Dose (MTD) of the combination of bevacizumab and whole brain radiation therapy for patients with brain metastases

The secondary objective is to assess the treatment-related parameters of tumor regression by a morphologic and functional MRI six weeks after the end of the treatment.

National Cancer Institute, France

Roche Pharma AG

Institut Curie

Centre Francois Baclesse

Skin and Connective Tissue Diseases

Breast Neoplasms

Capecitabine

Maleic acid

Antimetabolites

Brain radiation therapy: the dose and frequency of brain radiation therapy are determined by the doctor according to the patient's condition. Pyrrotini: 400 mg once a day, oral within 30 minutes after breakfast for 21 days. Cassitabine: twice a day, 800 mg / m2 orally within 30 minutes after each meal (one morning and one night, 12 hours apart, equivalent to a daily dose of 1600 mg / m2, one dose in the morning and one dose in the morning)

CAPECITABINE: 800 mg/m2 twice daily, taken orally within 30 minutes after meal (one in the morning and one in the evening, 12 hours apart, equal to a daily dose of 1600 mg/m2, with one dose in the morning and one dose in the morning) .

PYRROTINI

Brain radiation therapy: the dose and frequency of brain radiation therapy are determined by the doctor according to the patient's condition.

Brain radiation therapy

Jing Wang, MD

Xuejing Liu, MD

The aim of this study was to evaluate the progression time and efficacy of brain tumors in patients with brain metastases from HER2-positive breast cancer treated with Pyrrolidine and Capecitabine combined with brain radiotherapy.

Brain metastases are very common in HER2-positive breast cancer patients. The vast majority of patients with metastatic brain tumors are in advanced stages of the disease. If not treated in time, the natural course of the disease is extremely short. At present, the main treatment of brain metastases from breast cancer is radiotherapy, combined with chemotherapy and targeted therapy drugs. On the basis of previous clinical studies, the aim of this study was to explore the efficacy and safety of combined brachytherapy with Pyrrotidine and Capecitabine in patients with brain metastases from HER2-positive breast cancer, in order to provide a new, safer and more effective treatment for patients with brain metastases from breast cancer.

A Single Arm Study of Brain Metastasis in Patients With HER2-positive Breast Cancer

A Single Arm Study of Brain Metastasis in Patients With HER2-positive Breast Cancer Treated With Pyrrolidine Maleate and Capecitabine Combined With Brain Radiotherapy

Objective to evaluate the intracranial tumor progression time of piratinib and capecitabine combined with brain radiotherapy for HER2 positive breast cancer patients with brain metastasis

Objective to evaluate the progression free survival (PFS) of pirotinib and capecitabine combined with brain radiotherapy in HER2 positive breast cancer patients with brain metastasis.

objective response rate (ORR) of pirotinib and capecitabine combined with brain radiotherapy in HER2 positive breast cancer patients with brain metastasis.

Duration of treatment effect (DCR) of pirotinib and capecitabine It refers to the time between the first assessment of CR or PR and the first assessment of PD (Progressive Disease) or death from any causecombined with brain radiotherapy in HER2 positive breast cancer patients with brain metastasis.

Objective to evaluate the disease control rate of pirotinib and capecitabine combined with brain radiotherapy in HER2 positive breast cancer patients with brain metastasis

Objective to evaluate the clinical benefit rate of pirotinib and capecitabine combined with brain radiotherapy in HER2 positive breast cancer patients with brain metastasis

Objective to evaluate the overall survival of piratinib and capecitabine combined with brain radiotherapy in HER2 positive breast cancer patients with brain metastasis

Objective to evaluate the effect of pyrrolotinib and capecitabine combined with brain radiotherapy in patients with HER2 positive breast cancer with brain metastasis，The score of graded healing assessment was 0-4. The higher the score, the better the result

Tianjin Medical University Cancer Institute and Hospital

Respiratory Tract (Lung and Bronchial) Diseases

Rare Diseases

Adenocarcinoma

Lung Neoplasms

Adenocarcinoma of Lung

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Lung Adenocarcinoma

Amino Acids

Gefitinib

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Arm A : WBRT and Concurrent Gefitinib followed by Gefitinib Maintenance

External beam RT using a total dose of 30 Gy with ten daily fractions of 3.0 Gy given 5 days per week over 2 weeks + Gefitinib 250 mg/day

whole brain radiotherapy

Gefitinib (IRESSA)

Antoine CARPENTIER, MD,PhD

Multicentre randomised (1:1) trial assessing the efficacy of whole brain radiotherapy in addition to Gefitinib for the management of brain metastasis in lung cancer patients with a mutated EGFR.

Lung cancer patients with newly diagnosed CNS metastasis with- at least one brain lesion measuring \> 1 cm in longest dimension - not eligible for surgery or stereotactic radio-surgeryOpen-label, multicentre, national, randomised (1:1) phase II trialArm A: WBRT and Concurrent Gefitinib followed by Gefitinib Maintenance Arm B: Gefitinib

Assess the Efficacy of Whole Brain Radiation Therapy in Lung Cancer Patients With Brain Metastasis

Randomized to Assess the Efficacy of Whole Brain Radiation Therapy (WBRT) With Concomitant Gefitinib Followed by Maintenance Gefitinib, and Gefitinib Alone, in Lung Cancer Patients With Brain Metastasis

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Safety Evaluation of a Combination of Brain Radiation Therapy and Bevacizumab (Avastin®) for Treatment of Brain Metastasis	NCT01332929	Metastatic Mali...	Bevacizumab	18 Years - 70 Years	Centre Francois Baclesse
Safety Evaluation of a Combination of Brain Radiation Therapy and Bevacizumab (Avastin®) for Treatment of Brain Metastasis	NCT01332929	Metastatic Mali...	Bevacizumab	18 Years - 70 Years	Centre Francois Baclesse
A Single Arm Study of Brain Metastasis in Patients With HER2-positive Breast Cancer	NCT04767828	TTP	PYRROTINI Brain radiation...	18 Years - 75 Years	Tianjin Medical University Cancer Institute and Hospital
A Single Arm Study of Brain Metastasis in Patients With HER2-positive Breast Cancer	NCT04767828	TTP	PYRROTINI Brain radiation...	18 Years - 75 Years	Tianjin Medical University Cancer Institute and Hospital
Assess the Efficacy of Whole Brain Radiation Therapy in Lung Cancer Patients With Brain Metastasis	NCT01363557	EGFR-mutated Lu... Brain Metastasi...	whole brain rad... Gefitinib (IRES...	18 Years -	Assistance Publique - Hôpitaux de Paris
Assess the Efficacy of Whole Brain Radiation Therapy in Lung Cancer Patients With Brain Metastasis	NCT01363557	EGFR-mutated Lu... Brain Metastasi...	whole brain rad... Gefitinib (IRES...	18 Years -	Assistance Publique - Hôpitaux de Paris

Spots Global Cancer Trial Database for brain radiation therapy