Neoplasms

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Nervous System Diseases

Rare Diseases

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Glioblastoma

Glioma

Brain Neoplasms

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Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Oligoastrocytoma

Antineoplastic Agents

All Drugs and Chemicals

Amino Acids

Afatinib

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Afatinib tablets are taken by mouth. Dose Level 1: 80 mg every 4 days Dose Level 2: 120 mg every 4 days Dose Level 3: 180 mg every 4 days Dose Level 4: 280 mg every 7 days

Santosh Kesari, MD, PhD

The purpose of this study is to try to determine the maximum safe dose of afatinib that can be administered to people with brain cancer. Other purposes of this study are to:

* find out what effects (good and bad) afatinib has;
* see how much drug gets into the body by collecting blood and cerebrospinal fluid for use in pharmacokinetic (PK) studies;
* learn more about how afatinib might affect the growth of cancer cells;
* look at biomarkers (biochemical features that can be used to measure the progress of disease or the effects of a drug).

This is an open-label, single institution, Phase I 3+3 dose escalation study to describe the safety and tolerability of afatinib in patients with brain cancer having failed prior therapy and to determine the recommended phase II dose.

Eligible patients will receive afatinib in treatment cycles of 28 days that will consist of afatinib administered orally by mouth once every four days. Patients will be assigned to the dose level open at the time of their enrollment. Patients will continue dosing of afatinib until disease progression, unacceptable toxicity, withdrawal of consent, or treating physician determines it is in their best interest to stop. Guidelines for modifying study drug doses is provided for the management of adverse treatment effects.

All patients will have regular evaluations for assessment of safety parameters as detailed in the study flow chart. Lumbar puncture and blood draw for assessing afatinib levels will occur as detailed in the study flow chart.

Neurological imaging and assessment for response will be performed approximately every eight weeks. Tumor response will be assessed according to Response Assessment in Neuro-Oncology (RANO) Working Group criteria.

An end of treatment evaluation will occur when a patient permanently discontinues study drug, as detailed in the study flow chart. Patients will then be followed every four months for survival.

Safety Study of Afatinib for Brain Cancer

A Phase I Dose Escalation and Central Nervous System (CNS) Pharmacokinetic Study of the ErbB Family Inhibitor Afatinib in Patients With Recurrent or Progressive Brain Cancer

Number of side effects of study treatment that prevent an increase in dose or level of that treatment

The highest dose evaluated that does not cause unacceptable side effects

Type, number, grade and seriousness of adverse events reported after the first dose of study treatment

Measurement of afatinib concentration in CSF and blood at defined timepoints

Tumor response compared to baseline as assessed by the RANO criteria

Time between the start of treatment to disease progression

Time between the start of treatment to death

Boehringer Ingelheim

Santosh Kesari

Director, Neuro-Oncology

Musculoskeletal Diseases

Ependymoma

Craniopharyngioma

Adamantinoma

Ameloblastoma

Neoplasms, Nerve Tissue

Neoplasms by Histologic Type

Neoplasms, Vascular Tissue

Meningeal Neoplasms

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms, Glandular and Epithelial

Bone Neoplasms

Bone Diseases

Neuroepithelioma

Stereotactic conformal radiotherapy (SCRT)

Conventional radiotherapy Patients in this arm will be treated with conventional radiotherapy techniques being used at the moment in the department. This involves patient being immobilised with a customised thermoplastic mask after which they will have a contrast enhanced planning CT scan. The radiation oncologist will draw the tumour on the appropriate CT slices and a margin of 1-2 cms grown for the planning target volume. Beam arrangement will be relatively simple and typically consist of 2-3 coplanar fields using 6 MV photons. Conventional planning optimisation will be carried out by the use of wedges, beam weightage and corner shields as appropriate. Radiotherapy doses, prescription and fractionation schedules will be identical to the SCRT arm

Stereotactic Conformal radiotherapy

Conventional radiotherapy

Rakesh Jalali, MD

Rajiv Sarin, MD FRCR

Brain tumours are the commonest solid tumours in children and the second most common neoplasms overall in this patient population. Radiotherapy plays an important part in the management in a majority of these tumours. While the cure rates of these tumours, especially the benign and low grade ones are quite encouraging, the treatment itself may lead to some late sequelae, which could have significant implications in the quality of life in these long-term survivors.

Stereotactic conformal radiotherapy (SCRT) is a modern high-precision radiotherapy technique, which reduces the volume of normal brain irradiated and has the capability to minimise the doses to critical structures. The present study is designed to prospectively estimate the incidence and severity of neuropsychological, cognitive and neuroendocrine dysfunction following radiotherapy delivered with conventional and stereotactic techniques and would be one of the most comprehensive studies providing very important longitudinal and reliable data regarding these sequelae. The study involving 200 patients would be to the best of our knowledge not only the largest ever study conducted so far but also the only randomised trial assessing these sequelae in patients receiving focal brain irradiation.

The study also examines whether the physical advantages of modern technological progress translate in clinical benefit. This could have significant implications in the radiotherapeutic management of children and young adults with brain tumours. The study is unique in design in terms of evaluating the efficacy of SCRT with respect to conventional radiotherapy in terms of long term tumour control and treatment related complications.

1.0 BACKGROUND AND RATIONALE

Brain tumours are the commonest solid tumours in children and with appropriate treatment, nearly half of them achieve long term cure. Radiotherapy is essential in the management of a majority of these tumours. Conventional radiotherapy alone or in combination with surgery and/or chemotherapy in tumours such as optic gliomas, hypothalamic gliomas, craniopharyngiomas, germ cell tumours, and other low grade tumours achieves excellent long term control rates ranging from 70 to 95%. However, while the tumour control has been effective, there have been concerns about treatment related morbidity.

which included cognitive dysfunction in 38%, motor deficit in 25%, visual impairment in 20%, hormonal dysfunction in 20% and psychological-emotional problems in 14% of the survivors.

It is difficult to ascertain from these reports the exact contribution of each of these factors and how they interact with each other. Radiotherapy is believed to be at least partly responsible although its exact role is yet to be quantified. Most of the evidence regarding post-radiotherapy neuropsychological and cognitive dysfunction is from retrospective studies involving whole brain radiotherapy.

Neuroendocrine dysfunction is well-documented late sequelae following treatment of patients with brain tumours. This could either be due to direct involvement of the pituitary hypothalamic axis (PHA) by the tumour or as a result of surgical or radiation injury to this region. For tumours not directly involving the PHA, the commonest cause of neuroendocrine dysfunction is cranial irradiation. PHA region unavoidably receives radiation with whole brain radiotherapy or if the tumour itself is arising from this region. For the treatment of tumours adjacent to PHA but not involving it, it may be frequently a part of radiotherapy planning target volume, which includes the gross tumour and a margin to account for any microscopic disease and possible daily set up inaccuracies and thus receive significant doses. The region may also sometimes come in the entry / exit path of radiation beams during treatment of tumours even away from this region. Radiation induced hormonal abnormalities are generally dose dependent and may develop many years after irradiation. To reduce the impact of endocrine dysfunctions on physical, mental and sexual development, it is important to detect and treat them timely. Early growth hormone replacement is the only way to minimise growth retardation caused by its deficiency but the treatment is expensive with significant financial implications, especially in our country. The annual cost of GH replacement is approximately Rs 200,000.00, which is prohibitive for the vast majority of the Indian parents as is the cost of LHRH analogues, which is useful to prevent early epiphyseal fusion and stunted growth in children with post radiation or tumour related precocious puberty.

1.4 Evolution of Stereotactic conformal radiotherapy (SCRT) Conventional radiotherapy techniques generally involve the use of 2-3 radiation beams covering the tumour and a margin of 1-3 cms for any subclinical disease and physical inaccuracies in the daily treatment delivery. The last decade has seen tremendous technological advances in radiotherapy planning and accurate treatment delivery. Stereotactic radiosurgery (SRS) and stereotactic radiotherapy (SRT) techniques involve firm and accurate immobilisation with fixed or relocatable frames, high precision three-dimensional (3-D) target localisation with CT/CT-MRI fusion and focused radiation delivery. This is achieved either with a multiple source cobalt unit (gamma knife) or with multiple arcs using a modified conventional linear accelerator. Such conventional stereotactic irradiation techniques typically produce spherical high dose volumes and are therefore suitable only for small spherical lesions. A majority of the brain tumours considered for radiotherapy however are not spherical and frequently extend to adjacent structures. To treat large non-spherical volumes with conventional SRS requires the addition of multiple small spherical high dose volumes described as multiple isocentre treatment. The overlap of high dose spheres results in dose inhomogeneity, which has been associated with a higher incidence of radiation induced complications. It has been previously demonstrated that the optimum way of delivering high precision localised irradiation to larger non-spherical targets is with the use of multiple conformal fixed fields with individualised shielding of each radiation field conforming to the shape of the target. This principle of conformal therapy combined with the precision of stereotactic localisation and focused radiation delivery is described as stereotactic conformal radiotherapy (SCRT).

Traditionally, stereotactic irradiation has been delivered in a one session as single fraction radiosurgery. High doses of radiation given in one fraction are known to be associated with a high risk of radiation induced damage to normal tissue and this is particularly true for the central nervous system. Giving radiation in small individual doses allows the delivery of higher radiation doses without serious injury to the normal tissues, which is especially important for normal CNS structures. Single fraction SRS has been shown to be associated with considerable neurological toxicity to the optic apparatus the cranial nerves and normal brain. With the application of high precision relocatable non-invasive means of immobilisation, it has become possible to deliver stereotactic irradiation in a fractionated manner. The technique of SCRT combines the precision of focused radiation delivery and the radiobiological advantages of fractionation. It also ensures homogenous dose distribution within the irradiated volume further reducing the risk of damage.

The basic aim of high precision SCRT is to achieve a high dose differential between the tumour and the surrounding normal tissues. This allows for either an increase in the tumour dose to improve local control or for a potential decrease in radiation damage to the normal tissues. Further optimisation of the technique involving 3-4 conformal non-coplanar field arrangement has shown a significant dose reduction to the normal brain. Preliminary experience, mainly in adults has shown this technique to be feasible during the routine practice of a busy radiotherapy department. Early results in terms of local control are same as that with conventional radiotherapy, with an increased sparing of the surrounding normal brain and adjacent critical structures. While the experience is limited in young children, a few reports have suggested it to be feasible in this population also. The technique has the potential to minimise the dose to any critical site close to the tumour like pituitary-hypothalamic complex, cochlea, brain stem, optic apparatus and the mesial temporal lobes, which are believed to be the common sites of radiation injury leading to late morbidity.

NEED FOR THE PRESENT STUDY The finding of significant long-term effects in a large proportion of brain tumour survivors mandates the development of treatment strategies designed to minimise their impact on the quality of life. Although the precise role of radiotherapy in the causation of various post treatment sequelae is not established, it is generally believed to be at least partly responsible for these effects. There have been attempts to modify the management in terms of avoiding, delaying radiotherapy or reducing the total radiation dose to the tumour with a view to reduce its impact on the long-term toxicity. However, reduction of radiotherapy doses to the tumour has been shown to result in poorer local control rates. Also, a majority of the patients in whom the radiation is delayed eventually do require radiotherapy at later stages (37). There is also evidence that radiotherapy given upfront yields superior disease control than radiotherapy given at the time of tumour progression (38,39). In light of this data, there is therefore, an ever-increasing need to explore techniques of radiotherapy minimising the irradiation to the normal brain and critical structures without compromising radiotherapy doses essential for tumour control. SCRT is a modern high-precision radiotherapy technique, which reduces the volume of normal brain irradiated and has the capability to minimise the doses to critical structures.

The evidence of long term effects of focal irradiation so far is from retrospective studies and a few small prospective trials. There is therefore, a great need to evaluate this issue in a prospective manner in a large number of patients. The present study is designed to prospectively estimate the incidence and severity of neuropsychological, cognitive and neuroendocrine dysfunction following radiotherapy delivered with conventional and stereotactic techniques and would be one of the most comprehensive studies providing very important longitudinal and reliable data regarding these sequelae. The study involving 200 patients would be to the best of our knowledge not only the largest ever study conducted so far but also the only randomised trial assessing these sequelae in patients receiving focal brain irradiation.

The study also examines whether the physical advantages of modern technological progress translate in clinical benefit. This could have significant implications in the radiotherapeutic management of children and young adults with brain tumours. The study is unique in design in terms of evaluating the efficacy of SCRT with respect to conventional radiotherapy in terms of long term tumour control and treatment related complications.

If the present trial succeeds in reducing the incidence and severity of radiotherapy related sequelae by SCRT technique, it would undoubtedly result in a tremendous benefit to these patients. A possible reduction in the neuroendocrine sequelae not only will improve the quality of life of the patients but would also result in major financial saving. This is critical in patients living in the developing countries where the cost of endocrinological management in terms of hormonal assays and their replacement is largely prohibitive.

We have until Januray 2009 accrued 128 patients so far in the trial

SCRT Versus Conventional RT in Children and Young Adults With Low Grade and Benign Brain Tumors

Efficacy of Stereotactic Conformal Radiotherapy (SCRT) Compared to Conventional Radiotherapy in Minimising Late Sequelae in Children and Young Adults With Brain Tumours: a Randomised Clinical Trial

Terry Fox Foundation

Tata Memorial Hospital

Professor

Proton radiation therapy daily (Monday through Friday) for six weeks. This is a single arm study.

Once daily, Monday through Friday, for 6 weeks.

Proton Radiation Therapy

Helen A. Shih, MD, MS, MPH

In this research study, we are looking to study the side effects from the use of proton radiation in treating people with low-grade gliomas that are recommended radiation treatment. We expect response of the tumors to be the same with proton radiation as compared to standard 3D conformal radiation therapy, but also expect less side effects from radiation.

* Participants will receive radiation therapy for 6 weeks, given in daily doses, Monday through Friday, for a total of 30 treatments.
* A medical history and physical examination will be performed prior to the start of radiation treatment, weekly during the 6 weeks of radiation and after the finish of radiation performed at 3 and 6 months and then annually for 5 years.
* Hormonal function tests will be taken prior to the start of radiation treatment and after the finish of radiation treatment at 3 and 6 months, and annually for five years to assess the participants hormonal functions as they relate to the pituitary gland's function.
* A brain MRI will be performed prior to the start of radiation treatment and then performed at 3 and 6 months after radiation treatment then annually for 5 years.
* A neurocognitive exam will be performed prior to the start of radiation therapy, a limited exam 6 months after the completion of radiation therapy, and a complete exam annually for 5 years.
* Quality of Life and Emotional Well-Being Questionnaires will be done before radiation begins, 2 months after radiation treatment, 6 months after radiation treatment and then annually for 5 years.

Late Effects of Proton Radiation Therapy in Patients With Low-Grade Glioma

Clinical and/or radiographic assessments Percentages were estimated by Kaplan Meier

Percentages were estimated by Kaplan Meier

National Cancer Institute (NCI)

Massachusetts General Hospital

Attending Radiation Oncologist

Age, Continuous

Sex: Female, Male

United States

Region of Enrollment

All 20 baseline participants were included in analysis.

Helen A. Shih, MD

Number of Participants With Late Effects > 3 Months Post RT

1 Year

3 Year

5 Year

Percentage of Participants With Progression Free Survival

Percentage of Participants With Overall Survival

Proton Radiation Therapy daily (Monday through Friday) for six weeks. This is a single arm study.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Safety Study of Afatinib for Brain Cancer	NCT02423525	Brain Cancer	Afatinib	18 Years -	Saint John's Cancer Institute
SCRT Versus Conventional RT in Children and Young Adults With Low Grade and Benign Brain Tumors	NCT00517959	Low Grade Gliom... Craniopharyngio... Ependymomas Meningiomas	Stereotactic Co... Conventional ra...	3 Years - 25 Years	Tata Memorial Hospital
SCRT Versus Conventional RT in Children and Young Adults With Low Grade and Benign Brain Tumors	NCT00517959	Low Grade Gliom... Craniopharyngio... Ependymomas Meningiomas	Stereotactic Co... Conventional ra...	3 Years - 25 Years	Tata Memorial Hospital
Late Effects of Proton Radiation Therapy in Patients With Low-Grade Glioma	NCT00681473	Low Grade Gliom...	Proton Radiatio...	18 Years -	Massachusetts General Hospital
Safety Study of Afatinib for Brain Cancer	NCT02423525	Brain Cancer	Afatinib	18 Years -	Saint John's Cancer Institute

Spots Global Cancer Trial Database for low grade gliomas