Largest Ever Brain Cancer Study Provides Key Insight Into One of Its Deadliest Forms


This could change the way we think about brain tumours.

 
As far as cancers go, one of the worst is a type of brain cancer called glioma – the disease has a five-year survival rate of just 5 percent, and no reliable method for early detection.

A giant study that pooled genetic data from tens of thousands of people could change that, finding more than a dozen new mutations for physicians to hunt for in an effort to identify who is at risk of developing glioma.

 The results could end up boosting the chances of an early diagnosis, and saving lives in the process.

Together with researchers from the US and Europe, scientists from the Institute of Cancer Research in the UK carried out two studies on the human genome in an effort to spot differences that could result in cancer of the brain’s glial cells.

Our central nervous system relies on neurons to do its ‘thinking’ work, but they’re far from the only cell in the neighbourhood. For example, glial cells provide support for the neurons by insulating them, holding them in place, and helping them access nutrients.

But like a number of tissues in the body, changes in the genes inside these ‘nanny’ brain cells can cause them to grow out of control, prompting cancerous tumours to develop.

Glioma can be further broken down into categories, depending on the type of glial cell they started out as. Glioblastoma multiforme (GBM), for example, is a common form of brain cancer that begins as a type of glial cell called an astrocyte.

Tumours that grow into glioblastomas are particularly aggressive, killing around 95 percent of patients within five years.

 GBM develops in around 3 out of every 100,000 people, mostly striking in those over the age of 60, and claiming approximately 13,000 lives in the US and 5,000 lives in the UK each year.

While many researchers have been looking for new and innovative ways to treat gliomas, early detection has often been more accidental than intentional.

An Ohio State University study conducted in 2015 identified interactions between a pair of proteins and the newly developed tumour which could lead to a test that allows oncologists to diagnose a tumour as much as five years before symptoms appear.

But by identifying the genes that increase the risk of developing glioma later in life, researchers could potentially produce a program of diagnosis and quick treatment that might prevent tumours from growing in the first place.

This recent study didn’t stop at scanning the genome; it also analysed over 30,000 people included in a number of previous studies on GBM and non-GBM cancers, producing the largest ever study into brain cancer research.

All up, the research compared 12,496 cases of glioma with 18,190 people who didn’t have the cancer, finding 13 new locations on the genome which – if changed – could lead to glioma.

“The changes in the way we think about glioma could be quite fundamental,” says Richard Houlston from the Institute of Cancer Research.

“So, for example, what we thought of as two related sub-types of the disease turn out to have quite different genetic causes which may require different approaches to treatment.”

In total, researchers now have strong evidence for 26 locations on the genome that individually increase the risk of developing a form of glioma, in one case by up to 15 percent.

That might not seem like a lot, but when the odds are stacked against those with a metastatic brain tumour, every clue could make the difference between life and death.

“Understanding the genetics of glioma in such detail allows us to start thinking about ways of identifying people at high inherited risk, and will open up a search for new treatments that exploit our new knowledge of the biology of the disease,” said Houlston.

Combining past studies to increase the pool of data is a useful way to spot small differences which have otherwise been missed.

Hopefully this is one record we’ll see broken some time soon.

Source:http://www.sciencealert.com

‘Huge’ Survival Benefit, New Standard of Care in Glioma


Results were released early and are leading to talk about a new standard of care in glioma after an interim analysis showed a “huge difference” in survival between patients who received temozolomide in addition to radiotherapy, compared with those who received radiotherapy alone.

“It completely took us by surprise,” said lead author Martin van den Bent, MD, professor of neuro-oncology at the Erasmus MC Cancer Center in Rotterdam, the Netherlands.

Previous trials in glioma have not shown any difference after 5 to 6 years after randomization, but in this study there was a significant difference even at 2 years, and at 5 years the difference was “huge,” he said.

The findings come from the CATNON trial, conducted in 745 patients with grade 3 anaplastic glioma, all of whom did not have the 1p19q deletion, a genetic abnormality that is associated with better prognosis and chemosensitivity. In order to find the patients for this trial, more than 1400 patients were screened in 12 countries across three continents, and enrolment took 8 years, Dr van den Bent reported.

The results from the interim analysis, after a median follow-up of 27 months, show that 43% of patients treated with both temozolomide and radiotherapy were alive after 5 years, compared with 24% in the radiotherapy-alone group.

Put another way, the 5-year survival was 56% in those who received both temozolomide and radiotherapy, compared with 44% in those treated with radiotherapy alone (hazard ratio, 0.67; P = .003)

In this portion of the trial, temozolomide was administered after radiotherapy.
Dr Martin van den Bent
Two other groups in this trial are evaluating temozolomide given concurrently and temozolomide given both concurrently and after radiotherapy. “Further follow-up is required” to obtain answers on this, Dr van den Bent said. At the interim analysis, the efficacy boundary was not met, he said.
The required number of events for a full analysis of the results are likely not be collected until about 2024, which is when he will be retiring, Dr van den Bent joked.

“Adjuvant temozolomide clearly improves survival,” Dr van den Bent concluded, and he also emphasized that this was the first randomized clinical trial to show an overall survival benefit in glioma.

In answer to a question from a clinician in the audience, who asked whether this was practice changing and how he should treat his glioma patients now, Dr van den Bent emphasized that the result for adjuvant temozolomide is clear, and that it should now be used together with radiotherapy in patients such as the participants in this trial. “That is now evidence-based medicine,” he added. However, with the question remaining over concurrent temozolomide, he said that he remained hesitant, because it increases long-term toxicity.

An American expert not involved in the trial agreed that it was practice changing. In fact, adjuvant temozolomide plus radiation will become a standard of care in glioma, commented Brain Michael Alexander, MD, PhD, disease center leader for radiation oncology at the Center for Neuro-Oncology, Dana-Farber Cancer Institute, and associate professor of radiation oncology at Harvard Medical School in Boston.

Temozolomide plus radiation is already a standard of care in glioblastoma multiforme, he noted, on the basis of phase 3 trial results reported in 2005 (N Engl J Med. 2005;352:987-996).

Many clinicians have extrapolated from this to also use the chemoradiation combination in glioma, he told Medscape Medical News, but this has not been supported by direct data until now.

New Standard of Care

Adjuvant temozolomide is a new standard for these patients, David Reardon, MD, clinical director at the Center for Neuro-Oncology, told the meeting in his discussion of the abstract.

He congratulated the researchers on their “truly labor-intensive efforts,” and noted the significant difference in survival, with an increasing separation of the curves with time.

But he also added that the finding was “not too unexpected,” as the addition of chemotherapy to radiotherapy improving survival is a “recurring theme in neuro-oncology.”

In fact, a recently published study shows that the addition of the chemotherapy combination of procarbazine, lomustine, and vincristine to radiotherapy also prolonged survival in glioma (N Engl J Med. 2016;374:1344-1355).

Dr Reardon also noted that a question remains over the use of concurrent temozolomide in glioma, and he said he was looking forward to the final analysis from this trial, even if it takes until 2024.

Temozolomide was supplied free of charge by Schering-Plough/MSD. The study was funded by an unrestricted grant from Schering-Plough, and also grants from the European Organisation for Research and Treatment of Cancer (EORTC) and Cancer Research UK. Dr van den Bent reports a consulting or advisory role with Merck, Roche, Celldex, Novocure, AbbVie, Amgen; honoraria from Roche, Actelion, Celldex, Bristol-Myers Squibb, Merck, AbbVie, Novocure; and research funding from AbbVie and Roche. Dr Reardon reports honoraria from AbbVie, Bristol-Myers Squibb, Cavion, Celldex, Genentech/Roche, Inovio Pharmaceuticals, Juno Therapeutics, Merck, Midatech, Momenta Pharmaceuticals, Monteris Medical, Novartis, Novocure, Oxigene, Regeneron, Stemline Therapeutics; a consulting or advisory role with Bristol-Myers Squibb, Cavion, Celldex, Genentech/Roche, Inovio Pharmaceuticals, Juno Therapeutics, Merck, Midatech, Momenta Pharmaceuticals, Monteris Medical, Novartis, Novocure, Oxigene, Regeneron, and Stemline Therapeutics; and research funding from Celldex (Inst), Incyte (Inst), and Midatech (Inst).

 

American Society of Clinical Oncology (ASCO) 2016 Annual Meeting:

‘Huge’ Survival Benefit, New Standard of Care in Glioma


Results were released early and are leading to talk about a new standard of care in glioma after an interim analysis showed a “huge difference” in survival between patients who received temozolomide in addition to radiotherapy, compared with those who received radiotherapy alone.

“It completely took us by surprise,” said lead author Martin van den Bent, MD, professor of neuro-oncology at the Erasmus MC Cancer Center in Rotterdam, the Netherlands.

 Previous trials in glioma have not shown any difference after 5 to 6 years after randomization, but in this study there was a significant difference even at 2 years, and at 5 years the difference was “huge,” he said.

The findings come from the CATNON trial, conducted in 745 patients with grade 3 anaplastic glioma, all of whom did not have the 1p19q deletion, a genetic abnormality that is associated with better prognosis and chemosensitivity. In order to find the patients for this trial, more than 1400 patients were screened in 12 countries across three continents, and enrolment took 8 years, Dr van den Bent reported.

The results from the interim analysis, after a median follow-up of 27 months, show that 43% of patients treated with both temozolomide and radiotherapy were alive after 5 years, compared with 24% in the radiotherapy-alone group.

Put another way, the 5-year survival was 56% in those who received both temozolomide and radiotherapy, compared with 44% in those treated with radiotherapy alone (hazard ratio, 0.67; P = .003)

In this portion of the trial, temozolomide was administered after radiotherapy.

Dr Martin van den Bent

Two other groups in this trial are evaluating temozolomide given concurrently and temozolomide given both concurrently and after radiotherapy. “Further follow-up is required” to obtain answers on this, Dr van den Bent said. At the interim analysis, the efficacy boundary was not met, he said.

 The required number of events for a full analysis of the results are likely not be collected until about 2024, which is when he will be retiring, Dr van den Bent joked.

“Adjuvant temozolomide clearly improves survival,” Dr van den Bent concluded, and he also emphasized that this was the first randomized clinical trial to show an overall survival benefit in glioma.

In answer to a question from a clinician in the audience, who asked whether this was practice changing and how he should treat his glioma patients now, Dr van den Bent emphasized that the result for adjuvant temozolomide is clear, and that it should now be used together with radiotherapy in patients such as the participants in this trial. “That is now evidence-based medicine,” he added. However, with the question remaining over concurrent temozolomide, he said that he remained hesitant, because it increases long-term toxicity.

 An American expert not involved in the trial agreed that it was practice changing. In fact, adjuvant temozolomide plus radiation will become a standard of care in glioma, commented Brain Michael Alexander, MD, PhD, disease center leader for radiation oncology at the Center for Neuro-Oncology, Dana-Farber Cancer Institute, and associate professor of radiation oncology at Harvard Medical School in Boston.

Temozolomide plus radiation is already a standard of care in glioblastoma multiforme, he noted, on the basis of phase 3 trial results reported in 2005 (N Engl J Med. 2005;352:987-996).

Many clinicians have extrapolated from this to also use the chemoradiation combination in glioma, he told Medscape Medical News, but this has not been supported by direct data until now.

New Standard of Care

Adjuvant temozolomide is a new standard for these patients, David Reardon, MD, clinical director at the Center for Neuro-Oncology, told the meeting in his discussion of the abstract.

He congratulated the researchers on their “truly labor-intensive efforts,” and noted the significant difference in survival, with an increasing separation of the curves with time.

But he also added that the finding was “not too unexpected,” as the addition of chemotherapy to radiotherapy improving survival is a “recurring theme in neuro-oncology.”

In fact, a recently published study shows that the addition of the chemotherapy combination of procarbazine, lomustine, and vincristine to radiotherapy also prolonged survival in glioma (N Engl J Med. 2016;374:1344-1355).

Proteins Identified That May Help Brain Tumors Spread.


Scientists at the University of Alabama at Birmingham have identified a molecular pathway that seems to contribute to the ability of malignant glioma cells in a brain tumor to spread and invade previously healthy brain tissue. Researchers said the findings, published Sept. 19, 2013, in the journal PLOS ONE, provide new drug-discovery targets to rein in the ability of these cells to move.

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Gliomas account for about a third of brain tumors, and survival rates are poor; only about half of the 10,000 Americans diagnosed with malignant glioma survive the first year, and only about one quarter survive for two years.

“Malignant gliomas are notorious, not only because of their resistance to conventional chemotherapy and radiation therapy, but also for their ability to invade the surrounding brain, thus causing neurological impairment and death,” said Hassan Fathallah-Shaykh, M.D., Ph.D., associate professor in the UAB Department of Neurology. “Brain invasion, a hallmark of gliomas, also helps glioma cells evade therapeutic strategies.”

Fathallah-Shaykh said there is a great deal of interest among scientists in the idea that a low-oxygen environment induces glioma cells to react with aggressive movement, migration and brain invasion. A relatively new cancer strategy to shrink tumors is to cut off the tumor’s blood supply – and thus its oxygen source – through the use of anti-angiogenesis drugs. Angiogenesis is the process of making new blood vessels.

“Stop angiogenesis and you shut off a tumor’s blood and oxygen supply, denying it the components it needs to grow,” said Fathallah-Shaykh. “Drugs that stop angiogenesis are believed to create a kind of killing field. This study identified four glioma cell lines that dramatically increased their motility when subjected to a low-oxygen environment – in effect escaping the killing field to create a new colony elsewhere in the brain.”

Fathallah-Shaykh and his team then identified two proteins that form a pathway linking low oxygen, or hypoxia, to increased motility.

“We identified a signaling protein that is activated by hypoxia called Src,” said Fathallah-Shaykh. “We also identified a downstream protein called neural Wiskott-Aldrich syndrome protein (N-WASP), which is regulated by Src in the cell lines with increased motility.”

The researchers then used protein inhibitors to shut off Src and N-WASP. When either protein was inhibited, low oxygen lost its ability to augment cell movement.

“These findings indicate that Src, N-WASP and the linkage between them – which is something we don’t fully understand yet – are key targets for drugs that would interfere with the ability of a cell to move.” said Fathallah-Shaykh. “If we can stop them from moving, then techniques such as anti-angiogenesis should be much more effective. Anti-motility drugs could be a key component in treating gliomas in the years to come.”

Source: http://www.sciencedaily.com

Targeting Invasive Glioma Cells.


Name of the Trial
Phase I Trial of AZD7451, a Tropomyosin-Receptor Kinase (TRK) Inhibitor, for Adults with Recurrent Gliomas (NCI-12-C-0005). See the protocol summary.

Principal Investigators
Dr. Katharine McNeill, NCI Center for Cancer Research, and Dr. Howard Fine, New York University Cancer Institute

Why This Trial Is Important

Glioblastoma is the most common malignant brain tumor in adults, with about 12,000 new cases diagnosed each year in the United States. It is also one of the deadliest, with a median survival following diagnosis of about 14 months.

Surgery to remove as much of the tumor as possible is the standard primary treatment for glioblastoma. After surgery, doctors use radiation therapy and treatment with the chemotherapy drug temozolomide to try to delay the growth of the remaining cancer. Although these measures may delay disease progression for a while, they cannot prevent it, and death usually occurs within a few months. Currently, the only therapy that has proven effective in delaying death in patients with progressive glioblastoma is bevacizumab, which helps block the tumor’s ability to induce the formation of new blood vessels.

Glioblastoma is particularly difficult to treat because of its highly invasive nature. Although the bulk of the tumor may be well defined, malignant cells have usually migrated away from the tumor by the time it is discovered. Some of these cells inevitably remain behind after surgery and, if left unchecked, will eventually kill the patient.

Progress in the treatment of glioblastoma has been hampered by the absence of preclinical tumor models that mimic the invasiveness of the cancer. However, NCI researchers recently developed new cell lines from a subset of glioblastoma tumor-initiating cells that more accurately replicate the invasiveness of human glioblastoma in animal models. Using the new models, they were able to determine that cells near the edge of glioblastoma tumors express a set of proteins that help make them highly invasive. Subsequently, they identified a compound that may be effective in blocking the function of one of these key proteins.

A protein called tropomyosin-receptor kinase, or Trk, is commonly found on brain cells and helps regulate the development, function, and survival of nerve cells. In glioblastoma, Trk is highly expressed on the cells around the edges of the tumor and on the infiltrative cells that have migrated away from the tumor mass, whereas those cells in the bulk of the tumor show lower levels of Trk expression. Doctors want to see if inhibiting the function of Trk will help block the invasiveness of glioblastoma cells and reduce the likelihood that the tumor will progress.

In this first-in-class phase I trial, patients with glioblastoma that has not responded to standard postoperative therapy or that has progressed will be treated with varying amounts of a Trk inhibitor called AZD7451 to determine the maximum tolerated dose and the side effects of this drug. Doctors will also look for signs of clinical activity.

“Regardless of the extent of tumor resection, there are always residual tumor cells because these cells are highly invasive and infiltrate normal brain tissue,” said Dr. Fine, former chief of NCI’s Neuro-Oncology Branch. “So surgery is never curative in this disease; some type of postoperative therapy is always required to try to address these remaining infiltrative tumor cells.

“We became interested in trying to study this invasive process in the laboratory in hopes of identifying new molecular targets for therapy,” he continued. “We were able to find that this molecule called Trk was expressed specifically on glioblastoma cells that were invading and [that] Trk was signaling to these tumor cells in a way that was important for the cells to move within the brain. Further, by inhibiting Trk we were able to shut off the invasive process in these models.”

The trial is taking place at the NIH Clinical Center in Bethesda, MD, and at the New York University Cancer Institute in New York City.

STUDY PROTOCOL

AZD7451 for Recurrent Gliomas

Basic Trial Information

Phase

Type

Status

Age

Sponsor

Protocol IDs

Phase I Biomarker/Laboratory analysis, Treatment Active 18 and over NCI 120005
12-C-0005, NCT01468324

Trial Description

Summary

Background:

  • AZD7451 is a drug that may help interfere with brain tumor cell growth. It can prevent glioma cells from entering into normal brain tissue, and slow or stop the growth of additional tumors. Researchers want to see if AZD7451 is effective against gliomas that have not responded to surgery, radiation, or chemotherapy.

Objectives:

  • To see if AZD7451 is a safe and effective treatment for gliomas that have not responded to standard treatments.

Eligibility:

  • Individuals at least 18 years of age who have gliomas that have not responded to standard treatments.

Design:

  • Participants will be screened with a physical exam, medical history, blood and urine tests, heart function tests, an eye exam, and imaging studies.
  • Participants will take AZD7451 daily by mouth for 28-day cycles of treatment.
  • Participants will keep a medication diary and record any side effects. Treatment will be monitored with frequent blood tests and imaging studies.
  • Treatment will continue as long as there are no serious side effects and the tumor does not start growing again….

Further Study Information

BACKGROUND:

Recurrent glioma patients have very limited treatment options. A major cause of gliomarelated morbidity and mortality is the extensive infiltrative and invasive nature of glioma cells. Thus, inhibition of glioma invasion is a potentially promising strategy.

Work in the laboratory of Dr. Howard Fine has identified TrkA as an important signaling receptor for mediating glioma cell invasion. Both genetic and pharmacological inhibition of Trk potently inhibits glioma invasion and tumor progression in vitro and in vivo.

AZD7451 is a first in-class inhibitor of Trk.

OBJECTIVES:

To establish the maximally tolerated dose (MTD) of continuous once daily AZD7451 in patients with recurrent malignant gliomas not on enzyme-inducing anti-epileptic drugs (EIAED).

To generate pharmacokinetic data on continuous twice a daily AZD7451 dosing.

ELIGIBILITY:

Patients with histologically proven glioblastoma are eligible for this study. Patients should have failed prior standard treatment with radiotherapy.

DESIGN:

This study will accrue up to 60 evaluable patients. Cohorts of 3 to 6 patients will receive continuous AZD7451 twice a day orally for 28 days. The MTD will be based on the tolerability observed during the first 4 weeks of treatment only. Up to three patients may be enrolled simultaneously at each dose level. The dose of AZD7451 can be progressively escalated if only 0/3 or 1/6 patients experience a dose limiting toxicity at the prior dose level.

At the end of Cycle 1, patients may choose to continue to receive AZD7451 until disease progression or until they experience unmanageable drug related toxicity, as long as they are continuing to derive clinical benefit and do not fulfill any of the criteria for removal from protocol therapy. Each cycle during this extension period will last 28 days.

Eligibility Criteria

  • INCLUSION CRITERIA:
  • Patients with histologically proven malignant primary gliomas who have progressive disease after radiotherapy will be eligible for this protocol.
  • Patients must have an MRI scan performed within 14 days prior to registration and on a fixed dose of steroids for at least 5 days. If the steroid dose is increased between the date of imaging and registration a new baseline MRI is required.
  • Patients having undergone recent resection of recurrent or progressive tumor will be eligible as long as all of the following conditions apply:

1. Patients will be eligible four weeks after surgery if they have recovered from the effects of surgery.

2. Residual disease following resection of recurrent tumor is not mandated for eligibility into the study. To best assess the extent of residual disease postoperatively, an MRI should be done:

  • no later than 96 hours in the immediate post-operative period or
  • at least 4 weeks post-operatively, and
  • within 14 days of registration, and
  • on a stable steroid dosage for at least 5 days.

If the 96 hour scan is more than 14 days before registration, the scan needs to be repeated. If the steroid dose is increased between the date of imaging and registration, a new baseline MRI is required on a stable steroid dosage for at least 5 days.

  • Patients must have failed prior radiation therapy.
  • Ability of subject or Legally Authorized Representative (LAR) (if the patient is deemed by the treating physician to be cognitively impaired or questionably impaired in such a way that the ability of the patient to give informed consent is questionable) to understand and the willingness to sign a written informed consent document indicating that they are aware of the investigational nature of this study.
  • Patients must be greater than or equal to18 years old, and must have a life expectancy > 8 weeks. Because no dosing or adverse event data are currently available on the use of AZD7451 in patients < 18 years of age, children are excluded from this study, but may be eligible for future pediatric trials.
  • Patients must have a Karnofsky performance status of greater than or equal to 60
  • Patients must be at least 4 weeks from radiation therapy. Additionally, patients must be at least 6 weeks from nitrosoureas, 4 weeks from temozolomide, 3 weeks from procarbazine, 2 weeks from vincristine and 2 weeks from last bevacizumab administration. Patients must be at least 4 weeks from other cytotoxic therapies not listed above and 2 weeks for non-cytotoxic agents (e.g., interferon, tamoxifen) including investigative agents. With the exception of alopecia, all toxicities from prior therapies should be resolved to CTCAE less than or equal to grade 1.
  • Patients must have adequate bone marrow function (WBC less than or equal to 3,000/microl, ANC > 1,500/mm(3), platelet count of > 100,000/mm(3), and hemoglobin greater than or equal to 9 gm/dl), adequate liver function (AST, ALT and alkaline phosphatase less than or equal to 2.5 times ULN and bilirubin less than or equal to 1.5 times ULN), and adequate renal function (creatinine less than or equal to 1.5 times ULN and/or creatinine clearance less than or equal to 50 cc/min calculated by Cockcroft-Gault) before starting therapy. Patients must also have serum potassium greater than or equal to 3.5 mmol/L, magnesium greater than or equal to 0.75 mmol/L, phosphate and calcium levels within normal levels; supplementation is allowed. In cases where the serum calcium is below the normal range, 2 options would be available: 1) the calcium adjusted for albumin is to be obtained and substituted for the measured serum value. Exclusion is to then be based on the adjusted for albumin values falling below the normal limit. 2) Determine the ionized calcium levels. Exclusion is then to be based on whether these ionized calcium levels are out of normal range despite supplementation. These tests must be performed within 14 days prior to registration. Eligibility level for hemoglobin may be reached by transfusion.
  • Patients must either not be receiving steroids, or be on a stable dose of steroids for at least five days prior to registration.
  • The effects of AZD7451 on the developing human fetus are unknown. For this reason and because AZD7451 is known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or herpartner is participating in this study, the treating physician should be informed immediately.
  • A 12 lead electrocardiogram (ECG) to be performed within 2 weeks of trial entry with QTc less than or equal to 470 msec.
  • Patients must have normal left ventricular ejection fraction (LVEF greater than or equal to 55% or normal by NIH Clinical Center criteria).

EXCLUSION CRITERIA:

  • Patients who, in the view of the treating physician, have significant active hepatic, renal, pulmonary or psychiatric diseases are ineligible.
  • 2 Prior treatment with AZD7451.
  • History of hypersensitivity to active metabolites or excipients of AZD7451.
  • Clinically significant cardiovascular event (e.g. myocardial infarction, angina pectoris, coronary artery bypass graft, angioplasty, vascular stent, superior vena cava syndrome (SVC), New York Heart Association (NYHA, Appendix I) classification of heart disease > 2 within 6 months before entry; or presence of cardiac disease that, in the opinion of the investigator, increases the risk of ventricular arrhythmia.
  • Hemorrhagic or ischemic stroke, including transient ischemic attacks and other central nervous system bleeding in the preceding 6 months that were not related to glioma surgery. History of prior intratumoral bleeding is not an exclusion criterion; patients with history of prior intratumoral bleeding, however, need to undergo a non-contrast head CT to exclude acute blood.
  • Ventricular arrhythmias requiring continuous therapy or asymptomatic sustained ventricular tachycardia within 12 months before study entry. Continuous or intermittent atrial fibrillation requiring treatment. Patients with significant ECG abnormalities such as complete left bundle block and third degree heart block are not eligible.
  • QTc prolongation with other medications that required discontinuation of that medication.
  • Congenital long QT syndrome or 1st degree relative with unexplained sudden death under 40 years of age. QTc with Bazett’s correction that is unmeasurable, or > 470 msec on screening ECG. (Note: If a subject has a QTc interval > 470 msec on screening ECG, the screen ECG may be repeated twice (at least 24 hours apart). The average QTc from the three screening ECGs must be less than or equal to 470 msec in order for the subject to be eligible for the study. Patients who are receiving a drug that has a risk of QTc prolongation are excluded if QTc is greater than or equal to 460 msec.
  • Any concurrent medication that may cause QTc prolongation or induce

Torsades de Pointes 1) Drugs listed in Appendix H, Table 2, that in the investigator’s opinion cannot be discontinued are allowed; however, must be monitored closely.

  • Concomitant medications that are moderate or potent inducers or inhibitors of CYP3A4 are not permitted within the specified wash-out periods prior to or during treatment with AZD7451
  • Patients with a history of corneal disease such as corneal ulcers, corneal dystrophies, keratoconus.
  • Refractory nausea and vomiting or significant gastrointestinal impairment, as judged by the investigator, that would significantly affect the absorption of AZD7451, including the ability to swallow the oral solution.
  • Patients known to have active hepatitis B or C (testing not required for entry on study).
  • Other concomitant anti-cancer therapy except corticosteroids.
  • Patients with a peripheral neuropathy CTCAE > 1 in the prior 4 weeks or active muscle diseases (including dermatomyositis, polymyositis, inclusion body myositis, muscular dystrophy and metabolic myopathy) or family history of myopathy. Patients with pre-existing renal disease including glomerulonephritis, nephritic syndrome, Fanconi syndrome or renal tubular acidosis.
  • Evidence of active infection or active bleeding diatheses.
  • Pregnant women are excluded from this study because AZD7451 is an agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with AZD7451, breastfeeding should be discontinued if the mother is treated with AZD7451. Female patients must have a negative pregnancy test prior to start of dosing if of child-bearing potential or must have evidence of non-childbearing potential by fulfilling one of the following criteria at screening:
  • Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments.
  • Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.
  • Patients known to have a malignancy (other than their malignant glioblastoma) that has required treatment in the last 12 months and/or is expected to require treatment in the next 12 months (except for non-melanoma skin cancer, carcinoma in situ in the cervix or ductal carcinoma in situ).
  • Major surgery within 4 weeks or incompletely healed surgical incision before starting therapy.
  • Patients known to be HIV-positive (testing is not required for entry on study) and on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD7451. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.

Trial Contact Information

Trial Lead Organizations/Sponsors

National Cancer Institute

Howard A Fine, M.D. Principal Investigator

 

Tracy Cropper, R.N. Ph: (301) 402-6298
  Email: tcropper@cc.nih.gov

 

Howard A Fine, M.D. Ph: (301) 402-6298
  Email: hfine@mail.nih.gov

 

Source: NCI

 

 

 

Intraoperative subcortical electrical mapping of optic radiations in awake surgery for glioma involving visual pathways.


Preservation of the visual field in glioma surgery, especially avoidance of hemianopia, is crucial for patients‘ quality of life, particularly for driving. Recent studies used tractography or cortical occipital stimulation to try to avoid visual deficit. However, optic radiations have not been directly mapped intraoperatively. The authors present, for the first time to their knowledge, a consecutive series of awake surgeries for cerebral glioma with intrasurgical identification and preservation of visual pathways using subcortical electrical mapping.

Methods

Fourteen patients underwent awake resection of a glioma (1 WHO Grade I, 11 WHO Grade II, 2 WHO Grade III) involving the optic radiations. The patients had no presurgical visual field deficit. Intraoperatively, a picture-naming task was used, with presentation of 2 objects situated diagonally on a screen divided into 4 quadrants. An image was presented in the quadrant to be saved and another image was presented in the opposite quadrant. Direct subcortical electrostimulation was repeatedly performed without the patient’s knowledge, until optic radiations were identified (transient visual disturbances). All patients underwent an objective visual field assessment 3 months after surgery.

Results

All patients experienced visual symptoms during stimulation. These disturbances led the authors to stop the tumor resection at that level. Postoperatively, only 1 patient had a permanent hemianopia, despite an expected quadrantanopia in 12 cases. The mean extent of resection was 93.6% (range 85%–100%).

Conclusions

Online identification of optic radiations by direct subcortical electrostimulation is a reliable and effective method to avoid permanent hemianopia in surgery for gliomas involving visual pathways.

Source: Journal Of Neurosurgery.

 

 

 

Cognitive functioning early after surgery of gliomas in eloquent areas.


Patients with gliomas frequently have cognitive deficits, and surgery can exacerbate these deficits. Preoperative assessment is therefore crucial in patients undergoing surgery for glioma in eloquent areas, because the proximity of functional areas increases the risk of permanent postoperative cognitive disturbances. Although pre- and postoperative language and motor function in patients with glioma have been investigated frequently, data on good cognition studies are scarce. Most studies have focused on clinical neurological functioning or have only used brief neurological instruments. The authors investigated whether surgery for glioma in eloquent areas influences cognition early after surgery, by using an elaborate test protocol.

Methods

Twenty-eight patients with gliomas of the left hemisphere in language and nonlanguage areas were assessed before and 3 months after surgery with a comprehensive neuropsychological test protocol. The authors performed a correlation analysis between change in cognitive performance and tumor characteristics (that is, location, volume, pathological features, and histological grade) and between cognitive change and treatment-related factors (the extent of the resection and postoperative treatment with chemo- and radiotherapy).

Results

Both pre- and postoperatively, the mean performance of the patients was worse than the performance of the normal population in the language domain, the memory domain, and the executive functions (p < 0.05). Postoperatively, a decline was found in the language domain (t = 2.34, p = 0.027) and in the executive functions (t = 2.45, p = 0.022). However, cognitive change postsurgery was influenced by the location of the tumor; the decrease of cognitive score in the language domain was only observed in patients with tumors in or close to language areas (t = 2.33, p = 0.029). No effect on cognitive change was found for the other tumor characteristics and treatment-related factors.

Conclusions

This study underlines the importance of the use of a neuropsychological test protocol before and after surgery in patients with glioma, because several tasks in the domains of language, memory, and executive functions appeared to deteriorate after surgery. Tumor resection in language areas increases the risk of cognitive deficits in the language domain postoperatively.

Source: Journal Of Neurosurgery.

 

Use of 11C-methionine PET parametric response map for monitoring WT1 immunotherapy response in recurrent malignant glioma.


Immunotherapy targeting the Wilms tumor 1 (WT1) gene product is a promising treatment modality for patients with malignant gliomas, and there have been reports of encouraging results. It has become clear, however, that Gd-enhanced MR imaging does not reflect prognosis, thereby necessitating a more robust imaging evaluation system for monitoring response to WT1 immunotherapy. To meet this demand, the authors performed a voxel-wise parametric response map (PRM) analysis of 11C-methionine PET (MET-PET) in WT1 immunotherapy and compared the data with the overall survival after initiation of WT1 immunotherapy (OSWT1).

Methods

Fourteen patients with recurrent malignant glioma were included in the study, and OSWT1 was compared with: 1) volume and length change in the contrast area of the tumor on Gd-enhanced MR images; 2) change in maximum uptake of 11C-methionine; and 3) a more detailed voxel-wise PRM analysis of MET-PET pre- and post-WT1 immunotherapy.

Results

The PRM analysis was able to identify the following 3 areas within the tumor core: 1) area with no change in 11C-methionine uptake pre- and posttreatment; 2) area with increased 11C-methionine uptake posttreatment (PRM+MET); and 3) area with decreased 11C-methionine uptake posttreatment. While the results of Gd-enhanced MR imaging volumetric and conventional MET-PET analysis did not correlate with OSWT1 (p = 0.270 for Gd-enhanced MR imaging length, p = 0.960 for Gd-enhanced MR imaging volume, and p = 0.110 for MET-PET), the percentage of PRM+MET area showed excellent correlation (p = 0.008) with OSWT1.

Conclusions

This study describes the limited value of Gd-enhanced MR imaging and highlights the potential of voxel-wise PRM analysis of MET-PET for monitoring treatment response in immunotherapy for malignant gliomas.

Source: Journal of Neurosurgery

 

 

Therapeutic effect of neural stem cells expressing TRAIL and bortezomib in mice with glioma xenografts


 

Treatment of glioblastoma remains a challenge in neuro-oncology. We investigated if treatment with neural stem cells engineered to express membrane-bound TRAIL (NSCs-mTRAIL) alone or in combination with proteasome inhibitors is a feasible therapeutic approach for experimental glioma. Glioma cells showed resistance to soluble TRAIL and proteasome inhibitors alone, but responded well to their combined treatment. In co-culture with NSCs-mTRAIL, glioma cells appeared to be more prone to apoptosis than to treatment with soluble TRAIL, which was enhanced by proteasome inhibitor bortezomib. In vivo, the survival of animals bearing intracranial glial xenografts was significantly improved by NSCs-mTRAIL. The addition of bortezomib further enhanced the efficacy of NSCs-TRAIL treated group in one of examined tumor models. These data demonstrate that therapy with NSCs-mTRAIL is a potent cell based approach for treatment of glioma. Such an approach warrants further search for therapeutics capable of increasing sensitivity of glioma cells to mTRAIL in vivo.

source: cancer letter