TGen, Barrow, Ivy, Karmanos ‘Phase 0’ studies evaluate if drugs can reach cancer in the brain
Brain tumor experts at Barrow Neurological Institute at Dignity Health St. Joseph’s Hospital and Medical Center have launched a revolutionary fast-track approach to cancer research, giving new hope to brain cancer patients. In partnership with The Ben & Catherine Ivy Foundation, the Translational Genomics Research Institute (TGen) and the Barbara Ann Karmanos Cancer Institute, the Barrow studies are the first of their kind.
Called “Phase 0 Trials,” these early-phase clinical trials shorten the evaluation of drug therapies from an average of five years to only six months at a fraction of the cost.
During each single-patient trial, participants are administered an experimental drug already proven to be safe in other types of cancer. Within hours, Barrow neurosurgeons remove the brain tumor and within weeks it is determined if the experimental drug penetrated the tumor and whether it is having a positive effect on the tumor. If the drug reaches the tumor and shows activity, it moves into a Phase 2 clinical trial for patients. If it does not prove to be effective, the patient has the option to enter another study.
“Brain tumors are among the deadliest of all cancers and during the last 30 years, little progress has been made on successful treatments to increase life expectancy,” says Dr. Nader Sanai, Director of the Barrow Brain Tumor Research Center. “This Phase 0 approach for malignant brain tumors is a game changer in cancer research and our program is the first of its kind in the world.”
These studies are called Phase 0 clinical trials because they occur outside of the three lengthy phases that evaluate a drug’s safety, effectiveness, side effects and dosage. After years of research and millions of dollars, the vast majority of experimental drugs for brain tumors have proven ineffectual and never brought to market.
One of the major difficulties in treating brain tumors is finding drugs that can penetrate the blood-brain barrier, which buffers the brain from the rest of the body’s blood-circulatory system. Located along capillaries, the blood-brain barrier protects the brain from rapid changes in the body’s metabolic conditions and minimizes exposure to molecules that are toxic to neurons in the brain.
“The main question answered by these Phase 0 clinical trials is this: Does the drug get to the tumor?” said Dr. Michael Berens, TGen Deputy Director for Research Resources. “Next, we look at how much of the drug is enough, and if there are any signs of patient benefit.”
TGen is using its world-class expertise in genomic sequencing to analyze brain tumor samples and help determine which drugs might work best.
“Because of what is known about how each drug works, we think there are certain genetic mutations that would make certain patients more responsive to the drug,” said Dr. Berens, who also is Director of TGen’s Cancer and Cell Biology Division and TGen’s Glioma Research Lab.
Karmanos is analyzing samples of the resected brain tumors, following surgery, to determine how much of the drug accumulated in the tumor, and what effect, if any, the drugs have on the cancer.
Phase 0 trials were recently introduced by the FDA and have never before been widely used for brain tumor patients. This is the first non-governmental study coalition to push forward with these trials, an initiative that has drawn interest from some of the world’s largest cancer therapy developers. The first of these Phase 0 clinical trials was made possible largely through a generous grant by The Ben & Catherine Ivy Foundation.
“The absence of truly effective drugs for brain tumors is one of the medical community’s most critical unmet needs,” says Catherine Ivy, President of The Ben & Catherine Ivy Foundation. “These Phase 0 clinical trials are part of a much larger research strategy funded by the Ivy Foundation to address this need and give new hope to brain tumor patients worldwide.”
Dr. Sanai believes the trials will provide encouragement to brain tumor patients, who often feel abandoned.
“Because of the high cost of developing and testing drugs, there is very little in the pharmaceutical pipeline that has reached brain tumor patients,” says Dr. Sanai. “It has just been too expensive for drug companies to develop new therapies for the relatively small number of brain cancer patients. These Phase 0 trials can be the answer. They are safe, cost effective and quick to give us an answer. If a new drug doesn’t work, we move to the next one without the patient losing any time. For the first time, I can tell every brain tumor patient, ‘I have something new for you’.”
Eliminating ‘stroma’ could enable anti-cancer drugs to penetrated tumor tissues; extend patient survival
Like a stealth jet cloaks itself from radar, cancer cells cloak themselves within tumors by hiding behind a dense layer of cellular material known as stroma.
According to a new study by the Translational Genomics Research Institute (TGen), drugs that target and strip away the stroma would pave the way for drugs to reach the cancerous cells within the tumor, which could have a beneficial effect on the survival of pancreatic cancer patients.
Targeting stroma could potentially extend patient survival even among those with advanced stage cancer that has spread to other organs, said the TGen study in the journal Clinical Cancer Research, published online Feb. 18 by the American Association for Cancer Research. AACR is the world’s largest cancer research organization, representing more than 35,000 investigators.
The accumulation of stroma — the supporting connective tissue that includes hyaluronan and several types of collagen — prevents therapeutic anti-cancer drugs from reaching and destroying cancer cells, the study said, not only in the primary tumors in the pancreas but also in metastatic lesions when the cancer spreads to distant organs such as liver and lung.
“If we can target and reduce stroma, new cancer therapeutics could prove more effective and patients could experience longer survival,” said Dr. Haiyong Han, a TGen Associate Professor, head of TGen’s pancreatic cancer research unit, and the study’s senior author.
In what is believe to be the first study of its kind, the TGen paper found that metastatic lesions can have the same high level of stromal content as the primary tumors in the pancreas. And, significantly, these high levels of stroma correlate with poor patient survival.
The study examined the stromal content of primary tumors and metastatic lesions from among 50 patients with pancreatic ductal adenocarcinoma, which represents about 95 percent of all pancreatic cancer.
Among patients with low hyaluronan in their primary tumors, median survival was 24.3 months, compared to only 9.3 months for patients with high levels of hyaluronan. Likewise, among patients with low collagen in their primary tumors, median survival was 14.6 months, compared to only 6.4 months for patients with high levels of collagen.
The pancreas is an organ behind the stomach that produces digestive juices and several key hormones. This year, nearly 49,000 Americans will be diagnosed with pancreatic cancer, and more than 40,000 will die from this disease, making it the fourth leading cause of cancer-related death in the U.S.
Median survival for patients with advanced disease is less than 6 months following diagnosis, and the 5-year survival rate is less than 6 percent for all patients.
Pancreatic cancer’s lethal nature stems from its propensity to rapidly spread to distant organs. Because there is no early screening test, it usually is not diagnosed until its late stages, often when surgery is no longer an option, making it difficult to treat.
The TGen study shows by targeting and eliminating the stroma surrounding the cancer cells, anti-cancer drugs — as well as immunologic approaches — should be more effective not only within the pancreas, but also more effective on tumors throughout the body where the cancer may have spread.
“We are hopeful that in the future new therapeutics that target stroma will have a significant benefit for our patients, and lead to better outcomes,” said Dr. Daniel D. Von Hoff, TGen’s Distinguished Professor and Physician-In-Chief, and an author of the study. The TGen study — Desmoplasia in primary tumors and metastatic lesions of pancreatic cancer — was supported in part by R01 (CA169281) and U01 (CA128454) grants from the National Cancer Institute, a branch of the National Institutes of Health; in part by a Stand Up to Cancer (SU2C) Translational Research Grant, a Program of the Entertainment Industry Foundation administered by the American Association for Cancer Research (SUC2-AACR-DT0509); and by financial contributions from the Katz Family Foundation; and by a grant from the National Foundation for Cancer Research (NFCR).