Phase III Immunotherapy Trial for Migraine Shows Positive Results

An antibody therapy against a key inflammatory molecule involved in migraines reduces the number of headaches that chronic migraine patients experience per month in a phase III trial.

A new study of fremanezumab, an immunotherapy that counteracts one of the molecules released during migraine, was found successful in reducing the number of days that chronic migraine sufferers experienced headaches. The results of the phase III clinical trial were published November 29, 2017 in the New England Journal of Medicine.

The World Health Organization estimates that between 127 and 300 million people around the world experience chronic migraine, defined as 15 or more headaches per month for at least three months. The disease can be debilitating and although a number of interventions exist, many only work for a certain time before they fail to prevent or relieve pain.

“This therapeutic approach offers new hope for people whose migraines cannot be treated with existing medicine,” says Stephen D. Silberstein, M.D., principal investigator of the HALO CM trial, Professor of Neurology and Director of the Jefferson Headache Center at the Vickie & Jack Farber Institute for Neuroscience at Thomas Jefferson University Hospital. “Our worldwide effort to evaluate this novel therapeutic approach has shown positive results and was safe in patients.”

Fremanezumab, a monoclonal antibody developed by Teva Pharmaceuticals, is a biological agent that binds to and blocks the action of a migraine-associated protein called calcitonin gene-related peptide (CGRP). Mounting evidence of its importance in migraines has made CGRP a focal point of research and drug development. The peptide is released at high levels during migraine in response to inflammation, and triggers a cascade effect that stimulates more CGRP release. This results in increasing sensitivity of the brain to pain. By blocking this peptide, doctors hope to break the cycle of increasing inflammation and increased pain sensitivity that contributes to migraine headaches.

Researchers from 132 sites across nine countries enrolled 1130 patients and randomly assigned them to one of three groups: one that received quarterly treatments, a group that received one treatment per month, and one that received placebo injections. The trial lasted for 16 weeks, with a 12-week treatment window.

The results of the trial show that treatment with fremanezumab reduced the number of days patients experience headache by an average of 4.3 days with quarterly treatment and 4.6 days with monthly treatment. “We saw some patients with 100 percent reduction in migraine, others with 75 percent reduction,” says Dr. Silberstein. The level of response varied between patients.

The researchers also looked at how well the therapy worked relative to each patient’s headache burden. They calculated the percent of patients who had more than a 50 percent reduction in the number of days they experienced either a severe or moderate headache per month. Using this measure, the researchers saw that 37.6 percent of patients on the monthly regimen, and 40.8 percent on the quarterly regimen had at least a 50 percent reduction in the number of moderate headaches per month, compared to 18.1 percent in the placebo group.

The therapy had a favorable safety profile with the most common adverse event reported as irritation at injection site, which was reported in the placebo group as well.

“If approved, this treatment would provide physicians with an important new tool to help prevent migraine, reduce a patient’s migraine load, and potentially help patients return to normal” says Dr. Silberstein.

Alectinib halts lung cancer growth more than a year longer than crizotinib

Findings from a phase III clinical trial point to a more effective initial treatment for patients with ALK-positive non-small cell lung cancer (NSCLC). Compared to the current standard of care crizotinib (Xalkori), the newer ALK inhibitor alectinib (Alecensa) halted cancer growth for a median of 15 months longer and caused fewer severe side effects.

The study was featured in a press briefing today and presented at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting.

“This is the first global study to compare alectinib with crizotinib in ALK-positive lung cancer and establishes alectinib as the new standard of care for initial treatment in this setting,” said lead study author Alice T. Shaw, MD, PhD, Director of Thoracic Oncology at Massachusetts General Hospital Cancer Center in Boston, MA. “Alectinib was especially beneficial in controlling and preventing brain metastases, which can have a major impact on patients’ quality of life.”

About 5% of NSCLCs are ALK-positive, meaning they have a genetic rearrangement where the ALK gene is fused with another gene. In the United States, about 12,500 people are diagnosed with ALK-positive NSCLC each year.

Crizotinib, the first medicine to specifically target ALK, was approved by the FDA in 2011. Although the majority of patients initially benefit from crizotinib, the cancer typically starts growing again within a year. Alectinib is a more potent, next-generation inhibitor of ALK. It was initially approved in 2015 for use in patients with advanced NSCLC that worsens despite crizotinib.

“The fact that this second-generation targeted treatment halted advanced lung cancer growth for more than two years while preventing brain metastases is a remarkable result in this difficult disease,” said ASCO Expert John Heymach, MD, PhD. “Thanks to this advance, we are on the road to helping these patients live longer and better.”

About the Study

In this open label clinical trial (ALEX), researchers randomly assigned 303 patients with stage IIIB or IV, ALK-positive NSCLC to receive alectinib or crizotinib. The patients had not received prior systemic therapy for advanced NSCLC.

Key Findings

Alectinib reduced the risk of cancer progression or death by 53% compared with crizotinib. Based on independent review, alectinib extended the median time to progression by about 15 months (median progression-free survival was 25.7 months with alectinib and 10.4 months with crizotinib).

“Nobody imagined it would be possible to delay advanced lung cancer progression by this much. Most targeted therapies for lung cancer are associated with a median progression-free survival of roughly 12 months,” said Dr. Shaw.

While both treatments cross the blood-brain barrier, alectinib was more effective in preventing brain metastases than crizotinib, because it can better penetrate into the brain. At 12 months, the incidence of brain metastases was much lower with alectinib than with crizotinib (9% vs. 41%).

Overall, severe side effects were less common with alectinib than with crizotinib, occurring in 41% vs. 50% of patients. The most common side effects of alectinib were fatigue, constipation, muscle aches, and swelling, whereas crizotinib caused gastrointestinal problems and liver enzyme abnormalities.

Next Steps

The researchers will continue to follow patients on this study to see if those treated with alectinib live longer than those treated with crizotinib. Meanwhile, several ongoing clinical trials are comparing other next-generation ALK inhibitors to crizotinib in the first-line setting.

Clinical Trial Results Marks a Significant Accomplishment for Medicortex Finland

Medicortex Finland Oy, a biotechnology company developing a diagnostic kit for brain injury detection based on a medical breakthrough biomarker, recently completed analyzing the results from the first clinical trial. Medicortex is working towards the validation of a Traumatic Brain Injury (TBI) biomarker and incorporating it into a quick and reliable diagnostic kit that can be easily used by the first responders and healthcare professionals, and by people with no medical profession.

The trial consisted of patients that were hospitalized due to a head injury.  Medicortex collected body fluid samples of 12 patients who had sustained a head injury, and analyzed the presence of the novel biomarker between the patients and healthy control subjects.

“The biodegradation product we are targeting has never been used for TBI indication. The fact that we can readily find it in easily accessible body fluids such as urine and saliva enables us to develop a user-friendly diagnostic kit for TBI detection”, says Dr. Adrian Harel, Chief Executive Officer of Medicortex Finland.

“Collecting and testing human samples in a clinical trial is a significant accomplishment for us, and represents a meaningful step forward in the development of a fast and inexpensive diagnostic kit for head injuries,” added Dr. Harel. “Brain injuries are devastating, leading to mortality if not diagnosed. The opportunity to develop the first portable non-invasive kit to detect head injuries and concussion is so desperately needed,” added Harel.

Dr. Marten Kvist, Medical Director of Medicortex, says “We are excited of the clinical results which confirm the diagnostic potential of the unique biomarker, it will be further developed into a diagnostic aid for first responders and paramedics, it will help prioritize evacuation and reframe from administration of contraindicated medications.”

The clinical trial was supported and funded in part by Tekes (the Finnish Funding Agency for Innovation). Medicortex is currently raising money for the next step clinical development of the brain injury test. The planned multicenter clinical study including up to 160 study subjects will prove the validity of the new biomarker test for TBI diagnostics.

The general public can help contribute in the development of MediCortex’s diagnostic kit via a crowdfunding campaign at  Medicortex is issuing shares with the goal of raising capital to match funds the firm has already applied via Tekes.

Medicortex Finland Oy ( is a biotechnology company dedicated to improving the diagnostics and treatment of Traumatic Brain Injury (TBI). Its current focus is to develop biomarker diagnostics that evaluate the extent and severity of TBI. Once the company completes this test its next goal will be to develop an innovative drug to halt the progression of brain injury.

Prostate Cancer Clinical Trial Shows Treating with Precision Radiotherapy Reduces Course of Treatment by 50%

An Ontario-led international clinical trial with 1,206 men with localized prostate cancer shows that compressing radiation treatments into four weeks from eight delivers similar outcomes.

The findings, published online today in the Journal of Clinical Oncology, provide a new standard of care worldwide, which the participating centres have already adopted, says co-principal investigator Charles Catton, radiation oncologist, Princess Margaret Cancer Centre, University Health Network. Dr. Catton is also a Professor, Department of Radiation Oncology, University of Toronto.

“We conducted a randomized clinical trial looking at a way of improving radiation therapy for men with intermediate-risk prostate cancer. Using modern radiation therapy techniques that are very precise, we determined there was no noticeable difference between eight- and four-week treatment regimens in terms of cancer control or side effects of treatment,” says Dr. Catton. The trial participants were followed for six years.

“In fact, for some men, the shorter regimen meant slightly fewer side effects (particularly regarding bowel function) and therefore improved quality of life. The compressed course of treatment is of great benefit to patients and also to the system in terms of being able to treat more patients in less time,” he says. In Canada, 20,000 men are diagnosed with prostate cancer every year; many of whom have intermediate-risk disease that has not spread.

The trial was conducted with co-principal investigator Himu Lukka, radiation oncologist, Juravinski Cancer Centre, and Professor, Department of Oncology, McMaster University, and coordinated by the Ontario Clinical Oncology Group, Hamilton, Ontario. Twenty-seven cancer centres in Canada, Australia and France participated in the study, which began in 2005.

Dr. Catton says the trial further improved patient care by standardizing quality delivery of precision radiation techniques among participating institutions.

The research was funded by the Canadian Institutes for Health Research and The Princess Margaret Cancer Foundation.

New Clinical Trial Combines Two Methods to Defeat Ovarian Cancer

New clinical trial offers combination therapy to directly kill cancer cells and teach the immune system to keep them from coming back.

Fewer than half of women diagnosed with ovarian cancer live for five years or more. Sarah Adams, MD, hopes her new clinical trial will change this outcome. Adams recently opened a clinical trial at The University of New Mexico Comprehensive Cancer Center to test a new approach to defeat ovarian cancer. The clinical trial treats women whose ovarian cancer results from mutated BRCA genes. It uses one drug that kills the ovarian cancer cells and another that boosts the immune system in response to the dying cancer cells.

Ovarian cancer has unclear symptoms and no screening tests that catch it in its early stages. Often, ovarian cancer spreads to other organs before a woman even knows she has it. Surgery and chemotherapy can help women at the beginning of their treatment, and this gave Adams the idea for her new approach.

As a gynecologic oncologist, Adams performs surgery and prescribes chemotherapy for women with cancers of the female reproductive organs. Adams also conducts research. Her research suggested that women with BRCA-related ovarian cancer responded better to some chemotherapy drugs. Others’ research showed that other chemotherapy drugs not only kill cancer cells but also make the immune system more sensitive to them. Adams’ new treatment combines these approaches into what she thinks may be a powerful way to win against ovarian cancer.

BRCA is a set of genes we all carry. Each gene contains the instructions to produce a protein. BRCA proteins help DNA to repair itself when both of its strands break and completely split the molecule in two. If the BRCA genes are mutated, or changed, the resulting proteins do not work properly and the cell cannot repair its DNA. It dies unless it can resort to other repair methods.

Cells with mutated BRCA genes resort to using a DNA-repair protein called PARP. Adams’ therapy uses a type of drug called a PARP inhibitor, which keeps the PARP protein from its repair work. “If you knock out BRCA,” says Adams, “the cell can still live. If you knock out PARP, the cell can still live. But if you knock out both, the cell dies.”

The PARP inhibitor does not affect non-cancerous cells because they have working BRCA proteins to repair DNA. “It’s specific to cancer cells so it’s nicely targeted and there’s minimal toxicity,” says Adams. The therapy is also easy to dispense. “It’s a pill that people take orally,” she says.

Adams’ therapy combines the PARP inhibitor with a specific antibody. An antibody is a protein that attaches to a target cell. The antibody in Adams’ therapy helps one type of immune cell, called a T-cell, to find and devour ovarian tumor cells. Untreated ovarian tumors often produce chemical signals that keep T-cells away. But, the PAPR inhibitor combined with the antibody alert the entire immune system to the ovarian cancer cells.

Once the immune system can find the ovarian cancer cells, it can rid the body of them if the PARP inhibitor doesn’t kill them first. And because the immune system can remember how to respond to ovarian cancer cells, it can continue to rid the body of them if the cancer tries to come back. Adams hopes that this effect will give women long-lasting protection.

The clinical trial is currently open to women with BRCA1 or BRCA2 mutations. Either parent can pass these BRCA mutations to their children. People with BRCA mutations have a higher risk of getting breast and ovarian cancers and may have relatives who had these cancers at young ages.

In pre-clinical studies, this combination therapy got rid of tumors and helped mice to live longer. The clinical trial now makes the therapy available to women with BRCA gene mutations whose ovarian cancer has returned. “I’m very excited about the results we’ve seen so far,” says Adams, “and hopeful that this regimen can achieve long-term benefit for women with ovarian cancer.” Adams’s ultimate goal is to expand the therapy to help all women with ovarian cancer.

New Trial Hopes to Increase Survival for Kids With Cancer, Reduce Risk of Long Term Cardiac Damage

Imagine conquering childhood cancer, only to find out that years down the road your heart may fail. Unfortunately, many children who have battled cancer face this reality. While often lifesaving, the effects of chemotherapy treatment (drugs that kill cancer cells) can take a toll on the developing body of a child, potentially resulting in life-threatening late side effects like cardiac damage.

“You go through terrible chemotherapy, achieve remission, have a new lease on life and then your heart fails,” said Dr. Todd Cooper, director of the Pediatric Leukemia/Lymphoma Program and Evans Family Endowed Chair in Pediatric Cancer at Seattle Children’s. “It’s not fair, and we’re determined to change this reality.”

Cooper is leading a new nationwide clinical trial, conducted within the Children’s Oncology Group (COG), for children and adolescents with relapsed acute myelogenous leukemia (AML) to test a drug, CPX-351, which has been designed to kill leukemia cells while minimizing damage to the heart. According to Cooper, up to 30% of patients who undergo chemotherapy for AML will have late term side effects that affect the heart. For Cooper, that’s 30% too many.

AML is an aggressive type of cancer that affects the bone marrow and blood. AML can be difficult to treat and requires intensive chemotherapy and often bone marrow transplantation.

Cooper says previous trials testing the effectiveness and efficacy of CPX-351 have shown tremendous promise in adults, and so he’s hoping to bring that same success to pediatric patients.

Bringing hope to children with acute myelogenous leukemia
Because AML is difficult to treat, standard treatment commonly involves multiple chemotherapy medicines that are given at a higher dose in order to kill the cancer cells.

“The chemotherapy tends to be very intensive,” said Cooper. “Some of the most effective medicines work really well against leukemia, but the side effects, including damage to the heart, can be severe.”

CPX-351 delivers chemotherapy in a different way than standard chemotherapy. The medicines are contained in a liposomal formulation which is thought to be safer for the heart. The liposome is used as a vehicle to transport the drugs into the body and into leukemia cells in the bone marrow. We hope that by being housed inside the liposome, that less of the chemotherapy will be deposited into the heart.

In phase 3 trials for adults with high-risk, secondary AML, there was a statistically significant improvement in overall survival compared to patients who received a regimen using chemotherapy drugs delivered in the standard way. The use of CPX-351 reduced the risk of death by 31% compared to the use of the chemotherapy drugs cytarabine and daunorubicin.

“This trial not only offers hope for more children to be cured, but for more children to live longer, leading more productive lives without late term cardiac damage,” said Cooper. “I am thrilled to bring this therapy to children through the trial because I want kids to have access as soon as possible to these potentially lifesaving drugs.”

Although results from the trial will not be completed for a couple of years, Cooper is optimistic CPX-351 will improve outcomes for children with relapsed AML and may one day become a frontline treatment.

Drug Combination Therapy For Estrogen-Receptor–Positive Breast Cancer Passes Critical Step For Worldwide Approval

Building on earlier clinical trials, UCLA researchers have confirmed that the “breakthrough” drug palbociclib when used in combination with the traditional hormonal therapy letrozole delays progression of advanced breast cancer significantly and without the harsh side effects seen in some women prescribed letrozole alone.

The study, published online in the New England Journal of Medicine, is the phase 3 study following phase 1 and phase 2 clinical trials that led to the U.S. Food and Drug Administration approval of palbociclib in early 2015. Palbociclib was also approved in Europe for the first time earlier this month based on these results. In 2013, after women in a clinical study led by UCLA researchers showed a dramatic improvement, the FDA granted palbociclib “breakthrough therapy” status, allowing it to be fast-tracked for approval.

The drug combination is the first and only treatment for women with estrogen-receptor–positive breast cancer to show such significant results in a randomized phase 3 trial. Dr. Richard Finn and Dr. Dennis Slamon of the UCLA Jonsson Comprehensive Cancer Center led the laboratory studies and previous trials and are co-authors of the study.

“These results are a truly meaningful advancement for women in this patient population,” said Finn, who is also an associate professor of medicine in the David Geffen School of Medicine at UCLA. “The results of the phase 3 study will support the full approval of palbociclib in the United States and around the world.”

Palbociclib (marketed as IBRANCE by Pfizer, Inc.) is known as the first new drug that in combination with hormonal therapy has proven to be very effective in post-menopausal women with estrogen receptor-positive breast cancer. The ER+/HER2- subgroup represents the largest proportion of breast cancer cases and is traditionally treated with therapies, like tamoxifen or letrozole, that target the hormone receptor pathway. Palbociclib, which was developed by Pfizer Inc., prevents cells from dividing by targeting a key family of proteins (CDK4/6) responsible for cell growth.

Led by Finn and Slamon, an international team of investigators from 17 countries analyzed 666 women with advanced ER+/HER2- breast cancer. The people were treated with a combination of palbociclib and letrozole and had not received prior systemic therapy for their cancer. The results of the new study confirmed the previous findings of the multi-year phase 1 and phase 2 trials, which showed a significant increase in the time it took the cancer to progress compared to letrozole alone.

The phase 2 trial also demonstrated that survival without side effects nearly doubled—20.2 months for women who received palbociclib plus letrozole compared to 10.2 months in patients who received letrozole alone—representing a 42 percent reduction in the risk of disease progression. The new phase 3 trial further confirmed these findings.

“The results from both studies are really remarkable for the degree of benefit they provide in slowing the growth of estrogen-receptor positive breast cancer,” said Slamon, director of the Revlon/UCLA Women’s Cancer Research Program and director of clinical and translational research at the Jonsson Cancer Center. “The drug combination is very well tolerated and without the side effects of traditional chemotherapy, such as infections, nausea and significant hair loss.”

Palbociclib is the first CDK 4/6 treatment to be approved for cancer treatment and provides proof of concept that targeting this pathway is important for the treatment of women with ER+ breast cancer. The researchers said the phase 3 findings will open the door to further studies in breast cancer and other diseases.

High-Impact Clinical Trials Yield Results That Could Improve Kidney Care

The results of numerous high-impact clinical trials that could affect kidney-related medical care will be presented at ASN Kidney Week 2016, November 15–20 at McCormick Place in Chicago, IL.

• In the Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial, 9340 patients with type 2 diabetes and high cardiovascular risk were randomized liraglutide (a long-acting glucagon-like peptide-1 analog) or placebo. Over a median follow-up of 3.84 years, a composite outcome of kidney dysfunction or death due to kidney disease occurred in fewer participants treated with liraglutide (268 of 4668) than with placebo (337 of 4672), translating to a 21% reduced risk. “Liraglutide in addition to standard of care therapy reduced the progression of diabetic nephropathy,” the study’s investigators concluded.
Liraglutide and Renal Outcomes in Type 2 Diabetes: Results of the LEADER Trial

• In a trial that involved 406 adult live donor/recipient kidney transplant pairs, remote ischemic preconditioning (RIPC), a safe and virtually cost-free intervention, resulted in sustained improvement in kidney function after transplantation, reaching 13% by 5 years. “Given the resultant clinical, economic, and quality of life implications, we recommend that RIPC is adopted into routine care for these patients,” stated the trial’s investigators. The intervention involves reducing blood flow in both the donor and recipient as a preconditioning step before surgery, which can involve more significant and prolonged blood flow reductions. A blood pressure cuff placed on the upper arm that is inflated for short periods of time activates a reflex that makes internal organs more resistant to the harmful effects of low blood flow that occurs during transplantation.
Remote ischaemic preconditioning (RIPC) leads to sustained improvement in allograft function following live donor (LD) kidney transplantation: 5 year follow up in the REnal Protection Against Ischaemia Reperfusion in transplantation (REPAIR) study

• A study that randomized 615 kidney transplant recipients to receive either basiliximab induction with low dose tacrolimus, mycophenolate mofetil, and steroid maintenance therapy (arm A), or rapid corticosteroid withdrawal on day 8 (arm B), or rapid corticosteroid withdrawal on day 8 following rabbit antithymocyte globulin (ATG) instead of basiliximab (arm C), rejections at 12 months were similar in all groups (11.2%, 10.6%, and 9.9%, respectively). As a secondary endpoint, rapid steroid withdrawal reduced posttransplantation diabetes in arm B to 23.9% and in arm C to 22.7% compared with standard arm A with 39.2%. “Rabbit ATG failed to show superiority over basiliximab induction for the prevention of biopsy proven acute rejections after rapid steroid withdrawal within one year after renal transplantation. Nevertheless, rapid steroid withdrawal after induction therapy for patients with a low immunologic risk profile can be achieved without any loss of efficacy and is highly advantageous in regard to posttransplantation diabetes mellitus incidence,” the researchers wrote. Rabbit ATG, an infusion of rabbit-derived antibodies against human T cells, is used in the prevention and treatment of acute rejection in organ transplantation. Basiliximab is a monoclonal antibody that is an interleukin-2 receptor antagonist.
Rabbit-ATG or Basiliximab Induction for Rapid Steroid Withdrawal after Renal Transplantation: an Open-label, Multicentre, Randomized Controlled Trial

• In a trial of 99 individuals on hemodialysis, lower sodium levels in patients’ dialysate solutions did not effectively reduce their left ventricular mass, an indicator of heart health. Enlarged left ventricles, or left ventricular hypertrophy, contributes to premature cardiovascular mortality in dialysis patients. Other studies have shown benefits (such as reduced blood pressure) to lowering dialysate sodium concentrations.
The Sodium Lowering In Dialysate (SoLID) Trial: a Randomised Controlled Trial of Low Versus Standard Dialysate Sodium Concentration (DNa) During Hemodialysis (HD) for Regression of Left Ventricular (LV) Mass

• In a trial of 265 patients with lupus nephritis, 32.6% of patients receiving low dose voclosporin and 27.3% of patients receiving high dose voclosporin achieved complete remission at 24 weeks, compared with 19.3% of patients receiving placebo. Also, partial remissions were more common in patients receiving either low or high dose voclosporin than in those receiving placebo. Side effects were higher in the patients treated with voclosporin, consistent with increased immunosuppression. “These favorable data will help plan subsequent studies of voclosporin in lupus nephritis,” the study’s investigators wrote. Voclosporin is a novel calcineurin inhibitor, a type of immunosuppressant.
AURA-LV: Successful treatment of active lupus nephritis with Voclosporin

• In the phase 2 DUET trial that included 96 patients with focal segmental glomerulosclerosis (FSGS), which is characterized by scarring of the kidneys, sparsentan, a dual angiotensin II (Ang II) and endothelin type A receptor antagonist, reduced urinary protein excretion to a greater extent than blockade of Ang II alone. “In accord with prior studies in essential hypertension, sparsentan appears to be safe and well tolerated in patients with FSGS,” noted the study’s investigators.

Genetic Profiling Increases Cancer Treatment Options, Sanford Study Finds

Genetic profiling of cancer tumors provides new avenues for treatment of the disease, according to a study conducted by Sanford Health and recognized by the American Society of Clinical Oncology.

In 2014, Sanford developed and launched the Genetic Exploration of the Molecular Basis of Malignancy in Adults, or GEMMA, to determine if evaluating genetic information could help customize treatment options for adult patients whose cancer had progressed after the first line of treatment or was too rare for standard treatment. DNA was extracted from tumor samples and tested to identify targets for treatment.

Oncologist and cancer researcher Steven Powell, M.D., and his team used next-generation gene sequencing technology to analyze tumor samples for more than 100 patients. More than 90 percent of those patients had gene mutations that could impact their treatment, Powell reported. Some patients, for example, discovered they were eligible for a clinical trial or might benefit from other personalized medicine therapies. Nearly 40 percent of these patients were able to be treated with personalized therapies as a result of their testing. Many were treated on clinical trials with new drugs that previously would not have been available to them in this region.

“Molecular profiling programs like GEMMA don’t typically experience this degree of success,” said Powell. “Sixteen percent of our patients were able to go on clinical trials matching them to a personalized therapy; many academic centers are only able to do this five percent of the time. Our numbers indicate that the development of a molecular profiling program in a community setting in the Midwest is not only feasible but effective in getting patients access to the newest treatments.”

Enrollment concluded in late 2015, and results of GEMMA were outlined in an abstract published in conjunction with this year’s American Society of Clinical Oncology Annual Meeting held in Chicago last month. The published abstract can be found on the ASCO website.

Later this year, Sanford will begin the second version of GEMMA, which will integrate molecular profiling as part of standard cancer care. The study is called Community Oncology Use of Molecular Profiling to Personalize the Approach to Specialized Cancer Treatment at Sanford, or COMPASS. Sanford experts will analyze treatment plans based on molecular profiling to determine if outcomes improve. As part of GEMMA and COMPASS, the Sanford team has brought in more than 60 different personalized therapy options for patients through clinical trials in the past two years.

Novel Combination Therapy Developed at VCU Massey Cancer Center Shows Strong Response in Patients with Advanced Solid Tumors

A phase 1 clinical trial testing a novel combination therapy developed by scientists at VCU Massey Cancer Center slowed the growth of cancer in the majority of trial participants, which were patients with advanced solid tumors. Approximately 61 percent of these patients experienced some degree of tumor growth delay, with multiple partial responses and one complete response. A phase 2 study testing the same combination of the drugs sorafenib and pemetrexed in patients with recurrent or metastatic triple negative breast cancer is now open at Massey.

“Though phase 1 studies are designed to evaluate the safety of a new therapy, we had strong preclinical evidence suggesting this novel drug combination could work against a variety of cancers, so we hoped that we would see a response in our patients in this early phase trial,” said Andrew Poklepovic, M.D., lead investigator on the study. “With this trial, we established a safe dosing schedule, and we will now be testing the efficacy of the therapy in the phase 2 study.”

The results of the clinical trial were recently published online by the journal Oncotarget (PMID: 27213589). The study enrolled 37 patients between October 2011 and December 2014. Of those patients, 36 received treatment and 33 were evaluated for response. One patient had a complete response, meaning all detectable traces of the tumor disappeared, while four patients had a partial response, which means that the tumor volume shrank by at least 30 percent. The therapy stabilized disease progression in an additional 15 patients, with some of these patients responding for up to a year. The therapy was found to be particularly active in breast cancer patients.

“Some dose-limiting toxicities associated with pemetrexed were observed in one cohort of patients, but those who were eligible were switched to the dosing schedule of the second cohort, which was found to safe and tolerable,” says Poklepovic, medical oncologist and member of the Developmental Therapeutics research program at Massey as well as assistant professor in the Division of Hematology, Oncology and Palliative Care at the VCU School of Medicine.

The trial is based on pre-clinical research conducted by a team of Massey scientists led by Paul Dent, Ph.D., who is the Universal Corporation Chair in Cancer Cell Signaling and a member of the Cancer Cell Signaling research program at Massey, and Richard Moran, Ph.D., who recently retired after 22 years at Massey and more than four decades in the field. Pemetrexed was co-developed by Moran, and is now a first-line therapy for non-small cell lung cancer (NSCLC) and mesothelioma. Sorafenib is used to treat liver, kidney and thyroid cancer. In 2011, a research team led by Dent and including Moran discovered that the two drugs synergize to induce profound killing of cancer cells through a toxic form of autophagy, a process that normally re-cycles components of cells to provide energy for maintaining cell growth and survival. The drug combination hyper-activated the autophagy process within cancer cells, causing them to literally eat themselves to death (PMID: 21622715).

The phase 2 study is not the only continuation of the research. Because the initial results of the phase 1 study were so promising, Dent started a new project to discover the best “third drug” that could act to further enhance the anti-cancer properties of the pemetrexed and sorafenib combination. This work has also recently been published in Oncotarget, and it showed that the combination therapy could be enhanced by a class of drugs known as ERBB1/2/4 inhibitors (PMID: 27015562).

“We discovered in mouse models of breast cancer that the drugs lapatinib and vandetanib significantly enhanced the anti-tumor effect of the pemetrexed and sorafenib therapy without any apparent toxicity to normal tissue. We made a nearly identical observation when adding the drug afatinib in experiments involving non-small cell lung cancer,” says Dent. “Based on this data, we will be submitting a grant application to the National Cancer Institute for funding that will hopefully provide data that could allow us to open a future phase 1 trial testing the addition of an ERBB1/2/4 inhibitor to pemetrexed and sorafenib in patients with advanced solid tumors.”

Dent was able to determine that ERBB1/2/4 inhibitors could increase the effectiveness of the combination therapy by using a novel technology called a multiplex assay. The multiplex assay is a broad, unbiased screening approach that allows researchers to simultaneously examine the levels of multiple hormones in the blood and determine the activities of enzymes in cancer cells. Using this technology, the researchers discovered that the enzyme ERBB1 was activated in response to the pemetrexed and sorafenib therapy.

“Unlike alternative methods where a certain degree of guesswork is required, the multiplex assay allowed us to observe exactly how the cancer cells responded to therapy,” says Dent. “We were surprised to see that the enzyme ERBB1 was activated because it is ordinarily thought to protect cancer cells from chemotherapy. We went on to successfully use ERBB1/2/4 inhibitors as our third drug because of this unexpected data.”

The multiplex assay provided Dent’s team with such invaluable additional information about how the sorafenib and pemetrexed combination worked in the mouse models that they will now be using the assay in several of their clinical trials moving forward, including the new phase 2 trial of pemetrexed and sorafenib.

“The multiplex assay will allow us to track specific levels of hormones in the blood as patients undergo treatment, which could potentially give us a molecular ‘fingerprint’ of the point at which tumors develop resistance to the therapy,” says Dent. “Ongoing preclinical experiments show that it could be possible to pinpoint exactly how the cancer cells are developing resistance to therapies, which might eventually allow oncologists to develop in real time a personalized therapy designed to overcome drug resistance in an individual patient’s tumor.”

Despite Pressing Need, Survey Finds Most Americans Unlikely to Enroll in Clinical Trials

The lack of participation in clinical research may be the Achilles’ heel of today’s cancer community. According to a new survey of more than 1,500 consumers and nearly 600 physicians conducted on behalf of Memorial Sloan Kettering Cancer Center (MSK), only 35 percent of Americans indicated that they were “likely” to enroll in a clinical trial. Other studies have shown that only 4 percent of cancer patients enroll in clinical trials nationally each year.

Additionally, the new data shows that only 40 percent of Americans have a positive overall impression of clinical trials. Taken together, these statistics are sobering given that nearly every advance in cancer today was first evaluated in a clinical trial. Clinical research is increasingly dependent upon larger numbers of cancer patients participating. Fortunately, education makes a measurable and immediate difference. After reading a brief statement defining clinical trials, the number of respondents who had a positive impression of these studies jumped significantly, from 40 to 60 percent.

“When it comes to advancing cancer care, clinical research is the rocket fuel for better treatments, more accurate diagnoses, and, ultimately, cures,” said José Baselga, MD, PhD, Physician-in-Chief and Chief Medical Officer at MSK, where more than 900 cancer clinical trials are currently under way. “If this trend of low enrollment continues, we will face a crisis in cancer research and discovery. Further education is the key to participation and progress.”

Consumer respondents cited a range of concerns as barriers to clinical trial participation:

• Worry over side effects / safety (55 percent)
• Uncertainty about insurance and out-of-pocket costs (50 percent)
• Inconvenience of trial locations (48 percent)
• Concerns about getting a placebo (46 percent)
• Skeptical of a treatment that is not yet proven to work (35 percent)
• Worries over feeling like “guinea pigs” (34 percent)

Physicians were also asked about what they feel are the top barriers to patient participation. Their responses echoed consumer feedback, with side effect / safety worries and concerns about getting a placebo cited the most (both at 63 percent); even more physicians than consumers (53 percent) expressed concern that individuals would not want to feel like “guinea pigs.”

“While concerns regarding clinical trials are understandable, it is critical that the cancer community address common myths and misunderstandings around issues like effectiveness, safety, use of placebo, and at which point in treatment a trial should be considered,” said Paul Sabbatini, MD, Deputy Physician-in-Chief for Clinical Research at MSK. “For example, the vast majority of clinical trials do not involve a placebo.”

Viewed as a Last Resort by American Physicians

The survey also polled nearly 600 physicians around the country. While many clinical trials are available to patients during the earliest phases of treatment, 56 percent of physicians said they considered clinical trials late in treatment, with 28 percent saying they consider them “as a treatment of last resort.” Only one-third (32 percent) said they discuss the topic with their patients at the beginning of treatment.

“Failing to consider clinical trials at every stage of cancer diagnosis and treatment can represent a significant missed opportunity, primarily for patients, as well as for doctors and researchers trying to develop better therapies,” said Dr. Sabbatini. “It’s critical that we spread the word: Clinical trials offer our best thinking toward finding better ways to prevent, treat, and cure cancer, and there are options for patients and their families to consider early on in treatment.”

Hospital Choice and Access to Novel Cancer Treatments  

Most consumers (72 percent) see no difference in care between hospitals that offer clinical trials and those that do not. Yet when considering a hospital for cancer care, almost three out of four consumers (74 percent) indicate it is important that a wide variety of clinical trials are offered.

“When faced with cancer, patients want to know they have multiple options available to them, and this includes clinical trials,” said Dr. Sabbatini. “For example, participating in a clinical trial at a place  like Memorial Sloan Kettering offers patients the opportunity to receive drugs or therapies years before they are more widely available.”


MaPS / Millward Brown Analytics conducted a national survey on behalf of MSK among 1,511 consumers, ages 18 to 69, and 594 practicing physicians who have discussed clinical trials with patients, specializing in oncology/hematology, OB / GYN, gastroenterology, urology, ear / nose / throat medicine, neurology, pulmonology, or dermatology. The survey was conducted between October 23, 2015, and November 12, 2015.