publication date: Jun. 26, 2020

Clinical Roundup

FDA pilot program to communicate patient reported outcomes from cancer clinical trials

FDA has launched Project Patient Voice, an initiative of the FDA’s Oncology Center of Excellence that aims to communicate patient-reported outcomes from cancer clinical trials, making them more accessible to the public.

Through a new website, Project Patient Voice creates a consistent source of publicly available information describing patient-reported symptoms from cancer trials for marketed treatments. While this patient-reported data has historically been analyzed by FDA during the drug approval process, it is rarely included in product labeling and, therefore, is largely inaccessible to the public.

“Project Patient Voice has been initiated by the Oncology Center of Excellence to give patients and healthcare professionals unique information on symptomatic side effects to better inform their treatment choices,” FDA Principal Deputy Commissioner Amy Abernethy, said in a statement. “The Project Patient Voice pilot is a significant step in advancing a patient-centered approach to oncology drug development. Where patient-reported symptom information is collected rigorously, this information should be readily available to patients.”

Patient-reported data can provide additional, complementary information for healthcare professionals to discuss with patients, specifically when discussing the potential side effects of a particular cancer treatment. In contrast to the clinician-reported safety data in product labeling, the data in Project Patient Voice is obtained directly from patients and can show symptoms before treatment starts and at multiple time points while receiving cancer treatment.

The Project Patient Voice website will include a list of cancer clinical trials that have available patient-reported symptom data. Each trial will include a table of the patient-reported symptoms collected. Each patient-reported symptom can be selected to display a series of bar and pie charts describing the patient-reported symptom at baseline (before treatment starts) and over the first 6 months of treatment. This information provides insights into side effects not currently available in standard FDA safety tables, including existing symptoms before the start of treatment, symptoms over time, and the subset of patients who did not have a particular symptom prior to starting treatment.

In the first phase of this pilot website, only one trial will be included while the FDA seeks public feedback on how the information is presented. The FDA will use this feedback to consider improvements to the website in order to make the information as user-friendly as possible.

The visualizations and data included on the website are voluntarily provided by the drug companies that conducted the clinical trials. AstraZeneca is the first company to provide patient-reported outcome data for one of their FDA-approved drugs and has collaborated with the FDA to identify methods to display the information in a way that is informative to healthcare professionals and patients.

“There have long been calls to provide information to patients about how they may feel and function when receiving a cancer treatment. By initiating Project Patient Voice, we are moving towards standardized methods to display these outcomes, starting with patient-reported symptomatic adverse events,” Paul Kluetz, deputy director of the FDA’s OCE, said in a statement. “We encourage sponsors to collect this data systematically and look forward to welcoming additional sponsor collaboration as we work to help further serve the patient community.”

Project Patient Voice is not meant to replace the clinician-reported safety information that is available as part of a drug’s labeling. Data from Project Patient Voice should not substitute for advice from a health care professional. Rather, Project Patient Voice serves as a complement to FDA patient labeling and patient information, not a sole source of information on which to make decisions about medical care.

FDA will seek public feedback regarding the Project Patient Voice pilot effort at a virtual public workshop co-sponsored with the American Society of Clinical Oncology on July 17. The “Clinical Outcome Assessments in Cancer Clinical Trials” workshop will include healthcare providers, patients, health outcomes researchers, industry, advocacy groups and other stakeholders interested in rigorous measurement of symptom and functional outcomes. In addition to discussing trial design considerations to obtain patient-reported symptomatic side effects, the FDA will obtain feedback on the presentation of PRO symptomatic side effect data on the Project Patient Voice website to further ensure that the information is clear and meaningful to healthcare professionals and patients.


Black cancer patients better represented in publicly-funded clinical trials

Black patients are better represented in taxpayer-funded clinical trials testing new cancer treatments compared to trials run by pharmaceutical companies, according to a study conducted by SWOG Cancer Research Network, a member of NCI’s National Clinical Trials Network.

The study also found that black patients are not fully represented in cancer clinical trials.

The results are published in JNCI Cancer Spectrum, and were presented as a poster in the 2020 American Association for Cancer Research virtual annual meeting II.

A companion network to NCTN, the NCI Community Oncology Research Program runs prevention and cancer care delivery trials, and includes community and rural hospitals in its network, including sites with significant minority and underserved patient populations.

About 25% of all NCORP trial volunteers are racial and ethnic minorities. Both NCTN and NCORP trials are designed by doctors, paid for with public funds from the NIH through the NCI, and powered by patient volunteers.

The study compared black enrollment in NCI-sponsored trials and industry-sponsored trials.

“Everyone can get cancer, so everyone should have the same access to investigational cancer treatments,” Joseph Unger, a SWOG biostatistician and health services researcher based at Fred Hutchinson Cancer Research Center, who specializes in cancer disparities research with a focus on the impacts of insurance status, race and ethnicity, and income on health outcomes, said in a statement. “In addition, it’s very important from a scientific standpoint to evaluate new treatments in patients who reflect the demographics of the general cancer population.”

To conduct the study, Unger and his team used three databases. One was the SWOG trials database, used as a proxy to estimate the rate of participation among NCI trials. Unger’s colleagues, led by Kanwal P.S. Raghav, of MD Anderson Cancer Center and Jonathan M. Loree, of BC Cancer, created a database of pharmaceutical company-sponsored trials that supported new drug applications and included data on trial participation by race.

The team also used data from the NCI’s Surveillance, Epidemiology and End Results program, as well as data compiled by the U.S. Census Bureau, to estimate the expected rate of black participation in the cancers they studied.

Unger and his team analyzed data from a total of 358 trials—85 industry trials and 273 SWOG trials—that enrolled 93,825 patients being treated for 15 different cancer types. Enrollments spanned the years 2003-2018. In those 15 cancers, the rate of black enrollment in industry trials was 3% compared to 9% in SWOG trials, and 12% in the corresponding U.S. cancer population/.

“This study confirmed that black cancer patients are severely underrepresented in pharmaceutical company sponsored trials, with fewer than one in four of the expected number enrolled,” Unger said. “Black representation in industry trials was also far below that of NCTN trials, with only one black patient enrolled for every three enrolled in NCTN trials.”

FDA and AACR are examining how to improve representation of black patients in FDA registration trials. Registration trials are specially designed studies conducted with the expectation that the data they produce will be used to apply to the FDA for new drug approval, or to expand the uses of a currently approved cancer drug. Unger serves on this FDA and AACR task force.

“NCI sponsored trials have a broader mandate,” Unger said. “They reach beyond just the major cancer centers to serve patients in a more diverse community-based clinical setting. This could serve as a model for pharma trials aiming to increase representativeness of all patients.”

Unger’s study was funded by the NIH through NCI grant award CA189974 and CA189873 and in part by The Hope Foundation for Cancer Research and the Michael Smith Health Professional Investigator program.

Unger’s research team included Dawn Hershman, of Columbia University; Raymond U. Osarogiagbon, of Baptist Cancer Center; Anirudh Gothwal, of Baylor University; Seerat Anand, of MD Anderson Cancer Center; Arvind Dasari, of MD Anderson Cancer Center; Michael Overman, of MD Anderson Cancer Center; Jonathan M. Loree, of BC Cancer; and Kanwal Raghav, of MD Anderson Cancer Center.


AI dual-stain approach improved accuracy, efficiency of cervical cancer screening in NCI study

A computer algorithm improved the accuracy and efficiency of cervical cancer screening compared with cytology, the current standard for follow-up of women who test positive with primary human papillomavirus screening.

The new approach uses artificial intelligence to automate dual-stain evaluation and has clear implications for clinical care.

Findings from the study were published in the Journal of the National Cancer Institute. The algorithm was developed and the study conducted by investigators at NCI, in collaboration with researchers from several other institutions.

“Based on our results, [a fully automated approach] could increase the efficiency of cervical cancer screening by finding more precancers and reducing false positives, which has the potential to eliminate a substantial number of unnecessary procedures among HPV-positive women,” lead-author Nicolas Wentzensen, of NCI’s Division of Cancer Epidemiology and Genetics, said in a statement. “Women who test negative for HPV are at low risk for cervical cancer for the following decade, and even most cervical HPV infections—which cause positive HPV tests—will not result in precancer. The challenge is to identify which women with positive HPV test results are most likely to have precancerous changes in their cervical cells and should, therefore, have a colposcopy to examine the cervix and take samples for biopsy, or who need immediate treatment.”

Currently, women with positive HPV tests may have additional HPV tests or Pap cytology tests to assess the need for colposcopy, biopsy, or treatment.

Dual-stain testing has emerged as a way to more accurately predict the chance that a woman with a positive HPV test has precancerous cervical changes. The test measures the presence of two proteins, p16 and Ki-67, in cervical samples.

In two previous studies, Wentzensen and his colleagues found that women who had a negative result on a dual-stain test had a low risk of developing cervical precancer in the following five years and that fewer women test positive for dual-stain compared to Pap cytology. In March 2020, the manual dual-stain cytology test was approved by FDA for women who have received a positive result on a primary HPV screening.

The manual dual-stain test has a subjective component, in that a cytotechnologist must look at the slide to determine the results. In the new study, the investigators wanted to see if a fully automated dual-stain test could match or exceed the performance of the manual approach.

In collaboration with Niels Grabe and Bernd Lahrmann, of the Steinbeis Transfer Center for Medical Systems Biology, which is associated with the University of Heidelberg, they developed a whole-slide imaging platform that, after being trained with deep learning, could determine if any cervical cells were stained for both p16 and Ki-67. They compared this method with both conventional Pap cytology and manual dual-stain testing in samples from a total of 4,253 people participating in one of three epidemiological studies of HPV-positive cervical and anal precancers at Kaiser Permanente Northern California and the University of Oklahoma.

The researchers found that the AI-based dual-stain test had a lower rate of positive tests than both Pap cytology and manual dual-stain, with better sensitivity (the ability to correctly identify precancers) and substantially higher specificity (the ability to correctly identify those without precancers) than Pap cytology. AI-based dual-stain reduced referral to colposcopy by about a third compared with Pap (approximately 42% vs. 60%). The testing method was also robust, showing comparable performance in anal cytology.

The automated test surpassed the performance of the current standard, Pap cytology, reducing the number of false positive results and substantially reducing referral to unnecessary colposcopy procedures. The results also support further evaluation of the test as an option for anal cancer screening.

The researchers note that their approach has clear clinical application, and through cloud-based implementation, it would be globally accessible. Other applications of the platform include assisted evaluation, second opinion, and quality control.

Because the manual dual-stain test has only recently received FDA approval for screening of women who have HPV-positive test results, its use is just getting started. Additional regulatory approval will be needed to allow using a fully automated dual-stain test for screening of HPV-positive women.


IPATential150 study meets rPFS primary endpoint in mCRPC

The phase III IPATential150 study met its co-primary endpoint of radiographic progression-free survival in patients with metastatic castration-resistant prostate cancer, and whose tumors had PTEN loss.

In this patient group, ipatasertib in combination with abiraterone and prednisone/prednisolone provided a statistically significant reduction in the risk of disease worsening or death, compared to current standard of care (abiraterone and prednisone/prednisolone) plus placebo. The other co-primary endpoint of rPFS in the overall study population (intention-to-treat) was not met.

The trial is funded by Genentech, a member of the Roche Group.The safety profile for the combination of ipatasertib and abiraterone was consistent with previous analyses and known risks.

Overall survival benefit and additional secondary endpoints are not yet mature. The trial will continue until the next planned analysis and data will be shared with health authorities.

Ipatasertib is an oral, highly specific, investigational medicine designed to target and bind to all three isoforms of AKT, which blocks the PI3K/AKT signaling pathway—a key driver of cancer cell growth and proliferation in prostate cancer. The PI3K/AKT pathway has also been implicated in resistance to anti-androgen therapy as androgen receptor inhibition is associated with an increase in AKT pathway activation.

Functional loss of the tumor suppressor protein PTEN within the tumor, seen in approximately 40-60% of mCRPC patients, results in hyperactivation of the PI3K/AKT pathway and is associated with adverse outcomes such as increased tumor grade and stage, earlier biochemical recurrence after radical prostatectomy, metastasis, prostate-cancer-specific death, and androgen-independent progression.

Genentech’s clinical development program for ipatasertib focuses on tumors that are frequently found to have activation of the PI3K/AKT pathway. In addition to prostate cancer, ipatasertib is being studied in certain types of breast cancer including triple-negative breast cancer (TNBC) and hormone-receptor positive (HR+), HER2- negative breast cancer. Results are anticipated later in 2020.


City of Hope, TGen study shows T cells can predict how patients respond to immunotherapy

Scientists at City of Hope, working in collaboration with researchers at Translational Genomics Research Institute and other colleagues have found that the actions of circulating immune cells at the start of immunotherapy treatment for cancer can inform how a patient will respond to the therapy.

The team’s findings were published in the Proceedings of the National Academy of Sciences of the United States of America.

“We used an ecological population model to understand the interactions between circulating white blood cell abundance and tumor response to immunotherapy,” senior author Andrea Bild, professor in the Division of Molecular Pharmacology within the Department of Medical Oncology and Therapeutics Research at City of Hope, said in a statement.

In an effort to find ways of identifying who is more likely to respond to immunotherapy at the start of treatment, or possibly even before it starts, researchers used a mathematical model developed by Bild and colleagues.

The team used the model to analyze data from the results of patients with advanced colorectal or other gastrointestinal cancers who were enrolled in a clinical trial led by Sunil Sharma, deputy director of Clinical Services at TGen, an affiliate of City of Hope. The trial involved a chemotherapy regimen followed by a combination of chemotherapy and immunotherapy. It measured the strength of patients’ tumor-immune cell interactions, which was then related to different immune cells categorized by their behavior.

The findings highlight, for the first time, an important predator-prey relationship between circulating immune cell dynamics and a tumor’s response to immunotherapy. In particular, predator T cells showed increased differentiation and activity of interferon, a protein that exerts anti-tumor effects, during immunotherapy treatment in patients that respond to treatment, said Bild. This relationship was not found in patients during chemotherapy, nor was it seen in those who were non-responsive to immunotherapy.

“The study shows that subsets of immune cells in the blood indicate how each cancer patient responded to this combination of chemotherapy and immunotherapy,” Sharma, who also is director of TGen’s Applied Cancer Research and Drug Discovery Division and one of the study’s senior authors, said in a statement. “We found, using this combination drug approach, that the body’s own immune response and its activation correlated with a higher response to the therapy among cancer patients,” said Sharma.

Next steps include further testing the ability of circulating immune cells to reflect tumor response to therapy in a clinical trial at City of Hope in collaboration with TGen.

The study, titled “Circulating immune cell phenotype dynamics reflect the strength of tumor-immune cell 2 interactions in patients during immunotherapy,” features additional City of Hope authors and researchers from University of Utah, University of Minnesota, University of Texas Health Science Center at Houston and University of California Los Angeles.

Portions of the work were supported by a research grant from Merck Pharmaceuticals, NCI (P30CA042014, U54CA2099780), and the Cancer Prevention Research Institute of Texas Core Facility Support Award (RP170668).


Liquid biopsies using urine and plasma help detect NSCLC

University of Illinois College of Medicine researchers have developed an epigenetic-based approach that helps detect non-small cell lung cancer through liquid biopsies using urine and plasma.

In recent years, scientists have been using new techniques such as methylation-specific PCR – one of the most commonly used methods for epigenetic studies which assesses the changes in DNA expression without altering its sequence.

In a paper published in the Clinical Cancer Research, lead author Alicia Hulbert, assistant professor of surgery, suggests that liquid biopsy biomarkers based on methylation detection from plasma and urine could be used as an aid to computed tomography screening to help guide the decision to proceed with further invasive procedures.

“Urine samples have the potential to be easily implemented in a primary care practice,” Hulbert, who is also a member of the University of Illinois Cancer Center’s Translational Oncology Program, said in a statement. “Plasma and urine yield low false positive rates and the methylation of these genes is associated with a high risk of lung cancer independent of age, race or how much a person smokes.”

The strategy detects epigenetic changes in circulating DNA in blood and urine using a specific set of genes for lung cancer.

The National Lung Screening Trial, sponsored by NCI, was conducted to determine whether screening with low-dose helical computed tomography could reduce mortality from lung cancer. However, CT screening has a false discovery rate of nearly 96%.

“Biomarkers from liquid biopsy assays hold promise for enhancing the diagnostic accuracy of early stage lung cancer screening in conjunction with CT imaging,” Hulbert said. “In this regard, epigenetic molecular markers for early detection of lung cancer have been studied and developed for years.”

However, those methods had a significantly lower yield of detecting DNA in circulating liquid biopsies. Hulbert developed an improved DNA extraction method that allows for methylation detection from liquid biopsies with a process optimized and reduced to just six hours, along with the use of highly prevalent cancer specific methylation targets.

The study was funded by the University of Illinois Cancer Center, the NCI Early Detection Research Network, and U.S. Department Of Defense.


Online program significantly improves insomnia in adolescent and young adult cancer survivors

Dana-Farber Cancer Institute researchers found that an online program developed specifically for adolescent and young adult cancer survivors can significantly alleviate insomnia and improve overall quality of life.

Adolescents and young adults who have survived cancer often continue to suffer from insomnia long after treatment ends, interfering with a range of daily activities.

The study, published in Pediatric Blood and Cancer, shows that an online program developed specifically for AYA cancer survivors can significantly alleviate insomnia and improve overall quality of life.

The insomnia intervention tested in the study is known as SHUTi (Sleep Healthy Using the Internet) was developed by researchers at the University of Virginia and adapted for AYA cancer survivors by Zhou and Recklitis. The interactive program uses text, images, and video to explain how insomnia develops and how it can be overcome. In adapting the program, Dana-Farber researchers replaced vignettes—brief stories of individuals struggling with insomnia—from the original version with ones more relatable to young people.

The program discusses how sleep behaviors that helped patients weather cancer treatment can become maladaptive when they return to normal life.

In the study, 22 AYA cancer survivors–mean age 20.4 years–with insomnia enrolled to use the specially adapted SHUTi. As part of the program, participants kept a sleep diary, tracking when they slept, and entered the information into SHUTi, which adjusted its sleep recommendations accordingly.

At eight and 16 weeks after starting to use SHUTi, participants reported a significant lessening in insomnia severity, daytime sleepiness, and fatigue, and an overall improvement in quality of life.

The program, which consists of six, 20-30 minute sessions, shows how sleep habits that may have helped patients cope with their intensive cancer treatments can become obstacles to healthy sleep as survivors move beyond treatment. Its automated format makes it particularly well-suited to the moment, as telehealth and online programs that are already adopted by many hospitals and clinics, are becoming even more widely used as a result of the COVID-19 crisis.

“Cognitive-behavioral therapy for insomnia, which helps patients understand the behavioral and thought patterns that lead to long-term troubles with falling or staying asleep, has been shown to be very effective in adult cancer survivors. However, it has not been widely tested in the AYA survivor group, Eric Zhou who conducted the study, said in a statement. “We wanted to explore whether a CBT-I program, specifically tailored to AYA survivors and available online, could be helpful in this population.”

Zhou conducted the study with Dana-Farber’s Christopher Recklitis.

“Our results demonstrate that an internet-delivered CBT-I program targeting AYA cancer survivors reduced their insomnia and improved their quality of life,” Recklitis said in a statement. “Notably, our participants’ insomnia severity continued to get better after the intervention had ended, suggesting that the continued to make sleep-related decisions that helped their sleep even after they had finished using the program.”

Support for the study was provided by a Psychosocial Launch Grant from Alex’s Lemonade Stand Foundation.


Study: LifeTracDx blood test shows positive results in detection of early stage cancer in solid tumors

LifeTracDx, a blood test for the universal screening of early stage cancer, identified invasive cancer with 87% accuracy in a new study.

LifeTracdX is sponsored by Creatv MicroTech, a privately-held biotechnology company.

The results are from a training set of 10 cancer types, Cha-Mei Tang, chief executive officer of Creatv, said in a statement.

“The data shows that we obtained 85% sensitivity for all cancers (from 79% of patients in stage I and increasing to 95% of patients in stage IV), and also shows 100% specificity when tested against healthy normal controls,” Tang said. “This represents a significant step towards pan cancer screening by a routine blood draw with high sensitivity and specificity.”

The test analyzed the patient’s immune response to the presence of cancer by isolating stromal cells originating from cancer sites that have migrated into the bloodstream. Creatv has shown that a particular subtype of circulating stromal cell, Cancer Associated Macrophage-Like cells, can be used to identify patients with cancer but are absent in healthy persons.

CAMLs are phagocytic myeloid cells derived from the patient’s immunological response to active malignancy that have engorged cancer cells, thereby containing cancer protein markers and cancer DNA.

In a large multi-institutional study, 7.5mL of peripheral blood was taken from 308 cancer patients after a diagnosis of invasive malignancy, [stage I (n=76), stage II (n=73), stage III (n=72), stage IV (n=65) and unstaged non-metastatic (n=22)]. Patients were recruited with lung, pancreas, breast, prostate, esophageal, renal cell, hepatocellular, neuroblastoma, melanoma, and others. To compare specificity of the test, blood was also taken from 39 patients with untreated non-malignant conditions (i.e. benign breast masses, lupus, liver cirrhosis, etc.), and from 76 healthy volunteers. CAMLs were 87% accurate at identifying cancer patients when compared to healthy controls or from patients with non-malignant conditions.

These initial findings were granted funding from NCI/, Department of Defense and NCI/NIH for validation studies in the screening of 1,000 breast patients, 1,000 lung patients and 300 prostate patients.

Copyright (c) 2020 The Cancer Letter Inc.