Treatment Choices and Clinical Trials

The Clearity Foundation by Cory Bentley, PhD

A study presented at the Society of Gynecological Oncology meeting found that most women diagnosed with ovarian cancer are not receiving medical care that meets the guidelines of the National Comprehensive Cancer Network (NCCN). The study was presented in April by Dr. Robert Bristow of the University of California, Irvine and reviewed the medical records of more than 13,000 women with ovarian cancer. Surprisingly, the study found that only 37 percent of women were receiving the recommended standard of care. Importantly, the advanced stage patients who received the standard of care recommended by the NCCN guidelines lived longer than those who did not. Women treated by physicians with less experience treating ovarian cancer (those treating fewer than 10 cases per year) and women treated at “low-volume” hospitals (those treating fewer than 20 patients with ovarian cancer each year) were less likely to receive the standard of care. Faced with such a challenging environment, it is no wonder that many patients can be overwhelstock-footage-doctor-talking-with-her-patientmed and even skeptical.

At Clearity, we believe that one way to inform treatment selection is to use the results of tumor molecular profiling to help prioritize drugs among those recommended in the NCCN guidelines for recurrent ovarian cancer. Tumor profile reports can also be used to help select a drug or drug combination from among those that are currently in clinical trials.   When it comes to clinical trials, patients can have many reservations.

Dr. Teresa Gallagher has studied how patients consider clinical trial options. She explains that there are several important barriers that may deter women from deciding to participate in a clinical trial: Concern about being used as a “human guinea pig” to test potentially unsafe drugs; Mistrust of the drug companies and their motives; Fear of being assigned to a group where you will not receive the experimental treatment; Belief that you will not benefit from the trial drug — that currently available treatments are more effective than “experimental” treatments; Lack of awareness of appropriate trials that fit your molecular profile and other circumstances such as no available trials nearby and eligibility criteria. With all these questions and concerns, why would a patient consider a clinical trial? This question was put to Clearity’s scientific director, Deb Zajchowski, PhD.

According to Dr. Zajchowski, one compelling reason for participation in a clinical trial is the possibility of receiving a drug that could be a very effective treatment. “Many of the drugs that are now in clinical trials are predicted to work only in certain patients who can be identified by tumor molecular profiling approaches similar to those used by Clearity. It is hoped that by such selection, these new drugs will work in more patients than in the past when there was no selection process.” To those patients whose top concern is whether or not they receive the trial drug, Dr Zajchowski points out that randomized clinical trials compare a standard treatment with the same treatment with a new study drug added on top. Therefore, the patient who is in the placebo arm will still receive the standard treatment that is appropriate for her cancer. The clinical trial drug is in addition to the standard of care. A clinical trial makes a lot of sense for a patient when her molecular profile has matched her to the standard of care drug used in the trial as well as the new drug being tested. Another factor keeping women from participating in clinical trials is a concern about safety.

Safety issues are most pertinent for a phase I study, which is designed to evaluate the safety of a drug being used in human beings for the first time. Several aspects of a phase I study design help keep patients safe. First, substantial data is available on the safety of the drug in animal models; seconurld, patients are very closely monitored; third, the study starts with a very low dose and only increases to a higher dose after the lower dose proves tolerable; and lastly, a patient can withdraw from a trial at any time.

There is always a risk of experiencing side effects with a clinical trial drug, but Dr. Zajchowski explains, “The decision is a personal one where every patient must balance the risks with the possible benefits– the chance of receiving a new drug that could work better than any other drug to treat your cancer and the risk for a severe adverse reaction.” Both drug effectiveness and safety are critical to the success of any drug. Suspicion of drug companies’ motivations dissuades some patients from participating in clinical trials. Dr. Teresa Gallagher explains that unfortunately the pharmaceutical industry is being portrayed negatively in the media, which can cause patients to mistrust the drug companies and drug trials.

Cory Bentley, PhD, the author of this article, currently works in drug discovery and development for a biotechnology company, where real people are interested in making a real difference. In Dr. Bentley’s experience, people in drug companies and physicians running clinical trials are working to make a drug that will truly give something valuable to patients: extended life and quality of life. As patients look at clinical trials, there are so many issues to consider. Perhaps the most critical considerations are how well a trial drug matches her tumor molecular profile and practical concerns such as eligibility and distance from home. Clearity will help patients find their way to a treatment that best fits their molecular profile, whether that includes a trial drug or approved drug.

The information included in this newsletter is for educational purposes only. It is not intended nor implied that this information be a substitute for professional medical advice. You should always consult your healthcare provider to determine the appropriateness of the information for your own situation.


CA125 becomes a Target for Destruction of Ovarian Cancer by Phase I Drug

CA125 becomes a Target for Destruction of Ovarian Cancer by Phase I Drug

The Clearity Foundation

Dr. Cory Bentley, PhD

Most ovarian cancer patients have become familiar with CA125 blood level monitoring, but trial drug DMUC5754A from Genentech puts a new twist on this familiar blood marker of advanced ovarian cancer. CA125 (cancer antigen 125) also goes by the name mucin 16, Muc16 for short. Muc16 is overexpressed on the cell surface of most ovarian cancers compared to normal tissue. So while Muc16 in the blood may be a biomarker for ovarian cancer, on the tumor cell surface it targets the cell for destruction by DMUC5754A.
DMUC1DMUC5754A is a so-called therapeutic antibody that specifically binds to Muc16. It is much like the antibodies that one’s body naturally makes to fight off infection and invaders. DMUC5754A is also an armed antibody by its linkage to a highly toxic drug, MMAE (monomethyl auristatin E). An armed antibody is known as an ADC – antibody drug conjugate.
Phase I clinical trial data for ADC DMUC5754A were presented at this year’s American Association for Cancer Research (AACR) Annual Meeting in April. This phase I study evaluated several aspects of this drug in advanced recurrent platinum-resistant ovarian cancer, including safety and activity. This phase 1 trial had two parts; first, dose escalation to determine the maximum tolerated dose (MTD) and then expansion for further analysis at the MTD. Dose escalation design starts patients on a very low dose of the drug. These patients are closely monitored for side effects. If side effects are mild, the next group of patients receives a higher dose of the drug. Dose escalation continues in successive groups of patients until strong side effects are observed in greater than 30% of patients, establishing the MTD for DMUC5754A. The expansion part of the trial involved 22 more patients at this highest dose to test for potential efficacy and confirm the safety.
Of the 29 patients treated at the MTD, one complete response was observed (no evidence of cancer after treatment) and 4 partial responses were observed (decreased tumor size). All responses were seen in patients whose tumors expressed moderate to high levels of the targeted protein Muc16, suggesting that using Muc-16 expression on tumor cells will help to identify responsive patients in the future. Dr. Joyce Liu, who presented the phase I study, concluded that DMUC5754A “has an encouraging safety profile and evidence of anti-tumor activity in MUC16-expressing ovarian cancer.”
Finding responders in this group of patients is not a small feat. Patients in this study were heavily pre-treated, averaging 4 prior therapies, and platinum-resistant. This study exemplifies why clinical trials bring true hope to ovarian cancer patients. Although DMUC5754A must still prove its value in phase II and III trials, results from this phase I trial are hopeful.
The information included in this newsletter is for educational purposes only. It is not intended nor implied that this information be a substitute for professional medical advice. You should always consult your healthcare provider to determine the appropriateness of the information for your own situation.

Scientists find genetic variants key to understanding origins of ovarian cancer

New research by an international team including Keck Medicine of USC scientists is bringing the origins of ovarian cancer into sharper focus.

The study, published online June 15 in the peer-reviewed journal Nature Genetics, highlights the discovery of three genetic variants associated with mucinous ovarian carcinomas (MOCs), offering the first evidence of genetic susceptibility in this type of ovarian cancer. The research also suggests a link between common pathways of development between MOCs and colorectal cancer and for the first time identifies a gene called HOXD9, which turns genes on and off, and provides clues about the development of MOCs.

“It remains a mystery where these cancers come from,” said Simon Gayther, Ph.D., professor in preventive medicine, Keck School of Medicine of USC, corresponding author of the international genome-wide association study (GWAS). “By finding these genetic markers, we begin to understand more about the biology of the disease itself. This study tells us more about the biology of ovarian cancer from the early development stage than most research has.”

Ovarian cancer is the fourth leading cause of cancer in American women and seventh most common cancer in women throughout the world (World Health Organization). In 2015, more than 14,000 American women will die of ovarian cancer, according to the American Cancer Society.

Most ovarian cancers have low survival rates, typically because of the misunderstanding of symptoms and discovery of the cancer in later, less treatable stages. “Although MOCs are a less common type of ovarian cancer with generally good prognosis when diagovariancancernosed in early stages, they are twice as likely to be resistant to treatment at later stages,” said Andrew Berchuck, M.D., director of gynecologic oncology at Duke University Cancer Institute, and senior author of the study. “Our results will contribute to the identification of women at greatest risk of developing the disease with the long-term goal of prevention.”

The association analysis was based on 1,644 women diagnosed with MOC and more than 21,000 women without ovarian cancer. The research was conducted as part of the Collaborative Oncological Gene-environment Study (COGS), launched in 2009 with the goal of determining risks of breast, ovarian and prostate cancer.

“A major strength of this study is the large number of women with MOCs, which was made possible by pooling data contributed by investigators from over 40 international studies of ovarian cancer within the Ovarian Cancer Association Consortium,” said Linda Kelemen, Sc.D., associate professor and researcher at the Hollings Cancer Center at the Medical University of South Carolina, and co-first author. “By using a genome-wide scan, we could identify genetic variants that were significantly more common in with MOC compared to those without ovarian cancer.”

Co-first author Kate Lawrenson, Ph.D. of Keck Medicine of USC believes the research will lead the way to the development of risk prediction strategies followed by clinical interventions with the potential to prevent ovarian cancer altogether, rather than treating the disease once it has already taken hold.

“The five year survival rates for ovarian cancer have not changed much in the past 30 years and is partly from viewing ovarian cancer as a single disease,” she said. “Our results shed light on differences in genetic risk factors for the different such as MOCs. I’m hanging my hopes on prevention. My bet is that prevention approaches will be better than finding a cure for a disease that is often diagnosed late.”

The study, “Genome-wide significant risk associations for mucinous ovarian carcinoma,” was published online inNature Genetics on June 15. Also contributing to the study was Paul D.P. Pharoah (University of Cambridge).

Protein in Ovarian Cancers Deactivates Immune System Response

Cancer Network

By Leah Lawrence

Data from a new study has shown that ovarian cancer progression may be driven by the activation of an endoplasmic reticulum (ER) stress response factor called XBP1, which disrupts the function of dendritic cells and, subsequently, antitumor fighting T cells.
XBP1 is part of the ER stress response pathway—also called the unfolded protein response—that can allow tumors to grow and survive when they are deprived of nutrients and oxygen.

“Our findings suggest a strategy whereby a lethal cancer exploits the most conserved arm of the ER stress response in tumor-resident dendritic cells to disrupt their homeostasis, alter their local antigen-presenting capacity, and ultimately evade T cell-mediated immune control,” wrote study author Juan R. Cubillos-Ruiz, an instructor of immunology in medicine at Weill Cornell Medical College, and colleagues in the journal Cell.

imgres“While the ER stress response, and especially XBP1 activation, was previously shown to promote tumorigenesis, we now propose that this integrated cellular pathway further supports malignant progression by inhibiting the development of protective antitumor immunity via manipulation of normal dendritic cell function,” they wrote.

To make this discovery, Cubillos-Ruiz and colleagues examined the tumor microenvironment and found that ovarian cancer promoted the modification of proteins located in the ER, which, in turn, induced XBP1 activation and produced a buildup of lipid molecules within dendritic cells.

The researchers then tested whether or not XBP1 could be targeted. They injected mice with aggressive primary and metastatic ovarian cancer with nanoparticles, microscopic polymers that carried a genetic molecule that can silence the XPB1 gene. Dendritic cells detect the nanoparticles as invaders, and ingest them. Once inside, the nanoparticles delivered the molecule that turns XBP1 off, allowing dendritic cells to tell the immune system to attack the cancer.

“Activating T cell immunity to eliminate tumor cells is the most promising anticancer strategy since the development of chemotherapy, as demonstrated by the shrinkage of melanoma in response to checkpoint blockers,” the researchers wrote. “However, in most cases, the optimal cytotoxic activity of such tumor-reactive T cells is drastically reduced precisely because cancer-associated dendritic cells are unable to support T cell function.”

The results of this analysis show that deletion of XBP1 can transform tumor dendritic cells into ovarian cancer infiltrating T cells. If further developed, targeting XBP1 using nanotechnology-based system may help to slow or prevent the recurrence of ovarian cancers, the researchers wrote.

Chemo Dosing in Ovarian Cancer

Practice Update

Body size should not be a major factor influencing dose reduction decisions in women with ovarian cancer, according to a cohort study of 806 women with primary invasive epithelial ovarian cancers and receiving adjuvant first-line therapy of carboplatin and paclitaxel, with curative intent. Researchers’ results included:

•Compared with normal-weight women, obese class III women received 38% and 45% lower doses in milligrams/kilogram of body weight of paclitaxel and carboplatin, respectively.

•They also received lower relative dose intensity (RDI) for each agent and for the combined regimen, calculated as average RDI (ARDI).

•Lower ARDI was associated with worse overall survival and ovarian cancer-specific survival.

•At every BMI category, women with ARDI < 85% had worse survival than those without dose reduction.

Study could explain why ovarian cancer treatments fail

Survival rates for high-grade serous ovarian cancer patients have not changed significantly in 30 years
Survival rates for high-grade serous ovarian cancer patients have not changed significantly in 30 years

28 May 2015

Ovarian cancer cells can lock into survival mode and avoid being destroyed by chemotherapy, an international study reports.

Professor Sean Grimmond, from The University of Queensland’s Institute for Molecular Bioscience, said ovarian cancer cells had at least four different ways to avoid being destroyed by platinum-based chemotherapy treatments.

“One way involves breaking and rearranging big groups of genes – the chromosomes,” Professor Grimmond said.

“This is fundamentally different to other cancers where the disease is driven by smaller but more gradual changes to individual genes.

“It is essentially shattering big chunks of the cell’s hard drive and moving them around, rather than just changing bits in the files.”

The research used whole genome sequencing to analyse tumour DNA samples from 91 patients with high-grade serous ovarian cancer (HGSC).

HGSC is the most fatal form of ovarian cancer, a disease for which there are more than 1300 diagnoses in Australia each year.

Professor Grimmond said it was a recurrent form of cancer that often developed resistance to standard platinum-based chemotherapy treatments that aimed to damage tumour DNA beyond repair.

There have been no major changes in survival rates or treatments for HGSC patients in the past 30 years.

Professor Grimmond, now based at The University of Glasgow’s Wolfson Wohl Cancer Research Centre, and Professor David Bowtell from Melbourne’s Peter MacCallum Cancer Centre led the research team with Professor Anna deFazio from Sydney’s Westmead Millennium Institute for Medical Research.

They collaborated with a team of cancer researchers, including Dr Ann-Marie Patch from QIMR Berghofer Medical Research Institute, formerly from IMB, to interpret the sequencing results.

Professor Bowtell, head of Peter Mac’s Cancer Genomics Program and of the Australian Ovarian Cancer Study(AOCS) from which many of the patient samples were obtained, said until now there had been little information to guide clinicians when selecting a treatment for women whose cancer had returned.

“For decades clinicians around the world have watched HGSCs shrink under attack from chemotherapy before returning aggressively months or years later,” he said.

“By completely sequencing the cancers, sampled at different stages of disease, for the first time we can map their evolution under the selective pressure of chemotherapy and begin work on better interventions.”

Dr Patch, formerly from IMB and now at QIMR Berghofer’s Medical Genomics Group, acknowledged the support of patients and their families who had participated in the study

“The brave patients allowed their tumour samples to be collected so that we can find out what happens to the cancer cells after treatment and will allow us to work towards better treatments for women in the future,” she said.

Professor Grimmond said the research indicated a range of approaches would be needed to overcome resistance to treatment.

“We now know that not only are there many sub-types of this disease, but there are also different sub-types of resistant disease, which has huge implications for designing future treatments,” he said.

“We really need to continue to write the atlas for this complex disease and get more sophisticated about the amount of drug we give, when we give it, and the types and combinations of treatments in relation to each patient’s cancer.”

The study’s results are published today in Nature.

The study was supported by the National Health and Medical Research CouncilCancer Australia and World Wide Cancer Research (UK), and forms part of the International Cancer Genome Consortium.

Genomic LOH Signature Predicts PARP Inhibitor Response

Genomic LOH Signature Predicts PARP Inhibitor Response

The Clearity Foundation

Evan Friend, MD

Preliminary results from a Phase 2 clinical trial (“ARIEL-2”) testing the PARP inhibitor rucaparib in ovarian cancer patients with platinum-sensitive recurrent cancer were presented at the recent EORTC-NCI-AACR conference.  Much excitement has been generated from the interim analysis of this trial, since for the first time, a biomarker (“biological indicator”) consisting of an actual “signature” event identified from an individual patient’s tumor was found to correlate with favorable responses (to see the interim results, click here). Importantly, in addition to BRCA1/2 mutant patients, for whom PARP inhibitors have previously shown clinical effectiveness, the women without BRCA mutations whose cancer was positive for the identified genomic signature also derived significant benefit from rucaparib.

The signature event is described as “loss of heterozygosity (LOH)” within the genome.  This refers to the loss of an entire chromosomal region on one copy of the double-stranded DNA genome and is a sign of DNA damage that has occurred in the tumor.  As expected, high levels of this type of damage were found in the tumors of patients who have BRCA mutations.  Moreover, this genomic LOH signature seems to match the state of “BRCAness”, which describes BRCA mutation-negative women whose tumors behave as though there was a BRCA mutation, and have responded to PARP inhibitors in previous trials.  Now, for the first time, we have preliminary favorable results from a clinical trial that yields not only a specific biomarker protein or gene, but in this case, a specific molecular DNA “signature” which will hopefully allow clinicians to identify those patients who would be expected to derive the maximum benefit from the addition of PARP inhibitors to chemotherapeutic regimens, both in the relapse and maintenance settings.

An “ARIEL-3” (maintenance setting, platinum-sensitive patients) Phase 3 clinical trial is currently underway and will evaluate the effects of the PARP inhibitor rucaparib in women whose cancers have been tested for the presence of BRCA mutations as well as for this genomic LOH signature.  Thus, that study will prospectively show whether this signature is a significant predictor of rucaparib benefit.  Stay tuned!

The information included in this newsletter is for educational purposes only. It is not intended nor implied that this information be a substitute for professional medical advice. You should always consult your healthcare provider to determine the appropriateness of the information for your own situation.