DelMar Announces VAL-083 Clinical Trials Will Soon Start for Recurrent Ovarian Cancer

DelMar Announces VAL-083 Clinical Trials Will Soon Start for Recurrent Ovarian CancerThe U.S. Food and Drug Administration (FDA) has approved DelMar Pharmaceuticals’ investigational new drug (IND) application for VAL-083 for the treatment of ovarian cancer.

The IND approval allows the company to start clinical development of its lead drug candidate. A Phase 1/2 trial is set to begin patient enrollment in early 2018, depending on the availability of funding.

“The opening of this new IND to study VAL-083 in ovarian cancer marks a major milestone for our company as we continue to investigate this agent as an important potential therapy for the treatment of multiple cancers,” Jeffrey Bacha, DelMar’s president and CEO, said in a press release.

VAL-083, also known as dianhydrogalactitol, is a small-molecule chemotherapeutic agent that targets the DNA of cancer cells, promoting their death. VAL-083’s unique mechanism of action has the potential to overcome treatment resistance, representing a possible new treatment option for cancer patients.

Its anti-tumor activity was demonstrated in 42 Phase 1 and Phase 2 clinical trials sponsored by the U.S. National Cancer Institute. Clinical data collected from these studies have supported further evaluation of VAL-083 as a treatment for ovarian cancer and other gynecologic malignancies.

DelMar now will evaluate the effectiveness, safety, and tolerability of its drug candidate in the multicenter, VAL-083 REPROVe Trial (NCT03281681).

“The development of new treatments to overcome platinum resistance represents the largest unmet medical need in the treatment of ovarian cancer,” said Bradley J. Monk, MD, principal investigator of the trial and director of the Division of Gynecologic Oncology Research at Arizona Oncology. “Based on DelMar’s recent presentation of pre-clinical data demonstrating activity of VAL-083 against platinum-resistant ovarian cancer, we are enthusiastic about exploring the drug’s potential in this important clinical setting.”

The Phase 1 part of the trial is expected to include 24 participants with recurrent adenocarcinoma of the ovary, who have received at least two prior platinum-based chemotherapy regimens. All participants will receive intravenous VAL-083 once per week for up to 16 weeks or until disease progression.

The company expects to have interim results of the Phase 1 part within 18 to 24 months from treatment initiation. These results are expected to support expansion of the study into its planned Phase 2.

VAL-083’s effectiveness will be measured based on overall response rates, response duration, progression-free survival, and levels of the cancer biomarker CA-125.

“Based on our research, we believe that the REPROVe Trial has the potential to provide significantly improved outcomes for patients suffering from platinum-resistant ovarian cancer,” Bacha said.

To view this full article on Ovarian Cancer News Today, please click here.

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Precision Medicine Rapidly Being Incorporated Into Ovarian Cancer Care

Precision Medicine Rapidly Being Incorporated Into Ovarian Cancer CareWhile precision medicine has been a modern go-to approach by physicians in various malignancies, it is demonstrating a particular benefit in ovarian cancer, especially using the method for clinical trial enrollment and in determining whether patients are eligible to receive treatment with PARP inhibitors, according to Douglas A. Levine, MD.

For example, updated findings of a phase II trial presented at the 2017 ASCO Annual Meeting demonstrated that the combination of the PARP inhibitor olaparib (Lynparza) and the angiogenesis inhibitor cediranib maleate continued to show superior progression-free survival (PFS) versus olaparib alone for women with BRCA-negative recurrent platinum-sensitive ovarian cancer.

In the updated analysis, which was conducted after 67 PFS events, median PFS continued to favor the combination over monotherapy at 16.5 months versus 8.2 months, respectively (HR, 0.50; P = .007). Specifically, in patients without a known germline BRCA mutation, the updated median PFS was still superior in the cediranib/olaparib arm compared with monotherapy at 23.7 months versus 5.7 months (HR, 0.32; P = .002).

Additionally, an ongoing phase II trial is exploring the safety and efficacy of TPIV200/huFR-1, a multi-epitope antifolate receptor vaccine in combination with the PD-L1 inhibitor durvalumab (Imfinzi) in patients with platinum-resistant ovarian cancer (NCT02764333).

In an interview with OncLive, Levine, professor, Department of Obstetrics and Gynecology, director, Division of Gynecologic Oncology, NYU Langone’s Perlmutter Cancer Center, shared his insight on how the ovarian cancer landscape has developed a more personalized treatment approach. Levine co-chaired the 2017 OncLive® State of the Science SummitTM on Treatment Options in Ovarian Cancer, where he discussed the topic in greater detail.

OncLive: Can you provide an overview of your lecture?

Levine: I talked about incorporating precision medicine into gynecologic cancers, particularly in ovarian cancer. I began by talking about different sequencing methods and how far we’ve come with sequencing from the Human Genome Project to The Cancer Genome Atlas Project and the application of sequencing in precision medicine in daily clinical care. Specifically, we gave some examples of how to use precision medicine to direct people toward clinical trials, both for ovarian cancer and endometrial cancer, and how to use precision medicine to stratify patients for treatment with PARP inhibitors.

What are the sequencing challenges currently being faced in the ovarian cancer landscape?

The good thing about precision medicine is that doing the actual sequencing is quite easy nowadays. We’ve gotten pretty good at sequencing, and there are some established laboratories at interpreting the sequencing. Now, it is the interpretation that it is much more challenging than the actual sequencing.

Laboratories that have been around for a long time do this quite well. In some of the newer commercial labs, it is very important to figure out how the validation is done and make sure the details of the sequence analysis are done properly, which sometimes can be difficult to figure out. As far as doing the sequencing, we can now use sequencing to determine what mutations are in a patient’s tumor and then to direct that patient toward a clinical trial or possibly for off-label use of clinical therapies.

What has it been like for you to see the paradigm transforming to include a more precision medicine approach? 

Precision medicine has really been successful in part due to the importance of genetic testing for BRCA 1/2 mutations. That got the concept of sequencing into the clinic and to the patient population. Now, patients are coming in saying, “I want BRCA 1/2 sequencing.” Once we became familiar with that type of sequencing, it wasn’t a big stretch from sequencing the germline. Once we could sequence the tumors, people then became familiar with targeted therapies. Certainly, the FDA approvals of various PARP inhibitors have turned sequencing into an everyday event.

Speaking of PARP inhibitors, can you discuss their utility and selecting patients to receive them?

The PARP inhibitors do have different approved indications. Some are approved in the maintenance setting and some for active treatment or treatment of active disease. The PARP inhibitors themselves are similarly efficacious; they all work quite well. They all work the best in women who have BRCAmutations. They work second best in women who have dysfunction in DNA repair.

Then, one study suggested that there was some activity in women who have tumors without any defects when given in the maintenance setting. That effect was much more modest than for tumors in women who do have defects for DNA repair.

What types of ongoing trials in this space are geared toward your discussion?

We have a number of trials that [range from] testing standard agents, such as PARP inhibitors and angiogenesis inhibitors, to more interesting and sophisticated trials that take antibodies and combine them to antibody-drug conjugates, or test immunotherapy in ovarian cancer and endometrial cancers.

We have a number of trials that are really testing targeted inhibitors; we have a very exciting folate receptor trial in recurrent ovarian cancer, because ovarian cancers do express the folate receptor and there is some thought that even endometrial cancers might express the folate receptor. There is some discussion about developing a trial for the folate receptor antibody in endometrial cancer.

Other trials that are exciting in ovarian cancer include the combination of a PARP inhibitor and angiogenesis inhibitors. Cediranib and olaparib is one combination, and there are other combination therapies with PARP inhibitors.

Combining PARP inhibitors with other agents to treat women who do not have BRCA mutations is a very exciting area, because we know the PARP inhibitors work best in women who carry BRCA mutations either inherited or work in the tumor, and also work well in women with defects in DNA repair. How to combine them with agents to apply them to the rest of the population is something that we’re actively studying because, after all, 50% or less of women will benefit from those categories that I mentioned.

Another exciting area is the microsatellite-instability (MSI)-high positive endometrial cancers. MSI positivity accounts for about 35% of endometrioid endometrial cancers or about 20% of overall endometrial cancers. Now, a few months ago, a checkpoint blockade with pembrolizumab (Keytruda) was approved for use in MSI-high–positive tumors. Obviously, it is very exciting because it is approved for a molecular indication that would include endometrial cancers, colorectal cancers, gastric cancers, and really any cancer that happens to have MSI-positivity or be an MSI-stable disease.

The exciting part about immunotherapy is that it really capitalizes what we already knew about the endometrial cancers and, of course, some MSI-high tumors are actually inherited through a defect in mismatch-repair (MMR) genes, so that is also important for genetic screening and genetic counseling. We have another link between inherited genetic events that are now tangentially leading to actually very effective treatments. Therefore, we have the inherited BRCA mutations that put people at risk for ovarian cancer and are now a therapeutic target with PARP inhibitors.

Now, we have the MMR genes, which can put you at inherited risk for colorectal cancer and endometrial cancer, and now the therapeutic target with checkpoint blockade, so these are very exciting and gratifying solutions for years of research.

 

To read this full article on OncLive.com, please click here.

The Importance of Seeing an Ovarian Cancer Specialist

Renee Cowan, gynecologic oncology fellow at Memorial Sloan Kettering Cancer Center (MSK), discusses the importance of patients with ovarian cancer seeing an oncologist who specializes in the field.

Previous studies have shown that black women have worse ovarian cancer outcomes than white women. Further, they were less likely to be treated a a high-volume cancer center that may offer specialists for individual cancer types.

When conducted a retrospective analysis of nearly 1,000 women who were treated for ovarian cancer at MSK, she found no difference in outcomes from one race to another. This reinforced her notion that it is crucial for patients with ovarian cancer to see a gynecologic oncologist who treats at least 20 patients a year for ovarian cancer.

To view this entire article and the video on CureToday.com, please click here.

Physicians Perform Unique Procedure for Ovarian Cancer

Physicians Perform Unique Procedure for Ovarian CancerPhysicians at the University of Kentucky Markey Cancer Center are the first to perform a unique procedure to treat a rare and persistent type of ovarian cancer.

Surgical oncologist Dr. Lauren Baldwin and radiation oncologist Dr. Jonathan Feddock collaborated on the procedure, which involved resecting the tumor and installing a special internal radiation device known as a CivaSheet.

For nearly three decades, the patient who underwent the procedure has been living with a rare type of slow-growing ovarian cancer. Multiple rounds of chemotherapy and radiation failed to stop the disease. Prior to this procedure, she had undergone four previous surgeries at both a local community hospital and Markey to remove as much of the tumor as possible every few years as it grew back. Because of the location of the cancer, surgeons have only been able to safely resect about 90 percent of the tumor.

“This cancer is tricky to treat, because it is prone to recur but grows slowly,” Baldwin said. “That makes it relatively resistant to chemotherapy, which attacks fast-growing cells. Surgery is usually the best option, but each additional surgery becomes riskier for the patient.”

Before deciding to offer yet another tumor resection as an option to the patient, Baldwin sought help from Markey’s weekly multidisciplinary tumor conference to see if oncology experts in other fields had any ideas. Feddock, who specializes in brachytherapy – a form of radiation that involves using internal implants to disseminate radiation – suggested they try combining the surgery with an implantation of the CivaSheet.

The CivaSheet is a highly flexible membrane embedded with radioactive palladium. After Baldwin resected the tumor, Feddock sewed the CivaSheet directly to the remaining cancerous area. The radiation seeds are capped with gold on one side, so they provide direct, localized radiation to the area where the tumor has been growing back while sparing the other surrounding tissue from damage.

While the procedure may not cure the patient of her cancer, the hope is that the CivaSheet will inhibit the cancer’s growth, allowing many more symptom-free years to pass before the patient may need further treatment.

Because of the tumor’s slow-growing nature, Baldwin says it will take some time before they know how effective the procedure is, but she is hopeful about the outcome.

“This treatment has potential to offer control of this cancer for patients who don’t have any other options,” Baldwin said. “We’re hoping to add both quantity and quality of life for a patient in a difficult scenario.”

This is the first known instance of using the CivaSheet for ovarian cancer, but the device is used for other indications, including some gynecological, colorectal, head and neck, and pancreatic cancers as well as soft tissue sarcomas.

To read this entire article on MedicalXpress.com, please click here.

The Crisis in Gynecological Cancer Research

The Crisis in Gynecological Cancer ResearchAs an ovarian cancer patient whose life is being extended by a clinical trial, I was delighted to learn this summer that research on gynecological cancers is undergoing an unusually productive period. But I’m dismayed that at the same time there has been a steep decline in clinical trials available in the field.

For decades, the complexity of cervical, ovarian, endometrial and vulvar cancers stymied researchers; however, several advances have begun to extend women’s lives. The addition of new chemotherapy regimens and newly effective targeted drugs, like the PARP inhibitor I have been taking for five years to keep my cancer in check, are lengthening survival rates. (All resulted from clinical trials.) Ironically, too, in potentially lucrative areas of cancer research, there are too many clinical drug trials, and not enough patients.

While medical scientists are discovering the determinants that drive gynecologic tumor growth, clinical trials in gynecological cancer — translating that knowledge into specific strategies — dwindle. According to the Society of Gynecologic Oncology, enrollment in phase 3 National Cancer Institute clinical trials designed for gynecologic cancers declined 90 percent from 2011 to 2016.

In July, at the Ovarian Cancer National Conference in Chicago, a succession of experts expressed alarm about this: Dr. John Moroney from the University of Chicago, Dr. Carol L. Brown from Memorial Sloan Kettering, Dr. David Gershenson from MD Anderson Cancer Center, Dr. Daniela Matei from Northwestern University, and Dr. Alan D’Andrea from the Dana-Farber Cancer Institute.

Why has the number of trials plummeted? The drop, the experts at the conference said, was probably caused by the 2012 restructuring of cooperative groups sponsored by the National Cancer Institute, placing gynecological, surgical and radiation therapy under the same umbrella, and also by significant budget reductions of the National Institutes of Health.

As a beneficiary of an innovative drug trial, I was distressed by the news of this crisis. But it was time to head to a smaller room for a workshop I was leading: Writing About Cancer. I had not brought enough pencils and notebooks for the 30-some patients and caregivers who thronged through the door.

Surveying the group, which included people of every conceivable age, ethnicity, religion, race and sexual orientation, I realized that I was facing many people’s mothers, sisters, daughters, grandmothers, aunts, nieces and some of the men who helped them through the difficult passage from diagnosis and treatment to vigilant remission or anxious recurrence. Many wore ovarian cancer’s signature color: teal scarves, teal dresses, teal sweaters (because of the strenuous air-conditioning or chemo-compromised bodies), and (yes) teal wigs. Your average academic, I wore mostly black (and a gray wig).

It was humbling to anticipate all the testimonies waiting to be recorded. Writing, like yoga, I explained to the group, can promote flexibility, balance, detachment and a sense of achievement. Composition composes us, but it can also energize us and preserve our reflections as well as our memories. I did my bit, making a pitch for writing as a supplementary therapy and providing a few guidelines and prompts. Soon, virtually everyone in the room began scribbling.

The concentration was palpable when Dr. D’Andrea, the leader of the Ovarian Cancer Dream Team, walked in and sat down. My heart sank: He had arrived during the silent writing portion of the workshop, so he would be bored to tears. But I had promised participants a full 15 minutes of writing time, and I could not go back on my word.

After a few minutes, Dr. D’Andrea walked up to the front of the room to introduce himself. He commented on my profile in the conference booklet, where I had credited my family, my doctors and nurses, and my support group for my life. “You should include the researchers,” he said before shaking my hand, thanking me for my work, and taking his leave.

The rest of the session remains swaddled in a haze of excitement. In case participants felt shy about sharing their compositions, I had prepared various backup strategies: poems that I could recite or books that I could recommend. Imagine my delight when three women stood in succession to read their soaring, searing paragraphs while a thrill moved through all of us.

The first explained that cancer had given her a new identity and also a new community: since diagnosis she had become a patient advocate. The second, younger, described her distress when treatment damaged her hearing: She grieved over giving up music until she learned to play her violin by sensing its vibrations in and on her body. The third, younger still, produced a rap: A self-described cancer diva, she dissed her disease.

It was July 9, the date of a full moon. They were howling, decrying, persisting, transmuting their fears and transmitting them as well: Putting them on the moon. Words had provided a counterpoint to disease, a catalyst, a healing balm and a use for pain, a perfectly safe and exceptionally cheap drug.

Amid the laughter and tears, I realized that Dr. D’Andrea was right. We should credit the researchers and urge our legislators to fund much needed clinical trials. We must each in our own way stand up for the importance of government-sponsored efforts to sustain the lives of people with so many precious stories to tell.

To read this entire article on The New York Times, please click here.

Celsion to Present New Data from OVATION Trial at Ovarian Cancer Meeting

Celsion to Present New Data from OVATION Trial at Ovarian Cancer MeetingAll newly diagnosed ovarian cancer patients enrolled in the OVATION Phase 1b trial (NCT02480374) to date benefited from the addition of GEN-1 to standard of care, according to Celsion, the drug’s developer.

The new data, accepted for presentation at the American Association for Cancer Research (AACR) Addressing Critical Questions in Ovarian Cancer Research and Treatment Special Conference, Oct. 1-4 in Pittsburgh, shows that 100 percent of patients achieved at least stable disease and 86 percent saw a reduction in their tumors. Among those included in the highest dose level, all achieved a partial or complete response.

Celsion’s poster is titled “Immunological changes following intraperitoneal administration of a formulated IL-12 plasmid in combination with neoadjuvant chemotherapy in newly diagnosed advanced ovarian cancer patients,” and will be presented by Dr. Khursheed Anwer, Celsion’s executive vice president and chief scientific officer.

GEN-1 is a lipid vesicle containing the DNA of the pro-inflammatory protein interleukin-12 (IL-12), leading to its sustained production and release specifically in the tumor site. IL-12 has shown relevant anti-cancer immunity by activating immune cells that kill tumor cells. By delivering IL-12 directly into cancer cells, GEN-1 avoids the adverse effects of increased inflammation in other areas of the body.

GEN-1 has also generated promising early data as a monotherapy in patients with peritoneally metastasized ovarian cancer, and is being studied in combination with the anti-cancer therapy Adriamycin (doxorubicin) in patients with platinum-resistant ovarian cancer.

The dose-escalating OVATION study was designed to assess the safety and effectiveness of eight weekly treatment of GEN-1 (injected into the peritoneum) combined with chemotherapy in patients with newly-diagnosed advanced ovarian cancer who will undergo surgery after chemo.

The study includes four dose groups, designed to include three to six patients per group, to find the dose with the highest benefit and causing the fewest side effects.

In July 2017, Celsion announced the enrollment of the last patient in the trial and provided efficacy data from the first 14 patients who completed the therapy.

The results showed that, of the 14 treated patients, two achieved complete response, 10 had a partial response, and two maintained stable disease. The results correspond to a disease control rate of 100% and an objective response rate of 86%. The highest dose of therapy reduced tumor size in all five tested patients, with one complete response and four partial responses.

Celsion also reported that GEN-1 treatment correlated with successful surgical outcomes.

The tumor was successfully removed in 14 patients. In nine of these patients (64%), no gross or microscopic tumor remained after surgery. In the highest two dose groups, seven out of eight (87%) patients showed complete tumor resection. Importantly, the highest dose group led to complete surgical resection in all five patients.

In addition, all patients exhibited significantly decreased levels of cancer antigen (CA)-125 protein. This assessment is conducted to monitor certain cancers during and after treatment. In ovarian cancer, elevated CA-125 levels may also indicate tumor recurrence.

Of note, among the eight patients who received GEN-1 more than one year before the analysis and are still being followed, only two saw their cancer progress. This result is an improvement compared to data from similar patients who received only chemotherapy and surgery in earlier studies.

Now, the new poster presentation will summarize data from the OVATION study and provide additional understanding into GEN-1’s mode of action by showing changes in the tumor and immune cell population, as well the levels of cytokines (molecules, such as IL-12, released by immune cells) in the tumor’s microenvironment.

“We have completed enrollment of our OVATION study in newly diagnosed ovarian cancer patients, one goal of which is to determine GEN-1’s activity in combination with standard chemotherapy,” Michael H. Tardugno, Celsion’s chairman, president and CEO, said in a press release. “The remarkable surgical outcomes among all patients completing the prescribed eight weekly treatments reinforce our confidence in the promise of GEN-1’s ability to work safely and effectively in advanced ovarian cancer.”

The company will now discuss the results from the study in “an Advisory Board Meeting in late September 2017 with our clinical investigators and scientific experts from the Roswell Park Cancer Institute and M.D. Anderson Cancer Center,” Tardugno said.

The meeting is intended to “determine the next steps forward for this exciting new immunotherapy. With the endorsement and recommendations from the Advisory Board, we fully expect to file a next phase protocol with FDA later this year,” he added.

To read this article on Ovarian Cancer News Today, please click here.

Niraparib Maintains Quality of Life in Recurrent Ovarian Cancer

Niraparib Maintains Quality of Life in Recurrent Ovarian CancerAdministering niraparib to patients with recurrent ovarian cancer after a complete response (CR) or partial response (PR) to platinum-based chemotherapy may allow patients to continuously maintain their quality of life (QOL) during treatment, according to a study presented at the European Society for Medical Oncology (ESMO) 2017 Congress.

The ENGOT-OV16/NOVA trial (ClinicalTrials.gov Identifier: NCT01847274) previously demonstrated that niraparib significantly prolonged progression-free survival (PFS) in patients with recurrent ovarian cancer following CR or PR.

Study authors analyzed patient-reported outcomes (PROs) associated with QOL, and the Functional Assessment of Cancer Therapy-Ovarian Symptoms Index (FOSI) and European Quality of Life Scale 5-Dimensions (EQ-5D-5L) were used to evaluate individual patient-reported symptoms in the niraparib and placebo groups.

A mixed-effect growth-curve adjusted for 3 stratification factors and baseline demographics was formed to reflect the relationship between the PRO scores and treatment for each measure. Health status and PRO associations were determined by a cross-sectional analysis of adjusted EQ-5D-5L health utility index (HUI) scores.

Results of the study showed no significant difference in mean PRO scores between the niraparib and placebo arms. The adjusted HUI scores were comparable at baseline in both study arms, but average adjusted HUI scores prior to progression trended higher for the niraparib arm (0.812 vs 0.803 in gBRCAmut cohort; 0.845 vs 0.828 in non-gBRCAmut cohort).

Patients’ overall health utility was not negatively impacted by hematologic toxicities.

Reference

1. Oza AM, Matulonis UA, Malander S, et al. Quality of life in patients with recurrent ovarian cancer (OC) treated with niraparib: Results from the ENGOT-OV16/NOVA Trial. Presented at: ESMO 2017 Congress; September 8-12, 2017; Madrid, Spain. Abstract 930O.

To read this entire article in Oncology Nurse Advisor, please click here.