Ovarian Cancer Patients Actively Seeking PARP Inhibitor Therapy, Expert Says

Ovarian Cancer Patients Actively Seeking PARP Inhibitor Therapy, Expert SaysIn the treatment of advanced ovarian cancer, PARP inhibitors, including olaparib (Lynparza), rucaparib (Rubraca), and niraparib (Zejula), are stealing the limelight, explains Dennis Scribner, MD.

In an interview with Targeted Oncology, Scribner, a gynecologic oncologist at Arizona Oncology, discussed the treatment landscape for patients with recurrent ovarian cancer and how PARP inhibitors have enhanced the treatment options for this population.

TARGETED ONCOLOGY:  What did you discuss in your presentation?

Scribner: My talk was designed as a backbone to give the audience a general overview of how we treat ovarian cancer in the recurrent setting. Certainly, with a gynecologic oncology patient population—since there are so many treatment options for these patients in the setting of either platinum-sensitive or platinum-resistant disease—it’s [our responsibility] as clinicians to talk to patients. We have to understand what their disease burden is and the science behind what is the best treatment for them. However, when the treatments are kind of close to equal, many treatments have many different adverse effects (AEs). Therefore [in these instances, we are also] really looking at patients’ quality of life and understanding that in a recurrent setting, these patients are not going to be cured.

Unfortunately, that is a tough thing to swallow because they go through a lot, especially in the frontline setting. When they find out they have recurred, it’s a difficult situation for them and then we focus and change our modes of therapy. There are lots of options, and [making choices] incorporates not only what they experienced before, but how long they have been in remission, what the treatment AEs are, and what their goals in their lives are. It’s about really trying to focus and pick the best therapy for them in relationship to their goals, their understanding, their deficiencies, or the AEs of not only what they have had, but what they are potentially going to have with their new drugs.

We are looking ahead and understanding the PARP inhibitor concept, and this is a whole different category for us. There are people who are now living their lives and responding sometimes even better than [patients on] chemotherapy with oral agents. This is very exciting.

TARGETED ONCOLOGY:  Will these PARP inhibitors potentially replace chemotherapy in the future?

Scribner: Well, that’s a very interesting thing. I don’t think it will from a standpoint of primary therapy. When you look at drugs that we have, with the taxanes, platinum-based agents, and addition of bevacizumab (Avastin), we have a lot of patients who get into a progression-free interval in which they are in remission.

So, with advanced ovarian cancer—and unlike advanced colon or breast cancer—we go all out upfront with these big radical surgeries to reduce the tumor burdens and go all out with the most aggressive chemotherapies we have. You can talk about whether we give bevacizumab or not with that chemotherapy but, in truth, it’s hard to show a difference. We haven’t really [shown one] over many, many years of research.

When you ask about adding PARP inhibitors to that, well, is that going to make it better? Is that going to increase more patients in remission, or lead to longer remissions? With maintenance PARP inhibitors, there is a very good question there. There are a lot of data with the SOLO and ARIEL studies that are going to come out in the next 6 months to 1 year to try and help us answer that question.

TARGETED ONCOLOGY:  In addition to those trials, what ongoing data can we expect with novel agents or combinations?

Scribner: I partition my mind between upfront therapy and recurrent therapy. In upfront therapy, researchers are utilizing checkpoint inhibitors; the trials with avelumab (Bavencio) are very exciting. Utilizing this idea of turning on the person’s immune system to recognize that the tumor cells are not normal cells, but abnormal cells that they need to get rid of, is very fascinating. It is a really important part of the idea of advancing that knowledge in the frontline setting.

In the recurrent setting and in the platinum-sensitive category, the PARP inhibitors are really taking the limelight. We are looking at ideas of extending people’s lives and increasing progression-free intervals by 9 to 10 months. It’s even [occurring] in patients like those in the NOVA trial with niraparib, [where] patients had a benefit even if they were not somatic or germline BRCA-positive. You can actually look at that, and, with the FDA approval, everybody can get access to these drugs. It is going to be very exciting.

TARGETED ONCOLOGY:  What impact are these agents making already and how will they shift the paradigm going forward?

Scribner: Patients are coming into the office with discussions saying, “Tell me more about these PARP inhibitors. What does that mean?” The word is getting out, especially when you’re a patient with ovarian cancer. You’re trying to look at all of the data, trying to figure out for yourself what is best for you, and looking at oral agents that have minimal AEs—such as gastrointestinal discomfort that can be fairly managed, and anemia. You’re looking at a patient population that would automatically cling to that drug, especially with the preliminary data that we have.

TARGETED ONCOLOGY:  What are the take-home points for community oncologists who attended your lecture?

Scribner: From a gynecologic oncology perspective, we tend to be a little bit behind in regard to trying to find molecular targets. In lung cancer and breast cancer, there are very important and known molecular targets that drugs are now related to.

So finally, with ovarian cancer, because of the PARP inhibitors we do have a molecular target: the BRCA status, whether its germline or somatic. That is a super-important part because that, fortunately, will also stimulate the community oncologists taking care of these patients to test them for BRCA status. That not only helps them with downstream treatment options or current options, but it also helps them with their family in understanding what their family’s risks are and what they can do to prevent this disease.

To read this entire article on Targeted Oncology, please click here.

OS Improved With Bevacizumab in Recurrent, Platinum-Sensitive Ovarian Cancer

OS Improved With Bevacizumab in Recurrent, Platinum-Sensitive Ovarian CancerAdding bevacizumab (Avastin) to standard platinum-based chemotherapy demonstrated a clinically significant improvement in median overall survival (OS) in women with recurrent ovarian cancer, according to results from the phase III GOG-0123 trial published online in The Lancet Oncology.1

Median OS was 42.2 months (95% CI, 37.7-46.2) for the group assigned to bevacizumab with paclitaxel and carboplatin compared with 37.3 months (95% CI, 32.6-39.7) for the group receiving paclitaxel and carboplatin alone (HR, 0.83; 95% CI, 0.68-1.05; P = .056).

Researchers later noticed incorrect treatment-free interval stratification data for 45 patients, 7% of the total population equally balanced between both treatment groups. Sensitivity analysis of OS based on audited treatment-free interval stratification data resulted in an adjusted HR of 0.82 (95% CI, 0.68-0.996; P = .045).

“We show in this phase III trial that bevacizumab added to paclitaxel and carboplatin might favorably affect overall survival in women with platinum-sensitive recurrent ovarian cancer,” wrote the authors, led by Robert L. Coleman, MD, Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center. “We believe that the improvement in median overall survival of about 5 months in the bevacizumab group is clinically meaningful for both patients and clinicians.“Additionally, [bevacizumab] significantly improves progression-free survival and objective response. We did not observe any new safety signals nor toxicity that differentially increased treatment discontinuation.”

Median progression-free survival was 13.8 months in the bevacizumab group versus 10.4 months in the chemotherapy-alone group (HR, 0.63; 95% CI, 0.53-0.74; P <.0001).

Researchers performed an exploratory posthoc analysis of investigator-assessed objective response for 509 (76%) patients with measurable disease who could be assessed with serial imaging. Bevacizumab was associated with a much greater objective response rate (ORR) compared with chemotherapy (78% vs 59%). Furthermore, a higher number of patients in the bevacizumab group achieved a complete response (32% vs 18%).

Researchers at 67 treatment centers in the United States, Japan, and South Korea recruited women with recurrent measurable or evaluable epithelial ovarian, primary peritoneal, or fallopian tube cancer from December 2010 to August 2011. Eligible patients had achieved clinical complete response to primary platinum-based chemotherapy and had been disease-free for at least 6 months following their last infused cycle of platinum.

Patients in the control group (n = 337) were assigned to 175 mg/m² IV paclitaxel followed by carboplatin (AUC = 5). Patients in the experimental group (n = 377) also received 15 mg/kg IV bevacizumab (15 mg/kg bodyweight) sequenced between paclitaxel and carboplatin on the day of infusion.

Researchers replaced paclitaxel with 75 mg/m² IV docetaxel in patients who developed dose-limiting peripheral neuropathy or hypersensitivity.

In the maintenance phase, the same dose of bevacizumab was administered every 3 weeks until disease progression or unacceptably toxicity. Chemotherapy in both groups was planned for six 3-week cycles, but patients who demonstrated partial or complete response could undergo 2 additional cycles.

About 20% of patients received intraperitoneal chemotherapy as first-line therapy before going on-trial, while 89 (13%) had maintenance therapy following initial chemotherapy. Sixty-seven patients (10%) received prior bevacizumab. A cohort of patients (n = 107) equally represented in both study groups were considered surgical candidates and underwent randomization for a secondary cytoreduction cohort.

Bevacizumab was delayed until cycle 2 in patients who had surgery to avoid wound healing complications.

Patients in the bevacizumab group were more likely to experience at least one grade 3 or higher adverse event (AE). In the chemotherapy group, 282 of 327 patients (86%) experienced at least one grade 3 or higher AE compared with 317 of 330 patients (96%) in the bevacizumab group. The most frequently reported grade 3 or higher treatment-related AEs reported in the bevacizumab group were hypertension (12% vs 1% in the chemotherapy group), fatigue (8% vs 2%), and proteinuria (8% vs 0).

Writing in an accompanying editorial,2 Phillip Harter, MD, PhD, with Kliniken-Essen-Mitte in Essen, Germany, said that these results show that “clinicians now have a further option for the treatment of patients with platinum-sensitive recurrent ovarian cancer,” but that the physicians must take care to determine which patients should receive platinum-based chemotherapy and which should receive a PARP inhibitor.

“Is the patient symptomatic and in need of an urgent response or at risk for progressive disease under platinum retreatment?” he wrote. “This scenario would favor the addition of bevacizumab, which shows improved objective response compared with chemotherapy alone. Conversely, a positive BRCA status could help to select patients in whom treatment with a PARP inhibitor is the best option.”

References

1Coleman RL, Brady MF, Herzog TJ, et al. Bevacizumab and paclitaxel–carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): a multicentre, open-label, randomised, phase 3 trial [published online April 21, 2017]. Lancet Oncol. doi: 10.1016/ S1470-2045(17)30279-6.

2Harter P. A new standard of care or just another option for patients with relapsed ovarian cancer? [published online April 21, 2017]. Lancet Oncol. doi:10.1016/S1470-2045(17)30253-X

To read this entire article on Targeted Oncology, please click here.

Lowering the Risk of Venous Thromboembolism With Ovarian Cancer Treatment

Lowering the Risk of Venous Thromboembolism With Ovarian Cancer TreatmentTwenty-five percent of patients receiving neoadjuvant chemotherapy treatment for ovarian cancer develop venous thromboembolism (VTE), according to a new study published in the journal Obstetrics & Gynecology.1

Patients with ovarian cancer have historically been associated with developing VTE, and significant risk factors have included obesity, older age, advanced disease stage, debulking surgery, and use of anticoagulants. Development of this hematological condition can in turn lead to a poor prognosis or a reduced quality of life for the patient. While postoperative efforts have focused on reducing the incidence of thromboembolic events in women with ovarian cancer, the 4-week standard treatment that is currently offered may not be sufficient to reduce the long-term risk.2

With the hypothesis that neoadjuvant chemotherapy increases the incidence of VTE, the authors of the current study conducted a retrospective analysis among 112 patients with ovarian cancer who were being treated with neoadjuvant chemotherapy. Thirteen patients who presented with a symptom of VTE were disregarded prior to analysis. Thirty of the 112 patients at risk (26.8%; 95% CI, 19.3%-35.9%) experienced a venous thromboembolism. Thirteen patients (11.6%; 95% CI, 6.8%-19.1%) experienced this hematological event during the neoadjuvant chemotherapy treatment, 6 (5.4%; 95% CI, 2.4%-11.5%) developed the condition postoperatively, and 11 (9.9%; 95% CI, 5.5%-17%) developed VTE during adjuvant chemotherapy.

Based on these findings, the authors confirm that neoadjuvant chemotherapy positions patients with ovarian cancer at an extremely high risk of developing VTE. Highlighting the importance of prophylactic treatment in preventing the incidence of VTE, they note that prophylaxis could potentially improve survival in this patient population. This is especially important because of the rapidly growing population of patients with ovarian cancer who are administered neoadjuvant chemotherapy in the United States, they write.

References

1Greco PS, Bazzi AA, McLean K, et al. Incidence and timing of thromboembolic events in patients with ovarian cancer undergoing neoadjuvant chemotherapy [published online May 5, 2017]. Obstet Gynecol. 2017. doi: 10.1097/AOG.0000000000001980.

2Pant A, Liu D, Schink J, Lurain J. Venous thromboembolism in advanced ovarian cancer patients undergoing frontline adjuvant chemotherapy. Int J Gynecol Cancer. 2014;24(6):997-1002. doi: 10.1097/IGC.0000000000000164. – See more at: http://www.ajmc.com/newsroom/lowering-the-risk-of-venous-thromboembolism-with-ovarian-cancer-treatment#sthash.phxGj3B1.dpuf

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

Ovarian/Breast Cancer Vaccine Research Looks To Establish Therapeutic Efficacy

Ovarian/Breast Cancer Vaccine Research Looks To Establish Therapeutic EfficacyTargeting the immune system to fight cancer is not new: in 1891, New York bone sarcoma surgeon William B. Coley injected a patient with an inoperable malignant tumor with streptococcal organisms. His theory was that the resulting severe bacterial infection, erysipelas, would stimulate the immune system, shrinking the tumor.

His hunch was right, and over the next 40 years he treated nearly 1000 patients with bone and soft tissue sarcoma with what became known as “Coley’s Toxins.”

Dr Coley’s work has now earned him the title of “Father of Immunotherapy,” foreshadowing today’s research in several immunotherapeutic approaches, including vaccines.1

“Vaccines have great potential in this modern era of cancer prevention and therapy, both used alone and in combination with other types of therapeutics,” Keith Knutson, PhD, professor of immunology and director of the discovery and translational laboratories cancer research program at the Mayo Clinic in Jacksonville, Florida, told Cancer Therapy Advisor.

“We have only begun to understand how to make them and how to test in the clinic. Most prior vaccines were tested in advanced, bulky, heavily pretreated cancer, which we know now is not the appropriate setting for any type of vaccine, including those that target infectious disease.”

Several phase 1 and 2 clinical trials are evaluating 2 approaches for developing vaccines to treat and prevent breast and ovarian cancer. Both stimulate the immune system, 1 by reintroducing cells derived from a patient’s tumor along with a tumor-specific antigen, and the other by boosting T cell activity to recognize and attack tumors as well as residual cells.

Brian Czerniecki, MD, PhD, chair and senior member in the Moffitt Cancer Center department of breast oncology in Tampa, Florida, maintains that “vaccines would work best as adjuvants or in very early disease.” In fact, “vaccines have [a] very limited role in cancer immunotherapy. It is not simply ‘create a vaccine and it will automatically improve outcomes,’” he said in an interview with Cancer Therapy Advisor. “The type and stage of disease, the type of vaccine, antigens targeted, and staging can all affect outcomes of vaccines.”

In addition to having developed a dendritic cell (DC) vaccine targeting HER2/neu that regresses ductal carcinoma in situ (DCIS), Dr Czerniecki is pursuing the role of a HER2 pulsed DC vaccine in 2 trials to prevent invasive breast cancer recurrence, the first as an adjuvant (ClinicalTrials.gov Identifier: NCT02063724) and the second as a neoadjuvant treatment after chemotherapy (ClinicalTrials.gov Identifier: NCT02061423).

“We use the oncodriver HER2 because it is the main driver of the disease and eliminating it cripples cells,” he said. In DCIS, “our vaccine particularly targeted CD4 Th1 cells, which appear to be lost in HER2-expressing breast cancer.

“It appears these vaccines work best in early DCIS and may have an impact in preventing recurrence in patients with residual disease following neoadjuvant therapy. They will not work alone in active invasive breast cancer but may be critical to make other therapies like chemotherapy and HER2 targeted therapies more effective.”

Dr Czerniecki said he believes many vaccine trials have failed to date specifically because they lacked a critical target. “If you take it in the connotation of ‘just target anything, just because it’s on the cell,’ if it’s not important to the tumor, it doesn’t care about it. If you have an immune response against the tumor, it will just downregulate that protein if it doesn’t need it.

“What we haven’t paid so much attention to in the vaccine world is really going after drivers that the tumor needs to go,” he said.

Dr Knutson is conducting 2 phase 2 clinical trials using vaccines from TapImmune Inc., an immuno-oncology company based in Jacksonville, Florida, which licensed the technology from the Mayo Clinic in 2012. The vaccines — TPIV 110 and TPIV 200 — comprise proprietary peptide antigens that elicit both CD8+ and CD4+ immune responses.

In March, TapImmune received a $3.7 million grant from the US Department of Defense (DOD) for a phase 2 clinical study of women with DCIS using the company’s peptide HER2/neu-targeted T cell vaccine, TPIV 110. The trial, set to begin in the fall, will enroll 40 to 50 women with DCIS, which accounts for approximately 20% of US breast cancer cases. The vaccine will be administered 6 weeks prior to standard surgical resection.

“There are several vaccine approaches that are being tested in companies and academia that may be competitive for DCIS,” Dr Knutson said. “This, however, is a new indication for which there are few candidates.”

Glynn Wilson, PhD, chairman, president, and CEO of TapImmune, said in an interview with Cancer Therapy Advisor that results of a phase 1 study were presented at the 2015 San Antonio Breast Cancer Symposium and are expected to be published by the end of the year.2

The second phase 2 study, of which Dr Knutson is principal investigator, will use TapImmune’s TPIV 200 vaccine targeting folate receptor alpha to determine whether triple-negative breast cancer recurrence can be prevented.

The trial is expected to enroll 280 women and begin later this year. The study is fully funded by a $13.3 million, 5-year DOD Breakthrough Award grant. TapImmune is also conducting a phase 2 study of TPIV 200 as a standalone therapy in triple-negative breast cancer.

Dr Wilson said phase 1 results for the TPIV 200 vaccine, to be reported shortly, will show that some patients have immune responses going out to a year. “That’s a very long time in the vaccine field and we think that’s because broad stimulation of T cells that we’re seeing involves T memory cells.”

TapImmunue is also conducting 2 clinical trials of its TPIV 200 vaccine in ovarian cancer. The first, in collaboration with Memorial Sloan Kettering Cancer Center, is a phase 2 trial (ClinicalTrials.gov Identifier: NCT02764333) in combination with the PD-L1 checkpoint inhibitor, durvalumab, in women with platinum-resistant ovarian cancer.

The US Food and Drug Administration (FDA) granted Orphan Drug and Fast Track Designation for TPIV 200 in ovarian cancer. To date, the trial has more than 50% recruited, Dr Wilson said.

The company is also recruiting women with platinum-sensitive ovarian cancer for a phase 2 study (ClinicalTrials.gov Identifier: NCT02978222) of the TPIV 200 vaccine plus adjuvant GM-CSF vs GM-CSF alone.

“There is an added feature here which is very important,” Dr Wilson said. “If you look at the cancers we’re trying to treat — ovarian and breast cancer, whether it’s triple-negative or HER2 breast cancers…patients, after they have been treated, are at high risk of recurrence. So, one of the things we can do with a vaccine — it’s almost a perfect point to come in with a vaccine — is to stimulate the immune system to prevent recurrence. And, of course, that includes metastatic disease, too.”

To date, sipuleucel-T remains the first and only FDA-approved cancer treatment vaccine on the market and is used for some men with metastatic prostate cancer.3 Best estimates of clinical availability of a vaccine to treat breast and ovarian cancer range from 5 to 10 years.

Genentech, Inc., and Galena Biopharma are enrolling patients with HER2-positive breast cancer for 2 phase 2 trials (ClinicalTrials.gov Identifiers: NCT02297698 and NCT01570036) of the nelipepimut-S vaccine with trastuzumab vs trastuzumab plus GM-CSF alone in to prevent recurrence in the adjuvant setting.4

The National Cancer Institute is conducting a phase 2 study (ClinicalTrials.gov Identifier: NCT02636582) of nelipepimut-S plus GM-CSF in women with DCIS.

The National Cancer Institute is recruiting for a phase 1 trial (ClinicalTrials.gov Identifier: NCT01730118) of an adenoviral transduced autologous DC vaccine expressing human HER2/neu (AdHER2/neu) in adults with tumors — including breast, adenocarcinomas, and metastatic solid tumors characterized by HER2/neu expression — with 1 to 3-positive HER2/neu expression.

The University of Connecticut also recently announced open accrual of patients for “the world’s first personalized genomics-driven ovarian cancer vaccine clinical trial” using OncoImmune, which will be individualized for each patient.5

The phase 1 study (ClinicalTrials.gov Identifier: NCT02933073) will enroll up to 15 women with stage III/IV ovarian cancer in clinical remission after standard of care, with monitoring up to 5 years post-vaccination.

References

  1. McCarthy EF. The toxins of William B. Coley and the treatment of bone and soft-tissue sarcomas. Iowa Orthop J. 2006;26:154-8.
  2. Knutson KL, Kalli KR, Block MS, et al. Robust generation of T cell immunity to HER2 in HER2+ breast cancer patients with a degenerate subdominant HLA-DR epitope vaccine. Poster presented at: San Antonio Breast Cancer Symposium; December 10, 2015; San Antonio, Texas.
  3. PROVENGE (sipuleucel-T). Prescribing information. https://www.fda.gov/downloads/BiologicsBloodVaccines/ CellularGeneTherapyProducts/ApprovedProducts/UCM210031.pdf. US Food and Drug Administration website. Accessed May 2017.
  4. Galena Biopharma reports positive outcome from the data safety monitoring board on the two NeuVax (nelipepimut-S) clinical trials in combination with trastuzumab [news release]. San Ramon, CA: Galena Biopharma; February 6, 2016. https://globenewswire.com/news-release/2017/02/06/914171/0/en/Galena-Biopharma-Reports-Positive-Outcome-from-the-Data-Safety-Monitoring-Board-on-the-Two-NeuVax-nelipepimut-S-Clinical-Trials-in-Combination-with-Trastuzumab.html. Accessed May 2017.
  5. Woods L. Recruitment begins for world’s first ovarian cancer vaccine trial [news release]. Storrs, CT: University of Connecticut; April 20, 2017. http://today.uconn.edu/school-stories/recruitment-begins-worlds-first-ovarian-cancer-vaccine-trial/. Accessed May 2017.

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Combination Therapy May Be Effective Option For Treating Some Women With Ovarian Cancer

Combination Therapy May Be Effective Option For Treating Some Women With Ovarian CancerResearchers have been trying to understand why up to 85 percent of women experience recurrence of high-grade serous ovarian cancer — the most common subtype of ovarian cancer — after standard treatment with the chemotherapy drug carboplatin.

Preclinical research from Dr. Sanaz Memarzadeh, who is a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, has potentially solved this mystery and pinpointed a combination therapy that may be effective for up to 50 percent of women with ovarian cancer.

Memarzadeh’s research, published in the journal Precision Oncology, shows a new combination therapy of carboplatin and an experimental drug called birinapant can improve survival in mice with ovarian cancer tumors. Additional findings reveal that testing for a specific protein could identify ovarian tumors for which the treatment could be effective. Importantly, the treatment could also target cancers that affect other parts of the body, including the bladder, cervix, colon and lung cancer.

In 2015, Memarzadeh and her team uncovered and isolated carboplatin-resistant ovarian cancer stem cells. These cells have high levels of proteins called cIAPs, which prevent cell death after chemotherapy. Since the cancer stem cells survive carboplatin treatment, they regenerate the tumor; with each recurrence of ovarian cancer, treatment options become more limited. Memarzadeh showed that birinapant, which degrades cIAPs, can make carboplatin more effective against some ovarian cancer tumors.

“I’ve been treating women with ovarian cancer for about two decades and have seen firsthand that ovarian cancer treatment options are not always as effective as they should be,” said Memarzadeh, director of the G.O. Discovery Lab and member of the UCLA Jonsson Comprehensive Cancer Center. “Our previous research was promising, but we still had questions about what percentage of tumors could be targeted with the birinapant and carboplatin combination therapy, and whether this combination could improve overall survival by eradicating chemotherapy-resistant ovarian cancer tumors.”

In this new study, the research team first tested whether the combination therapy could improve survival in mice. Half of the mice tested had carboplatin-resistant human ovarian cancer tumors and the other half had carboplatin-sensitive tumors. The team administered birinapant or carboplatin as well as the two drugs combined and then monitored the mice over time. While birinapant or carboplatin alone had minimal effect, the combination therapy doubled overall survival in half of the mice regardless of whether they had carboplatin-resistant or carboplatin-sensitive tumors.

“Our results suggest that the treatment is applicable in some, but not all, tumors,” said Rachel Fujikawa, a fourth year undergraduate student in Memarzadeh’s lab and co-first author of the study.

To assess the combination therapy’s rate of effectiveness in tumors, the team went on to test 23 high-grade serous ovarian cancer tumors from independent patients. Some were from patients who had never been treated with carboplatin and some were from patients who had carboplatin-resistant cancer.

With these samples, the researchers generated ovarian cancer tumors utilizing a method called disease-in-a-dish modeling and tested the same treatments previously tested in mice. Once again, carboplatin or birinapant alone had some effect, while the combination of birinapant and carboplatin successfully eliminated the ovarian cancer tumors in approximately 50 percent of samples. Importantly, the combination therapy worked for both carboplatin-resistant and carboplatin-sensitive tumors.

The researchers also measured cIAPs (the target for the drug birinapant) in the tumors. They found a strong correlation between cancer stem cells with high levels of cIAP and a positive response to the combination therapy. Since elevated levels of cIAPs have been linked to chemotherapy resistance in other cancers, the researchers wondered if the combination therapy could effectively target those cancers as well.

The team created disease-in-a-dish models using human bladder, cervix, colon and lung cancer cells and tested the combination therapy. Similar to the ovarian cancer findings, 50 percent of the tumors were effectively targeted and high cIAP levels correlated with a positive response to the combination therapy.

“I believe that our research potentially points to a new treatment option. In the near future, I hope to initiate a phase 1/2 clinical trial for women with ovarian cancer tumors predicted to benefit from this combination therapy,” said Memarzadeh, gynecologic oncology surgeon and professor at the David Geffen School of Medicine at UCLA.

 To read this full article on News-Medical.net, please click here.

J&J Loses $110 Million Verdict Over Talc Cancer-Link Claim

J&J Loses $110 Million Verdict Over Talc Cancer-Link ClaimJohnson & Johnson was ordered by a St. Louis jury to pay more than $110 million to a Virginia woman who blamed her ovarian cancer on the company’s talcum products.

Imerys Talc America, which provided the talc to J&J, was ordered by the jury to pay about $100,000. Imerys Talc is a unit of Paris-based Imerys SA.

There are more than 3,000 lawsuits accusing the world’s largest health-care company of ignoring studies linking its baby powder and Shower to Shower talc products to ovarian cancer and failing to warn customers about the risk.

J&J lost jury verdicts of $72 million, $55 million and $70 million last year, while winning the first trial in 2017. J&J, based in New Brunswick, New Jersey, is appealing the trial losses. A New Jersey state court judge last year threw out two talc cases set for trial, finding inadequate scientific support for the claims. That decision is also on appeal.

J&J will appeal Thursday’s verdict, said Carol Goodrich, a spokeswoman.

“We are preparing for additional trials this year and will continue to defend the safety of Johnson’s Baby Powder,’’ she said.

J&J’s trial win in March and the New Jersey dismissal last year “highlight the lack of credible scientific evidence behind plaintiffs’ allegations,” Goodrich said.

Baby Powder

The jury’s verdict is contrary to the consensus of government and professional scientific organizations that have determined talc is safe, Gwen Myers, a spokeswoman for Imerys, said in an emailed statement.

“This verdict serves to undermine efforts by the scientific community to determine the true causes of ovarian cancer,’’ she wrote in the statement.

St. Louis plaintiff Lois Slemp, 62, said she used J&J’s baby powder and Shower to Shower talc products for more than 40 years before her diagnosis with ovarian cancer in 2012. J&J sold its Shower to Shower brand in 2012.

“Once again we’ve shown that these companies ignored the scientific evidence and continue to deny their responsibilities to the women of America,” said Ted Meadows, one of Slemp’s attorneys. “They chose to put profits over people, spending millions in efforts to manipulate scientific and regulatory scrutiny.”

Asbestos Claim

Slemp, whose cancer has since spread to her liver, also claims J&J talc was contaminated with asbestos, a rare allegation in these cases. A company lawyer told jurors that J&J’s products didn’t cause Slemp’s cancer and don’t contain asbestos.

The lawsuit is among more than 1,000 filed in St. Louis by women across the U.S., taking advantage of a Missouri law that allows suits to be brought there by people with no connection to the state.

The company faces trial in another talc claim in St. Louis city court next month, brought by the family of a former competitive figure skater who died of ovarian cancer. The trial after that is set for July in Los Angeles.

J&J didn’t warn women of studies linking talc to ovarian cancer to protect the company’s image, Allen Smith, Slemp’s attorney, told jurors.

“What is the corporate image of Johnson & Johnson?’’ Smith asked. “It’s a mother and baby.’’

Slemp, a retired nurse’s assistant, is undergoing chemotherapy and was too ill to attend the trial.

J&J doesn’t need to warn women about talc because there is no link, company lawyer Orlando Richmond argued at trial. The Food and Drug Administration was asked in 2014 whether a warning label should be put on baby powder, he said.

“They said ‘No.’ The science doesn’t warrant it,’’ Richmond said.

The jury didn’t agree.

Punitive Damages

“I felt that J&J was withholding information about its products that was vital to women –vital to women like me,” said juror Nancy Kinney, who described herself as over 50 years old.

The jury’s verdict included $105 million in punitive damages against J&J, a figure Kinney said was derived from a formula starting with the number of years since the International Agency for Research on Cancer classified talc as a possible carcinogen. That was in 2006.
Juror Lindsay Polley said that science was increasingly pointing toward talc being a cancer risk factor.

“The J&J documents acknowledge that,” she said. “If we could, we would make them put on a warning label.”

Juror Jeremy King, 32, called the J&J documents “mindblowing.”

The $110 million verdict is the eighth-largest jury award in the U.S. so far in 2017, according to data compiled by Bloomberg. The largest, for $500 million, was awarded to ZeniMax Media Inc. over its claim that the virtual reality headset maker acquired by Facebook Inc. used stolen code.

The case is Slemp v. Johnson & Johnson, 1422-CC09326, Circuit Court, City of St. Louis, Missouri.

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

Durvalumab Plus Olaparib or Cediranib Active and Tolerable in Female Cancers

Durvalumab Plus Olaparib or Cediranib Active and Tolerable in Female CancersDurvalumab plus olaparib or intermittent cediranib is clinically active and tolerable in treating female cancers, according to results from a phase 1 study published in the Journal of Clinical Oncology.1

Olaparib is a PARP inhibitor and cediranib is a VEGFR 1-3 inhibitor.

“We hypothesized that increased DNA damage by PARP inhibitor and/or reduced VEGF signaling by the VEGFR inhibitor may complement the antitumor activity of immune checkpoint inhibition,” wrote the authors.

This dose-escalation, phase 1 study evaluated the pharmacokinetics, antitumor activity, and safety of durvalumab plus olaparib or cediranib.

The study treated 26 women with recurrent or metastatic solid malignancies who had not received prior immune checkpoint inhibitor therapy. Cancer types included ovarian, triple-negative breast, cervical, and uterine.

All patients received durvalumab 10 mg/kg every 2 weeks or 1500 mg every 4 weeks. Olaparib was administered as 200 or 300 mg twice daily and cediranib was administered as 20 or 30 mg once daily or 20 mg for 5 days then 2 days off.

The recommended phase 2 dosing was 1500 mg every 4 weeks of durvalumab plus 300 mg twice daily of olaparib or 20 mg of intermittent cediranib. There were no dose-limiting toxicities associated with durvalumab plus olaparib.

Treatment-emergent adverse events were hypertension, diarrhea, pulmonary embolism, pulmonary hypertension, and lymphopenia.

Durvalumab plus olaparib resulted in an objective response rate (ORR) of 17% and a disease control rate of 83%. There were 2 partial responses that lasted at least 11 months and 8 patients achieved stable disease for at least 4 months.

The ORR was 50% and the disease control rate was 75% with durvalumab plus cediranib, with 6 partial responses of at least 5 months and 3 achieved stable disease for at least 4 months.

PD-L1 expression levels did not influence response.

According to the authors, these findings warrant additional studies. Single-arm phase 2 expansion trials are ongoing.

Reference

1Lee JM, Cimino-Mathews A, Peer CJ, et al. Safety and clinical activity of the programmed death-ligand 1 inhibitor durvalumab in combination with poly (ADP-ribose) polymerase inhibitor olaparib or vascular endothelial growth factor receptor 1-3 inhibitor cediranib in women’s cancers: a dose-escalation, phase I study. J Clin Oncol. 2017 May 4. doi: 10.1200/JCO.2016.72.1340 [Epub ahead of print]

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