Lorraine Myers

The attenuated vaccinia virus, GL-ONC1, demonstrated safety and clinical benefit when delivered intravenously with concurrent chemoradiation therapy in patients who have locoregionally advanced head and neck carcinoma (LA-HNC), according to a phase I study, making this class of therapies an interesting potential treatment strategy.

The trial was the first to establish the safety of intravenous (IV) GL-ONC1 in patients who have LA-HNC, undergoing concurrent chemoradiation therapy.

&ldquo;This was a phase I trial primarily designed to test for toxicity and feasibility. We were trying to determine if there is still a potential to cure head and neck cancer by adding an oncological vaccinia to the standard regimen of chemoradiation. To do that, we needed to get patients through that toxic regimen and then see if there is enough efficacy to warrant testing in a phase II study,&rdquo; said Loren K. Mell, MD, chief, Head and Neck Malignancy Service, associate professor, University of California, San Diego, in an interview with

The trial consisted of 19 patients who were evaluated from May 2012 to December 2014. Seventy-eight percent of the 18 patients completing chemoradiation therapy had 3 cycles of cisplatin, while 22% had 2 cycles. The median follow-up was 17 months, and the Kaplan-Meier estimate of 1-year progression-free survival was 82%. In addition, the overall survival was 87%, and the maximum-tolerated dose was not reached.

According to Mell, this study was the first to demonstrate that GL-ONC1 could be delivered intravenously to patients receiving chemotherapy and radiation simultaneously. He and his team were able to get patient outcomes, when comparing success rates to historical rates.

Toxicities grade 2 or higher consisted of rigors (47% of patients), thrombocytopenia (32%), and fever (26%). A rash of grade 1 or higher was reported in 21% of patients; it was confirmed to be viral in origin in two patients. Mell stated that the rash was pox-like, but it was short-lived and mild. Viral shedding was not detected on urine or oral swab 1 to 2 days post infusion of GL-ONC1.

According to Mell, flu-like symptoms were experienced a few hours after administration of the vaccine as well. &ldquo;GL-ONC1 is a genetically modified vaccinia that is related to cowpox, so it does not naturally infect humans. That makes it desirable for this purpose. We believe the safety profile to be good. There was prior evidence that showed it was safe to deliver; however, we were unsure that, if we delivered it at the same time as chemotherapy and radiation, it would be a tolerable regimen for patients to undergo. Nevertheless, it was tolerable,&rdquo; he said.

Mell thinks that oncolytic viruses are a particularly interesting class of therapies. He noted many studies in preclinical models demonstrating that these drugs are effective and may increase the efficacy of radiation and chemotherapy.  Patients with LA-HNC tend to present in stage IV of the disease, and their tumors are either very large, or they advance in the lymph nodes in the neck. Mell and his colleagues are aware that outcomes for standard chemotherapy are not very great, especially those associated with smoking and drinking, so they would like to improve on that.

&ldquo;The next step is a phase II clinical trial designed to test the therapy against a control arm versus the approach we used in this trial to see if their outcomes are better. Those are usually larger trials that enroll 120 patients, while the phase I study only included 19 patients,&rdquo; concluded Mell.

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The attenuated vaccinia virus, GL-ONC1, demonstrated safety and clinical benefit when delivered intravenously with concurrent chemoradiation therapy in patients who have locoregionally advanced head and neck carcinoma (LA-HNC).

Oncolytic Vaccines With Chemotherapy Show Survival Benefit in Head and Neck Cancer

Radium-223 dichloride (Xofigo) has shown a significant survival advantage in the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have symptomatic bone metastases, and a multidisciplinary approach to treatment has become more widely practiced in community clinics.

&ldquo;It is important that all of the disciplinesradiation oncology, medical oncology, and urology&mdash;work as a team to address the problem,&rdquo; said Joseph F. Renzulli, II, MD, director of prostate surgery, Miriam Hospital, Adult Urology, and assistant professor of surgery (urology) at Alpert Medical School of Brown University, in an interview with

. He is also the lead author of a paper published in the

titled, &ldquo;Radium-223 dichloride: illustrating the benefits of a multidisciplinary approach for patients with metastatic castration-resistant prostate cancer.&rdquo;

He and his colleagues chose radium-223 because it is the only radionucleotide with an OS advantage, while others are more palliative, said Renzulli. He also stresses the importance of distinguishing between them, as there are many different treatments for mCRPC.

According to Renzulli there is not one specialty that is able to solely administer the radium-223, because administration requires referral to a radiation oncologist or nuclear medicine practitioner from an oncologist or urologist. The process requires a dual interaction, or possible a tri-interaction, between specialties, in order to successfully integrate radium-223 into practice and to work toward a successful outcome for patients.

If solo practitioners want to incorporate a multidisciplinary approach, Renzulli suggests that they team up with a radiation oncologist and/or a nuclear medicine physician and create a protocol for patients who may be candidates for radium-223, and then decide how to manage this protocol.

&ldquo;I think we need to move away from the constant dogma of multidisciplinaryit doesn&rsquo;t have to be a &lsquo;true&rsquo; multidisciplinary center where patients are seen by all three doctors at once, but rather it should be a collaborative effort where the doctors have created an arrangement where there are going to be multiple doctors caring for the patient in the advanced prostate cancer setting,&rdquo; said Renzulli. Although in his clinic, patients see all three doctors at once and at the same time, he notes that this practice is not feasible in many models.

If a multidisciplinary approach is used, Renzulli feels the ideal clinicians would be urology, radiation oncology, and medical oncology.

In terms of sequencing treatments, Renzulli and his team have started to no longer use oral therapies back-to-back, due to the cross resistance. If a patient is on an oral therapy, such as abiraterone and prednisone, and the treatment starts to fail, then Renzulli and his team would use chemotherapy or radium-223 before going back to an oral therapy; if there is a nice response, the patient may go back to enzalutamide.

In light of the STAMPEDE trial and the CHAARTED data, urologists have to be comfortable treating with chemotherapy for metastatic prostate cancer, according to Renzulli.  He does not think that they have to be the ones administering the chemotherapy, but rather that they need to coordinate care in a multidisciplinary fashion with an oncologist who they feel they can provide that service to their patients safely and effectively. &ldquo;I think that is of paramount importance now in prostate cancer,&rdquo; commented Renzulli.

Radium-223 is a novel therapy for patients who have mCRPC because it can provide them with a survival advantage, according to Renzulli. He concludes that it is best to coordinate the care between the urologist, as well as the radiation and medical oncologists, to ensure the patient completes the therapy and avoids issues that may arise, which could interfere with completing 6 full cycles of treatment.

Radium-223 dichloride (Xofigo) has shown a significant survival advantage in the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have symptomatic bone metastases, and a multidisciplinary approach to treatment has become more widely practiced in community clinics. 


Multidisciplinary Approach to Radium-223 Treatment Favored for Metastatic Prostate Cancer

A novel immunotherapy, EGEN-001, combined with pegylated liposomal doxorubicin (PLD) has demonstrated clinical benefit in recurrent or persistent epithelial ovarian, fallopian tube, or primary peritoneal cancer patients, according to a recent NRG/GOG study.

Although the study examined a small population, the results are promising for the potential of immunotherapy agents in ovarian and other similar cancers, according to lead study author Premal H. Thaker, MD, associate professor, obstetrics and gynecology, Division of Gynecologic Oncology, Washington University School of Medicine/Siteman Cancer Center in an interview with

EGEN-001 combines a human IL-12 plasmid that encodes for functional IL-12 with a synthetic DNA delivery system polyethyleneglycol-polyethyleneimine-cholesterol that facilitates plasmid delivery into cancer cells.

Intraperitoneal injection of EGEN-001 is associated with increases in IL-12 levels and its downstream cytokines in the tumor environment without a significant increase in systemic circulation.

The study&rsquo;s dose escalation model evaluated 3 dose levels of EGEN-001 in 16 evaluable patients. Patients received PLD every 28 days and EGEN-001 on days 1, 8, 15, and 22 of a 28-day cycle. Cycles were repeated every 28 days until disease progression.

A clinical benefit of 57.1% (PR, 21.4%; SD, 35.7%) was found in the 14 patients with measurable disease, with the highest number of partial responses found at dose level three (28.6%). The maximum tolerated dose was not reached.

&ldquo;We found that we had an almost 86% clinical benefit in our highest dose level, which was level three,&rdquo; said Thaker. &ldquo;This was very exciting because, in this patient population, we do not have many treatments available. It was also encouraging, because we did not even have to reach our maximum tolerated dose. We are excited to use this therapy in future studies.&rdquo;

Efficacy was seen across all three dose levels; however, patients administered dose level three demonstrated the highest level of stabilization of disease. Two patients in the high-level group also had partial responses.

&ldquo;We found that to be very encouraging because the patient population had been heavily pretreated and do not have many options. The idea of putting together standard chemotherapy and immunotherapy and giving it intraperitoneally, which is a novel administration method for ovarian cancer, is very exciting,&rdquo; Thaker said.

Side effects included anemia, abdominal pain, and neutropenia. Thaker felt that the toxicity profile was encouraging and hopes to try and push the doses further to determine if better responses may be reached.

Thaker noted that immunotherapy has been studied in ovarian cancer for 20 years, but severe side effects have often occurred in these studies. &ldquo;With this new agent, we were able to synthesize it differently. Now, we are not seeing those side effects. We are seeing benefit without those harsh side effects. Because of that, we are actually able to combine it with chemotherapy and other agents.&rdquo;

According to Thaker, determining the maximum tolerated dose will be the next step in the research of this combination. She thinks the novel agent might soon be tested in combination with bevacizumab. &ldquo;We already know that bevacizumab has a good safety profile in this patient population when paired with chemotherapy, so adding an immunotherapy agent may target a different aspect of the cancer and give us a better result. With these types of novel therapies, we may be able to improve women&rsquo;s lives.&rdquo;

Thaker P, Brady W, Bradley W, et al. Phase I study of intraperitoneal IL-12 plasmid formulated with PEG-PEI-cholesterol lipopolymer administered in combination with pegylated liposomal doxorubicin in recurrent or persistent epithelial ovarian, fallopian tube, or primary peritoneal cancer patients: an NRG/GOG study.

A novel immunotherapy, EGEN-001, combined with pegylated liposomal doxorubicin (PLD) has demonstrated clinical benefit in recurrent or persistent epithelial ovarian, fallopian tube, or primary peritoneal cancer patients.

New Immunotherapy With Chemotherapy Shows Results in Ovarian Cancer

The fully human PD-L1 IgG1 antibody, avelumab, demonstrated clinical activity in patients who have previously treated, recurrent/refractory (R/R) ovarian cancer, according to data from a phase Ib open-label expansion trial that was the first and longest study done in ovarian cancer with these types of immunotherapies to date.

&ldquo;The study began in November 2013 and enrolled 75 patients into an ovarian cohort until November 2014,&rdquo; said Jeffrey R. Infante, MD, director, Drug Development Program, and principal investigator at Sarah Cannon Research Institute, in an interview with

The study looked at patients with previously treated R/R ovarian cancer. Study investigators examined data after 23 patients made it through 2 months of treatment. Infante thought the responses in ovarian cancer were exciting, because although melanoma and kidney cancer were always thought to be immunogenic, ovarian cancer has typically been more questionable.

The benefit was originally unclear, according to Infante, but the responses were ultimately confirmed and patients did well. &ldquo;We had some atypical responses where the tumor looked like it was progressing and then, all of a sudden, it started to respond. That was very unique,&rdquo; said Infante.

Seventy-five percent of patients, 68% of whom received three or more prior therapies, were given treatment with intravenous avelumab at 10 mg/kg biweekly. The objective response rate by RECIST criteria was 10.7% (95% Cl, 4.7-19.9) after a median follow-up duration of 5 months.

Of patients still on the study, 33% were progression-free after 6 months of treatmentone-third of patients continued to benefit after 6 months.

There was a stable disease rate of 44%, and a disease control rate of 54.7%. In addition, the median duration of treatment was 12 weeks, with a median time to response of 9 weeks. The median duration of response was 21 weeks, with 62.5% of responses ongoing.

&ldquo;From a tolerability standpoint, the PD-L1 inhibitors are, overall, very similar to what has been seen with the PD-1 inhibitors. The majority of these patients do well. There are a small number of patients, around 10% to 15%, who have side effects that are autoimmune-related. These include diarrhea, nausea, and skin rashes, but these are usually manageable,&rdquo; said Infante. &ldquo;There are a few patients who have infusion-related reactions, but they [the reactions] are tolerated with antihistamines. The vast majority of patients don&rsquo;t feel as if they are getting standard chemotherapy. Most of the side effects are grade 1/2 and are manageable and mild. There were no serious adverse events that were thought to be treatment-related in this study.&rdquo;

Avelumab is also being studied in several tumor types, and other cohorts are already enrolling patients, according to Infante. He hopes to see combination strategies with immunotherapies in the future, in hopes that this will further increase survival. Infante would like to see an increase in PFS by 10% or 15%, with the key being tolerability.

Because of the demonstrated tolerability and durability of avelumab, Infante thinks that as long as avelumab continues to show efficacy in patients with R/R ovarian cancer, it may soon be moved up the sequence of treatment.

The fully human PD-L1 IgG1 antibody, avelumab, demonstrated clinical activity in patients who have previously treated, recurrent/refractory (R/R) ovarian cancer.

Avelumab Shows Efficacy in Ovarian Cancer

The development of novel targeted drugs, such as brentuximab vedotin (Adcentris), against discrete cell surface proteins, such as CD30, has awakened a new way of thinking about targeted cancer biology, according to Owen A. O&rsquo;Connor, MD, PhD, professor of medicine and experiment therapies, coprogram director, Lymphoid Development and Malignancy Program, Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center.

&ldquo;CD30 is a defining protein expressed on the surface of anaplastic large cell lymphoma and to a very high extent in patients with Hodgkin lymphoma,&rdquo; said O&rsquo;Connor. &ldquo;It is variably expressed in other types of lymphomas, such as cutaneous T-cell lymphoma, peripheral T-cell lymphoma, and diffuse large B-cell lymphoma.&rdquo;

In an ongoing phase II trial, examining patients with advanced diffuse large B-cell lymphoma (DLBCL), brentuximab vedotin with standard R-CHOP yielded objective responses in 80% of patients.

In the study, patients were randomized in a 1:1 ratio to standard R-CHOP plus brentuximab vedotin at a dose of either 1.2 mg/kg (n = 30) or 1.8 mg/kg (n = 23). Brentuximab vedotin was administered on day 1 of each 21-day cycle, for a maximum of 6 cycles. Upon review, the higher dose was eliminated after the first 10 patients in each arm completed treatment, due to safety concerns. &nbsp;

Forty-one patients (80%) in the trial achieved an objective response, including 34 (67%) complete remissions and 7 (14%) partial remissions. Five patients (10%) had progressive disease

Another multicenter phase II study investigated the use of brentuximab vedotin in place of bleomycin in the standard ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) regimen for nonbulky stage I/II Hodgkin lymphoma.

Thirty-four patients received a lead-in cycle of brentuximab monotherapy 1.2 mg/kg on days 1 and 15, followed by a PET scan. Patients then received 4 to 6 cycles of brentuximab plus AVD. By the end of treatment, 88% of patients (n = 30) had a complete response, 2 had progressive disease, and 2 discontinued due to toxicity. At a median follow-up of 14 months, progression-free survival (PFS) and overall survival were 90% and 97%, respectively.

&ldquo;Early on, there was a sentiment that the amount of CD30 expressed on the surface of anaplastic large cell lymphoma turned out not to be an important determinant of response to brentuximab vedotin,&rdquo; said O&rsquo;Connor, stressing that patients with relatively low levels of CD30 responded similarly to patients with relatively high levels. &ldquo;What we are seeing now, as brentuximab vedotin migrates away from its original FDA approvals in anaplastic large cell lymphoma and Hodgkin disease, is that there are variable response rates across those diseases, and that the level of CD30 expression can span from zero all the way up to an excess of 90%.&rdquo; O&rsquo;Connor recently presented data suggesting that patients who had CD30-negative diffuse large B-cell lymphoma responded to brentuximab vedotin and had showed some duration of benefit.

&ldquo;Overall, those benefits were found to be much less than what we saw in patients that had CD30-positive disease,&rdquo; he said. &ldquo;This raises two questions. First, do those patients even respond if they don&rsquo;t have the target? Second, should we be measuring the drug in a more reliable way, so we can target the drug and try to improve the outcome?&rdquo;

O&rsquo;Connor pointed to a number of studies conducted that seem to suggest that, outside of the context of anaplastic large cell lymphoma and Hodgkin lymphoma, there may be a threshold effect. &ldquo;A recent study from Stanford University, in which patients with mycosis fungoides and cutaneous T-cell lymphoma were examined, suggests that patients with expression on less than 5% malignant lymphoma cells seem to have a very low likelihood of responding to brentuximab vedotin, while patients with greater than 5% malignant lymphoma cells seem to have a reasonably good probability of responding,&rdquo; he said.

O&rsquo;Connor said these findings do not look like a continuous variable. &ldquo;It doesn&rsquo;t appear that patients with 20% or 30% expression do any worse than those with 80% or 90% expression,&rdquo; he said. &ldquo;However, there may be an important threshold effect. It really comes down to how we measure CD30 on these cells. There is a lot of interlaboratory and interinstitutional variation. How it is measured, in terms of the details of the assays that people use to measure, really varies,&rdquo; he said.

The FDA has asked Seattle Genetics to develop a companion diagnostic to obtain a more quantitated, more reproducible handle on measuring CD30 across different lymphomas to help medical oncologists better understand the relative importance of CD30 expression as a detriment for response to brentuximab vedotin.

The next steps in the investigation of brentuximab vedotin within lymphoma may include two lines of clinical research, according to O&rsquo;Connor.  One will focus on trying to integrate brentuximab vedotin into some classic chemotherapy regimens, but most of the research right now is focused on therapies used in Hodgkin lymphoma with ABVD, O&rsquo;Connor maintained. &nbsp;

&ldquo;There was data presented that asked the question, &lsquo;Is it possible to eliminate one of the drugs in the ABVD backbone?&rsquo; The suggested drug was bleomycin, which has a lot of associated pulmonary toxicities. It was suggested to replace it with a novel active agent, such as brentuximab vedotin, and reshape that backbone for Hodgkin lymphoma,&rdquo; said O&rsquo;Connor. &ldquo;Early data suggest that eliminating bleomycin and replacing it with brentuximab vedotin could produce responses and PFS that are right in line with what we would expect with standard chemotherapy.&rdquo;

O&rsquo;Connor pointed to a second strategy that looks at adding brentuximab vedotin to a standard backbone, like R-CHOP chemotherapy for diffuse large B-cell lymphoma, as a way to improve the response rates of R-CHOP chemotherapy.

&ldquo;One study investigated two different doses of brentuximab vedotin and stratified patients by high and low levels of CD30. It was not a randomized study; therefore, it was difficult to see if the addition of brentuximab vedotin added any benefit to R-CHOP. However, it seemed to suggest that adding it was safe and produced fairly high complete response and overall response rates.&rdquo;

However, according to O&rsquo;Connor, the data showed that those who were CD30 negative did not do as well as those who were CD30 positive. This fact reinforces the need to develop better companion diagnostics and better assays that allow for more precise measurement of the relative expression of CD30 on an individual cell, as well as the expression of CD30 across all the cells in a particular tumor.

Abramson J, Arnason J, LaCasce A, et al. Brentuximab vedotin plus AVD for non-bulky limited stage Hodgkin lymphoma: a phase II trial.

The development of novel targeted drugs, such as brentuximab vedotin (Adcentris), against discrete cell surface proteins, such as CD30, has awakened a new way of thinking about targeted cancer biology

Lorraine Myers | Authors

Articles

Oncolytic Vaccines With Chemotherapy Show Survival Benefit in Head and Neck Cancer

Multidisciplinary Approach to Radium-223 Treatment Favored for Metastatic Prostate Cancer

New Immunotherapy With Chemotherapy Shows Results in Ovarian Cancer

Avelumab Shows Efficacy in Ovarian Cancer

Anti-CD30 Therapies in Lymphoma Change Treatment Decisions