Imunon Inc (IMNN) 2015 Q4 法說會逐字稿

Good morning. My name is Angel and I will be your conference operator today. At this time, I would like to welcome everyone to the Celsion fourth-quarter 2015 earnings conference call. (Operator Instructions). I would now like to turn the call over to Mr. Jeffrey Church, Senior Vice President and Chief Financial Officer of Celsion. Please go ahead.

Thank you. Good morning, everyone, and thank you for joining us today to discuss our fourth-quarter and full-year 2015 financial results, which we announced this morning before the market opened. Today's call will be archived and the replay will be available beginning tomorrow and will remain available by phone until April 13, 2016. Today's call will also be on our website for 30 days.

Before we begin the call, we wish to inform participants that forward-looking statements are made pursuant to the Safe Harbor provision of the Private Securities Litigation Reform Act of 1995. You are cautioned that such forward-looking statements involve risk and uncertainties, including, without limitation, the risk of clinical failures, delays or increased costs; unforeseen changes in the cost of our research and development activities; possible acquisition of other technologies, assets or businesses; and possible adverse action by customers, suppliers, competitors, regulatory authorities and other risks detailed from time to time in the Company's periodic reports filed with the Securities and Exchange Commission. Following our formal remarks today, we will open the call for questions. I'd like to turn the call over to Mr. Michael Tardugno, Chairman, President and CEO of Celsion. Mike?

Thank you, Jeff. Good morning. I'd like to start by thanking all of you for taking the time to join us today. I'm here with Dr. Nicholas Borys, Celsion's Chief Medical Officer, and with Jeffrey Church from whom we have just heard, our Chief Financial Officer.

As always, we are pleased to have this opportunity to update you on the progress that Celsion is making and, in particular, with its two clinical investigational stage products in primary liver cancer, recurrent chest wall breast cancer, ovarian cancer and our upcoming program in glioblastoma, or brain cancer.

As you can tell from our press release this morning, Celsion has had a very productive fourth quarter and if you look back even further, you would see that the Company has posted an impressive record of accomplishment throughout this past year of 2015. I'd like to highlight a few of them -- completing the integration of EGEN, this marvelous, gene-focused development stage company in Huntsville, Alabama, was accomplished.

Doing so, we rationalized the clinical strategy for the EGEN, now Celsion, technologies and launched the OVATION Study in first-line ovarian cancer patients. The study is supported with translational data demonstrating exciting immunotherapeutic potential of our first product from EGEN, GEN-1.

We established early-stage feasibility programs with development partners in one of the most exciting new fields of medicine, microRNA, to determine if our lung-directed delivery platform, TheraSilence, combined with certain miRs, microRNAs and anti-miRs developed by these companies, can have a positive effect on the course of disease in preclinical models. We'll know the outcome of this research and whether it will lead to a partnership soon.

We obtained approval in China for the OPTIMA Study, one of the few companies to do so, the few non-China companies to do so in this past year and are recruiting as planned in our global study of the largest unmet medical need remaining in oncology that's primary liver cancer or HCC.

We closed and published remarkable findings from our US RCW trials and are moving quickly to initiate a European-based study organized spontaneously by leading radiation oncologists in Europe and we reduced significantly our overall cost structure, eliminating over $4 million in annualized expenses from the combined Celsion/EGEN entity.

Celsion, now a 27 person company with a range of development stage research programs, utilizes our platforms in chemotherapy, gene-mediated immunotherapy and lung-directed RNA therapy. Celsion is well-positioned for 2016 and with multiple opportunities for clinical success as we move forward with some of the most important trials in our generation.

Now I'd like to take some time, particularly for those who may be new to Celsion, to quickly renew the strength of our science focusing primarily on our two clinical stage platforms, that is heat-sensitive liposomes and therapeutic plasmids, or TheraPlas. Both of these platforms provide us with the capability to deliver well-known, well-characterized therapeutics in highly effective dosage forms. Both have broad pipeline capability. Both are designed to enhance clinically meaningful therapeutics and both are engineered to local regionally targeted early-stage cancers.

So let's talk first about the heat-sensitive liposome to which Celsion has the exclusive license from Duke University. The distinctiveness of this 100 nanometer that's a submicroscopic lipid vessel is that, in the presence of tissue heated to just above body temperature, that's about 40 degrees centigrade, it releases its therapeutic payload in locally very high concentrations. The upshot to the heat-triggered mechanism is just this, a safe dose is administered intravenously and it results in a very high local dose when the tissue is heated with FDA-approved devices to the transition temperature.

We've shown clearly that this mechanism can increase the effective local concentration by over 25 times. I like to think of this liposome as so simple that it's elegant. Administered intravenously, targeting tissue with heat, driving high local concentrations with therapeutic value. This platform is robust. We demonstrated the capability to incorporate a number of chemotherapies, including platinum compounds and taxanes, among others.

Our first drug, however, on the platform is ThermoDox. As the name implies, ThermoDox is incorporating doxorubicin into the heat-sensitive liposome. ThermoDox represents our most advanced investigational product. It is in late-stage development for primary liver cancer and recurrent chest wall breast cancer. For primary liver cancer, or HCC as I pointed out earlier, we're conducting the Phase III OPTIMA Study, a global trial that combines ThermoDox with radiofrequency ablation, a heating technology used to treat newly diagnosed intermediate stage patients.

If successful, OPTIMA will support product approval filings in all major international markets, including China, Southeast Asia, South Korea, the European Union, Canada and the USA for the largest unmet need remaining in oncology. With over 800,000 new cases annually, where median survival is less than 30 months and five-year survival is less than 10%, our study immediately addresses, even by the most conservative estimates, a $1 billion plus international market opportunity.

As many of you know, OPTIMA is not our first attempt in HCC. It was preceded by the HEAT study, a trial, while failing to meet its primary PFS endpoint, taught us a great deal. Without question, I say this unequivocally, without question, we know more today about RFA and intermediate stage primary liver cancer than just about any company on the planet.

Among our learnings, we know that RFA must be used within its engineered design limits to be successful. Intermediate stage tumors require no less than 45 minutes of heating time to be fully ablated. Longer heating time correlates well with higher local concentrations of ThermoDox, which we have prospectively proven in large animal preclinical studies and in computational models.

We learned that patients in our study had unexpectedly long overall survival. As a consequence, patients with poor liver health scores died primarily of their underlying disease, not of the cancer.

And the final point, what we learned, and has been mentioned by a number of thought leaders in liver cancer, is that ThermoDox, used with the appropriately conducted RFA, can now be considered for a cure.

What's our basis for all of these learnings? For the past three years, we've been following a well-balanced, well-bounded subgroup of patients from the HEAT study whose RFA treatment time is greater than 45 minutes. With each quarterly data sweep, clinical benefit in the ThermoDox arm improves and statistical significance gets better. Every quarter, the findings improve, every time.

Now it's a median, results are considered stable by statisticians. These data, along with corroborating multi-variant analyses, have been reported and updated in five international medical conferences and have been the subject of two international liver cancer-specific symposia. I can report that there has been no significant challenge to the analyses and/or -- nor our thesis. And our thesis is just this. In intermediate stage disease, ThermoDox plus RFA standardized to a minimized -- a minimum of 45 minutes is a significant benefit over RFA alone standardized to a minimum treatment time of 45 minutes.

The subgroup survival data is astounding. The median overall survival in the ThermoDox plus standardized RFA arm is greater than 80 months, or over 6.5 years, which in oncology one would consider curative. In contrast, the optimized RFA arm alone, that's RFA conducted alone at 45 minutes minimum, resulted in a median survival of 54 months from our HEAT study.

As a comparison to other competing therapies, for example, chemo embolization, one of the more widely used local treatment options for this population. Survival shows a median ranging from 37 months to 54 months. Again, I'll remind you that ThermoDox plus standardized RFA arm, standardized at greater than 45 minutes, consistently showing 80 months survival benefit with statistical significance.

It's not surprising that some of the most respected investigators, thought leaders and regulatory agencies indicate their impressive support for continued research and for our follow-on OPTIMA Study. The OPTIMA Study is based on, of course, (inaudible) findings and is evaluating ThermoDox in combination with optimized RFA, which will be standardized to a minimum of 45 minutes across all investigators and all clinical sites for treating lesions 3 to 7 centimeters versus standardized RFA alone.

The study is expected to enroll up to 550 patients globally in up to 75 sites, and as I mentioned, in the United States, Europe, China and Asia Pacific. The study is powered to detect a 33% improvement in overall survival and that's compared to the 50% that we see in the HEAT study subgroup. In my view, this gives us plenty of margin for success.

Just a note about China. China represents the most important market for ThermoDox with approximately 50% of the 800,000 new cases diagnosed annually originating in China. To support Chinese registration, we will enroll 200 Chinese patients, which is the minimum required by the CFDA to file a new drug application. We continue to be very optimistic about the potential of ThermoDox plus standardized RFA in this region and look forward to an updated data set from the Chinese cohort in the near future, hopefully at the median, perhaps in the third quarter.

All in all, while we are pleased with the progress that we've seen with our OPTIMA trial and remain on track to complete enrollment by the end of 2017 or early first-quarter 2018, this will be followed by the first interim efficacy readout in the second half of 2018.

In addition to the OPTIMA study, we are also advancing our development program for ThermoDox in recurrent chest wall breast cancer, or RCW cancer. We had the opportunity to present data from our DIGNITY Phase II study at the San Antonio Breast Cancer Conference Symposium in September. The data demonstrated a combined local response rate of 62% among evaluable patients treated with ThermoDox. In our view, an outstanding result in this highly refractory form of breast cancer associated with poor quality of life and very limited treatment options.

We are building on this treatment's potential with our Euro-DIGNITY Study. This study will evaluate complete and partial responses, both clinically meaningful, after three cycles of ThermoDox plus hyperthermia and radiation, as well as local regional breast tumor control in patients undergoing this tri-modal therapy. The stat plan calls for 70 patients in an open-label trial with site activation beginning next month and first interim assessment expected in the first quarter of 2017, just a year from now.

As a reminder, costs for this trial are being offset with funding in kind from the device manufacturer, MedLogics, in investigational sites in Italy, Poland, and the Czech Republic. I want to share with you -- and we talked about a lot of accomplishments -- but I do want to share with you one note of disappointment. We filed a request for breakthrough designation with the FDA in quarter four last year. Unfortunately, while cordial in their response, FDA indicated that we did not have enough data to grant our request. They did indicate, however, that we could reapply. But given the slow enrollment history of our past three studies, amounting to about 50 patients over seven years, we're unlikely to do so. Instead, we will focus on Europe where thermal therapy is the standard of care for this population.

Now I'd like to focus on our second and equally, if not more important, platform, therapeutic plasmids, or as Dr. Anwer likes to call it, TheraPlas for short. TheraPlas is a synthetic, nonviral vector, engineered to deliver DNA plasmids that are coded for therapeutic proteins into living cells. Its formulation is a patented polymer with a cholesterol agent that promotes absorption of this nanoparticle into the cell. Once in the cell, the DNA plasmid begins a process of using the cellular machinery to construct proteins for which the DNA is sequenced.

The proteins, now with therapeutic value, are secreted for an extended period of time and, in some cases, for the life of the cell. TheraPlas is often compared to various viral vectors, which are commonly used to deliver DNA sequences into the cellular environment. And while viral vectors are known to be more efficient having high transfection rates, they do have limitations. TheraPlas, we believe, addresses some limitations and is superior in other important aspects and more compelling for local regional treatment.

TheraPlas is not subject to neutralizing antibodies as our viral vectors and can be administered repeatedly and as a maintenance therapy if so indicated. TheraPlas is shown to be very safe. We have seen virtually no SAEs or overlapping toxicities when combined with other therapeutics or chemotherapies. So it is well-suited as a combination therapy with standard of care chemotherapy, allowing for evaluation importantly in oncology, along for evaluation in first and second-line patients, particularly when evaluating an immunotherapeutic where the immune system has not been compromised by repeated therapies.

Now our first drug on this platform is called GEN-1. GEN-1 is an IL-12 coated DNA plasmid formulated into the TheraPlas nanoparticle. This therapy causes sustained local production and secretion of the IL-12 protein. IL-12 is a cytokine that mediates and recruits multiple anticancer mechanisms of the immune system. While it has been recognized as one of the most powerful immunotherapies in cancer, its development as a standalone treatment has been hindered with the serious toxicities associated with poor pharmacokinetics with factory-produced or recombinant IL-12 protein.

In a sentence, recombinant IL-12, because of its short half-life, requires high doses; high doses cause serious safety concerns. GEN-1 overcomes these limitations by promoting persistent, local production and endogenous production of IL-12. Data from our GOG-conducted Phase Ib study of platinum-resistant ovarian cancer patients demonstrate that intraperitoneally-administered GEN-1 produces a distinct IL-12 protein that is localized at the tumor site. It lasts for up to one week after a single treatment.

We noted that concomitant increases in interferon, an anti-angiogenic protein, and TNF alpha, indicate that the IL-12 GEN-1 treatment is immunologically active. Clinical findings from the same trial were also impressive with a partial response or stable disease observed in 100% of patients treated at the highest dose. This compares favorably to an overall clinical benefit of less than 50% for the current standard of care in published studies.

We are now conducting a Phase I dose escalation study in newly diagnosed ovarian cancer patients in the neoadjuvant setting, known as the OVATION study. This trial is designed to enroll 3 to 6 patients per dose cohort and will evaluate safety and efficacy and will define an optimal dose for a follow-on Phase I/II study combining GEN-1 with Avastin and Doxil, the standard of care for platinum-resistant recurrent patients.

In February, we reported that the first two patients in the OVATION study who completed treatment have shown promising results. Both patients demonstrated improvement with a dramatic drop in the CA-125 protein levels of 89% and 98%, respectively. For context, we would note that a 50% reduction in CA-125 levels is considered meaningful. Now for those of you who are asking the question, CA-125 is a protein that is a prognostic indicator of tumor cell burden where lower levels are better.

Last week, our DMC met and gave the okay to enroll the second cohort, a 30% increase in dose. With the first cohort now completed, I'm pleased to report that the first three patients in this now approved second cohort have been identified. Assuming no DLTs, we can expect the third and perhaps final cohort to enroll beginning in the third quarter.

The study, of course, is -- the study goal, of course, is to identify a safe, therapeutic dose of GEN-1. In this case, we will not use a traditional means to find the dose, but typically in oncology, on doses escalated until you find the maximum tolerated dose, as Dr. Borys points out repeatedly, the maximum dose, maximum therapeutic dose of GEN-1 will largely be determined by the activity of the immune system.

The data from this Phase I study will be used to inform the Phase I/II study evaluating GEN-1 in combination with Avastin and Doxil, the Phase I/IIb study that I just referred to earlier. The combination with Avastin and Doxil (inaudible) supported was very impressive, I would consider exciting preclinical data, which demonstrates potential synergy of this combination to substantially inhibit tumor growth. Our studies now show convincingly that GEN-1, when combined with Avastin and Doxil, demonstrate a 98% reduction in tumor burden when compared to the untreated control group.

These findings represent a statistically significant reduction in tumor burden and disease progression when compared to the in vivo studies of the combination of Avastin and Doxil alone. Analysis of serum chemistry and hematology demonstrated no overt toxicities associated with combination treatments. The study and its findings will be presented at the AACR next month.

In the meantime, we are finalizing the Phase I/II clinical trial protocol in recurrent ovarian cancer patients for FDA submission later this year. And while our efforts for GEN-1 are primarily focused on our ovarian cancer program, we continue to see great promise in glioblastoma multiforme. Our preclinical work is ongoing and is focusing on the mechanism of administration, dosing protocols and toxicity studies. We expect to complete work in the pre-clinic by year-end.

In the meantime, we will continue to focus our resources and give full attention to drive the ovarian cancer program. The potential for both GEN-1, immunotherapy and ThermoDox is exciting to say the least and we look forward to providing you with updates as we advance these programs through the clinic. Now let me turn the call over to Jeff Church for a review of our financials. Jeff?

Thank you, Mike. Starting with cash, we ended the year with over $20 million of total cash and investments. For the year ended December 31, 2015, we reported a net loss of $22.5 million or $1.03 per share and that compares to a net loss of $25.5 million or $1.38 per share in 2014.

Cash used for operations in 2015 was $20.8 million compared to $21.4 million in the same period of last year. We reported in our last call that we implemented a reorganization following the full integration of our EGEN operations. We evaluated our current organizational structure and have aligned our resources and clinical programs with our near-term development objectives.

As Mike discussed earlier, we have tightened our development focus when OPTIMA and Euro-DIGNITY for ThermoDox and advancing GEN-1 in ovarian cancer. As a result of this action, we expect to realize a 15% to 20% reduction in personnel and related annual operational costs going forward into 2016. We estimate that our average 2016 cash usage for operating activities will be approximately $4 million per quarter and that reflects the full implementation of the OPTIMA study and our clinical development plans for the GEN-1 program.

We continue to monitor our cash expenditures to ensure the most efficient use of cash to create shareholder value and project that our cash will support operations through 2016, pass many of the milestones outlined earlier. R&D costs were $14.7 million in 2015 compared to $15 million last year. Our R&D expenditures in 2015 were focused on the startup and clinical site initiation for the Phase III OPTIMA study, as well as the first of two clinical studies using GEN-1 to treat ovarian cancer, and also, the production of the clinical supplies needed to support these clinical initiatives.

General and administrative expenses were $6.7 million in 2015 compared to $8.9 million last year. This 25% decrease was primarily the result of lower personnel and operating costs resulting from the reorganization and staff reductions announced in the third quarter of 2015, lower insurance premiums and a tighter clinical development focus on those programs that we believe will drive shareholder value in the near term through the readout of the pivotal Phase III OPTIMA Study anticipated in 2018.

I'll now turn the call back over to Mike.

Thanks, Jeff. I hope that it's clear that we are advancing clinical programs that are based on leading edge technology platforms and that ThermoDox and GEN-1, our two clinical stage investigational products, are addressing significant markets and have the potential to provide patients with safer, more effective treatments. And we remain fully committed to bringing forward this portfolio of therapies to address the unmet treatment needs of patients with cancer worldwide.

Our balance sheet remains strong, which we believe will allow us to execute on many of the upcoming milestones that we've discussed this morning. The progress we've made over the last several months has set the stage and positions us for what we believe will be a very successful 2016. As always, we greatly appreciate your interest in the Company and we look forward to updating you on our progress as we continue to move forward with these very important clinical programs.

We will now open the call to questions, operator. And for those on the line interested in asking questions, we would ask you to keep them to no more than two.

(Operator Instructions). Jason McCarthy, Maxim.

Hi, Michael; hi, Jeff. Sounds like things are going well for you guys. I know we're waiting for OPTIMA -- enrollment's going well. It's a next year event to complete enrollment and we're really focused on GEN-1 in the immuno-oncology space and can you talk to me a little bit about the open-label nature of the neoadjuvant study and if you are dosing patients, 3 to 6 patients per cohort, do you plan to release data as you get data periodically over the next quarter to two quarters because, in our opinion, we could see a little bit of immuno-oncology data really going a long way for a company?

Thanks for the question, Jason. I -- so we have already, in the first two patients in the neoadjuvant study, we've released some information regarding the response to the treatment following the debulking surgery. It would be our intention certainly with the agreement of our investigators to continue to report results as we are confident in the outcomes. So yes, as an open-label study, I think it's important for us as we see the benefit of (inaudible) or otherwise to the benefit of our therapy, we will be reporting it to the investment community, probably not on a patient-by-patient basis, but more in groups of patients.

I do want to point out something that may not be clear. Also associated with this trial is the collection of translational data, so we are collecting with each patient tissue samples that should give us an indication of the value of the immuno-stimulating capability of IL-12 with various markers in proteins and the like both systemically and locally.

So our plan is to collect enough translational data from -- or tissue samples from the first two cohorts. We believe that we can draw a line between two points -- begin to draw a line, maybe begin to see a trend from the first two cohorts and we will be reporting that -- the results of that translational analyses. That could likely come later in the -- or earlier in the third quarter of this year.

Okay, great. And just a brief question on ThermoDox and the DIGNITY Study. I know you are planning to do a study in a slightly different population in Europe. Do you have plans to advance ThermoDox in recurrent chest wall here in the US?

Yes, so we've studied that very carefully. Part of our strategy, I think with the -- as we talked about a little bit of a disappointment that we had with breakthrough. There is no doubt that the -- in this refractory population -- that the results that we've seen are nothing short of remarkable. The fact that the end is so small has been a challenge for us. We were hopeful that with breakthrough designation, there would be the support, implicit support from the FDA to assist us with advancing recruitment in the United States.

Without that, however, it's difficult, frankly, for us to consider a separate US trial. So what Nick has been talking about is including at least one US site in the Euro-DIGNITY study. It's a little bit of a challenge, but he's reached out to a few investigators who have indicated their strong interest in thermal therapy plus ThermoDox for these patients.

The challenge for us is this. We've standardized the Euro-DIGNITY study on a device that's not sold in the United States and it's an advanced device. We think it represents a next generation superficial hyperthermia technology, so while we've essentially standardized the European study on this non-US allowed device.

So our challenge is not only finding an investigator site that will recruit patients in the US, we think we may have done that, but it's also now to convince FDA to combine an IDE with an IND, so we're working on it. We would like to have some representation from at least one US site in the Euro-DIGNITY study to give us a voice, if nothing else, with FDA as we consider registrational programs. I hope that (multiple speakers).

Thank you very much, guys.

Keith Markey, Griffin Securities.

Good morning, Mike, Jeff, Nick. Couple of questions. First, I was just wondering can you tell us how many actual sites in China are enrolling patients at this point and when do you think this whole complement will be up and running?

Yes, Nick will take that.

Hi, this is Nick. We just initiated our first site just about two weeks ago now. We just had our investigator meeting just a few weeks before that, so we're looking at a pretty rapid startup. We don't have a magic number of sites that we want to have up and running in China, but you could expect well over 20, maybe 25 sites. So China is very important to us. We have great enthusiasm and I think we're going to have good enrollment.

Great. Thank you.

Keith, I would like to just add to that. So I attended the investigator meeting, the kickoff meeting for the Chinese contingent. We had all of the most important thought leaders in China, along with I think a very motivational review of the HEAT study data and its potential by Professor Poon, who we all know is globally recognized as a thought leader in primary liver cancer.

Without a question, without question, the enthusiasm for this study I think largely driven by the incidence -- I mean it's overwhelming -- HCC is overwhelming the healthcare system in China, but it's very clear to us that among interventional oncologists, they believe that there is an opportunity here to substantially improve outcomes and provide a health economic solution that is far superior to what they are currently experiencing.

Great. Thank you. And then I was just wondering, as far as the R&D and G&A expenditures go for this year, should we look for them to be comparable to what you posted for 2015?

Hi, Keith; this is Jeff. We actually anticipate a lower level in 2016, to the tune of around 10% to 15%, largely due to the full-year effect of the reorganization that we implemented last year. And then as we discussed during the call, just a tighter focus around the ThermoDox programs in primary liver cancer and recurrent chest wall breast cancer and then the ovarian focus for GEN-1. So we anticipate that our operating expenses, R&D and G&A will be approximately $4 million a quarter for next year.

Okay, great. Thank you.

Mark Breidenbach, H.C. Wainwright.

Hi, guys. Just a few -- just a couple questions for you this morning. First, I was hoping you could help us frame the serum biomarker results we saw from the first two patients in OVATION. We see that the first couple patients had substantial drops in CA-125 levels. Can you remind us if this particular biomarker was monitored in the Phase Ib GOG study and, if so, can we draw any conclusions about GEN-1 working better or worse when deployed in earlier neoadjuvant setting?

Hi, Mark; this is Nick. That's a very good question and in the original GOG study, first of all, you have to keep in mind that was a different patient population.

Sure.

In this current study, these are newly diagnosed patients, so they had bulky disease on presentation and so here, it's not a perfect marker, but it's an encouraging marker, as Mike was mentioning in his talk. So that particular marker in an advanced setting, you are looking for it to really rise and we weren't recording that in the GOG study, so I'm not sure if we could make the comparison. But you could take this data and go to literature and take a look to see what this drop really means in other neoadjuvant studies.

Got it. Okay. Did I hear correctly that the third cohort will be the last cohort for OVATION? And that was the 61 mg per meter squared dose or did I mishear that?

No, I think perhaps -- I said perhaps the third and final -- if there's an indication that we have not reached the NadR or the upper level of activity of the immune system, we reserve the right to go on to a fourth cohort. But I think after a fourth cohort, that would likely be the end of the trial, so the third cohort is -- optimistically, we are looking at the third cohort to conclude the study, but there's always a chance we may continue to dose-escalate into cohort number four.

Understood. And if I can just tack on a really quick follow-up, is there a particular set of efficacy criteria you are looking for before making a go or no go decision with continued development in the neoadjuvant setting given that the next planned trial is moving back into a platinum-resistant setting?

No. The number one issue is the safety issue. We want to see that we could come up with a maximal safe dose, so that is number one. So things could happen at this cohort or at the next cohort and then we're carefully monitoring a whole host of immunological markers to see if we could -- as Mike was saying, if we're looking for some sort of plateau or indicator that we've gotten there.

As you probably know, in many immunological drugs under investigation right now, they haven't been able to reach toxic doses or high doses or MTDs and so we're trying to balance what we learned from the markers and what we're learning from the toxicity. So there isn't any one thing that we will be able to point to except for safety that will dictate a stop to the trial.

I just point out also that we may not reach the maximum therapeutic dose in the neoadjuvant study, which would give us a basis to -- for the Phase I/II study -- combining with Avastin and Doxil to give us a basis to start at a higher dose -- ostensibly at a higher dose -- and continue to dose-escalate in the Phase I portion of the Phase I/II study.

Okay, understood. All right. Thanks for taking the questions and we're looking forward to seeing the GEN-1 presentation at AACR. Thank you.

Hartaj Singh, BTIG.

Hey, good morning, Mike, Jeff. Just quick question, two actually, I'm sorry. Very, very quick. One is just any update on Europe and just the programs you've got there, any kind of the commercialization and the discussions you're having with authorities there on the right chest wall breast cancer program. And then, secondly, just can you walk me through over the next 6 to 12 months what are the important data and just clinical trial/readouts because you've actually got a lot going on and it would be nice to hear what specifically you're expecting over the next 6 to 12 months? Thanks, Mike.

Okay, Hartaj. So let me start with Europe and -- so on the -- with regard to the Euro-DIGNITY Study, about six months ago, we decided that it would be -- the study would be better managed -- we believe it would be better managed not as a spontaneous study, but as a study that is industry-sponsored, so we changed the leadership.

In doing so, we are filing separately with the regulatory agencies in the various countries, the necessary documentation to initiate the study. That documentation is being submitted as we speak. I suspect, as I said in my prepared comments, that our first investigator site will be up and enrolling patients in April. Our goal is to have the balance of the investigator sites in the Czech Republic, Poland, Italy, Israel and potentially one in the United States. Although the US one would come a little bit later, to have them all up and running by the third quarter of this year. The goal is to complete enrollment by the end of 2017.

With regards to the early access program, as you know, we have announced the hiring of an executive who resides in Europe to provide leadership not only for our early access program, but also to oversee some of our clinical trial interests and our relationships with key thought leaders in Europe.

With regards to the EAT, progress has been slow, not because of a lack of interest, but the registrational requirements we are finding out to be a little bit more challenging than we originally anticipated. I also continue to believe that we will have a successful program, just taking us a little bit more time to file the appropriate documentation and get the regulatory support necessary for physicians to be able to prescribe ThermoDox to patients who have exhausted their treatment options.

With regards to milestones, upcoming milestones over the next 6 to 12 months, there is a lot going on. We expect to be able to, on a cohort -- as I mentioned earlier, on a cohort-by-cohort basis, provide results from the dose escalation, neoadjuvant study in OVATION. We will be presenting data from the first two cohorts, the translational data from the tissue analysis from the patients enrolled in the first two cohorts. We expect to provide final data from this neoadjuvant study by the end of the year.

We expect to submit and initiate the Avastin combination study in quarter four 2016 and initiate the Euro-DIGNITY study, again, with data as it's an open-label study being presented throughout the year and completion of that study in 2017. And of course, if things continue to be on track by the end of 2017, announce the completion of enrollment in the OPTIMA study.

Great. Thanks, Mike. Appreciate that.

(Operator Instructions). There are no further questions at this time. You may continue.

Okay. Again, I want to thank all of you for attending today's conference call. As always, we are excited to communicate with our investors and shareholders and the investment community generally. We appreciate your interest and look forward to providing you with updates as our milestones are achieved over the course of the coming year. Thank you again very much.

This concludes today's call. Thank you for your participation. You may now disconnect.