Dare Bioscience Inc (DARE) 2015 Q3 法說會逐字稿

Good afternoon, and welcome to the Cerulean second-quarter 2015 conference call. This call is being recorded.

My name is Tamara, and I will be your operator for today.

With us today from the Company are Chris Guiffre, President and Chief Executive Officer; Gregg Beloff, Chief Financial Officer; and Alejandra Carvajal, General Counsel.

Mr. Guiffre, please proceed.

Thank you. Good afternoon, everyone, and thank you for joining Gregg, Adrian, Alejandra and me for this call.

To begin, I will ask Alejandra to comment on forward-looking statements that may be made during this call. Alejandra?

Thanks, Chris.

Certain remarks that we make during this call about the Company's future expectations, plans, and prospects constitute forward-looking statements for purposes of the Safe Harbor provisions under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the Risk Factors section of our most recent quarterly report on form 10-Q, which is on file with the SEC and can be accessed on our website.

In addition, any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. While we may elect to update these forward-looking statements at some point in the future, we specifically disclaim any obligation to do so, even if our views change. Therefore, you should not rely on these forward-looking statements as representing our views as of any date subsequent to today, November 16, 2015.

Back to you, Chris.

Thanks, Alejandra.

In August, I introduced Gregg Beloff on his first quarterly call as CFO. Today, I'm introducing Adrian Senderowicz on his first quarterly call as our CMO.

Adrian is a talented clinical oncologist with deep industry and FDA experience, so he is well-suited to lead the development of CRLX101 toward approvals in multiple indications. And he is equally well suited to do the same thing with CRLX301 and the other NDCs that we plan to create with our platform.

Adrian?

Thank you, Chris.

Cerulean is doing something that the industry and academia have tried to do for decades: targeting tumors while sparing healthy tissue. This is exciting to me because I know how effective chemo is at killing cancer cells, but it's also -- but I also know how hard it is for patients to tolerate chemo. Having had the chance to review the CRLX101, the CRLX301 data before I joined, I believe that we are on the right path to make highly active and well-tolerated indices that can be used either alone or in combination with other cancer treatments.

I will turn it back to you, Chris.

It's great to have you on our team, Adrian.

Shortly after we appointed Adrian as our CMO, we welcomed David Walt to our Board. David is an acclaimed scientist, and successful entrepreneur. His track record of success as the founding scientist of Illumina speaks for itself. As we continue to develop our platform and expand the potential pipeline it enables, David's experience and insights will be invaluable to a platform-based, product-driven company like Cerulean.

NDCs are an important innovation in cancer treatment, because they preferentially concentrate cancer treatments in tumor tissue, are taken up inside cancer cells, and slowly release their payload from within the cancer cells. We have abundant preclinical data demonstrating our unique mechanism of action. Now, for the very first time, we have proven our mechanism of action in humans.

At the so-called triple meeting earlier this month, we presented data generated by Mark Davis from Caltech, an oncologist from the City of Hope. In this study, pre- and post-tumor treatment biopsies show the presence of CRLX101 in tumors and an almost complete absence of CRLX101 from the surrounding normal tissue. Importantly, Doctor Davis was able to show topo and HIF inhibition in post-treatment biopsies. These data represent a major milestone in the validation of our platform, and our original premise is intact.

Now, let's move to program updates: first, CRLX101. In October, we announced that our randomized Phase 2 trial completed enrollment. We remain on track to report the top line data from this study in the first half of 2016.

The CRLX101 IST data previously presented at ASCO led the FDA to grant fast-track designation to this program. We are actively engaging with the agency and, if all continues to progress well, we will launch our Phase 3 registration trial in the second half of 2016.

The Cerulean team is proud to be part of a paradigm shift in the treatment of advanced kidney cancer. Today, advanced kidney cancer patients often receive a TKI in first line, then a TKI in second line, and a TKI in third line. Occasionally, patients receive an mTOR inhibitor in second or third line.

The current treatment paradigm is sub optimal, but it is undergoing rapid changes for the better. We expect that immuno oncology products such as nivolumab will displace sunitinib in first line. We expect new TKI combinations such as lenvatinib plus everolimus and a new TKI called cabozantinib will displace axitinib in the second line. And in third and fourth line, we expect that CRLX101 plus Avastin will eliminate the current need to reuse a TKI after a prior TKI failure. Assessing how the new RCC treatment paradigm impacts CRLX101 is central to the Cerulean investment thesis, so we welcome any questions you may have on this topic in the Q&A portion of this call.

RCC is our most advanced indication. But it is important to remember that CRLX101 is a drug with potential use in multiple cancers. Adrian reminds us regularly of the potential for this drug in multiple combinations, indications, and dosing schedules.

One of Adrian's first suggestions at Cerulean was to test whether CRLX101 can be dosed weekly to increase the therapeutic index because we must commit to the best possible regimen before investing in expensive registration studies. We are exploring weekly dosing in a trial in advanced solid tumors, and we will test this new schedule in other trials. By doing so, we will have the information we want before we launch a registration study in both RCC and ovarian.

Now, turning to our ovarian programs, you may recall that MGH conducted a study of CRLX101 as monotherapy in relapsed ovarian cancer. That setting -- excuse me -- that study met its standpoint and showed that CRLX101 is active in this setting. With support from Genentech, MGH launched the current study to see if CRLX101 plus Avastin could provide even greater benefit for these patients. In September, we announced that the CRLX101 Avastin combination achieved a predetermined stage gate, allowing the trial to advance to stage 2.

Overall, there were 18 patients in stage 1. At least three of these patients had to achieve six months PFS in order to advance to stage 2. So far, we have nine patients who have achieved at least six months PFS, and two patients are being treated as we speak who have been on study for less than six months. Of the 18 patients treated in stage 1, there were 16, 17 and 18 evaluable patients for six months PFS, response rate and CA 125 levels respectively. So let me tease that out for you just a bit more.

So far, 9 of 16 patients, or 56% achieved at least six months PFS, which is almost 3 times more than the historical 20% seen in this setting. 3 of 17 patients or 18% achieved a RECIST response, and 14 of those 17 patients, or 82% achieved stable disease per RECIST criteria. Lastly, 8 of the 18 patients, or 44% experienced a 50% or greater decrease in CA 125 levels.

Clearly, CRLX101 plus Avastin provides greater benefit for these patients than CRLX101 alone. We have done some analyses that show that the median PFS for patients on the combo study is almost double what we saw in the monotherapy study. That is great news for these patients, and it is great news for the CRLX101 Avastin combo in this setting because it shows the synergy we expected.

It also is encouraging news for this combination in other tumor types including RCC, which I discussed previously. And because the CRLX101 Avastin combination appears to be generally well tolerated, we do not see any reason why tolerability would prevent us from exploring this combination in other tumor types.

The second combination we are exploring in ovarian cancer is CRLX101 plus weekly paclitaxel. We are conducting this trial in collaboration with the GOG Foundation. We are off to a promising start in that trial, and we intend to provide data on this combo in the first half of 2016.

So at this point, we know we have a drug candidate that is active and well-tolerated in relapsed ovarian cancer. Despite Avastin's approval in combination with chemotherapy in this setting, relapsed ovarian cancer remains an area of high unmet need, and we are committed to this space.

Phase 3 trials are big commitments, and we think it is important to have as much information as possible before we select our preferred path forward. So we are studying two combination approaches, and each of the combinations will be explored on both the current every other week dosing schedule, and on a weekly dosing schedule. Data from both of these trials will inform our registration strategy in ovarian cancer.

Finally I will talk about the combination of CRLX101 and chemoradiotherapy in the treatment of locally advanced rectal cancer. This trial studies CRLX101 as a radio sensitizer.

Topoisomerase or topo inhibitors such as irinotecan have been studied as radio sensitizers, but they have been limited by toxicity. Because CRLX101 is a topo inhibitor, we want to know if it can be a better-tolerated radio sensitizer. This is very different than our RCC and ovarian trials, which do not involve radiotherapy, and which do involve HIF inhibition as opposed to topo inhibition.

We recently completed assessment of 22 evaluable patients in our rectal IST. And four those patients achieved a pathological complete response or PCR, resulting in a PCR rate of 18%. The combination appears to be generally well-tolerated.

Although these data support the combined ability of CRLX101 with chemoradiotherapy, the PCR rate is not as high as we had hoped for, so we will not launch a randomized trial in this indication, at least for now. Instead, we will explore weekly dosing in this tumor type to find out if it will increase PCR rates. If weekly dosing increases PCR rates, we may explore a registration path in this setting. But in order to tackle the significant regulatory risk associated with seeking an approval based on PCR rates alone, we would want to see much higher PCR rates than what we've seen so far.

Accordingly, the trial will continue to explore whether CRLX101 can be a better tolerated radio sensitizer, but it will shift from studying the every other week dosing regimen to a weekly dosing regimen. We will provide a further updates on this trial during the second half of 2016.

Now let's talk about some interesting data from our second platform-generated clinical candidate, CRLX101 -- excuse me, CRLX301. As you may know, CRLX301 is an NDC with a docetaxel payload.

In our dose escalation trial, we have completed the first five dosing cohorts. We started at 7.5 mgs per meter squared, once every three weeks. And we escalated to 15, 30, 60, and then 75 mgs per meter squared once every three weeks. 75 mgs per meter squared every three weeks is the highest cohort completed so far, and it is equivalent to the standard dose level and schedule for commercial docetaxel. Now we have been approved to go above the standard docetaxel dose, and we have opened the 90 mgs per meter squared dosing cohorts.

In the first five cohorts, we saw no DLTs, so we have not yet declared an MTD. We will continue to does escalate until we find an MTD on the once every three weeks schedule. And we also will explore a weekly dosing schedule to determine the MTD for that regimen. These parallel paths will allow us to determine the recommended Phase 2 dose with the preferred dosing schedule.

We would not expect to see activity at the lower doses studied, but we have activity data from a few of the patients dosed at 75 mgs per meter squared, and we already have seen an interesting sign of activity. One patient with BRAF mutant carcinoma of unknown primary who previously failed prior BRAF-directed therapy has experienced tumor shrinkage. The patient experienced a 13% decrease of target lesions and a 35% decrease on non-target lesions from baseline. Based on these promising results, we expect to begin the Phase 2a portion of this trial in the first half of 2016.

Now I will turn it over to Gregg for a financial update and a recap of upcoming milestones. Gregg?

Thanks, Chris.

Let me briefly highlight our financial results for the third quarter of 2015, which are included in the form 10-Q that was filed after market closed today.

For the third quarter, we had a net loss of $10.3 million compared to a net loss of $5.6 million for the third quarter of 2014. The increase in net loss for the 2015 period was due principally to expenses associated with our ongoing clinical development programs, specifically, costs related to our randomized Phase 2 RCC trial for CRLX101 and a Phase 1 trial for CRLX301, both of which commenced in 2014.

We ended the third quarter with cash and cash equivalents of approximately $77.6 million. We believe we will have the cash necessary to fund operations into 2017. We expect to achieve a number of key accomplishments within that period.

In particular, we expect to achieve the following milestones. Announce top line data from the randomized Phase 2 RCC trial of CRLX101 in combination with Avastin in the first half of 2016. Announce data from the ongoing Phase 1b trial with the GOG Foundation of CRLX101 in combination with weekly paclitaxel in relapsed ovarian cancer in the first half of 2016. Provide additional CRLX301 data from the Phase 1 portion of the Phase 1 2a trial in the first half of 2016. Launch the Phase 2a portion of the CRLX301 study in the first half of 2016.

Provide data from the CRLX101 weekly dosing trial in the second half of 2016. Announce additional interim CRLX101 data from the ovarian and rectal ISTs in the second half of 2016. And, finally, pending review of the randomized data, we expect to initiate a Phase 3 trial of CRLX101 plus Avastin in third and fourth line RCC by the end of 2016.

With that, let's open the call up for Chris, Adrian and me to take your questions.

Thank you.

(Operator Instructions)

Jon Eckard, Barclays.

Hi. This is Bryan sitting in for Jon. I was just curious if you could discuss the preclinical data and rationale of the combination of 101 and PARP inhibition.

And additionally, if this were to go into the clinic, what cancers would you target? What would be the most rational cancers to target?

Sure. Thank you very much for the question. This is Chris. I will start off, and then I will obviously ask Adrian to chime in.

Your question relates to the use of CRLX101 in combination with PARP. It is a great question because as many people know, it is an obvious synergy that exists between PARP inhibitors and Topo1 inhibitors. Topo1 inhibitors damage DNA, and PARP inhibitors prevent the repair of DNA damage.

So we're not the first people to think of this combo. You can read the literature and you can see many people have tried.

Because you are familiar with the Company and the combination, you are probably well aware that those combinations today have been plagued by toxicities. Not only the toxicities inherent with the PARP inhibitors, but more importantly, the toxicities associated with the -- excuse me, with the Topo inhibitors. So what the PARP space needs and I believe is looking for is a better tolerated Topo1 inhibitor. That's what we believe we have, and therefore we have made a point of telling people that sometime next year, we would like to be in the clinic with a PARP Topo combo.

We, as you are aware, obviously have a number of examples of combining our drug with PARP inhibitors pre-clinically. We have not disclosed a lot of that data. But I can assure you that we would not be talking to you about it on this call right now as something I wanted to do next year if it weren't for the fact that we A, saw the synergies that you'd expect to see between the Topo1 inhibitor and the PARP inhibitor, and B, saw that it was more combinable than what other people have tried.

So with that in mind, I think I will turn it over to Adrian to talk a little bit about what he would hope to achieve in the clinic next year. Adrian.

Thank you for the questions. It is a very exciting question, and this is a question I've been thinking for so many years. Since I was at the Food and Drug Administration and when I moved to AstraZeneca, I was very interested in the PARP space. And based on my interest in cell cycle regulation when I was at the NCI working with DNA damage control.

So as you are quite aware, there is this concept of synthetic lethality. So tumors have in general some abnormal DNA damage response controls. And the inhibition with PARP inhibitors -- and as you know, there are many in the clinic -- can induce cell death by these augmentation of these endogenous DNA damage control that these tumor cells have.

Moreover, adding Topo1 inhibitors as Chris mentioned will enhance the DNA damage response and the presence of the PARP inhibitor and other DNA damage response inhibitors will enhance anti-tumor effects of Topo1 inhibitors. So too many -- sorry.

The important issue is that, as Chris mentioned, there were a lot of efforts from multiple different sponsors to combine Topo1 inhibitors with PARP inhibitors. And there was a significant bone marrow toxicity induced by the combination, and in principle, up to this point, these combinations are not tolerable in cancer patients.

And sponsors need to sacrifice Topo1 doses -- all PARP doses in order to have that synergistic effect that is not feasible in humans. So we believe that CRLX101 is a Topo1 inhibitor that is much better tolerable. And as Chris stated, we are really focused in testing these combinations in the clinic, based on our very profound anti-tumor effects that we've seen in preclinical models.

You asked me or actually you asked Cerulean what will be the tumor type of interest, and certainly, there is an obvious indication as you know. There is so far one drug -- one PARP inhibitor indicated at this moment in the US. It's patients who have germ-line BRCA-deficient ovarian cancer patients.

So one consideration is to add Topo1 inhibition based on the CRLX101 to this indication. And there are many other indications where PARP inhibitors are useful that we can discuss hopefully in the next call. I can tell you that there are multiple shots on goal. I don't know if I was able to address these issues.

No. That's very helpful. Thank you very much.

And then on another note, I was curious about the IST for CRLX101 in combo with Avastin. What's your ultimate signal that you want to see at the end of this trial that will help to clarify the path forward? Thank you very much.

Thank you. So I will turn it over to Adrian briefly.

But I want to be clear that what we're trying to do in these studies is improve the lives of these women with ovarian cancer. And there are many different ways to assess therapeutic benefits.

Adrian will talk to you about how we think about it. It doesn't mean that's the way everyone thinks about it, but that's certainly how we're going to assess this when we decide where to invest in a registration setting. Adrian?

This is a very good question, and I'm trying to read your mind that you are thinking about some of the data that was recently published by our colleagues from Genentech with Avastin. Let me give you my two cents, and I hope that this helps you understand the clinical activity for any agent. You need to understand the clinical safety for any agents.

The clinical activity is not only where are the response rates for any agent, but the duration of response, tumor shrinkage, PFS, OS, and effects on biomarkers such as CA125. So in general, we think in a multidimensional way and not in unidimensional way. So in order for us to advance to the next stage, we need to see several different readouts for the anti-tumor effect.

And so far what we have seen in -- you heard in our press release is that not only is the combination of Avastin and 101 have bona fide partial responses. But we have three PRs and 80% of the other additional patients who have stable disease. Moreover, we have a PFS6 of approximately 56%, and based on the GOG benchmark data, in the system patients, only 20% of patients had PFS6.

And the other additional interesting response that we have saw is around 50% of patients have a 50% decrease or more above CA125 levels. So certainly there is activity for this combination, but we have not decided which of the two ongoing combinations we are going to move forward for registration.

As you know, we have the combination of 101 and Avastin, via the IST, and we have the 101 weekly paclitaxel with the GOG. And this combination is doing well. And at the end of this exercise, meaning these two clinical trials -- and as you know, we are also exploring the weekly administration -- we will have multiple choices to advance the best schedule and regimen for registration. So I hope that this addresses your question.

Yes. It does. Thank you very much.

Thank you.

Michael Schmidt, Leerink Partners.

Hey. Good afternoon and thanks for taking my questions.

Hi Michael.

Hey. So I had one on the rectal cancer study. You said you're switching now also here to the weekly dosing schedule. Can you remind us what the hurdle for success is and what response rate -- or PCR rate, rather, one would expect for chemoradiation alone in this indication?

Yes. So historical data shows that the PCR rate for standard of care which is chemoradiotherapy is anywhere in the10% to 20% range depending on which study you look at.

The randomized studies are a little different than the single arm studies, there's some bigger, there are some small. But we have consistently said that standard of care gets you anywhere from 10% to 20%.

We'd also said previously that we would like to see at least a 30% PCR rate in order to take on the conversation with the agency and ask them if they were willing to essentially blaze a new path with us and look at approval in this setting based on PCR rate alone. So we clearly do not have a 30% PCR rate, and therefore we will not be trying to convince the FDA to approve this drug on PCR rate alone. And instead we will focus on seeing whether a different dosing schedule will drive up those PCR rates as we originally hoped for.

Yes. And remind me, have you seen some dose response to this study?

Yes. I'm not sure how to answer that. We had three patients at 12, and we had one of three at a PCR rate. The rest have been at 15 mgs per meter squared, and we have three of them that were -- that had PCRs.

So I guess you could, if you look at real small numbers, you can actually say the PCR rate is higher at 12 mgs per meter squared than at 15, and we know that's not all that logical. So I don't think we have anything other than that to point you to, Michael.

Yes. Small numbers.

And then, a question on CRLX301. Can you remind me of the plan for the Phase IIa study, what tumor types are you going to look at there?

And then ultimately, where do you see that drug finishing strategically? Do you look at this as a preferred combination agent similar to 101, or do you see an opportunity for this as a single agent therapy?

Sure. Well I'm going to let Adrian take most of this question.

But I want to be very clear that a better tolerated and more active taxane is a very interesting market opportunity as a monotherapy and in combination. So it's not an either/or, to answer your question, it's a both. But with that, Adrian, would you like to add additional?

Absolutely. Yes. I completely agree with Chris, his statement that this is a proposal for monotherapy and combination based on the great availability we have seen so far with 301.

And certainly, there are multiple indications that we can explore, and we have -- we are in the process of finalizing these cellular indications. But I can tell you that we are not ready to share with you exactly which tumor types. But you can imagine that taxanes in general are very active in multiple tumor types.

Some of those tumor types are approved in the label. Some of those tumor types are not approved, and that gives us some truth of where to move forward in a very small, rapid and hopefully cheap proposition in order to reach to the markets. So we are very attentive to this particular way forward, and you will hear that soon.

That's terrific.

Sorry. Did I address this question?

Yes. You did. Thanks so much.

And then last question, you -- it looks like you're doing more now than you originally planned, and I was wondering if your cash guidance is still intact or changed in any way?

Yes. The cash guidance has stayed the same. We expect to have cash to last us into 2017. So nothing has changed from any prior quarter.

Thanks. Thanks so much and congrats on the progress.

Thank you, Michael.

John Newman, Canaccord.

Hi guys. Thanks for taking the question.

Hey, John.

Hey, Chris. So the first question I had was just, if you could talk to us a little bit about the thinking behind exploring a little bit different dosing schedule. And I was -- just wanted to double check if you had said that you would be exploring the weekly dosing in both RCC and ovarian or just in ovarian?

And then the second question I had was, Chris, I was just wondering if you could talk to us a little bit about how a drug like 101 going forward could be interesting in combination with some of the current therapies that are out there now since some of those therapies seem to work extremely well. But some of accommodations that we're seeing are not as clear on the tox. Thank you.

Okay. Terrific. Thank you, John.

I have the two questions. I will start off on the weekly dosing and then turn it over to Adrian. And then when he's done, then I will address your question about combinations.

So to be very clear -- if I was not more clear in the script, I apologize. We are exploring weekly dosing in general. So what that means is we started a trial about a month ago, we have now put a press release out announcing we are studying weekly dosing in solid tumors. That will help us understand whether weekly dosing is an option for us or not.

In addition, we are going to be exploring in the rectal trial a change from the every other week dosing to the weekly dosing. And in addition, we will do the same thing in the ovarian cancer trials.

I imagine that we will continue to think about weekly dosing in other tumor types as we continue to develop 101, and you also heard Adrian say that we are exploring weekly dosing for CRLX301. So there is no one area that we are exploring it, there is no area that it's being left out. It is something that is important for us to understand before we start investing in expensive registration studies.

But with that, since it was Adrian's idea, I will let him talk you through the rationale that he brought to Cerulean. Adrian?

Thank you, Chris. So let me share my two cents about the weekly administration.

So as soon as I joined Cerulean, it was obvious to me that based on the mechanism action of 101, namely the Topo1 inhibitor and HIF 1 and 2 inhibitor, a more protracted exposure may enhance the therapeutic index of 101 due to further increase in anti-tumor activity. Thus, we acted very quickly and started a new trial of weekly 101 monotherapy and 101 in combination with Avastin.

The good news is that we will have safety and activity for the combination before studying our Phase III randomized RCC trial. So that if this new combo schedule is more active than the every other week, we can choose this weekly schedule for our Phase III trial. Moreover, this novel combo schedule may be used for other registration trials, namely the ovarian cancer precision trial.

I believe that after this novel weekly trial, we will create more shots on goal with additional schedules to choose from. This creates choice, and choice is a good thing in cancer therapeutics.

Great. Thanks Adrian. Now let's talk about what to do with these different dosing schedules.

So John's question was basically where do you think you can combine? And John, if I shape the question the wrong way, feel free to jump back on and redirect me, but I think there are a number of opportunities to combine.

I think the folks who follow us know us as the HIF/VEGF combo. We've talked a lot about using our drug in combination with Avastin in kidney cancer and in ovarian cancer. We have announced some pretty interesting data in both tumor types with this combo.

And by the way, Avastin is not the only VEGF inhibitor out there. TKIs inhibit VEGF. About $5 billion a year of VEGF products are sold each year, they all do a terrific job at shrinking tumors, but in some cases -- I would argue in many cases -- they don't do as good a job as we'd like translating into OS. So I would love to think that our drug will be used ultimately in combination with multiple VEGF inhibitors to improve outcomes for patients been treated with those very common forms of drugs.

Second, you've heard that we want to think about our drug also as a Topo1 inhibitor. And in that context, there are already two areas that we've talked about quite extensively in one case, which is using our drug as a radio sensitizer.

And that could be in locally advanced rectal cancer, it could be in other tumor types, it could be used in PCR as an end point, and it could be used in other end points. But using our drug as a radio sensitizer in combination with other chemoradiotherapy regimens is an important frontier. And so those are two.

The third that you heard us start talking about more recently and which we addressed just a few minutes ago in the Q&A section of the call is this notion of using a Topo1 inhibitor in combination with PARP. That is also a very exciting opportunity because as I think many people on this call are aware, there are a number of PARP drugs that are in late stage development.

AstraZeneca has already gotten Olaparib approved in its initial indication, and they are working on expanding the label. Other companies out there see the promise of PARP inhibitors, and they are all racing towards approvals.

So in the next two, three years, you might have four or five PARP inhibitors on the market. I think that our drug can help differentiate those PARP inhibitors if used in combination.

There are certainly other combinations that we think about and talk about here. We've not really talked about any of them publicly because we don't like to speculate, but what we try and do is generate a good hypothesis, read the literature, do the preclinical work. And then when we're ready to move forward, just as we did a few months ago with PARP, we let the world see our preclinical data and then we announce our plans in the clinic.

Does that address the question, John?

Yes. And I also wondered -- I'm sure you have thought about this, but I also wondered if you have any thoughts with regard to the PD-1. And I'm sure you get asked the question.

The reason that I'm curious is because it seems like the PD-1s work really well in some patients, but as those drugs have been combined with other drugs, it seems like the toxicity level has gone up quite a bit. And so I'm just curious if that's an area that you are also thinking about.

So I think it's obviously a terrific question. I wondered if that was what was on your mind when you asked the question, and you're not going to let me dodge you, so let me be more direct.

Of course, as an oncology company in today's world, we are very aware of the advances being made with immuno oncology. We're super excited about it, and we often give thought to how we can enable that terrific progress. But that's about all I am willing to say at this point.

Okay. Great. Thanks, Chris.

Okay. Thank you.

Mike King, JMP Securities.

Thanks for taking my call, but I think you just obviated my question with your previous answer.

Okay. Thank you.

Thank you.

David Nierengarten, Wedbush.

Thanks for taking the questions. I had a question about --

Hey, David.

The design and some of the characteristics of the RCC study. So first off, when you think about the division between third and fourth line patients and how that affects your assumptions on the powering.

And then second, on the mixture of physician's choice for those -- for the patients in the control or -- well, the control arm and if those assumptions are -- what they are based on and just how that reflects in the statistical design of the study? Thanks.

So thank you. You are discussing about the Phase II trial? That's your question?

The ongoing study.

Ongoing study. Perfect. Yes.

So as you know, Cerulean made the decision to have a Phase II randomized trial of the Avastin 101 versus dealer's choice. And the choice were either Avastin or several TKIs. And we are very pleased that we were able to accrue the whole number of patients, 115 patients, in -- we accrue everybody in October.

And we have seen -- I'm trying to understand the trend of what is feasible for the next clinical trial. And I can tell you that, at least in the US, a significant number of patients receive Avastin as a control arm as opposed to other TKIs and then, other TKIs as the control arm.

So we are very pleased that Avastin at least in the US is being used in the third and fourth line setting. And if we decide to go against Avastin in a Phase III trial, we believe we want to have a reasonable way forward with that particular control arm. So I don't know if that addresses your question.

That helps, and then one other aspect of it.

Sure.

For the third and fourth -- for the third line patients in the study, are they going on to subsequent treatment? Thanks.

So you mean, subsequent tumor after progression?

Yes. After progression.

Yes. Well, this is a blinded study. We don't have much information about how the patients are being treated.

But if the question is whether there is crossover in these studies, we are not allowing a crossover. So patients obviously are receiving some therapies if the patients are in good shape to receive therapy.

Some patients, unfortunately -- they are so advanced that they may end up with some palliative care and support and typical support. So I don't have that information, and hopefully in the second quarter of next year, we will have the top lines result and we will give you all the details about this information.

All right. Thanks.

Thank you.

Thanks, David.

(Operator Instructions)

Katherine Genis, Edison.

Hello, everybody.

Hey, Katherine.

Hi there. I have some questions related to 2016.

You had quite an impressive list of data in trial, the news flow coming out in the first half of 2016, which led me to a couple of questions. The first is in regards to the Phase II in RCC.

Just wondering, I know it's a moving target, but as you see it now, if you could be a little more specific as to when the results could be coming out. Will it be more toward the very end of the first half of 2016? And then, following on to that, and a more general information you could provide on a potential follow-up Phase III trial?

And that really leads us -- me to the third question which is, any guidance you might have for R&D in 2016 with all this activity going on? So vis-a-vis, say the $26 million or so that we are seeing in 2015. Thank you.

Okay. I'm going to take the first two, and I will let Gregg talk to you about the financial guidance.

So the timing of RCC data, your question is can I be more specific? I guess the answer is no, I really can't, unfortunately.

Obviously, we just completed enrollment about a month ago. You know that we need 70 events. We appear to be tracking sort of as expected, and I think that if we had an announcement maybe early in the first half, then that would be disappointing because patients are coming off study.

But beyond that, I can't really be more specific. And I guess to be very honest with you, Katherine, the longer it takes, I guess the better the patients are doing, so --

Sure.

I'm not -- it is what it is. When the data is ready, we will be very excited to tell you because we've been waiting a while now to have the opportunity to announce these positive randomized data, but we have to wait until the 70th event.

Of course. No news is good news.

And in terms of the timing of the next study, the Phase III study, our guidance has been and continues to be that we would like to start preparing in parallel. That is one of the potential advantages of having fast-track designation, we get to talk to the FDA.

We will certainly not launch that study until it's ready to go, and that requires a number of things, not the least of which, of course, is seeing the data and getting the results that we expect from the Phase II trial. But as you've also heard from Adrian, we would like to understand whether this weekly dosing schedule is something we should consider before we go forward in an expensive Phase III study.

So we have a few hurdles to jump over, but I think our view is we can jump over those hurdles in due course next year and before the year is over, get going on that important registration study. Okay?

But okay. Thanks.

And now I actually frankly forgot the third question, but Gregg, if you remember it, go right ahead.

So the third question, a good one, how much do we expect to spend next year. As you know, we have historically not given operating expense guidance. In all candor we haven't yet presented our budget and had it approved by the Board, so I couldn't even do that prematurely if we were allowed.

What I can say is that we -- again, let me just reiterate that we will have cash into 2017 with all of the activity that we're doing next year. I think it's fair to say that we will spend more next year than we did this year.

But I can't really give you much more in terms of order of magnitude simply because we historically haven't given that guidance. And as of yet, we just from a procedure standpoint don't have a fully approved budget that I could even articulate.

Okay. Thanks. Do you think you will be providing any guidance maybe after your full-year results and once the budgets go through?

Katherine, I know that you and a number of our other analysts have asked us about more specific items than we provide. And I assure you that as we mature as a Company, we will get into providing the type of guidance that you seek.

But right now as a very small company, and our spend is so lumpy based on these clinical trials, that we actually think it can be more harmful than helpful to get into a breakdown. And that's why we decided to stick with just runway guidance for now. And I honestly can't tell you at what point in our evolution we're going to make that switch, but it's coming as you'd expect.

Sure. Okay. Great. Thank you.

Okay. Thank you.

That is all the time we have, so I will turn the call over to Mr. Guiffre to conclude the call.

Thanks everyone for joining us today. We look forward to reporting on continued progress in March. Have a good night.

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