October 10, 2015

Brakes, Gas Pedals, Steering Wheels, Roads, Planes, Trains and Automobiles

Pharmaceutical industry consultant (and former Big Pharma clinical researcher) Dr. Sally Church, PhD recently published an article (on LinkedIn) titled Stepping on the Gas against Cancer Cells and associated podcast entitled Episode 6: Stepping on the Gas. She highlights Stanford's Dr Holbrook Kohrt, MD, PhD who was mentioned in an August 2015 Reuters article entitled Pfizer, Bristol revive cancer drugs that rev up immune system, which discussed agonist 4-1BB (aka CD137).

In the LinkedIn article, Dr. Church wrote:
"In Stepping on the Gas we take a look at immune agonists, those agents that boost the numbers of killer T cells in the tumour.  In a simple motor car analogy, we first release the brakes (using a checkpoint inhibitor) and then put our foot on the accelerator (by adding an immune agonist) to move the car forward.   
The star of the latest show is Dr Holbrook Kohrt (Stanford), who also talks about the importance of the steering wheel (antigen targeting) as well as avoiding important pitfalls such as over-revving the immune system, potentially causing unwanted autoimmune disorders in cancer patients." {Underlined emphasis is mine}
Fully understanding that analogies are not perfect, they may allow us to conceptualize and visualize, and depending on the closeness of fit, implement.

According to Dr. Church, we release the brakes of the immune system first, and step on its gas pedal or accelerator second. Together, these actions contribute to moving the car (the immune system) forward. The aforementioned assume I am correct in analogizing her analogy. Dr. Kohrt adds to the anology with the inclusion and importance of a steering wheel, and warning of not over-revving the car.

Steering wheels, gas pedals, and brakes. But, what about the road? Is the car at the top of a hill of some inclinde, or a flat stretch of road? If I try to extend the analogy, there is the immune system — the car — and, I imagine, the road (?) — immunogenicity.

As background/context, Chen & Mellman's The Cancer Immunity Cycle highlights stimulatory and inhibitory factors (agonists and antagonists, respectively). I also added some edits to reflect thoughts and questions I have.
Click to enlarge. Original image source
Before the discussion of agents that revved up the immune system entered the dialog, it seemed that releasing the brakes was THE solution by those enamored by immune checkpoint inhibitors. Sure, if the car is on an incline of sufficient angle, releasing its brakes should cause the car to move forward. Melanoma tumors are immunogenic; the car is on a hill where releasing its brakes will get it going. How much or fast the car moves presumably is influenced or strongly influenced by the incline of the road on which it sits/runs (the amount of immunogenicity). But if the road is flat (i.e., the cancerous tumors are non-immunogenic), releasing the brakes won't move the car forward.

Provectus's PV-10 has a two-prong approach to fighting cancer. Step #1 is act of tumor ablation, which causes immunogenic cell death (i.e., Step 1 of The Cancer Immunity Cycle). Is tumor ablation akin to turning on the engine?

Step #2 is the generation of a tumor-specific immune response, which Moffitt Cancer Center's SITC 2015 abstract title implicated HMGB1 (i.e., Step 2 of The Cancer Immunity Cycle). Does that mean, in addition to potential being a primer or activator of the immune system, PV-10 via HMGB1 (and who knows what else) is a steering wheel too?
Click to enlarge. Image source
PV-10's dual mechanisms of action, or two-prong approach, of course, have been independently reproduced by separate research organizations in multiple solid tumor cancers.
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But let's return to the car analogy. The below originally was blogged on February 18, 2015 as The Early Obsolescence of Checkpoint Inhibitors.

Take as a starting point Inman et al.’s 2007 article entitled Costimulation, coinhibition and cancer, and their statement therein:
If sufficient co-stimulation is provided in the presence of adequate tumor-associated antigenic stimulation, the immune system will act against tumor antigen and, thus, destroy early tumors before they become fully established. Contrarily, if co-inhibitory signaling dominates, the immune system will be tolerized to tumor antigens, and the tumor will be permitted to grow unfettered and unmolested by the immune system. If neither co-stimulatory nor co-inhibitory signals dominate, the adaptive immune system may remain in a tenuous state of equilibrium, militating against tumor outgrowth with varying degrees of success.” {Underlined emphasis is mine}
The essence of the authors’ view might be that the immune system is capable of decisively acting against cancer only in the situation where or circumstance that co-stimulation dominates co-inhibition. Take also as context to this starting point, however, that what we don’t know about the immune system probably dwarfs what we know about it.

The notion of “releasing the brakes” in the medical literature and mainstream press describes the approach of inhibiting cancer’s ability to suppress or block the body’s immune system from acting, and thus to evade attack. Although possibly coined in the early-2000s (see, for example, Tirapu et al.’s 2002 article entitled Effective tumor immunotherapy: start the engine, release the brakes, step on the gas pedal,...and get ready to face autoimmunity), use of the releasing-the-brakes phrase may have grown more widespread starting in the late-2000s and around the time of Dr. James Allison, Ph.D’s seminal work of blocking (inhibiting) the CTLA-4 protein receptor (using Bristol-Myers’ ipilimumab) and, later, the follow-up scientific exploration of blocking (inhibiting) PD-1 and PD-L1 ligands too (and associated PD-1 therapeutics pembrolizumab and nivolumab, for example, from Merck and Bristol-Myers, respectively).

Medical literature has more sparsely touched on, and mainstream press much less so, the other two components of the get-the-car-moving analogy (where the car is the immune system), “starting the engine” and “stepping on the gas pedal,” where these phrases relate to different aspects of stimulating the body’s immune system.

Possibly over-using the car analogy further, with the potential risk of over-simplifying it inappropriately, consider T cell immunity as a car at rest. More immunogenic tumors and their associated cancers like melanoma are like a car sitting on a slight incline. Release its brakes by treating the tumors (and thus the cancer) with checkpoint inhibitors, and the car may roll forward move some distance, notable or otherwise. With other less or non-immunogenic cancers, think of the car as sitting on a flat surface. Releasing the brakes does not enable the car to move any meaningful distance, if at all.

If you want to get the car to really move, you have to start its engine, and then step on its gas pedal. Releasing the brakes might help the car move farther and faster, but it also is quite possible the car may be able to move sufficiently without the need for further action other than to start its engine and/or stepping on its gas pedal.

The continued use of get-the-car-moving analogy of course requires the assumption the car can drive by itself; that is, the immune system can handle its own business once it has been started, and is appropriately up and running from stepping on the gas pedal.

Now consider Winograd et al.’s 2015 article entitled Induction of T cell immunity overcomes complete resistance to PD-1 and CTLA-4 blockade and improves survival in pancreatic carcinoma. In particular, note my underlined emphasis from the article’s abstract:
Disabling the function of immune checkpoint molecules can unlock T cell immunity against cancer, yet despite remarkable clinical success with monoclonal antibodies (mAb) that block PD-1 or CTLA-4 resistance remains common and essentially unexplained. To date, pancreatic carcinoma is fully refractory to these antibodies. Here, using a genetically engineered mouse model of pancreatic ductal adenocarcinoma in which spontaneous immunity is minimal, we found that PD-L1 is prominent in the tumor microenvironment, a phenotype confirmed in patients; however, tumor PD-L1 was found to be independent of IFN-γin this model. Tumor T cells expressed PD-1 as prominently as T cells from chronically infected mice, but treatment with PD-1 mAb, with or without CTLA-4 mAb, failed in well-established tumors, recapitulating clinical results. Agonist CD40 mAb with chemotherapy induced T cell immunity and reversed the complete resistance of pancreatic tumors to PD-1 and CTLA-4. The combination of αCD40/chemotherapy plus PD-1 and/or CTLA-4 induced regression of subcutaneous tumors, improved overall survival, and confered curative protection from multiple rechallenges, consistent with immune memory not otherwise achievable. Combinatorial treatment nearly doubled survival of mice with spontaneous pancreatic cancers although no cures were observed. Our findings suggest that in pancreatic carcinoma, a non-immunogenic tumor, baseline refractoriness to checkpoint inhibitors can be rescued by the priming of a T cell response with αCD40/chemotherapy.”
CD40, for example, is a co-stimulatory protein, while chemotherapy has been understood to act in a stimulatory fashion through the subsequent release of cancer antigens by causing cell death.

Achieving T cell immunity almost if not actually by definition should mean overcoming resistance to cancer, thus overcoming checkpoint blockade and mitigating the need to artificially release the brakes.

Should stimulation via stimulatory therapeutics and therapies start the engine and enables the gas pedal to be stepped on sufficiently and appropriately (i.e., with minimal or manageable side effects or adverse events) so as to achieve T cell immunity, brakes may not be necessary once the car is moving (in context, and given the car [the immune system] can drive itself and not careen off the road because it then should know what it is doing).

Image source
Over time, however, road friction may start slowing the car down to the point where waning immunosurveillance (the immune system recognizing and eliminating continuously arising cancerous cells) no longer can protect the patient from relapse (analogous to how waning varicella zoster antibody titers may result in a bout of shingles). Keeping the brakes disengaged, especially with non-immunogenic tumors, should have some role going forward, making Merck, Bristol-Myers, Roche, AstraZeneca, Pfizer and other companies’ checkpoint inhibitors not necessarily obsolete as much as persnickety.

And we haven't even begin to talk about steering wheels...

September 25, 2015

provectus IS a t-cell company

H/t InvestorVillage poster bradpalm1: A research team from the University of Illinois at Chicago (UIC) published a paper in July entitled The Potential of Intralesional Rose Bengal to Stimulate T-Cell Mediated Anti-Tumor Responses (Maker et al., J Clin Cell Immunol 2015, 6:4). This same team previously published results of their murine model work and research on PV-10 for colon cancer. See June 5, 2015 blog post Intralesional Injection of Rose Bengal Induces an Anti-tumor Immune Response and Potent Tumor Regressions in a Murine Model of Colon Cancer.

Blog post takeaways:
  • Rose Bengal (PV-10)/PV-10 (Rose Bengal) induces/generates/creates/leads to anti-tumor immunity. To some the so-called Holy Grail of cancer therapy is achieving durable [system- or body-wide] anti-tumor immunity in a cancer patient.
  • PV-10 can prime the immune system (through the direction injection of the compound into cancerous lesions), and help it defeat distant cancerous lesions around the body.
  • The compound exposes antigens to the immune system that otherwise would not be exposed, or that otherwise would escape detection by (and thus presentation to) the immune system.
  • PV-10 can help with T cell generation & circulation, even after treatment with immune checkpoint inhibitors fails.
  • UIC's work reproduced Moffitt Cancer Center's (Moffitt's) work, which reproduced Provectus' founders' work.
Recall that Provectus has a two-prong approach to fighting (killing) cancer: (i) local effect/tumor ablation (anti-tumor cytotoxicity) and (ii) systemic effect/tumor-specific immune response (induction of anti-tumor immunity)
Click to enlarge. Image source
UIC and Moffitt independently reproduced the veracity of both prongs:
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UIC's paper reviews PV-10's agnosticity in destroying tumors into which it is injected (i.e., anti-tumor cytotoxicity):
  • Melanoma,
  • Breast cancer,
  • Ovarian cancer,
  • Gastric cancer, and
  • Sarcoma.
The paper discusses PV-10's agnosticity in generating anti-tumor immunity resulting from local tumor injection (i.e., from resultant anti-tumor cytotoxicity):
  • Melanoma,
  • Breast cancer, and
  • Hepatocellular carcinoma (HCC).
The UIC team appears to have conducted murine model work on PV-10 in HCC, noting "Our current research is establishing the role of RB in generating anti-tumor immune responses in gastrointestinal cancer and liver metastases:"
"Furthermore, in syngeneic orthotopic models of murine hepatocellular carcinoma (HCC), RB similarly induced chemoablation in all treated tumors. Twenty-one to 81 days after RB treatment, when re-challenged with the same tumor, durable immunity was demonstrated in 14/14 animals without measurable tumor formation, whereas B16-F10 melanoma tumors, i.e., non-HCC cells, were able to be established in 13/13 animals [20]. Additionally, immunity to establishment of a new HCC tumor could be created through adoptive transfer of splenocytes from treated animals. This was an interesting finding given that analysis of splenic composition from animals with B16 melanoma that experienced distant lung tumor regression after RB treatment of flank tumors did not demonstrate any difference in the percent of T cells, Tregs, NK cells, B cells, myeloid derived suppressor cells, or macrophages [15]. The authors further demonstrated that bystander lesions disappeared or decreased in size in HCC models, whereas, no bystander tumors were ever observed to resolve in nude mice without a competent T-cell immune system. These experiments established that, similar to melanoma, in immunocompetent mice with orthotopic primary hepatocellular carcinoma flank tumors, an anti-tumor response can be induced by priming the animals with RB treatment of tumors. These experiments raise the possibility that RB induced cytotoxicity exposes antigens and mounts an immune response that may protects animals from additional tumor formation that can be adoptively transferred to other animals using splenocytes." {Underlined and bolded emphasis is mine}
Speaking of antigens, it's all about the antigens:
"These experiments established that in human and murine melanoma and breast cancer, there appeared to be an antigen-driven T-cell response that has the potential to activate T-cells and impart antitumor responses in bystander lesions and distant metastases."
Why are antigens important? Because they facilitate the priming of the immune system through their presentation to it:
"These findings may imply that tumor response in the primary lesion may be able to prime the immune system of patients for activity against distant lesions."
The UIC team's conclusions could be profound, among them:
  • "RB-mediated tumor cell death may expose tumor antigens that may otherwise evade immune detection."
  • "Though most profoundly described in melanoma cells, clearly an immunoreactive malignancy, the effect has been shown to be not limited to one specific type of malignancy. 
  • "Decrease in tumor burden and stimulation of an immune response with PV-10 has been demonstrated in animal models of metastasis, and correlations of these responses in clinical studies is consistent with such results." Provectus' CTO Dr. Eric Wachter, PhD has said in a 2013 white paper: "PV-10 murine research demonstrated unambiguously, Dr. Wachter noted, that tumor burden is a critical variable in predicting response to a combination therapy." See Radiation (September 22, 2015) on the blog's Current News page.
  • "That PV-10 treatment can potentially increase circulating cytotoxic T-cells, even in patients who were previously treated with immune-activating checkpoint blockade, supports the possibility that RB induced cytotoxicity may activate T-cells that are responsible for the bystander effect on untreated lesions."
  • As such, intralesional therapy with RB may be a promising new mode of therapy to stimulate T-cell mediated anti-tumor immune responses."
UIC's work was conducted in part under an NIH grant.

September 20, 2015

Special Proxy Vote

A blog post also known as Special Meeting/Proxy Vote, part 5 (Sunday version).

Image source

Provectus is seeking shareholder approval of a proposed increase in the number of the company's authorized common shares from the current figure of 300 million to 400 million. The special meeting of stockholders by which time voting would be completed takes place on October 1st. According to the electronic ballots we received, shareholders appear to have until 11:59 pm EDT on September 30th to digitally cast their votes.

My Ballot
Click to enlarge.

I will vote our shares for the proposal because:
  • First, it would be prudent for the company to have enough authorized shares available for issuance to potentially satisfy the company's accounting firm BDO (in regards to maintaining Provectus' going concern status) and the New York Stock Exchange (NYSE) (in regards to maintaining the company's listing status). In additiion, it is possible management could require some of these newly authorized shares to advance their business and corporate development efforts. Resources necessary to further advance the company's clinical development program goes without saying, and
  • Second, it is possible-to-probable under certain assumptions that management does not need to raise money until after the interim analysis data readout of Provectus' pivotal melanoma Phase 3 trial. The readout is projected in early-3Q16. The trial's interim analysis is a key catalyst for the company and its share price.
The above decision was based on my analysis of/reflections on discussions with:
  • Management in recent days and weeks,
  • Two individuals from two different PVCT shareholder groups, who themselves are distinct and different. I believe them to be intelligent and pragmatic with extensive, substantive and relevant experience. They have been involved with Provectus for a long time, have maintained intelligent long-term perspectives for the company and its drugs' prospects (notwithstanding certain management limitations), and also have had discussions with management in recent days and weeks. As an aside, their direct share ownership and influence over additional ownership in sum are greater than what we own, and
  • A few shareholders with smaller share ownership who I believe to be intelligent, pragmatic and experienced, have maintained intelligent long-term perspectives too, may or may not vote in favor of the authorized share proposal, and whose views over time I very much appreciate and value (and sincerely thank them for continuing to share and debate such opinion).
Tactical and Strategic Share Availability. I previously wrote the reasons management has given for their proposal are possibilities that may turnout to be potentialities (or even realities). Simply put, I believe, Provectus requires more authorized shares (whether they issue them or not, whether they issue some, most or all of them) for the company to remain viable and relevant to BDO and the NYSE, and provides management more flexibility and less headache & heartburn as they seek to optimize Provectus' extrinsic valuation as peak investibility approaches.

Becoming unviable or irrelevant under this scenario, however, does not mean the end of the world for shareholders or the end of Provectus, or the end of the potential for a good investment return. See Special Meeting/Proxy Vote, part 3 (September 4, 2015) on the blog's Current News page. As such, I question whether management really needs to increase the authorized share number by one hundred million more common shares at this time. What about 50 million or another smaller number? I also don't put much if any stock (pardon the pun) into management's possible anti-takeover effects rationale. Nevertheless, the proposal in front of shareholders is what has to and will be voted upon.

Flexibility for management to make Big Pharma pay, and pay dearly for Provectus' fully owned cancer asset, is reason enough [for me] to vote for the proposal. As the company approaches peak investability, I agree it's not worth distracting management or detracting from their potential business and corporate efforts (i.e., it's not worth voting no [in my view]).

Catalysts, Key and/or Otherwise. Flexibility, less headache & heartburn, few or fewer distractions, not detracting, etc. are all well and good, but they mean nothing if management cannot execute or executes weakly or poorly. Execution specifically means the timely generation of randomized [controlled trial ("RCT")] data, whether randomized data (or RCT data) means data generation in the context of a pivotal trial or data generation in the context of Phase 1b trials that would lead to pivotal ones.

In 2013/14 management established an initial pathway to approval for their advanced investigational
oncology drug PV-10, a new category of ablative immunotherapy and made from active pharmaceutical ingredient Rose Bengal: treatment of [unresectable or unresected] locally advanced cutaneous melanoma — that is, cancer in Stage III melanoma patients. Execution here requires a successful interim analysis data readout in early-3Q16, which requires a sufficient number of patients to be recruited, enrolled, treated, observed and clinically assessed in order to demonstrate statistical significance of progress-free survival curve spearation between the PV-10 treatment arm and the systemic chemotherapy control arm. That is not to say successful execution does not preclude an earlier positive outcome that could result via regular safety & efficacy looks into the data by the trial's indepedent data monitoring committee.

In 2015 I believe Provectus may have established at least two other pathways to approval for PV-10. As noted above, the first pathway is the use of PV-10 as a montherapy for the treatment of Stage III melanoma patients. The second pathway would be the use of PV-10 in combination with an immune checkpoint inhibitor for the treatment of Stage IV melanoma patients. The third pathway would be the use of PV-10 for both hepatocellular carcinoma (HCC) and cancers metastatic to the liver.

Thus, while the key catalyst for PV-10 as a monotherapy in melanoma is the pivotal Phase 3 trial's interim analysis (a secondary but uncertain one [as it relates to probability and timing] is an earlier positive outcome), other catalysts for PV-10 could be:
  • The filing of a Phase 1b trial protocol of PV-10 and pembrolizumab for advanced melanoma (managament's prior guidance is by the end of 3Q15), and the commencement of this trial itself (the end of 4Q15), and
  • The filing of the relevant Phase 1b trial protocols for HCC and/or liver mestastses, and (perhaps) the commencement of one or more of these trials.
All of these point to more and more generation of randomized data necessary to potentially move the company valuation higher, of course, and where it needs to be to garner management's end-game monetization expectiations.

A key question for melanoma combination therapy must be, given Keytruda's (pembrolizumab's) reimursability, will management run their own Phase 1b trial?

Management's regulatory and clinical development approach to liver cancers also is not fully clear. Such approach would underscore the veracity of a pathway (or pathways) to approval for PV-10 in liver cancers in the U.S. and internationally. In regards to Asia, how will they approach Asia? We presume they will file an investigational new drug (IND) application in China. But, what geographies could or would be included in an Asian/Pacific Phase 1b trial protocol for HCC?

The expanded Phase 1 trial in the U.S. comprises study work on patients related to HCC and liver mets, and sorafenib. This trial for all intents and purposes seems to me to be a pseudo-Phase 1b trial. Will the outcome(s) of the expanded trial lead to one or more pivotal trials?

Other items on this topic from the blog's Current News page:
  • Special Meeting/Proxy Vote, part 4 (Saturday version) (September 12, 2015),
  • Special Meeting/Proxy Vote, part 3 (September 4, 2015),
  • Tuesday (September 1, 2015), item 3,
  • Special Meeting/Proxy Vote, part 2 (August 28, 2015), and
  • Pfizer's Just Not That Into You (August 21, 2015), item Mo' shares.
Other topics

H/t InvestorVillage poster Area51: Provectus' lawyers filed their Reply in Support of Motion to Dismiss on September 17th. See Tuesday (September 1, 2015), Item 2. Lawyers on the blog's Current News page. From Area51's post:
Introduction: Because Plaintiff has failed to state a colorable claim for securities fraud under the heightened pleading standards of the Private Securities Litigation Reform Act of 1995 (the “PSLRA”), this Court should dismiss this action with prejudice. Plaintiff’s Complaint fails for two reasons: (1) it does not identify a single actionable misrepresentation that Defendants allegedly made during the Class Period; and (2) it fails to allege facts to suggest that any purported misrepresentation was made with a “strong inference of scienter,” a requirement under the PSLRA. For these reasons, the Court should dismiss the Complaint with prejudice. 
As a preliminary matter, this is not a typical motion to dismiss governed by Rule 12(b)(6). In a standard motion to dismiss, a plaintiff must meet the “plausibility” standards espoused in Ashcroft v. Iqbal, 556 U.S. 662 (2009), and Bell Atlantic v. Twombly, 550 U.S. 544 (2007). Class action claims for securities fraud under the PSLRA, in contrast, must satisfy a more stringent legal standard. Recognizing the potential for abusive, vexatious litigation from investors who lost money on risky investments, Congress passed the PSLRA to heighten the standards of securities fraud class actions. Under the PSLRA, a plaintiff must not only plead facts with particularly to show that the defendant made a false statement of material fact that caused injury. He must also plead specific facts that give rise to a strong inference that the defendant acted with a culpable state of mind with respect to each allegedly fraudulent or misleading act or omission. 15 U.S.C. § 78u-4(b)(2). Federal courts have explained this standard in the following manner: 
The plaintiff must allege and prove that the defendant acted with scienter, which means intent or severe recklessness. “Severe recklessness is limited to those highly unreasonable omissions or misrepresentations that involve not merely simple or even inexcusable negligence, but an extreme departure from the standards of ordinary care, and that present a danger of misleading buyers or sellers which is either known to the defendant or is so obvious that the defendant must have been aware of it.” Oppenheim Pramerica Asset Mgmt., S.A.R.L. v. Encysive Pharmaceuticals, Inc., No. Civ.A.H.-06-3022, 2007 WL 2720074 (S.D. Tex. Sept. 18, 2007) (quoting Southland Securities Corp. v. INSpire Ins. Solutions, Inc., 365 F.3d 353, 366 (5th Cir. 2004)). 
When determining whether a plaintiff has alleged facts that give rise to the requisite “strong inference of scienter,” a court must find that, after considering all plausible, non-culpable explanations for a defendant’s conduct, a reasonable person would deem the inference of scienter cogent and at least as compelling as any opposing inference that could be drawn from the alleged facts. Tellabs, Inc. v. Makor Issues & Rights, Ltd., 551 U.S. 308, 324 (2007). The Complaint fails to meet this high pleading standard because Plaintiff cannot identify a single misrepresentation made by Provectus during the Class Period. Instead, Plaintiff attempts to construe Provectus’s truthful disclosures and optimistic opinions about PV-10 as fraudulent due to the fact that the FDA did not unequivocally endorse the Phase 2 data used to support PV-10’s BTD application. As discussed herein, and in the Motion to Dismiss, Plaintiff’s allegations do not rise to the level of actionable securities fraud. 
The FDA denied PV-10’s BTD application, which was unfortunate for Provectus and its shareholders. However, this does not entitle Plaintiff, an investor who knowingly invested in a development-stage micro-cap pharmaceutical company, to utilize the securities laws as a defacto insurance policy to recoup his investment losses. Plaintiff fails to state a claim for which relief can be granted under the heightened standards of the PSLRA. Accordingly, this Court should dismiss this entire action with prejudice.

September 5, 2015


[In no particular (including chronological) order:]

September 2, 2015 / The undifferentiation of immune checkpoint inhibitors? Incyte Corporation (Nasdaq: INCY), a nearly $21 billion biopharmaceutical company as of a 9/4/15 share price close, announced a global license and collaboration agreement with China's Jiangsu Hengrui Medicine to develop and commercialize the latter's investigational anti-PD-1 agent (SHR-1210). Under the agreement, Incyte would have exclusive worldwide rights to SHR-1210 except for mainland China, Hong Kong, Macau and Taiwan.

Possible or potential item takeaway: For the deal structured and money paid by Incyte, it didn't want or couldn't get from Jiangsu Hengrui Medicine China and SARs.

According to the Incyte press release "SHR-1210 is expected to enter proof-of-concept studies for the treatment of patients with advanced solid tumors in the coming months." {Italicized emphasis is mine}

As backdrop, as FierceBiotech's John Carroll writes, "[a] little more than a year ago Incyte swiftly lined up combination deals that matched its IDO1 inhibitor, epacadostat (INCB24360), with PD-1 and PD-L1 drugs from Bristol-Myers Squibb ($BMY), Merck ($MRK), Roche ($RHHBY) and AstraZeneca ($AZN). INCB24360 is an immunotherapy designed to amp up an immune system attack on cancer, while the checkpoint programs are designed to dismantle cancer cells' cloaking mechanism that prevents an assault from happening." The idea of the combination therapy approach above is/was the use of an immune system amper upper — Incyte's IDO1 inhibitor epacadostat (INCB24360) — to help/assist/partner with the back-end — immune checkpoint inhibitors or co-inhibitory blockade agents like anti-PD-1 and anti-PD-L1 agents from the above mentioned companies.

Last year, for example, Roche partnered up with NewLink and its IDO inhibitor (NLG919). Later, in 2015, Roche partnered with India's Curadev Pharma and its IDO inhibitor.

According to Chen and Mellman's 2010's Oncology Meets Immunology: The Cancer-Immunity Cycle, IDO inhibitors do not appear to be front-ends or immune system accelerators or amper uppers or stimulatory factors or agonists or co-stims but rather back-ends or inhibitors or antagonists.
Click to enlarge. Image source (Figure 2)
Possible or potential item takeaway: Incyte brought an immune checkpoint inhibitor in-house because...
  • Combination therapies [of some sort] will become standard of care for advanced-stage cancer (eschewing [making obsolete] monotherapeutic use of immune checkpoint inhibitors)?
  • It is better to own both parts of the pairing for various clinical and/or business reasons?
  • If it is better to own both parts, differentiation of co-inhibitory blockade is more business (or marketing) than clinical?
  • Win or lose, Bristol-Myers PD-1-related lawsuit against Merck is irrelevant (or its outcome de minimis)? "Every" biopharmaceutical company, including Chinese companies for their own domestic (as well as for international collaboration purposes), has or will have an immune checkpoint inhibitor?
September 1 / A new class of immunotherapy.
Image source
If/when PV-10 stands on the cusp of approval (in T-Vec's case, while not certain, probable approval would occur by or before the drug's October 27, 2015 PDUFA date), it would be a new class of immunotherapy. And St. Luke’s University Health Network's Dr. Sanjiv Agarwala would be PV-10's Dr. Howard Kaufman, MD. See Assessing Provectus' Pivotal Melanoma Phase 3 Trial, Part I (July 13, 2015) on the blog's Current News page.

Possible or potential item takeaway: What is PV-10? An ablative immunotherapy? An autologous vaccine? An oncolytic immunotherapy? PV-10 has no specific target, receptor or pathway; however, this item cannot be properly discussed at the current time because knowledge and discussion presumably definitively relies on the presentation/publications of the results of Moffitt Cancer Center's mechanism(s) of action study due later this year. See August 29, 2015 blog post PV-10 has much better gas mileage.

September 1, 3 and 4, 2015 / Tinkering with Mother Nature. The official blog of AACR posted a 9/1 entry by Dr. Srivani Ravoori, PhD entitled Advances in Immunotherapy: Fine-tuning CAR T Cells. On 9/3 FierceBiotech's Carroll wrote an article entitled Novartis team tracks remissions of 4-plus years in a pioneering CAR-T study. In The Pipeline's Dr. Derek Lowe, PhD blogged CAR-T Follow Up on 9/4.

Ravoori wrote about scientists from the University of Pennsylvania and The University of Texas MD Anderson Cancer Center tinkering with the target-binding end of CAR T cells to make them safe for patients with solid tumors:
"CAR T cells designed to target CD19 in B-cell cancers are not selective. They cannot distinguish cancerous B cells that have high levels of CD19 from normal B cells that have physiological (lower) levels of the same protein. But this does not severely impede treating B-cell malignancies because a patient’s immune system can function even when normal B cells are depleted. This form of immunotherapy, however, is not readily adaptable to solid tumors because targetable proteins present on the cancer cells of solid tumors, such as ErbB2 and EGFR, are also present on normal cells that form the vital organs of the body. While losing normal B cells when treated with CD19 CAR T-cell therapy poses manageable side effects in a patient, loss of normal cells that are part of vital organs when treating solid tumors with CAR T-cell therapy can damage these vital organs, which has serious consequences. In fact, in a case report, CAR T cells designed to target ErbB2 present in metastatic colon cancer cells also attacked cells in the patient’s lungs that had low levels of ErbB2, resulting in severe toxicity and death. So, it became evident that if CAR T-cell therapy were to work for solid tumors, engineering T cells that can selectively target cancer cells and spare normal cells is inevitable." {Underlined emphasis is mine}
But, according to Ravoori:
Enter scientists from the University of Pennsylvania and The University of Texas MD Anderson Cancer Center, two teams that used different approaches to answer the same question: Will lowering the affinity of CAR T cells to the target protein make them selective to cancer cells that have high levels of the protein and spare normal cells that have low levels of the same protein? Based on the data the two teams published independently in the AACR’s journal Cancer Research, it appears the answer is “Yes.”
Carroll wrote:
Five years after the University of Pennsylvania began recruiting a small group of 14 patients with hard-to-treat chronic lymphocytic leukemia, researchers are still tracking three of them who are still alive with no signs of their cancer returning after being treated with a first-generation CAR-T therapy...Out of the 14, four experienced complete remissions, meaning their cancer was no longer detectable. One of those four later died of other causes. Four patients had partial responses, with two of them dying after 10 months and 27 months of therapy. One of the partial-response patients died from a pulmonary embolism, and the other was switched to a different therapy after 13 months and died after three years.
But, according to Carroll:
All of the patients who responded to the therapy experienced a potentially life-threatening case of cytokine release syndrome, sometimes called a cytokine storm, with the drug triggering high fevers and in several cases difficulty with breathing and low blood pressure. Doctors responded with the antibody drug tocilizumab and steroids, and all of the patients survived...In a small study like this, investigators can learn as much from failure as they can from success. Testing the 6 patients who did not respond, the scientists said that their customized T cell populations did not expand as aggressively as in the patients who were first flattened by a cytokine storm in their first response to the solo treatment. 
Finally, Lower wrote (about the Novartis study):
"So there’s definitely something major here, and definitely room to improve it. That’s what Novartis, and Juno, and Kite (and who knows who else) are frantically working to do right now. The biggest prizes are to extend this idea to more tumor classes, and to make it scalable to larger numbers of patients. The second one is a big challenge, and the first is even bigger. People have been antigen-hunting for quite a while now, looking for something that’s fit to turn the immune system on in other types of tumors, and it’s slow going. But you have to be sure, because if the immune system can strip a couple of pounds of aberrant white blood cells out of your system, so vigorously that it nearly overloads your kidneys, then it can do the same with lots of other tissues, too, some of which you might prefer to keep. Ripping out a couple of pounds of motor neurons or Kupffer cells would be suboptimal, to say the least."
Possible or potential item takeaway: Safety, specificity, durability? Questions UPenn/Novartis and MD Anderson are a long, long way from fully answering.

September 4, 2015 / A Rumsfeldian Perspective. Lowe, in his 9/4 blog post, wrote "People have been antigen-hunting for quite a while now, looking for something that’s fit to turn the immune system on in other types of tumors, and it’s slow going."

US Secretary of Defense Donald Rumsfeld was once quoted as saying"...because as we know, there are known knowns; there are things we know we know. We also know there are known unknowns; that is to say we know there are some things we do not know. But there are also unknown unknowns – the ones we don't know we don't know."

As Provectus' Chairman and CEO Dr. Craig Dees, PhD has discussed with me almost from the beginning of my due diligence and share ownership (paraphrasing in Rumsfeldian), there antigens we know, antigens we don't know, and antigens we don't know we don't know.

And this knowledge or lack of knowledge (crucially relevant in the treatment of cancer because antigens equal targets) is but one aspect of Dees, President Dr. Tim Scott, PhD and CTO Dr. Eric Wachter's belief that killing cancer tumors in the correct way held the key to successful medical treatment because a proper approach could enable the immune system to stimulate cancer-killing cells throughout the body.

Properly destroying cancer tumors means killing only tumors and doing so completely, quickly and, very importantly, safely (that is, leaving healthy tissue unharmed). They believe this approach is the only effective way of sustainably stimulating a person’s natural anti-cancer defenses. Instead of bathing the entire body or even parts of it with radiation, or filling the bloodstream with oral or intravenous chemotherapies or present-day immunotherapies, Dees et al. firmly hold the position that stimulating the immune system is best achieved through treating tumor tissue by injecting into it a drug capable of destroying the entire tumor as quickly as possible without damaging surrounding healthy cells. Completely also means everything from visible tumor tissue to occult or hidden cells in and immediately around the injection site. Quickly means having the drug processed through and excreted from the body in short order. Antigens generated from the tumor destruction caused by drug injection then can be presented to the body’s cells responsible for selecting the best and most relevant antigens in order to encourage cancer-killing cells to replicate themselves throughout the body. Importantly, tumor antigens have to be viewed in context; physical tumor destruction techniques such as heating or freezing tissue destroyed fragile antigens and disrupted their relevant contextual structures. Disruption of cell membranes and removal of lipids, proteins, and complex carbohydrates destroy the antigens’ context, which is to what immune system cells respond. Thermal destruction denatures potential antigens, changing their chemical structure so that they were no longer representative of the tumor cell. In order to work rapid destruction of tumors has to preserve both antigenic structure and biological context. (Paragraph source, with slight edits by me for verb tense: MicroCap Review, pp. 6-8, September 2015)

Possible or potential item takeaway: For Craig et al. to have PV-10, and themselves, more fully recognized, all constituents of the biopharmaceutical ecosystem are going to have to embrace the above.

August 29, 2015

PV-10 has much better gas mileage

Paul Rennert's SugarCone Blog has been and continues to be a good read for this project. Take, for example, his July 18th blog post How far can a CAR get you? The post primarily discusses CAR T cell therapy (CAR = Chimeric Antigen Receptor), concluding with:
"So my hope is that we can engineer CAR T cells with sufficient machinery to “rescue” CAR T technology from the reality of an antigen-poor landscape. The technology is stunning, but I wonder if in the face of such challenges one ought not to look around, and perhaps take another approach. As it turns out, nearly all cellular therapy companies that have taken on the CAR T field have begun to diversify - we’ve been asking what problems we are solving with these clever twists on the basic technology – and this is well worth pursuing. However in the face of a limited pool of targets, lets perhaps consider a technology with a much much larger target list: tumor neoantigens as recognized by T Cell Receptors (TCR). TCR and TIL technologies offer some interesting solutions, and their own unique challenges…" {Underlined emphasis is mine}
Rennert highlights several well known problems of the CAR T field, the below taken verbatim from his post:
  1. CAR T cells must be highly selective for the target cancer to avoid unwanted killing of other cells, tissues, organs
  2. CAR T cells must proliferate and persist once injected into the patient (i.e. in vivo)
  3. Since most CAR T technologies are based on a personalized medicine approach – your cancer attacked by your engineered T cells – there is a fair amount of cell culture to do between harvesting your T cells, altering them (via retroviral or other cell transduction technique), expanding those altered T cells so there are enough to “take” upon injection back into the patient. All of this is expensive, with a typical guess at the price tag of 500K USD
  4. CAR T therapy is dangerous (although a bit like Formula One racing – very dangerous and just barely controlled). The danger comes from the potential for off-tumor cell killing but also from tumor lysis syndrome, which happens when large numbers of tumor cells are suddenly killed – all sorts of cellular signals get released and this causes an intense and systemic physiological breakdown – very dangerous, but controllable in an appropriate intensive care unit (so recovery care is also very expensive)
  5. CAR T therapy to date has had limited success outside of refractory acute lymphocytic leukemia (ALL). Now, while refractory ALL is a poster child of an indication – intensely difficult to treat, with many pediatric patients – there are about 4000 such patients in the US each year. Commercially, this is limiting.
  6. Cancer-specific targets suitable for CAR T technology are very rare.
His list of CAR T technology/company problems are a perfect foil for PV-10 and its own solutions. I believe a new narrative about PV-10 goes something like this: A compound that both agnostically ablates tumors and perfectly primes the immune system. Being copiously liberal with Rennert's list, consider the following below about PV-10.

A. Highly selective
  • Provectus: PV-10 itself exhibits antitumoral activity targeted only on diseased tissue while sparring normal tissue (SITC 2012)
  • Moffitt: “The cells we took from mice treated with PV-10 were indeed activated against B16 melanoma tumors. We demonstrated that by showing that they could be transferred to untreated mice with the same tumor and produce an antitumor response. This is the definitive way to test for a tumor-specific T-cell response.” Against MC-38 adenocarcinoma tumors, the T-cells from treated B16 mice had no significant effect. “This is a very specific response to the B16 tumor,” Dr. Pilon-Thomas said. (AACR 2013)
B. Tantamount to in vivo vaccination
  • Provectus: PV-10's immuno-ablative response is tantamount to "in situ vaccination" (SITC 2012). After all, isn't that what leads to systemic anti-tumor immunity?
C. Inexpensive
  • A 5 mL single-use vial costs tens of dollars to manufacture
  • A melanoma patient may average 6 vials
  • Early-stage liver trial patients thus far may have averaged 5-10 mL (receiving single injections of drug product)
D. Safe
  • 1923: "The patient, a Chinaman with a carcinoma of the pancreas with complete biliary obstruction, showed no toxic effects after the intravenous injection of 100 mg. of the dye. In fact, while observing interest the injection of this beautifully colored “medicine” he stated that he felt much better and wanted more. Frequent injections on this patient gave no toxic effects and led to the subsequent injection of some two to three hundred others."
  • Provectus: PV-10 is not metabolized in the body and has a 30-minute half-life once in the bloodstream.
  • No off-tumor cell killing, no tumor lysis syndrome
E. Broadly indicated
  • Melanoma & Breast Cancer/Moffitt: "These studies have demonstrated that intralesional PV-10, in addition to reducing the growth of a directly injected tumor, leads to the induction of a robust anti-tumor T cell response and supports the use of PV-10 to induce systemic anti-tumor immunity for the treatment of metastatic melanoma and breast cancer." (AACR 2013)
  • Colorectal/University of Illinois at Chicago: "Rose Bengal induced potent cell death in human and murine colon cancer cells in vitro. Intralesional injection in established tumors induced an anti-tumor immune response and significant tumor regressions in vivo. These studies establish that intralesional PV-10 therapy warrants further study as a potential immunotherapeutic agent in colorectal cancer and metastases." (SSO 2015)
I have not included the initial Phase 1 liver data because it only addresses PV-10's tumor ablation, and not yet on the drug's systemic effect.

F. No specific target, receptor or pathway

This item cannot be properly discussed at the current time because knowledge and discussion relies on the presentation/publications of the results of Moffitt Cancer Center's mechanism(s) of action study due later this year.

August 23, 2015

Assessing Provectus' Pivotal Melanoma Phase 3 Trial, Part VII

The seventh in a series of blog posts and news items assessing the company's pivotal Phase 3 trial for unresectable locally advanced cutaneous melanoma (Stage III patients, and not metastatic [Stage IV] melanoma).
  1. Win or lose: Will the trial succeed in meeting or fail to meet its primary and/or secondary endpoints?
  2. Time-to-success or -failure: How long might it take for the trial to succeed or fail?
  3. Good or bad process: Are there process steps and aspects thereof that may provide hints of potential future trial success or failure.
This blog news item, 3. Good or bad process: The consistency of melanoma patient outcomes from chemotherapy.

Blog post takeaways
  • Stage 3 melanoma patients treated with systemic chemotherapy (dacarbazine or temozolomide) are not more likely to respond than Stage IV patients,
  • A 30-year experience overview of dacarbazine in metastatic melanoma (Stage IV patients) noted an approximately reproducible 20% objective response rate (complete response + partial response), and
  • Thus, Provectus' pivotal Phase 3 trial for locally advanced cutaneous melanoma (exclusively Stage III patients) should see high rates of disease progression (comparable to trials involving Stage IV melanoma patients) occur quickly in its control arm.
Prior analysis (categorized on the blog as Assessing Provectus' Pivotal Melanoma Phase 3 Trial, Parts I-VI, among other posts and news items) primarily utilized Middleton et al. (2000) — Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma (J Clin Oncol. 2000 Jun;18(11):2351). This work yielded chemo disease progression response rates (PD) of 65-70% and median progression-free survival (PFS) of 1.5-1.9 months in primarily Stage IV patients.

Shah et al. (Correspondence author: Chapman) (2010) — Phase II trial of neoadjuvant temozolomide in resectable melanoma patients (Ann Oncol. 2010 Aug;21(8):1718-22) — noted the following in a study of mostly Stage III patients (14 of 19; 5 Stage IV patients):
  • 63% disease progression (12 of 19 patients),
  • Of the 12 patients that had progression of disease, progression was detected at week 4 or 8 (a single cycle or less) in 11 of them. One patient with a mixed response received 4 weeks of a second cycle (less than a second cycle) before progression of disease was evident, and
  • Most patients (12 of 19) only received a single cycle or less of chemo, where a cycle lasted 8 weeks. Six patients received 2 cycles. One patient, who had a complete response (CR), received 3 cycles.
The Shah et al. (inc. Chapman) study outcome is consistent with outcomes in earlier studies despite the earlier stage of disease and the aggressive treatment regimen.

In another study, Rietschel et al. (Correspondence author: Chapman) (2008) — Phase II Study of Extended-Dose Temozolomide in Patients With Melanoma (J Clin Oncol. 2008 May 10;26(14):2299-304) — noted the following in a study of both Stage III and IV patients (25 Stage III/IV M1a/IV M1b patients in one cohort, and 25 Stage IV M1c patients in a second):
  • Objective response rates (CR + PR) in both cohorts were 12.5% (no CRs).
In Serrone et al. (2010) — Dacarbazine-based chemotherapy for metastatic melanoma: thirty-year experience overview (J Exp Clin Cancer Res. 2000 Mar;19(1):21-34) — the authors noted:
  • 13 trials involving single agent dacarbazine for advanced melanoma,
  • Objective response rates varying from 12-25%, and
  • Observing, overall, an approximately reproducible 20% objective response rate with median response duration of 5 to 6 months [f/n 1] and complete response rates of 5%.
[f/n 1] Response duration refers to the durability of objective responses, CR and PR, and is not the same as PFS.

Previous entries in the series:
  1. 3. Good or bad process: Patient enrollment. See Assessing Provectus' Pivotal Melanoma Phase 3 Trial, Part I (July 13, 2015) on the blog's Current News page,
  2. 3. Good or bad process: Designing an interim analysis for efficacy into Provectus' pivotal melanoma Phase 3 trial. See July 16, 2015 blog post Assessing Provectus' Pivotal Melanoma Phase 3 Trial, Part II,
  3. 3. Good or bad process: Patient crossover. See Assessing Provectus' Pivotal Melanoma Phase 3 Trial, Part III (July 20, 2015) on the blog's Current News page,
  4. 2. Time-to-success or -failure: Triggering the interim analysis. See July 23, 2015 blog post Assessing Provectus' Pivotal Melanoma Phase 3 Trial, Part IV,
  5. 3. Good or bad process: Patient-reported outcomes. See Assessing Provectus' Pivotal Melanoma Phase 3 Trial, Part V (July 24, 2015) on the blog's Current News page, and
  6. 1. Win or lose: Predicting outcomes, (ii) 2. Time-to-success or -failure: An unusual response in one of the randomized controlled trial arms, and (iii) 3. Good or bad process: Multiple triggers. See August 4, 2015 blog post Assessing Provectus' Pivotal Melanoma Phase 3 Trial, Part VI.

August 15, 2015

Clinical & Business Value Proposition Pillar #5

Image source
On Provectus' August 6th 2Q15 business update conference call, the company's COO/CFO Peter Culpepper introduced five clinical and business value proposition pillars for PV-10:
  1. Intellectual property
  2. Drug supply chain (both substance and product)
  3. Regulatory support
  4. Mechanisms of action
  5. Rational clinical study designs for randomized data generation
Blog post takeaway
  • The focus of this post is pillar no. 5, more data generation, and specifically data generation related to the combination of PV-10 and an immune checkpoint inhibitor (pembrolizumab, and maybe other co-inhibitory blockade agents) in patients with advanced melanoma (Stage IV).
  • Randomized data generation is a process, which starts with a dose escalation component (in this case, the escalation of PV-10's dose in context given the approved Keytruda dose).
  • I'm looking to Provectus' 3Q15 business update conference call potentially in early-November (e.g., Thursday, November 5th) for the company's CTO Dr. Eric Wachter, PhD to discuss and/or have filed the combination therapy Phase 1b and 2 trial protocols. Whether one refers to it as a Phase 1b/2 (as was the case for T-Vec + ipilimumab) or a Phase 1b/3 (T-Vec + pembrolizumab), the second part of the clinical study process is a randomized controlled trial (RCT).
We assume generating randomized clinical data already has started with the commencement of the company's pivotal Phase 3 trial of PV-10 versus systemic chemotherapy in patients with unresectable locally advanced cutaneous melanoma (Stage III). More data is more than likely required to potentially further increase company value.

For advanced melanoma (Stage IV), step #2 of randomized data generation — the RCT component of the melanoma combination therapy two-step clinical study process — starts with step #1, single-arm data generation from a dosing (of the intralesional agent [IL]), safety and response rate evaluation of a pairing of compounds.

On Provectus' March 13th 4Q14 business update conference call Eric said:
"Throughout our consultations with key clinical opinion leaders, we’ve also been attuned to the need to address the needs of patients with more advanced disease. With enrollment now complete in the mechanism of action study of PV-10 of Moffitt Cancer Center, and initial results reported on that study and on the companion nonclinical study to assess combination of PV-10 with immune checkpoint inhibition, we are making progress on design of our proposed study to assess PV-10 in combination with immune checkpoint inhibition in patients with advanced melanoma. 
We continue to expect this to be structured as a Phase 1b/2 study with a modest sized single arm Phase 1b component and expedited safety and efficacy endpoints supporting expansion to a larger randomized Phase 2 component. Endpoints for Phase 1b are likely to comprise acute safety as a combination regimen and objective response rate at three to four months. For Phase 2, we anticipate endpoints of progression free survival at overall survival. With three agents now approved in the US and also available in other key locations abroad, I expect to have very concrete details on this work to discuss at our next quarterly conference call. Importantly now that we have options for this systemic agent, this study can commence with or without the assistance of a partner." {Underlined emphasis is mine}
On the company's May 7th 1Q15 call he said:
And in addition to the progress on the combination therapy patent front that Pete mentioned, we've also made substantial progress towards commencement of our proposed clinical study of PV-10 in combination with immune checkpoint inhibition. We have identified the investigators who will lead this work, the agent to be used in conjunction with PV-10, the patient population and the dosing schedule for both agents along with the study end-point. To assess potential benefit of PV-10 for patients with advance melanoma, this phase 1b/2 study will incorporate a modest sized single arm Phase 1b component with expedited safety and efficacy end point supporting expansion to a larger randomized Phase 2 component. 
End points for phase 1b are expected to comprise assessment of acute safety of the combination regimen and objective response rate at three to four months. For the Phase 2 portion, end points will be progression-free survival and overall survival. 
Once the protocol addressing each of these areas is complete, we believe the pieces are in place to commence clinical work on this important second development path for PV-10 and melanoma. Since the checkpoint inhibitor we expect to use is licensed in the U.S., we can commence this study with or without the systems or a partner." {Underlined emphasis is mine}
By protocol I think Eric means both Phase 1b and RCT protocols (whether one refers to the latter as a Phase 2 or Phase 3 trial).

On the company's August 6th 1Q15 call he said:
"Turning to the other primary component of our development plan for melanoma, we've continued to move towards commencement of a post-clinical study of PV-10 in combination with a new checkpoint inhibition in patients with advanced metastatic melanoma. After thorough consultation with leading investigators who will conduct this work, we have a study design that is undergoing final investigator review and anticipate completing the protocol before the end of the present quarter. 
This includes comprehensive definition of patient population, dosing schedule for both agents, and the study endpoints. As I've indicated previously, to assess potential benefit of PV-10 for patients with advanced melanoma, this Phase Ib/II study will incorporate a modest-sized single arm Phase I key--Phase Ib component of 24 patients with expedited safety and efficacy endpoints. 
Completion of this initial phase is expected to support expansion to a larger randomized Phase II component having an estimated 120 patients. The actual size of the Phase II component will be determined by modeling and response data among Phase Ib participants, that is the socalled observed effect size. 
Endpoints for Phase Ib will comprise assessment of acute safety of the combination regimen and objective response rate at three to four months. For the Phase II portion, endpoints will be overall survival, progression-free survival, and objective response rate. 
We anticipate using the anti-PD1 drug pembrolizumab, also known as Keytruda, as the checkpoint inhibitor. This class of drug has been shown to work favorably with PV-10 in mouse models with melanoma, as presented by our colleagues at Moffitt last November at the Annual Meeting of the Society for Immunotherapy Cancer, and as anticipated in our allowed drug patent application with Pfizer, the two drugs have largely unrelated or orthogonal side effect profiles. 
These factors provide justification for conducting the study. Also, since pembro is standard of care for the study of patient population, it is standard practice to conduct these kinds of studies in an add-on mode where all patients receive standard of care. 
We're optimistic that we can leverage existing investigator and site relationships to commence this study by the end of the calendar year. And since pembrolizumab is licensed in the US, we can commence this study with or without the assistance of a partner. If ongoing negotiations with prospective corporate partners lead to interest in testing PV-10 with a different checkpoint inhibitor, the study is designed to facilitate use with other drugs to enable such testing in a straightforward manner. {Underlined emphasis is mine}
With the Phase 1b and Phase 2 protocols not ready (and thus fileable on ClinicalTrials.gov) all Eric could say was the above. When filed on the .gov site both the T-Vec + ipilimumab and T-Vec + pembrolizumab protocols were two-step ones, as shown below, respectively:
Click to enlarge. Image source. Fuzzy purple emphasis is mine
Click to enlarge. Image source. Fuzzy purple emphasis is mine
In extending my door analogy from August 12th blog post The Door, Eric would have to had to design and construct the first door, design as well as perhaps mostly construct the second in consultation with the FDA (with emphasis on the second door, a presumably pivotal study). There would be placeholders (specifically the size of Phase 2 trial N) for the second door that would be modified pending the outcome of the initial Phase 1b study: "The actual size of the Phase II component will be determined by modeling and response data among Phase Ib participants, that is the socalled observed effect size." (Eric's comments, August 6th business update call).

Securing the keys to the doors from the regulator would require reaching the threshold of each door. I would wonder if yet assume Eric has discussed the path to and through the first door and the path to the second with the FDA. Maybe it's the [paths'] the utilization of a portion of the data (a fraction of the trial N) from the Phase 1b trial — if successful and appropriate — to apply for breakthrough therapy designation, followed by commencing the pivotal study, and the utilization of a portion of the data (a fraction of the trial N1) to be considered for accelerated approval — if successful and appropriate. Of course, maybe that's not entirely or actually the process.

And discussing cost and how to fund these paths (i.e., pros and cons of available and potential options) in the greater context of the company and its overall burn rate is an important matter for another discussion and post.