Checkpoint Inhibition Differentiation or Death: Proprietary Combinations with Protectable Agents

Updated below.

From this project's Twitter feed: Dr. Sally Church, PhD, ‏@MaverickNY

Click to enlarge. Tweet image source

How would Big Pharma distinguish each of its immune checkpoint inhibitors (CIs) from another? Efficacy? Tolerability? Cancer indication? Cost? Within groups (e.g., PD-1s, PD-L1s, etc.), efficacy and safety should equivalent. Different antibodies — for example, with the PD-1s, like nivolumab/Opdivo and pembrolizumab/Keytruda — function in almost identical fashion and differ only by means of manufacture and corporate decisions made with regards to clinical development (e.g., dose schedule, target indication). Magically, there is parity in pricing.

Based on drug sales to date and sales projections thus far, captured in part by @grhyasen's tweet graphic above, Bristol-Myers (nivolumab/Opdivo) and Merck & Co. (pembrolizumab/Keytruda) may be in no serious rush to differentiate their CIs beyond their current, respective corporate strategies. But Roche (atezolizumab/Tecentriq), AstraZeneca (durvalumab) and Merck KGaA/Pfizer (avelumab), all with "late to market" CIs, surely must be thinking about ways to differentiate their respective compounds.

Does meaningful, sustainable and profitable differentiation come in the form of combination, and thus in the form of a partner compound for a CI? In other words, could combination create branded differentiation — ultimately based on efficacy, tolerability, indication and cost of the combination. Proprietary combinations with protectable agents.

Novartis, one Big Pharma without a "lead CI" but having PD-1, TIM-3, LAG-3 and PD-L1 CIs within its pipeline, seems to have begun its brand differentiation by expanding its strategic thinking to include or focus on first-in-class combinations. See Pharmaceuticals and Oncology Business Units, Meet Novartis Management, May 24-25, 2016:

Click to enlarge. Fuzzy orange rectangle is mine

Click to enlarge. Fuzzy orange rectangle is mine

PV-10's, and thus Provectus', value proposition to the likes of Roche, AstraZeneca, Merck KGaA, Novartis, etc. might be to (a) combine their CI with PV-10 and (b) use Provectus' combo patent* to defend the unique combination thus formed — a proprietary combination with a protected agent.

* United States Patent No. 9,107,887, Eagle et al., August 18, 2015, Combination of local and systemic immunomodulative therapies for enhanced treatment of cancer

Updated (6/11/16): Deena Beasley, Reuters, June 11th, Regulator says too many drugmakers chasing same cancer strategy:

"A new type of cancer drug that takes the brakes off the body's immune system has given drugmakers some remarkable wins against the deadly disease, but a top U.S. regulator says too many companies are focused on the same approach. 

Dr. Richard Pazdur, head of the Food and Drug Administration's office of oncology products, was referring to therapies designed to disable the PD-1 protein that tumors use to evade the immune system...  

"People should ask themselves ... would we be better off spending those resources into looking at more novel drugs?" Pazdur told Reuters during the annual American Society of Clinical Oncology (ASCO) meeting in Chicago this week.... 

"As with everything in drug development, it is about reduction of risk," he said. But the number of similar drugs in development at the same time is a first in the oncology field, and latecomers to the PD-1 market will likely be relegated to "niche" indications, he added. 

Drug company executives disputed Pazdur's critique. In interviews with Reuters, they argued that the science around cancer is advancing rapidly, with a focus on how to best combine therapies to attack multiple mechanisms of the disease, determine which patients are most likely to respond to them and how long patients will need to be treated."

Blumenthal and Pazdur, Response Rate as an Approval End Point in Oncology, JAMA Oncol. 2016;2(6):780-781.

"Overall response rate (ORR) as a surrogate end point in oncology drug approval has a long history. In the 1970s, the US Food and Drug Administration (FDA) usually approved drugs on the basis of ORR. In the 1980s, after discussions with the Oncologic Drug Advisory Committee, the FDA determined that cancer drug approval should be based on more direct evidence of clinical benefit, such as improvements in overall survival (OS), tumor-related symptoms, or physical function.1 In the past decade, due to an improved understanding of the genomic underpinnings of cancer, better molecular characterization of tumors, and more precisely targeted agents, unprecedented rates of response have radically altered the therapeutic landscape in a number of malignant neoplasms. Therefore, ORR and duration of response as assessed in single-arm trials has served as the basis of accelerated approval and at times regular approval in a number of refractory malignant neoplasms, including non–small-cell lung cancer (NSCLC), lymphoma, melanoma, and myeloma."

This presumably works [very well] only for systemic drugs using standard RECIST. Provectus' pivotal melanoma Phase 3 is employing [standard] RECIST 1.1.

Road tripping:

My proxy vote should be posted by June 14th.

Rose Bengal (PV-10) at ASCO 2016

[Colored emphasis below is mine.]

A phase 2 study of intralesional PV-10 followed by radiotherapy for localized in transit or recurrent metastatic melanoma.

Author(s): Matthew C Foote, Bryan H Burmeister, Janine Thomas, Tavis Read, Bernard Mark Smithers; Princess Alexandra Hospital and University of Queensland, Brisbane, Australia; Princess Alexandra Hospital, Brisbane, Australia

Background: Intralesional rose bengal (IL PV-10) can elicit ablation of injected tumors and a T-cell mediated abscopal effect in untreated lesions. Phase 2 testing in patients with Stage III-IV melanoma yielded a 51% objective response rate (ORR) with 50% complete response (CR) when all disease was injected. Three patients who progressed received external beam radiotherapy (XRT) to their recurrent lesions with an impressive response without an increased radiation reaction. Methods: An open-label, single-arm phase 2 study was performed to assess efficacy and safety of IL PV-10 followed by XRT. Eligibility included recurrent localized dermal, subcutaneous, in-transit or metastatic malignant melanoma (stage IIIb / IIIc) suitable for intralesional therapy and XRT. Patients received a single course of PV-10 into lesions treatable within a localized radiotherapy field. If CR was not achieved patients received 30 Gy (6 fractions of 5 Gy twice weekly over 3 weeks) 3D conformal radiotherapy (photons or electrons) commencing 6-10 weeks after PV-10. Outcome assessments included ORR and clinical benefit (CR+PR+SD) of in-field target lesions by RECIST criteria, toxicity using CTCAE V3.0, and progression free survival (PFS). Results: There were 15 patients enrolled with 13 completing the radiotherapy component. Two patients had rapidly progressive distant disease following PV-10 injection. The mean age of patients was 69 years. With a median follow up duration of 19.3 months the overall response rate was 87% (CR 33%, PR 53%) with 93% clinical benefit on an intent-to-treat basis. The mean time to best response was 3.8 months, mean duration of complete response (PFS) 12.2 months, overall loco regional progression rate 80% and melanoma specific survival 65.5 months. Size of metastases ( < 10mm) predicted potential for lesion complete response. Treatments were well tolerated with no treatment associated grade 4 or 5 adverse events. Conclusions: The combination of IL PV-10 and radiotherapy resulted in lesion specific, normal tissue sparing, ablation of melanoma tumors with minimal local or systemic adverse effects. The study results justify expanded evaluation in a randomized trial.

Intralesional rose bengal for treatment of melanoma.

Author(s): Sanjiv S. Agarwala, Robert Hans Ingemar Andtbacka, Kristen N. Rice, Merrick I. Ross, Charles Raben Scoggins, Bernard Mark Smithers, Eric D. Whitman, Eric Andrew Wachter; St. Luke's Hospital and Health Network and Temple University, Bethlehem, PA; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; Medcl Onc Assoc of San Diego, San Diego, CA; The University of Texas MD Anderson Cancer Center, Houston, TX; University of Louisville, Louisville, KY; Princess Alexandra Hospital and University of Queensland, Brisbane, Australia; Atlantic Melanoma Ctr, Morristown, NJ; Provectus Biopharmaceuticals, Inc, Knoxville, TN

Background: Intralesional rose bengal (PV-10) is an investigational small molecule ablative immunotherapy that can elicit primary ablation of injected tumors and secondary T-cell activation. Phase 2 testing in Stage III-IV melanoma yielded a 51% objective response rate (ORR) with 50% complete response (CR) when all disease was injected. PV-10 is currently undergoing phase 3 testing as a single agent in patients with locally advanced cutaneous melanoma and phase 1b testing in combination with immune checkpoint inhibition for more advanced disease. Methods: Study PV-10-MM-31 (NCT02288897) is an international multicenter, open-label, randomized controlled trial of PV-10 versus investigator’s choice of chemotherapy (dacarbazine or temozolomide) or oncolytic viral therapy (talimogene laherparepvec). A total of 225 subjects with locally advanced cutaneous melanoma (Stage IIIB or Stage IIIC recurrent, satellite or in-transit melanoma) randomized 2:1 will be assessed for progression free survival (PFS) by RECIST 1.1 (using blinded Independent Review Committee assessment of study photography and radiology data). Comprehensive disease assessments, including review of photography and radiology data, are performed at 12 week intervals; clinical assessments of progression status are performed at 28-day intervals. Study PV-10-MM-1201 (NCT02557321) is an international multicenter, open-label, sequential phase study of PV-10 in combination with pembrolizumab. Stage IV metastatic melanoma patients with at least one injectable cutaneous or subcutaneous lesion who are candidates for pembrolizumab are eligible. In the current phase 1b portion of the study, up to 24 subjects will receive the combination of PV-10 and pembrolizumab (PV-10 + standard of care). In phase 2 an estimated 120 participants will be randomized 1:1 to receive either PV-10 and pembrolizumab or pembrolizumab alone. The primary endpoint for phase 1b is safety and tolerability with PFS a key secondary endpoint; PFS is the primary endpoint for phase 2. Clinical trial information: NCT02288897

"Going to be a leading player in 2nd wave of combos."

Blog post title attribution: From a tweet by @lisamjarvis below:

Click to enlarge. Image source

Provectus issued a press release yesterday, Confirms First Patients Dosed in Trials of PV-10 for Melanoma, which also included the sub-headline "Phase 1b/2 Trial of PV-10 In Combination with Keytruda® for Stage IV Metastatic Melanoma." See my initial comments under "FPFV" (January 12, 2016) on the blog's Current News page.

As I noted in January 10th's blog post Generating Clinical Data, I believe the ideology behind Provectus' pivotal melanoma Phase 3 trial (that is, management's consequential ideas and ideals) is a clear and present focus on the earlier treatment of cancer patients — in the pivotal study's case, the treatment of patients with locally advanced cutaneous melanoma, otherwise mostly known as Stage III (specifically, Stage IIIB-C recurrent, satellite or in-transit cutaneous or subcutaneous melanoma). The ideology is evidenced if and only if/when and only when the trial's hypotheses are proven: (i) complete response of injected tumors is tantamount to elimination of disease symptoms, and (ii) PV-10 can forestall or prevent the spread of the disease from Stage III to Stage IV if all of it is treated.

Provectus management, however, acknowledges that while the greater unmet need in melanoma is the silent masses of earlier stage patients with no real good treatment options, therapy or therapeutic, a potentially much greater driver of value for this indication for a company like Provectus (and thus valuation or market capitalization) lies in combining PV-10 with an immune checkpoint inhibitor like pembrolizumab (Keytruda) in patients with advanced melanoma (Stage IV disease), which comprises a fraction of the total population of people afflicted with this cancer.

The company's CTO Dr. Eric Wachter, PhD's first quote in the PR is interesting:

"With patients starting treatment in both of these studies, the clock is ticking to interim results and ultimately the completion of these studies. Our recruitment activities are moving ahead and we are hopeful that these studies will play critical roles in demonstrating effectiveness and safety of PV-10 in melanoma." {Underlined emphasis is mine}

Eric has the tendency to be [very] precise, on occasion, I believe, at the detriment of accuracy, in context. Nevertheless, "the clock is ticking," at least for me, is sort of odd in its usage in that sentence. Or is it? "clock is ticking, the:" The time (for something to be done) is passing quickly.

Later, in the PR, in regards to the Phase 1b/2 combination study, the release (Eric) notes:

"Up to 24 subjects will be enrolled in the Phase 1b portion of the study. Each subject in this cohort will receive the combination of IL PV-10 and pembrolizumab. The expected completion date is in 2016 for the Phase 1b portion of the study." {Underlined emphasis is mine}

When would be an interim data readout be undertaken; sometime in 2016 (if the completion date is planned for this year as well), but when exactly?

Eric's second quote in the PR says:

"Current research suggests that using anti-cancer drugs in combination can have additive or synergistic effects that can improve the outcomes patients experience. KEYTRUDA® and PV-10 together may prove more effective than either agent alone in treating certain cases of melanoma. We believe that our current Phase 3 study that tests PV-10 on its own for Stage III patients is designed to prove its effectiveness, but we also believe that we should examine combination therapies to maximize potential benefit to patients, especially those with advanced disease." {Bolded and underlined emphasis is mine}

As I also noted in Generating Clinical Data, the crux of the Phase 1b/2 study is showing PV-10 can work in combination with another drug or drug compound, proving orthogonality from both safety and efficacy perspectives. This study's hypothesis in my view is PV-10, together with a checkpoint inhibitor, can benefit patients (Stage IV melanoma) with disease inaccessible to PV-10 injection, with a management ideology of demonstrating a PV-10 solution for late-stage patients with heavy tumor burdens and visceral disease.

An interim data readout of the Phase 1b study might be based on about half of the target number of patients (it might not be, but my baseline guess is half), or about 12 (i.e., half of "up to 24 subjects"). In 4Q15 I heard speculation 5 to 6 patients had been treated (by that time). If PV-10 plus Keytruda makes for a potent combination, how many cycles would a patient require to show meaningful response [rates] and progression-free survival? Provectus' completed Phase 2 Study of Intralesional PV-10 for Metastatic Melanoma saw complete responses mostly require 1-2 injections of Rose Bengal, but in some cases up to 4 treatments. Patients in the Phase 1b study will have up to 5 treatments of both therapies.

Could the trial have recruited enough patients for an interim data readout, and could those patients have received 1-2 cycles of PV-10 and Keytruda?

Click to enlarge.

Takeaway: In saying the clock is ticking to interim results, is Eric actually saying the Phase 1b study in particular is nearly there?

As for the title of this blog post, Pfizer is a part-owner of Provectus' intellectual property regarding combination therapy: Combination of local and systemic immunomodulative therapies for enhanced treatment of cancer (including continuation #1, continuation #2).

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.

Potential Catalysts & "Catalysts"

Caveat: I have been hilariously off-base in the past. See, for example, my August 31, 2014 blog post Potential Catalysts.

Updated (8/9/15): To reflect a longer period of pivotal melanoma Phase 3 site activation, and to include as a catalyst the potential approval of Amgen's intralesional agent for metastatic melanoma talimogene laherparepvec (T-Vec).

Updated (8/9/15): To reflect a year-end start to a Phase 1b trial combining PV-10 and an immune checkpoint inhibitor in patients with advanced melanoma.

Click to enlarge.

Click to enlarge.

"Provectus Biopharmaceuticals' Novel Synthesis Patent Application Allowed by Chinese Patent Office"

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Provectus issued press release Provectus Biopharmaceuticals' Novel Synthesis Patent Application Allowed by Chinese Patent Office on Monday, noting the company "...received notification of allowance from the Chinese Patent Office for its patent application protecting the synthetic process used to produce the small molecule Rose Bengal, the active pharmaceutical ingredient (API) in PV-10, the Company's lead oncology drug candidate."

The synthesis patent, according to Provectus, "...covers the process under which pharmaceutical grade Rose Bengal and related xanthenes are produced, reducing the formation of certain previously unknown transhalogenated impurities that currently exist in commercial grade Rose Bengal in uncontrolled amounts. The requirement to identify and control related substances is in accordance with International Conference on Harmonisation (ICH) guidelines for manufacture of API suitable for clinical trial material and commercial pharmaceutical use."

A screenshot of the allowance is below:

Image source

The joint Provectus-Pfizer combination patent application filed in China also is below and, according to Provectus, "...covers a method of treatment of cancer that comprises administering a therapeutically effective amount of an intralesional chemoablative pharmaceutical composition in combination with a therapeutically effective amount of a systemic immunomodulatory anticancer agent. The systemic immunomodulatory anticancer agent comprises anti-CTLA-4 antibodies including ipilimumab and tremelimumab." Claims not yet made public purportedly include anti-PD-1 and anti-PD-L1 antibodies.

Image source

Both patent applications were submitted at the same time to their respective geographic regulatory agencies. That is, the synthesis patent was filed on September 17, 2010 with both the U.S. and Chinese patent offices, and the combination patent was filed with both agencies on March 9, 2012. According to Eric (paraphrasing), Provectus files Patent Cooperation Treaty ("PCT") versions of the company's PTO patent applications simultaneously in designated jurisdictions within their respective PCT deadlines. Such filings may be made months after the U.S. case is filed. This allows management to obtain initial input from U.S. examination before the process commences in earnest in other jurisdictions, and to fine tune claims before international prosecution starts. Additionally, Provectus also typically elects to file first in certain key jurisdictions the company has learned are both important and rigorous, which allows management to further refine their international claims before proceeding with other jurisdictions. See IP & China (December 26, 2014) on the blog's Archived News II page.

Protecting intellectual property around the world is good process, and a valuation driver for Provectus. An important component of the company's upcoming pivotal Phase 3 trial for locally advanced cutaneous melanoma would be clinical sites in international locations, such as Australia (a given based on prior participation in Provectus' metastatic melanoma Phase 1 and 2 trials), Western Europe, and so-called emerging market/developing countries.

A China site, and its associated investigator, should be on the roster when the trial starts, or shortly thereafter. The site, at least one of them in the country, should be the Peking University Cancer Hospital (also known as, or having the other titles of, the Beijing Cancer Hospital, the Beijing Institute for Cancer Research, and Peking University School of Oncology). Clinical studies registered on ClinicalTrials.gov for the Beijing Cancer Hospital may be found here (there are 3 that are recruiting).

The investigator should be  Professor and Dr. Jun Guo, M.D., Ph.D (Vice President of Clinical Oncology, Peking University; Deputy Director, Beijing Institute for Cancer Research; Director of Department of Melanoma & Renal Cancer, Peking University School of Oncology). Clinical studies registered on ClinicalTrials.gov for Dr. Gou may be found here (there are 102 of them of various statuses). See also The Asia Melanoma Group (November 26, 2014) on the blog's Archived News II page.

St. Luke's University Health Network's and Provectus' lead melanoma Phase 2 trial investigator Dr. Sanjiv Agarwala spoke at Dr. Guo's October 17th-19th Beijing melanoma conference (2014 Beijing International Melanoma Congress), which was co-chaired by Dana-Farber/Harvard Cancer Center's Professor and Dr. Keith Flaherty, M.D. See 2014 Beijing International Melanoma Congress (October 7, 2014) on the blog's Archived News II page.

Dr. Guo is the head of the Asia Melanoma Group, the establishment of which was announced at above mentioned Beijing conference. See China Daily article New group offers hope to melanoma sufferers:

"The new group consists of 17 leading melanoma experts from countries including China, Singapore, Korea and Hong Kong. "Given Asian patients' differences in genetic background and disease types to Europeans, it is high time Asian experts stand together to form a group that will break down barriers in research on melanoma," said Guo Jun, deputy director of the Beijing Cancer Hospital and head of the newly-established group. The incidence of melanoma is higher among white people than Asians but Asian people have a much higher probability of mucous melanoma than Caucasians, which usually has a poorer prognosis than melanoma on the skin, Guo explained."

Dr. Guo also is a member of Melanoma International Foundation's Scientific Advisory Board, which is co-chaired by Dr. Flaherty.

Amgen's pivotal metastatic melanoma Phase 3 trial for T-Vec did not include any clinical trial sites in China. International locations included sites in Canada, South Africa, and the United Kingdom

Provectus notebook

Pilon-Thomas & Moffitt Cancer Center. Frequent medical writer of PV-10 Janet Fricker has an article out in Medical News Today today about Moffitt's poster presentations at SITC 2014 entitled Melanoma shows improved regression with combination of PV-10 and checkpoint inhibitor.

The article has an interesting quote from the cancer center's Dr. Shari Pilon-Thomas, Ph.D. about their work:

"The spirit of our study was to determine whether combining PV-10 with a checkpoint inhibitor would enhance the systematic immune responses of the initial injection of PV-10."

Phrased via slightly different editing: The spirit of the study was to determine whether combining ABC with XYZ would enhance the systematic immune responses of ABC. Not, whether combining XYZ with ABC would help XYZ.

Pfizer. Pfizer announced Monday it had (i) a PD-1 agent and (ii) licensed a PD-L1 agent from Merck KGaA (Germany), thus changing the competitive landscape to look more like the below:

Click to enlarge.
See blog post "Together, these studies support the induction of increased tumor-specific immunity after co-inhibitory blockade in combination with IL PV-10 therapy."

Interestingly and notably, Pfizer immediately guided 2014 and 2015 earnings downward as a result of the transaction and to recognize its upfront payment as a certain significant item.

Some preliminary opinions on the deal include:

Jacob Plieth, EP Vantage: "This disproves the notion that a handful of big names – Merck & Co, Bristol-Myers Squibb and  Roche – had already seized all the early promise in  PD-1/PD-L1 inhibition."

The Deal Pipeline: "Pfizer in May walked away from AstraZeneca after painting itself into a corner by describing a takeover proposal - one of a series - as "final..." The deal would have also given Pfizer access to AstraZeneca's own immuno-oncology treatment, which are known as anti-PD-L1 compounds...The New York company has now found a less contentious way to access the technology." 

Pfizer's view of its immuno-oncology pipeline now, in cancer-immunity cycle terms, is:

Click to enlarge. Pfizer presentation, November 17, 2014.

Merck & Co., (U.S.A.). Merck announced positive results from a Keytruda (PD-1) melanoma trial on Sunday. The comparator for late-stage patients in this trial was systemic chemotherapy, the co-primary endpoints were progression-free survival ("PFS") and overall survival ("OS"), a secondary endpoint was overall response rate ("ORR"), and additional data was collected on duration of OR, patient-reported outcomes (the EORTC QLQ-C30 questionnaire) and safety (adverse events).

Provectus' upcoming melanoma Phase 3 trial of earlier stage patients whose disease has not spread to distant sites (which is not late-stage disease, where the disease indeed has spread) has a comparator of systemic chemotherapy, a primary endpoint of PFS, and secondary endpoints of complete response rate ("CRR"), duration of CR, patient-reported outcomes (the Skindex-16 questionnaire), OS and safety (adverse events).

China. I thought the comments by Sinopharm A-THINK's CEO in Provectus' PR Provectus Biopharmaceuticals Extends Memorandum of Understanding with Sinopharm-China State Institute of Pharmaceutical Industry and Sinopharm A-THINK Pharmaceutical Co., Ltd that "...it is hopeful that a contract will be finalized in the coming weeks" were interesting. They become notable if and when a meaningful and material deal is consummated. I don't doubt part of the deal process is for both parties (Sinopharm and Provectus) to interact with the China Food and Drug Administration.

The Cancer-Immunity Cycle. The Medical News Today article about Moffitt, PV-10 and SITC also noted:

"The mechanism, [Dr. Pilon-Thomas] adds, is thought to be that injection of PV-10 into melanoma lesions results in tumor cells releasing antigens that induce T cell immunity, with the checkpoint inhibitors then "releasing the brakes" on the resulting T cells. Next, the team plans to investigate the types of immune cells released at the tumor site." {Underlined emphasis is mine}

"[T]he types of immune cells released at the tumor site" refers to cycle steps 5 and 6 in Chen & Mellman's (2013) Oncology Meets Immunology: The Cancer-Immunity Cycle:

"In the first step, neoantigens created by oncogenesis are released and captured by dendritic cells (DCs) for processing (step 1). In order for this step to yield an anticancer T cell response, it must be accompanied by signals that specify immunity lest peripheral tolerance to the tumor antigens be induced. Such immunogenic signals might include proinflammatory cytokines and factors released by dying tumor cells or by the gut microbiota (Figure 2, Table 1). Next, DCs present the captured antigens on MHCI and MHCII molecules to T cells (step 2), resulting in the priming and activation of effector T cell responses against the cancer-specific antigens (step 3) that are viewed as foreign or against which central tolerance has been incomplete. The nature of the immune response is determined at this stage, with a critical balance representing the ratio of T effector cells versus T regulatory cells being key to the final outcome. Finally, the activated effector T cells traffic to (step 4) and infiltrate the tumor bed (step 5), specifically recognize and bind to cancer cells through the interaction between its T cell receptor (TCR) and its cognate antigen bound to MHCI (step 6), and kill their target cancer cell (step 7). Killing of the cancer cell releases additional tumor-associated antigens (step 1 again) to increase the breadth and depth of the response in subsequent revolutions of the cycle." {Underlined emphasis is mine}

Click to enlarge. Chen & Mellman, Figure 1, http://www.cell.com/immunity/abstract/S1074-7613(13)00296-3

Australia. In November 2010 Provectus wrote in their press release Provectus Meets with the Therapeutic Goods Administration to Review Path for Approval of PV-10 in Australia:

"The recent meeting focused on manufacturing, characterization and specifications for PV-10, along with a review of clinical data and anticipated Phase 3 study design and endpoints. The proposed primary endpoint of progression free survival, which Provectus proposed to the U.S. Food and Drug Administration (FDA) earlier this year in its first end-of-Phase-2 meeting with FDA, was deemed appropriate for assessment of efficacy in light of established European Medicines Agency (EMEA) standards adopted by TGA. Use of interim data from the first half of Phase 3 study subjects, in conjunction with safety data collected in earlier studies of PV-10 for melanoma, was discussed to allow early evaluation for marketing approval for metastatic melanoma, and TGA agreed that these data should be sufficient for this review if the analysis confirmed efficacy."

I learned from folks in Australia that management will be there around the time of the annual scientific meeting of the Clinical Oncology Society of Australia (December 2nd to 4th). I would think visiting the TGA, Australia's FDA, would be on their trip itinerary.

In addition to sites in Australia for Provectus' melanoma Phase 1 and 2 clinical trials and the company's compassionate use program, and the work therein, investigator-initiated work was and is being done combining PV-10 with radiotherapy. Preliminary work (3 patients) was published in 2010 as A novel treatment for metastatic melanoma with intralesional rose bengal and radiotherapy: a case series in Melanoma Research. Follow-up investigator-initiated work by the same lead (Dr. Matthew Foote, M.D.) appears to be one patient short of full enrollment and treatment (25 patients).

Click to enlarge. Above screenshot taken from a presentation
by Dr. Sanjiv Agarwala, M.D. at the 2nd European Post-Chicago Melanoma Meeting (2010)

The average cost of drug R&D. A study by the Tufts Center for the Study of Drug Development out today said developing a new prescription medicine that gains marketing approval costs $2.6 billion. A related article on the study by FierceBiotech author John Carroll framed Tuft's estimate in the context of an estimate by Doctors Without Borders of $186 million.

Through September 30, 2014, Provectus has spent (balance sheet item Accumulated Deficit) $157 million for multi-indication viable PV-10.

"These murine studies support combination therapy with IL PV-10 and co-inhibitory blockade."

Provectus issued a press release, filed an associated 8-K and made available Moffitt Cancer Center's PV-10-related poster from the 29th annual meeting of the Society for Immunotherapy of Cancer ("SITC") Monday. Of the conclusions provided by Moffitt, it struck me the key one was the first:

Moffitt affirmed there is a clinical rationale and value proposition, based on pre-clinical murine model work, to undertake a study (studies) combining PV-10 and each/any of the anti-PD-L1, -PD1 and -CTLA4 therapeutic agents.

❐ Moffitt's initial murine model work investigating PV-10 as a monotherapy -- "Intralesional Injection of Melanoma with Rose Bengal Induces Regression of Untreated Synchronous Melanoma In a Murine Model," Society of Surgical Oncology Annual Meeting, March 2012, and "Intralesional Injection with PV-10 Induces a Systemic Anti-tumor Immune Response in Murine Models of Breast Cancer and Melanoma," American Association for Cancer Research Annual Meeting, April 2013 -- demonstrated:

• Regression in both injected and un-injected melanoma tumors,
• Anti-tumor immunity (T-cell generation & activity), and
• Increased survival (in mice).

❐ Moffitt followed up their mousie work with a human feasibility study of PV-10 as a monotherapy -- "Assessment of immune and clinical efficacy after intralesional PV-10 in injected and uninjected metastatic melanoma lesions," American Society of Clinical Oncology Annual Meeting, June 2014 -- that demonstrated:

• Regression in both injected and un-injected melanoma tumors, and
• Anti-tumor immunity (T-cell generation & activity).

❐ Moffitt continued their murine model work investigating PV-10 in combination with each of three categories of checkpoint inhibitors (anti-PD-L1, -PD1, -CTLA4) -- "Efficacy of Intralesional Injection with PV-10 in Combination with Co-Inhibitory Blockade in a Murine Model of Melanoma," Society for Immunotherapy of Cancer Annual Meeting, November 2014 -- that demonstrated:

• Regression in both injected and un-injected melanoma tumors,
• Anti-tumor immunity (T-cell generation & activity), and
• Increased survival (in mice).

All of Moffitt's work, murine and human, involved a single intralesional injection of PV-10 per injected lesion. It would appear what Moffitt is doing with PV-10 the way they are doing it is procedural, meaning the cancer center is trying to better understand PV-10's tumor-specific immunity with scientific experimental methods, rather than with specific clinical or clinically translational approaches at this time. Ultimately, it seems Moffitt wanted to know if PV-10 worked, found out it did, then wanted to know how well it worked, and then found out how much it did -- as a single agent, and in combination with other agents.

All Moffitt posters -- SSO 2012, AACR 2013, ASCO 2014, SITC 2014 -- have been exclusively co-authored by Moffitt researchers/employees. It is interesting to note Provectus, it appears, freely allowed the cancer center to undertake this work without, it would seem, involvement or interference. I imagine the company, in addition to providing PV-10 drug product to Moffitt, compensates or pays or contributes funding to the cancer center and/or researchers in some form or fashion, like other biopharmaceutical companies do.

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The Methods section of Moffitt's SITC 2014 poster was sparse on experimental method detail, as was the Methods section of their AACR 2013 poster. As such, we will have to wait for an/the associated peer-reviewed paper that would describe the method(s) of the SITC work (as their 2013 PLOS One paper did for the AACR poster and work); specifically, the modifications the cancer center made to their PV-10 injection approach (contrasted with the AACR work's approach) to elicit and elucidate the value of PV-10 in combination with checkpoint inhibitors.

The 2013 "monotherapy" poster/paper appeared to show relatively greater interferon gamma production relative to control than the 2014 "combination therapy" poster did. PV-10's propensity to completely destroy and/or dramatically reduce injected and un-injected tumors -- the subject of Moffitt's August 2013 Single Injection May Revolutionize Melanoma Treatment, Moffitt Study Shows press release-- must have required modifications to the experimental design in order to facilitate the combination therapy murine model work (i.e., don't kill the tumor completely but "partially kill" it so as to observe and measure the subsequent effect of a checkpoint inhibitor on PV-10-damaged-but-not-destroyed-tumor), such as treating part of a large tumor, reducing PV-10 dose per volume, or diluting the concentration of the drug.

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Peter noted in the company's third quarter 10-Q:

We also have begun to consider co-development transactions with one or more pharmaceutical or biotech companies to combine PV-10 with immunology agents such as those referred to as immune checkpoint inhibitors...Furthermore, the strategy of the Company for the benefit of stockholders is a series of partnerships followed by an acquisition of the Company along the lines of Celgene-Abraxis, although there can be no assurance that such partnerships or acquisition will occur. An interim transaction could be a co-development deal like Roche-NewLink, Bristol-Celldex or AstraZeneca-Incyte. {Underlined emphasis is mine.}

NewLink published preclinical combination study work (their drug + anti-PD1/PD-L1 antibodies) at AACR 2014 (April)*, co-conducted by NewLink employees and Georgia Regents University Research Institute researchers/employees.

• The company licensed their drug to Genentech/Roche in October 2014.

* "The current preclinical studies suggest a mechanistic rationale for a combining IDO pathway

inhibitors with agents targeting the PD-1/PD-L1/PD-L2 pathway."

Celldex published preclinical combo work (their drug + checkpoint blockade therapies) at SITC 2013 (November)*, conducted by Celldex employees.

• The company announced a combination collaboration of their drug with Bristol-Myers' PD-1 agent in May 2014.

* "These studies...support the initiation of combination trials with conventional and immune-based therapies."

Incyte filed a protocol for combining its subject drug with Bristol-Myers' anti-CTLA-4 agent Yervoy in 2012. From what I can gather (and I may be wrong) the trial of the combination therapy was initiated alone by Incyte (I cannot find any publication of preclinical work that may have preceded this trial). At an ASCO 2014 presentation of a Phase 1/2 melanoma study, principal investigators (that included Moffitt Cancer Center's Dr. Jeffrey Weber, M.D., Ph.D.) noted "[p]reclinical data support antitumor synergy for INCB024360 when administered with an antibody antagonist to checkpoint receptors," referencing a October 2013 (submitted)/February 2014 (published) SITC journal paper* (the paper, however, does not present preclinical combo work on the subject drug but another related Incyte compound), co-conducted by Celldex employees and the University of Chicago researchers/employees

• The company announced combination collaborations of their drug with Merck's PD-1 agent in February 2014, AstraZeneca's PD-L1 agent in May 2014, and Bristol-Myers' PD-1 agent also in May 2014.

* "These three combinations are attractive to pursue clinically..."

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Provectus published preclinical combination study work (PV-10 + anti-CTLA-4 mouse antibodies) in April at AACR 2013. Moffitt published their preclinical combination study work (PV-10 + anti-PD-L1, -PD1, and -CTLA4) in November at SITC 2014, of course.

The company should have sufficient data to establish the rationale for a combination study with a Big Pharma partner:

• Preclinical from Moffitt's poster, and additional material not included on it,

• Clinical, perhaps, and in context, from Moffitt's human feasibility study ("Six of 8 patients had metastatic disease refractory to previous ipilimumab, anti-PD-1 and/or vemurafenib therapy"), and

• Clinical, possibly, from Provectus' compassionate use program ("CUP"), where patients previously on checkpoint inhibitors who recurred from these may have sought help from PV-10 (Phase 2 patients were refractory to a median of 6 previous interventions, including immunotherapy (21%)).

Arriving at an agreement on business terms of a so-called co-development deal is/will be another story; however, this information should be the hard data of PV-10's immunological activity (most of it generated independently of Provectus by Moffitt) that may facilitate a discussion, or two, with Big Pharma.

Potential Catalysts

Potential catalysts through 1Q15 could include:

Click to enlarge.

Commencing enrollment of its pivotal late-stage trial for melanoma (locally advanced unresectable/unresected cutaneous melanoma) is a key milestone and important catalyst for Provectus because the eventual outcome should provide clarity about the prospects for PV-10's regulatory validation (i.e., the drug's initial pathway to approval).

Securing a good-to-great regional transaction or two, in these cases for the world's two most populous countries, among other things (i) validates the drug's commercial prospects, (ii) more than bolsters Provectus' balance sheet with non-dilutive monies, (iii) brings partners to the fore that can facilitate late-stage trials in their respective geographies for primary liver cancer (and potentially breast cancer), further strengthening PV-10's multi-indication viability, and (iv) establishes a viable non-U.S. centric go-to-market strategy.

Moffitt Cancer Center's presentation of pre-clinical work underscoring their contention (initially conveyed at the 2014 annual meeting of the American Society of Clinical Oncology, and later at the 4th European Post-Chicago Melanoma & Skin Cancer Meeting) -- intralesional PV-10 may be rationally combined with systemic immunotherapy for the treatment of metastatic melanoma, and PV-10 would be a good candidate to evaluate in conjunction with available systemic therapies and new agents in development (respectively) -- could be the catalyst for a drug combination study of PV-10 and an anti-PD-1 agent like nivolumab or pembrolizumab. I think a study only materializes if (because) the data is sufficiently compelling to encourage one of the Big Pharmas to accede to more favorable non-clinical-related terms and conditions than to what other combo study partners have agreed. This data should be presented by Moffitt at the 2014 annual meeting of the Society for Immunotherapy of Cancer in early-November.

"IL PV-10 may be rationally combined with systemic immunotherapy for the treatment of metastatic melanoma"

PV-10 can be a significant resource for oncologists treating earlier stages of disease (i.e., locally cutaneous advanced melanoma, for one). The drug also may play a key role for physicians in combination therapies for patients with late to very late stage disease (i.e., metastatic melanoma).

Key opinion leaders in melanoma, like Europe's Dr. Axel Hauschild, M.D., Ph.D., see a role for intralesional agents in combination with other agents to treat metastatic melanoma. Hauschild, a member of OncoSec's Melanoma Advisory Board (OncoSec [OTCQB: ONCS] treats melanoma tumors using intratumoral electroporation of plasmid interleukin-12), led a poster highlights session for melanoma/skin cancers at ASCO 2014. In regard to all intralesional agents he noted (paraphrasing) they have no systemic toxicity, have high CR rates, and are good candidates for combinatorial use due to immune priming {underlined emphasis is mine}.

A very interesting conclusion from Moffitt's Assessment of immune and clinical efficacy after intralesional PV-10 in injected and uninjected metastatic melanoma lesions ASCO poster was "IL PV-10 may be rationally combined with systemic immunotherapy for the treatment of metastatic melanoma" (where IL means intralesional).

Moffitt's Dr. Vernon Sondak, M.D. will speak further about PV-10 at a symposium (see below) of the 4th European Post-Chicago Melanoma Meeting: Interdisciplinary Global Conference on News in Melanoma.

Click to enlarge

Provectus has considered the role of PV-10 in combination therapies for some time.

Ex. #1-P (2011) The company began working with strategic advisory board member Dr. Craig Eagle, M.D. (Pfizer) as early as sometime in 2011 (I think) on joint Provectus-Pfizer patent application Combination of Local and Systemic Immunomodulative Therapies for Enhanced Treatment of Cancer. Although the patent was filed in March 2012, its priority data date was October 3, 2011, which coincidentally is the same date as AstraZeneca's MedImmune's MedImmune in-licenses cancer immunotherapy tremelimumab from Pfizer press release: "Under the terms of this agreement, MedImmune will assume global development rights to tremelimumab and Pfizer will retain the rights to use tremelimumab with specified types of combination therapies."

Ex. #2-P (2012) The company presented murine model data on PV-10 combination therapy -- PV-10 and systemic chemotherapy 5-fluorouracil -- applied to hepatocellular carcinoma and melanoma tumors at the October 2012 Society for Immunotherapy of Cancer annual meeting (see Provectus Presents Nonclinical Data on Antitumor Immune Response to PV-10 Immuno-Chemoablation): "Treatment of mice with systemic chemotherapy (i.e., 5-fluorouracil, "5-FU") had minimal effect on either tumor, while combination of intralesional PV-10 with systemic 5-FU elicited maximal response in uninjected tumors."

Click to enlarge
Generation of an antitumor response and immunity using a small molecule drug (PV-10)

Ex. #3-P (2013) Provectus presented murine model data on PV-10 combination therapy -- PV-10 and a systemic immunotherapy anti-CTLA-4 antibody at the April 2013 American Association for Cancer Research ("AACR") annual meeting (see Provectus Presents Data on PV-10 Combination Therapy at American Association of Cancer Research Annual Meeting): "PV-10 and PV-10 plus 9H10 exhibited robust response in both treated and untreated tumors. The combination therapy was most effective in the low dose model, where advantages in tumor growth and survival benefit were most pronounced. Increased apparent toxicity of 9H10 at the higher dose levels highlighted the need for establishment of an optimal dose in future mechanism studies and clinical trials...This work shows that, as hypothesized, addition of the immunologic effects of an anti-CTLA-4 agent augments the benefits of PV-10. For visceral or other inaccessible disease, combination of PV-10 with CTLA-4 blockade offers important potential for synergy...PV-10's ability to reduce tumor burden and elicit tumor-specific immunologic stimulation make it a logical potential complement to anti-CTLA-4 agents, such as ipilimumab."

Click to enlarge
Combination of PV-10 Immuno-chemoablation and Systemic Anti-CTLA-4 Antibody Therapy in Murine Models of Melanoma

Ex. #4-P (2013) The company again discussed important contexts for PV-10 combination, such as "While more frequent dosing could potentially improve outcomes, for patients with extensive tumor burden inaccessible to PV-10 injections a combination therapy strategy may be attractive" (see June 2013's PV-10 Moves Forward): "In phase 2 and 3 clinical trials, Dr. Wachter pointed out, the higher doses of ipilimumab were associated with an increase in immune-related adverse effects, presumably mirroring the dose response seen in murine models with 9H10. Dr. Wachter concluded, “Examples of successful treatment of established B16 tumors in murine models are rare. These results demonstrate that when all existing tumor is accessible for injection, PV-10 is highly effective both in animal models and clinically in cancer patients. Given that tumor ablation with PV-10 induces tumor-specific immunity, the combination of PV-10 with CTLA-4 blockade has important potential for synergy.” Speaking further in an interview, he said, “I think the case has been made successfully for PV-10’s role as a potent stimulator of specific anti-tumor activity. This is evident in clinical data from Phase 1 and 2 testing, where regression of untreated bystander tumors correlated with ablation of tumors, and in these nonclinical mechanism studies. And, our recent murine studies show that this stimulation works robustly in combination with CTLA-4 blockade.”"

Ex. #5-P&M (2013-2014) Moffitt's Dr. Jeffrey Weber, in addition to his history of regulatory approval contributions to ipilimumab (Yervoy) and vemurafenib (Zelboraf) as monotherapies for metastatic melanoma, has successfully contributed to the approval of combination therapies (see Moffitt Cancer Center reports key role in FDA approval of Mekinist/Tafinlar for melanoma): "“This new combination therapy is a huge step in the right direction for the treatment of melanoma, and our researchers played a large role in bringing this treatment option to patients,” Jeffrey S. Weber, MD, PhD, director of Moffitt’s Melanoma Research Center of Excellence, Tampa, Fla., said in a press release...“A clinical trial in which Moffitt was the major contributor showed a 76% success rate for patients treated with the Mekinist and Tafinlar combination,” Weber said. “We also found this therapy reduced the incidence and severity of some of the toxic effects patients experienced when the drugs were used alone.”"

In the same Provectus-sponsored white paper referenced in Ex. #4-P (2013) above, Eric is further quoted: "Further studies designed to confirm the apparent synergy are underway, including one with only the low 9H10 dose/ PV-10 combination. A phase 1/2 anti-CTLA-4 dose escalation trial with PV-10 is warranted, Dr. Wachter said. Similarly, models for kinase inhibitors and an analogue for vemurafenib are being sought. Vemurafenib, like PV-10, rapidly reduces tumor burden. PV-10 murine research demonstrated unambiguously, Dr. Wachter noted, that tumor burden is a critical variable in predicting response to a combination therapy. It has been suggested that earlier research into therapeutic melanoma vaccines faltered because tumor burden grew beyond the immune system’s capacity for control before the vaccine could develop its full effect. “We think that the combination of PV-10 with something like a kinase-inhibitor has the potential to dial back or reduce tumor burden even better than an anti-CTLA-4 agent while the systemic PV-10 immunologic effect is developing. The kinase inhibitor would do the early work against visceral disease until PV-10 can catch up and take the baton across the finish line.” While the PD-1 And PD-L1 drugs will be interesting candidates for combinations, because none are approved, testing is currently impractical."

Recall Eric's comments regarding Moffitt from the May 23rd conference call presented in my post "Why did it take four years...to arrive at this point?": "We began a dialogue with researchers from Moffitt Cancer Center early in 2011." This dialogue resulted in work conducted by Moffitt that was presented at:

• The March 2012 annual meeting of the Society of Surgical Oncology (see Intralesional Injection of Melanoma with Rose Bengal Induces Regression of Untreated Synchronous Melanoma in a Murine Model),
• The April 2013 AACR annual meeting (see Intralesional Injection with PV-10 Induces a Systemic Anti-tumor Immune Response in Murine Models of Breast Cancer and Melanoma), 
• The April 2014 AACR annual meeting (see Induction of anti-melanoma immunity after intralesional ablative therapy [poster not yet released by Moffitt]), and
• The April 2014 American Society of Clinical Oncology ("ASCO") (see Assessment of immune and clinical efficacy after intralesional PV-10 in injected and uninjected metastatic melanoma lesions). 

Moffitt authors of the first three above mentioned posters include (i) P. Toomey, K. Kodumudi, L. Martin, A. Mackay, A. Sarnaik and S. Pilon-Thomas, (ii) S. Pilon-Thomas, A. Weber, K. Kodumudi, L. Kuhn, P. Toomey, and A. Sarnaik, and (iii) H. Liu, K. Kodumudi, A. Weber, A. Sarnaik and S. Pilon-Thomas. Moffitt's PV-10 ASCO poster [not yet released] was authored by A. Sarnaik, G. Crago, H. Liu, K. Kodumudi, A. Weber, T. McCardle, J. Weber and S. Pilon-Thomas {underlined emphasis is mine}.

• Co-author: Jeffrey S. Weber
• Poster abstract: "Further studies are ongoing to determine the mechanism by which PV-10 increases tumor-specific T cell responses as well as to establish the interaction of intralesional PV-10 with combination checkpoint protein inhibition" {underlined emphasis is mine}
• Poster conclusion: "IL PV-10 may be rationally combined with systemic immunotherapy for the treatment of metastatic melanoma."

The focus of Moffitt's ASCO poster was the center's work with PV-10 in its human feasibility study. As such, I presume Moffitt/Weber's combination exploration and work (presumably murine model studies) will be presented at a later date.

Provectus: "“We think that the combination of PV-10 with something like a kinase-inhibitor has the potential to dial back or reduce tumor burden even better than an anti-CTLA-4 agent while the systemic PV-10 immunologic effect is developing. The kinase inhibitor would do the early work against visceral disease until PV-10 can catch up and take the baton across the finish line.”"

"Whenever T cells and B cells are activated, some become "memory" cells. The next time that an individual encounters that same antigen, the immune system is primed to destroy it quickly. This is active immunity because the body's immune system prepares itself for future challenges" (Source material: Understanding Cancer Series: The Immune System, National Cancer Institute).

In elucidating PV-10's mechanism of immune response (the second of the drug's two-step mechanism of action, the first step being ablation) Provectus noted Moffitt researchers, in their AACR 2014 poster (human feasibility study), showed "...significant decreases in melanoma cells in injected tumors and uninjected bystander tumors 7-14 days after PV-10 injection as evidenced by pathologic evaluation confirmed with immunohistochemical staining of biopsy specimens for melA (a marker of melanoma)... were accompanied by increased populations of CD3+, CD4+ and CD8+ T cells along with NKT cells in peripheral blood." Moffitt concluded in their ASCO 2014 poster that "IL PV-10 can enhance tumor-specific reactivity in circulating T-cells."

It seems to me chemoablation via PV-10 ablation causes antigenization, antigenization causes immunization. PV-10 causes antigenization. Antigenization causes immunization. Antigenization is the expression of antigens, in a tumor into which PV-10 has been injected, in context. Immunization is "the process by which...[the] immune system becomes fortified against an agent." PV-10 facilitates the relationship between antigenization and immunization.