July 16, 2014

PV-10, and the Cancer Immunity Cycle

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July 10, 2014

2014 Annual CEO Letter (pt. 1)

On Tuesday Provectus management published their annual CEO letter.
Our financial position and corporate governance are such that we expect to continue to meet the relevant listing requirements of NYSE MKT. We believe our efforts to obtain regulatory clarity will be helpful to facilitate such transactions with potential partners. Additionally, the existing and forthcoming clinical and nonclinical mechanism of action data for both PV-10 and PH-10 are expected to further aid in both regulatory clarity and transactions with potential partners. The Company's current cash position is sufficient to meet our obligations. In addition, management is returning $8.96 million to the Company as a result of the previously announced settlement of a shareholder derivative lawsuit (subject to a 2:1 credit to the executives, such that total actual repayment by the executives may be $1.12 million per executive) and further enhanced our strength by management's recent exercise of options. In total, we have adequate funds to operate without a further injection of capital through mid-2015.
The relevant verbiage of the paragraph, "[i]n total, we have adequate funds to operate without a further injection of capital through mid-2015," is inartful when one (or two, both Peter and Eric) previously said the company has adequate capital to reach the point of an interim data readout of the Phase 3 trial for unresected locally advanced cutaneous melanoma. "Previously" would refer to the conference calls (e.g., May 23rd, June 3rd, June 19th), yet we have the above from the July 8th CEO letter. If we take Eric's previous comment Provectus would have interim data as early as 15 months after the Phase 3 study starts accruing patients, and previous guidance of a 3Q14 trial commencement (say, September 2014), data would (could) be available five quarters later starting in 4Q15 (say, November 2015).

Quarterly cash burn has trended downward, and the company projects a go forward, 12-month annual expense run rate (not including Phase 3 trial expenses) of $10 million (an average of $2.5 million a quarter), which would include salaries, overhead, PV-10 and PH-10 mechanism of action study costs, liver study costs (expanded Phase 1), FDA regulatory affair consulting costs, etc.
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Without consideration of the melanoma Phase 3 trial, the projected cash balance should look something like the below. At a projected $2.5 million average quarterly burn, Provectus would approach its accounting firm BDO LLC's minimum cash threshold figure of about $4 million in the 4Q15 timeframe (potential fund raising would occur before that so the threshold is not met of course).
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Now, layering on potential expenses related to the Phase 3 trial -- e.g., per patients costs of $25-50K, pay-as-you-go CRO expenses, enrollment of about 12 patients per month, a September 2014 start to enrollment -- the company would approach BDO' threshold (the purple colored lines below are Phase 3 trial adjusted cash balance scenarios) in 3Q15 timeframe.
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With a 210-patient study (N), 105 progressions (i.e., 50%) [P] are required to occur before the data are examined by the independent data monitoring committee. The study would be deemed a success if the necessary differential occurred in the events between the two arms. The greenish line above tabulates cumulative patients enrolled; consider 1 progression event occurrence per patient and 1 progression for every 2 patients accrued/enrolled/treated. An interim readout (interim meaning half of the patients) would require half of the above mentioned progressions (P1 would equal about 53), which would suggest accrual/enrollment/treatment of about 103 patients (N1).

When Eric said interim data would be available as early as 15 months after the study started accruing, I think he meant interim data on N=210 (I could be wrong of course), and not N1=103:
  • Assume about 12 patients are enrolled per month (about 36 per quarter), which comes from a 210 patient figure and an accrual/enrollment period of 18 months (210 ÷ 18 = 11.67),
  • Assume all patients irrespective of arm would progress, and
  • 105 progressions requires 105 patients accrued, which would take about 9 months (105 ÷ 11.67 = 9).
If there is a non-normal distribution of events (e.g., a substantial fraction of patients in one arm are not progressing within the projected timeframe) or an unexpected distribution of events (e.g., patients in one arm are faring much better than predicted), the time to accumulate the necessary number of events could be delayed. To address this possibility I imagine Eric would have designed the study to trigger a review of the data upon the first of (i) accumulating the necessary number of events or (ii) reaching a prescribed period of time after which said events would be expected (e.g., two or three times the predicted progression free survival ("PFS") for the last patient in the PV-10 arm).

Predicted PFS for the PV-10 arm would derive from the projected hazard ratio ("HR") of the Phase 3 trial, which we do not know; however:
  • Assume the projected HR is 0.545 (from the 180-patient, SPA-designed Phase 3 trial), or 0.6-0.65 (if the HR inched upward to reflect the increased number of patients). See my Trial Math: Meeting the Primary Endpoint, Pt. 1 blog post,
  • Assume a projected comparator (DTIC) PFS of 1.5 months,
  • Calculate a projected PV-10 trial PFS of 2-3 months (1.5 ÷ 0.545 = 3, rounded, or 1.5 ÷ 0.636 = 2, rounded) and
  • Calculate a prescribed period of time after which the necessary number of events would be expected of 6 months (PFS of 3 months × 2 = 6, or PFS of 2 months × 3 = 6).
15 months, for N, then should comprise 9 months of accrual time and 6 months of time as the prescribed period after which the necessary number of events would be expected.

N1, however, might suggest a 10.5 month period (three-and-a-half quarters). Assuming a 3Q14 trial commencement (i.e., September 2014), such data could be available starting in 3Q15 (say, July 2015).
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Understanding that the above is a rough analysis, that there are ranges to every figures used (i.e., give or take, plus or minus), and that folks can have different starting points and assumptions, I think one could make a reasonable argument Provectus may have enough money to provide an interim readout (N1) without a further injection of capital.

June 29, 2014

Properties of PV-10

Presentation statements about PV-10 by Moffitt Cancer Center's Dr. Vernon Sondak on Friday, June 27th at the 4th European Post-Chicago Melanoma Meeting.

1. Simple to store, handle and use and reuse

2. Modest local toxicity and minimal to no systemic toxicity

3. Rapid and complete induction of necrosis/antigen release in injected lesions

4. Excellent healing of the injected site after tumor necrosis

5. Reliable and reproducible induction of regional and systemic immune effects capable of destroying occult tumor cells, "bystander lesions" and distant metastatic lesions regardless of prior treatments

[My note: An occult tumour is one that is hidden, or so small that it can't be found, even by the most detailed scans. His disclosures included that he is a compensated consultant for Provectus, Merck, Bristol-Myers, GlaxoSmithKline, Amgen and Novartis, and that Provectus provided support to Moffitt for research related to his presentation.]

June 26, 2014

Trial Math: Meeting the Primary Endpoint, Pt. 2

We firmly believe that Phase 3 testing should not be started unless you can adequately predict the outcome. It's critical to understand what the drug is doing, which patients are most likely to benefit, what other options those patients have, and which endpoints would be most convincing for government agencies to approved the labelled indication for the drug. -- Provectus' Eric Wachter, June 19th conference call
In my blog post Trial Math: Meeting the Primary Endpoint, Pt. 1 I noted DTIC's PFS is likely to be around 1.5 to 2 months for the stage of patient being recruited for the trial's comparator arm. The performance of systemic chemotherapies DTIC and TMZ are well documented, and generally yield a normal distribution of events (e.g., Middleton et al.). I also noted that in Provectus' metastatic melanoma Phase 2 trial the median PFS for Stage III patients (similar to those who would be enrolled in the Phase 3 trial) was at least 9.7 months (median PFS for Stage III subjects was not reached during the 12-month study interval), and the mean PFS of the all disease treated subgroup of the Phase 2 trial was 9.8 months. So, 9.7-9.8 months for PV-10 PFS > 1.5-2 months for DTIC/TMZ PFS.

That is all well and good, but for Provectus' upcoming Phase 3 trial to meet its primary endpoint of progress free survival ("PFS"), the confidence interval ("CI") for response in the PV-10 (test) arm cannot overlap the CI for response of the DTIC/TMZ (comparator) arm. The trial's power is 90%, and statistics are two-sided with an alpha of 0.05, which means there is a 5% chance the true response is above or below a 90% CI.

Information about DTIC/TMZ PFS figures abound for applicable patient populations, together with 95% CIs. These intervals can be converted or adjusted to present 90% CIs (applicable to the Phase 3 trial design).

Provectus provided durable objective response  ("DOR") data for the all disease treated subgroup from its Phase 2 trial on its ASCO 2014 poster.
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DOR, or durable response rate, is complete response ("CR") plus partial response ("PR") that is durable, and is measured in months. PFS is essentially CR + PR + SD (stable disease), in that the disease does not progress or become "PD" (progressive disease). I say SD because shrinkage is neither sufficient to qualify for PR nor a sufficient increase to qualify for PD. As such, PFS ultimately will be a greater figure than DOR. I utilized the CI for PV-10 DOR as a guide to estimate the CI for PV-10 PFS. Comparison of 95% and 90% CIs for DTIC and PV-10 are below.
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Neither PV-10's actual Phase 2 DOR nor estimated Phase 3 PFS CI overlap DTIC CIs. While the bottom DOR intervals are within spitting distance of the top DTIC intervals, there is substantial daylight between the PFS endpoint bottom intervals and the top DTIC ones. This would suggest the likelihood of the Phase 3 trial meeting its primary endpoint of PFS.

June 23, 2014

Trial Math: Meeting the Primary Endpoint, Pt. 1

We firmly believe that Phase 3 testing should not be started unless you can adequately predict the outcome. It's critical to understand what the drug is doing, which patients are most likely to benefit, what other options those patients have, and which endpoints would be most convincing for government agencies to approved the labelled indication for the drug. -- Provectus' Eric Wachter, June 19th conference call

There are important aspects of Provectus' upcoming pivotal Phase 3 trial for unresected locally advanced cutaneous melanoma to consider and assess, including but not limited the design itself, total trial cost and cost per patient, likelihood of success at completion, and likelihood of success at or by the interim assessment. The trial design is discussed on Provectus' ASCO 2014 poster (bottom right hand corner). Could the trial be successful, and if so why (or why not)? Could it be stopped early, and if so when and why (or why not)? How much could the trial cost?

The sample size (N) of the pivotal trial is estimated at 210 patients and randomized two-to-one (2:1). There would be 140 patients in the PV-10 arm and 70 patients in the comparator/systemic chemotherapy (DTIC [dacarbazine]/TMZ [temozolomide]) arm. The trial's primary endpoint is progression free survival ("PFS"). The study assumes the null or base hypothesis of the two arms having the same response -- that is, PFS for both PV-10 and the systemic chemotherapy (DTIC/TMZ, or DTIC for short) would be the same. The trial is powered to detect the alternate hypothesis or outcome of the PV-10 and DTIC arms having different responses -- that is PFS for PV-10 would be different from PFS for DTIC.

The alternative hypothesis or difference in response -- this difference in PFS between patients in the PV-10 arm versus those in the control or comparator (DTIC) arm -- may be expressed as a hazard ratio ("HR"), which essentially is the ratio of the response (PFS) of the control arm divided by the response (PFS) of the PV-10 arm. The smaller the HR, the larger the effect size (or impact of investigational drug), and thus the more clinically relevant the observed difference between the two arms is.
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In the example above, for this pivotal trial, a target DTIC PFS of 1.5 months and a predicted HR of 0.545 would lead to a predicted PV-10 PFS of 2.8 months -- that is, assuming a target control arm PFS of 1.5 months and using a set HR of 0.545, the goal of the trial would be for patients in the PV-10 to demonstrate a PFS of at least 2.8 months.

DTIC and TMZ are well known systemic chemotherapies (the former is administered intravenously, the latter is a pill). Their performance is well documented. For example, refer to Middleton et al., where median PFS was 1.9 months for TMZ and 1.5 months for DTIC. There are various other randomized control trials and studies utilizing DTIC/TMZ as control arms (in similar settings to Provectus' pivotal trial), and PFS may be as high as 2 months (so x above might be 3.7 months). Thus far the pivotal Phase 3 trial's HR is not known. I'm using the HR from 2012/2013 when Eric was discussing a Phase 3 trial design under a sought after special protocol assessment with the FDA (see below). The target HR for the current trial may be higher or lower, but I doubt it is materially different.
Click to enlarge. Provectus corporate presentation, March 15, 2013
In Provectus' metastatic melanoma Phase 2 trial, median PFS for Stage III patients (similar to those who would be enrolled in the pivotal Phase 3 trial) was at least 9.7 months (median PFS for Stage III subjects was not reached during the 12-month study interval) (see below).
Click to enlarge. Immuno-chemoablation of metastatic melanoma with intralesional rose bengal, October 2012
Another way of looking at potential PV-10 PFS in the pivotal Phase 3 trial is considering the mean PFS of the all disease treated subgroup of the Phase 2 trial (see below).
Click to enlarge. Locoregional Disease Control in Metastatic Melanoma: Exploratory Analyses From Phase 2 Testing of Intralesional Rose Bengal, September 2013
9.7-9.8 months for PV-10 PFS > 2-3.7 months for PV-10 PFS "predicted" > 1.5-2 months for DTIC/TMZ PFS.

Historical PV-10 PFSs may be indicative of potential pivotal trial success because the figures are substantially greater than the possible or likely DTIC PFS; however, the above analysis is very rough and not the lease bit "loose." Additionally, trial success is achieved when the PV-10 arm's confidence interval ("CI") for response -- the CI for PV-10's PFS -- does not overlap or cross DTIC's CI for response -- the CI for DTIC's PFS. Nevertheless, the large difference between PV-10's possible pivotal trial's PFS and DTIC's may present a large enough cushion between the two figures, and the potential for trial success when the time comes.

Perhaps this is what Eric might have meant, in part, when he said "[w]e firmly believe that Phase 3 testing should not be started unless you can adequately predict the outcome" on the June 19th conference call.

"Intralesional Rose Bengal in patients receiving injection of all existing melanoma"

In the video below, Dr. Agarwala discusses PV-10, and Provectus and Moffitt's ASCO 2014 posters.

I think Dr. Agarwala raises a key point. Many Phase 2 patients in Provectus' PV-10 trial were elderly, and received multiple prior therapies and treatment for melanoma that did not work (a "fairly refractory group of patients"). See below; the median number of prior treatments was 6.
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Despite treating patients who appear to have run out of answers and solutions to treat their melanoma before finally receiving PV-10, and presumably having weakened or compromised immune systems, PV-10 nevertheless generated an objective response rate ("ORR") of 51% and achieved a complete response ("CR") of 26% in injected lesions, as well as a 54% ORR in non-injected lesions and a 23% CR in them. Or, about half of the patients in the trial had their tumors shrink (had a response), and a quarter of patients had their tumors shrink completely (go away). Additionally, more than half of the patients had non-injected tumors shrink (had a response), and about a quarter had their non-injected tumors shrink completely (go away).

"Of the 13 consented patients [in Moffitt's feasibility study], 5 had no previous treatment, 6 received ILI or ipilimumab [sold as Yervoy], and 2 received PD-1 blocking antibody; 6 received two or more prior systemic therapy." ILI refers to isolated limb infusion. Other systemic therapies included vemurafenib (sold as Zelboraf), temozolomide or "TMZ" (an orally administered systemic chemotherapy), and carbotaxol (another systemic chemotherapy).

It would seem Provectus' pivotal Phase 3 trial may prove PV-10 has the potential to be better (much better) than what's available today and on the horizon for patients, both in terms of "new melanoma drugs" (e.g., anti-CTLA-4, BRAF and anti-PD-1 agents) and standards of care (i.e., systemic chemotherapy). In particular, the trial would take patients that have progressed on systemic immunotherapies (i.e., anti-CTLA-4 and anti-PD-1 agents), have not responded to them, or cannot receive them.

June 10, 2014

“PV-10 might offer the perfect way to prime the immune system”

Two articles on PV-10, and Provectus and Moffitt ASCO 2014 posters came out today: Provectus outlines path forward for PV-10 and PV-10 produced complete response in 50% of advanced melanoma patients. The articles are variations on the same themes and quotes.

For a moment, think about this verbiage: "The study showed that following intralesional PV-10, both PV-10-injected and uninjected study lesions had pathologic complete response (pCR) in four of the eight patients and that all eight patients exhibited at least partial regression of the injected lesion," and "It is noteworthy that six of eight patients had metastatic disease refractory to previous ipilimumab, anti PD-1 and/or vemura[f]enib therapy." Said another way, perhaps, Moffitt achieved 100% "objective response" in injected lesions and at least 50% in uninjected lesions (there is no mention in the article about whether there was partial regression in the uninjected lesions of the four patients who did not achieve pCR.

Interestingly, Moffitt's Dr. Jeffrey Weber, M.D., Ph.D. said “This data provides more and more evidence that you are altering both local and systemic immunity in a positive way. It also provides a rationale for combination trials of PV-10 with check point protein inhibitors, such as ipilimumab, pembrolizumab and nivolumab. PV-10 might offer the perfect way to prime the immune system” {bold emphasis is mine}.

In April 2014 Dr. Weber said: "“Checkpoint inhibitors are quickly becoming the standard of care for metastatic melanoma, but 50 to 60% percent of patients do not benefit from these agents." The relevancy of PV-10 and other intralesional ("IL") agents to metastatic disease is their potential to make the combination (of the intralesional agent and the checkpoint inhibitor) better for patient in terms of efficacy, safety and tolerability, presumably more so than combinations of checkpoint inhibitors and other checkpoint inhibitors, or drug XYZ and drug ABC.

For example: "The combination of anti-CTLA-4 immunotherapy with agents that prime immune responses have been successfully employed in multiple tumor models and highlight the importance of immune priming for successful anti-CTLA-4 immunotherapy" (Source: Joseph Grosso and Maria Jure-Kunkel, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey, 2013). Or: "An immune system primed to properly identify and destroy tumor cells would eliminate errant cells in nearby lymph nodes and distant metastases, thus solving one of the most difficult problems in cancer therapy—the treatment of patients with late-stage disease (stage III or IV)" (Source: Jedd Wolchok, Memorial Sloan-Kettering Cancer Center, 2008). Or the 32 times "priming" is mentioned in Combining immunotherapy and targeted therapies in cancer treatment (Matthew Vanneman and Glenn Dranoff, Nature, 2012).

IL agents can prime the immune system. See PV-10 & Amgen's Talimogene Laherparepvec  (June 9, 2014) under the blog's News tab. According to Weber, "PV-10 might offer the perfect way to prime the immune system." For metasatic melanoma, does PV-10 make ipilimumab (Yervoy), pembrolizumab (MK-3475) and nivolumab relevant?

June 7, 2014

"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.
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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."
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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."
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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:
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.