July 26, 2014

Combinations & Permutations, Sequencing

Provectus' upcoming, presumably pivotal, Phase 3 trial for unresectable, locally advanced cutaneous melanoma is a potential pathway to approval for PV-10. Management noted in their July 8th annual CEO letter that: "Our development plans for PV-10 stem from the results of our phase 2 study. In that trial, tumors were no longer detectable in 50% of patients with locally advanced cutaneous melanoma who had all of their existing lesions injected. Results from these patients support the potential of PV-10 as a single agent, and provide rationale for a phase 3 randomized controlled trial in patients with unresectable, locally advanced cutaneous melanoma."

Management went on to write: "Provectus is not alone in advocating for an intralesional approach in the treatment of cancer. For melanoma patients with recurrent or in-transit disease confined to their skin this approach has been used to treat patients for many years, as evidenced by guidelines published by the National Comprehensive Cancer Network (NCCN Guidelines®) defining the standard of care for cancer treatment in the United States. Intralesional injection with BCG and certain immunomodulatory agents, local ablation, topical therapy for superficial lesions and regional radiotherapy are consensus interventions for these patients, while systemic therapy remains an option and participation in a clinical trial is the preferred option. We believe that, in this context, PV-10 is well positioned to show superiority in phase 3 testing as a single agent."

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Percent of Cases by Stage at Diagnosis: Melanoma of the Skin
According to the Melanoma Research Foundation, "[m]elanoma that occurs on the skin, called cutaneous melanoma, is the most common type of melanoma." The Phase 3 trial should enroll primarily or exclusively Stage IIIB and IIIC melanoma patients, where the goal, for this patient population, is to clearly demonstrate PV-10's superiority to consensus and other interventions. PV-10, however, is applicable to localized and regional melanoma (i.e., earlier stages), where in due course the drug should demonstrate superiority to surgery and other appropriately suggested interventions. PV-10's sparing of tissue -- injected tumors (i.e., diseased tissue) go away, but healthy tissue is spared -- together with its efficacy should provide a compelling value proposition and alternative to surgery. Localized and regional melanoma, according to the National Cancer Institute, represents 90-95% of melanoma of the skin cases by stage. First and foremost, however, the contemplated Phase 3 trial must be run and the initial pathway to approval achieved.

Beneficial options for patients with distant or metastasized cancer -- in this case, metastatic melanoma -- have dramatically increased in number (and thus choice) and improved in efficacy; however, there obviously still remains a sizable unmet need because the narrative has changed over the last several years from monotherapeutic approaches to treatment (particularly, after each one fails, is to pursue another approach) to combining treatments (whether two treatments are delivered concurrently, or treatments are knowingly delivered sequentially). The goals of combination therapy is to delivery more efficacy and to overcome resistance. I suppose the goal of any cancer therapy is to delivery better efficacy than what came before it, and to overcome resistance (or recurrence), and thus prolong survival.

And that's where the industry's thinking has evolved, by embracing the cancer immunity cycle to progress towards harnessing the body's immune system to fight cancer and thus better deliver on the promise of better efficacy and overcoming resistance. In this case, sequencing the delivery of a permutation of treatments (drugs, therapies) is what constitutes combination.
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Eggermont (2012) writes: "The immune system can be leveraged to fight cancer via four broad, overlapping strategies, comprising priming/boosting of the immune system, T-cell modulation, reducing immunosuppression in the tumour microenvironment and enhancing adaptive immunity." As the author further write: "As immunotherapies function by distinct mechanisms, it is possible that their combination with other treatment modalities may be synergistic."

What does Moffitt Cancer Center's Dr. Jeffrey Weber think? At a minimum he thinks:
  • Injectable therapies are making a comeback, where one would use an intralesional agent to prime the immune system of a patient with late stage and/or visceral disease, and then boost it with a checkpoint protein inhibitors (or combination of inhibitors). Unfortunately, he sees Amgen's T-Vec as limited ("I see this as a niche drug that would be best used to prime the immune system and follow up with a drug such as pembrolizumab, nivolumab, ipilimumab, or a combination of those."). See 'Pretty Darn Impressive' PD-1 Data in Melanoma, Ribas and Weber, June 12, 2014.
  • Moffitt's Phase 1 feasibility study of PV-10 provided "...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."
  • In response to my question of how to assess the utility or value of an agent or compound as an immune system primer: "Simply its ability to synergize with the immune agent in question in terms of clinical effect when given prior to the second agent...the priming agent would simply add to the effect of the immune agent, when used at the same dose and schedule."
The priming agent above would be PV-10 (or T-Vec), while the immune agent would be one of the checkpoint inhibitors.

Weber previously said he is hard pressed to see a systemic role for IL therapies like T-Vec in patients with significant disease burden and visceral M1c disease. Stages IIIB-C and IV M1a patients could be treated with IL therapy. To expect, however, significant clinical and biologic systemic benefit (affect) with any IL therapy -- as we now know them -- in patients with significant disease burden and visceral M1c disease is very low. For now, for him and those he seeks to help, he sees PV-10's role, it would appear, as a potentially powerful (dare I say perfect) immune system primer to help patients with significant disease burden and visceral M1c disease. In addition to its role as a monotherapy for cutaneous melanoma, management wrote in its annual CEO letter about PV-10's role as part of a sequenced combination therapy for metastatic melanoma: "And for those patients who do not have all disease accessible to injection, medical oncologists have stated that using an agent like PV-10 to prime the immune system could be synergistic in combination with a systemic agent."

Management previously recognized of the benefit and value of combining PV-10 with other treatments and therapies:
  • 2006 patent and Foote et al., 2010 regarding PV-10 plus radiotherapy;
  • Dees et al., SITC 2012 regarding co-administration of PV-10 and other systemic therapy (i.e., systemic chemotherapy);
  • 2012 patent regarding PV-10 plus systemic immunomodulative therapy; and,
  • Wachter et al., AACR 2013 regarding PV-10 plus anti-CTLA-4 antibody therapy.
Moffitt previously concluded for AACR 2014 that "IL PV-10 may be rationally combined with systemic immunotherapy for the treatment of metastatic melanoma," and the same for ASCO 2014. Moffitt and Weber would seem to be key clinical players (i.e., site, lead/sole principal investigator) in any combination study.

Management, however, historically has been reticent to pursue combination therapy on their own dime (or spend significantly on it), aside from providing the drug for study, unless someone else (i.e., another company) stepped up to the plate. The situation appears to have changed, per their comments on recent conference calls regarding potential combination studies and related relationships. Experience would suggest (because of the aforementioned comments they made "now") the phone rang, Provectus picked it up, and management listened to what the party(ies) on the other end had to say. The company typically has not talked publicly about things until there is sufficient activity (with of course no certainty of closure or timing thereof) to warrant comment.

Utilizing the table I prepared in my July 24th Combinations news item (see below),...
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...Weber's support and contemplated use of PV-10 (and his industry associations and relationships), and other due diligence, likely, potential or possible interest (or lack thereof) is:
  • Anti-CTLA-4: Bristol-Myers, obviously, but unlikely. Although an approved drug, it would appear anti-PD-1 agent nivolumab ultimately will supersede it (together with other PD-1 and PD-L1 agents), and PV-10 is potentially a more powerful priming and activation agent vis a vis steps in the cancer immunity cycle in order to combine with a PD-1 or PD-L1 agent.
  • Anti-PD-1: Bristol-Myers and/or Merck.
  • Anti-PD-L1: AstraZeneca, potentially. Roche is more likely to engage in combination studies utilizing investigational agents in its own pipeline that represent the distinct cycle steps, and thus not look to outside parties yet for combinations.
Grading any so-called co-development deal should Provectus be able to enter into one, more so than merely the design of the clinical studies, would be based on (among other things):
  • Who pays for the trial (aside from, and above and beyond Provectus contributing drug product),
  • Who conducts, operates (and sponsors) the trial,
  • Whether Provectus, like Celldex, would receive an upfront payment, and if so how much,
  • What exclusivity might constrain PV-10 to combine with other agents, and
  • What right of first something(s) might accompany a co-development deal.

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?