It will take more than just checkpoint inhibition to achieve the next step forward in oncology

Image source

Updated below: 11/3/16 {twice} and 11/5/16.

(alternative blog post title: Can Clever Chronological Combos Cure Cancer?)

Clinicians and medical researchers around the world are growing in their realization that current immuno-oncology is not mission accomplished. It will take more than just checkpoint inhibition to achieve the next step forward in oncology.

Even immunologist Dr. James Allison, PhD, whose work led to the development of anti-CTLA-4 drug ipilimumab (Yervoy), highlighted this "look forward" in Laura Panjwani's October 31st OncLive article entitled "James Allison Says Rational Combinations Key to Immunotherapy Success in "Cold" Tumors:"

"The success of immunotherapies in those cancers—which are likely seeing a better rate of response due to their high mutational burden—is now paving the way for what are known as “cold” tumors, those that don’t have a heavy mutational burden or significant T-cell infiltration. 

There is enough progress being made across the board that I think we can start thinking about some of the colder tumors responding if we just keep studying and making rational combination decisions. As we understand this better, we can rationally put two things together that won’t just duplicate or cancel each other out, but will do different things that can at least be additive, if not synergistic."

Among various combinations of therapies and therapeutics with checkpoint inhibition, Dr. Allison discussed radiation, chemotherapy and targeted therapy in the OncLive article:

"Most of the activity now, at least that I know about, is in radiation...There is also some chemotherapy combination research going on... 

Relatively few targeted therapies are being investigated with immunotherapies, although that research is happening. One of the problems is that there are so many options for combinations; the temptation is there to just combine something from column A, something from column B, and something from column C, and see if it works. That is the way it used to be done back in the empirical days of chemotherapy, but we know enough now to not do that."

PV-10's (Rose Bengal's) clinical & pharmacoeconomic value proposition is clear, simple and straightforward:

Click to enlarge. Sample image source, Sidoti Fall 2016

Germane to this blog post is the value proposition PV-10 provides a combination partner: agnosticism, orthogonality, and synergism:

Click to enlarge. Same sample source as above.

PV-10's combinatorics drug development program/portfolio to date comprises chemotherapy, radiotherapy, and checkpoint inhibition in pancreatic cancer, melanoma, and liver cancer:

• November 2016, SITC: preclinical (murine models), PV-10 + chemotherapy (gemcitabine/Gemzar®), pancreatic cancer, Moffitt Cancer Center,

• Updated (11/3/16).1: June 2016, ASCO/trial-in-progress: clinical, PV-10 + radiotherapy, melanoma, Princess Alexandra Hospital

• September 2015, trial-in-progress: clinical, PV-10 + anti-PD-1 [checkpoint inhibition] (pembrolizumab, Keytruda®), melanoma (Stage IV), Provectus,

• November 2014, SITC: preclinical (murine models), PV-10 + co-inhibitory blockade [checkpoint inhibition] (anti-CTLA-4, anti-PD-1, anti-PD-L1), melanoma, Moffitt Cancer Center,

• April 2013, AACR: preclinical (murine models), PV-10 + anti-CTLA-4 [checkpoint inhibition], melanoma, Provectus,

• November 2012, SITC: preclinical (murine models), PV-10 + chemotherapy (5-fluorouracil/5-FU, Adrucil®), hepatocellular carcinoma (HCC), Provectus, and

• Updated (11/3/16).1: (i) September 2012, trial-in-progress:* clinical, PV-10 + targeted therapy (sorafenib, Nexavar®), HCC, Provectus; (ii) January 2014, Xenobiotica: preclinical (in vitro), PV-10 + "sorafenib" (CYP and UGT enzymes), HCC (HLM and CHHs), XenoTech and Provectus. 

* There is not yet sufficient information to suggest patients on a course sorafenib have been treated with PV-10 (see May 10, 2016 1Q16 business update conference call, pp 44-45).

Updated (11/3/16).2: A table of the bullet points above is below.

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Updated (11/5/16).3: Speaking of old oncology therapeutics and therapies ("In cancer, it’s back to the future as old treatments make cutting-edge ones more effective," Stat, Sharon Begley, August 4th):

"New cancer drugs that unleash the immune system on tumors are all the rage, getting credit for curing former President Jimmy Carter’s advanced melanoma and inspiring tech billionaire Sean Parker to pledge $250 million to cancer research. Behind the excitement, however, is the hard truth that these therapies work in only a minority of patients. 

Now scientists are finding hints of a solution in an unexpected place: Older, out-of-favor cancer treatments such as chemotherapy and radiation may make the cutting-edge immune-based drugs effective against more cancers — even hard-to-treat ovarian and pancreatic tumors... 

One answer: through chemotherapy or radiation. When these old-line treatments begin to kill tumor cells, those cells release molecules that can attract T cells to join in the attack. “They have the potential to prime the pump for immunotherapies,” said Dr. Gary Gilliland, president of the Fred Hutchinson Cancer Research Center in Seattle... 

Radiation, which was first used against cancer at the turn of the 20th century, can also turn cold tumors hot. In a study published in June, scientists led by radiation oncologist Dr. Ralph Weichselbaum of the University of Chicago Medical Center found exactly that in mice with pancreatic cancer, which is notorious for being nearly untreatable, as well as for not attracting tumor-destroying T cells. (The only immunotherapy having any effect on pancreatic cancer in people slowed tumor growth in a mere 8 percent of them.) 

“We think radiation turned a cold tumor into one that attracts T cells, while the immunotherapy kept the T cells from being disabled,” Weichselbaum said. “I think some cancers that aren’t now treated with radiation might be,” as long as immunotherapy follows." {my underlined emphasis} 

Dr. Weichselbaum's paper is here: "Combination of radiotherapy and vaccination overcomes checkpoint blockade resistance," Oncotarget, Zheng et al., June 7, 2016.

"ABSTRACT 

The majority of cancer patients respond poorly to either vaccine or checkpoint blockade, and even to the combination of both. They are often resistant to high doses of radiation therapy as well. We examined prognostic markers of immune cell infiltration in pancreatic cancer. Patients with low CD8+ T cell infiltration and high PD-L1 expression (CD8+ TloPD-L1hi) experienced poor outcomes. We developed a mouse tumor fragment model with a trackable model antigen (SIYRYYGL or SIY) to mimic CD8+ TloPD-L1hi cancers. Tumors arising from fragments contained few T cells, even after vaccination. Fragment tumors responded poorly to PD-L1 blockade, SIY vaccination or radiation individually. By contrast, local ionizing radiation coupled with vaccination increased CD8+ T cell infiltration that was associated with upregulation of CXCL10 and CCL5 chemokines in the tumor, but demonstrated modest inhibition of tumor growth. The addition of an anti-PD-L1 antibody enhanced the effector function of tumor-infiltrating T cells, leading to significantly improved tumor regression and increased survival compared to vaccination and radiation. These results indicate that sequential combination of radiation, vaccination and checkpoint blockade converts non-T cell-inflamed cancers to T cell-inflamed cancers, and mediates regression of established pancreatic tumors with an initial CD8+ TloPD-L1hi phenotype. This study has opened a new strategy for shifting “cold” to hot tumors that will respond to immunotherapy."

In Moffitt Cancer Center's upcoming SITC 2016 poster presentation of its PV-10-related work, "Intralesional injection with rose bengal and systemic chemotherapy induces anti-tumor immunity in a murine model of pancreatic cancer," (Provectus press release) (a) Rose Bengal more than likely was administer before chemotherapy (not after, like in Weichselbaum's murine model work of radiation plus checkpoint inhibition), and (b) PV-10 plus chemotherapy induced, elicited, generated, etc. anti-tumor immunity, unlike Weichselbaum's work.

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

Advancing from “occasional cures” to “routine cures”

On the blog's Current News today I compared an article in The Australian from last month, April 2016, "Melanoma drug Keytruda denied full listing on PBS," to one in The ABC from June 2015, about a year later, "'Revolutionary' melanoma drug worth $150,000 a year listed on PBS, saving Australian patients thousands."

Last year, Australian patients with advanced melanoma gained access to Merck & Co.'s anti-PD-1 or immune checkpoint inhibitor drug pembrolizumab (Keytruda) following its initial, "partial" listing on the country's Pharmaceutical Benefits Scheme (PBS). This year Keytruda was denied full listing on the PBS because there was insufficient evidence of clinical benefit to justify its cost — with The Australian calling Keytruda "a much-hyped melanoma drug."

The above dialog from Australia is one part of an ongoing, maturing, global discussion with respect to this topic: whether current “revolutionary” drugs are truly revolutionary, and ultimately worth the requested price. A paragraph from The Australian's article goes to the very heart of this topic:

"The knock-back comes less than a year after the PBAC flagged concerns about a “substantial mismatch” between the public’s expectations for the so-called “breakthrough drug” and the supporting scientific data." [PBAC is Australia's Pharmaceutical Benefits Advisory Committee]

Keytruda (aka lambrolizumab) received the FDA's breakthrough therapy designation (BTD) for advanced melanoma in 2013.

Since the beginning of 2016 there has been an increasing realization that declaring “mission accomplished” in the fight against cancer might be premature. At the Vatican's recent 2016 healthcare conference, Cellular Horizons: How Science, Technology, Information and Communication will Impact Society, it was noted that the current immuno-oncology (I-O) drugs lead to “occasional cures,” but that this outcome is not good enough. Part-and-parcel with this view is the realization that combinations — combinations of different cancer treatments, whether therapies or therapeutics — likely will be paramount to advancing from occasional cures to routine cures.

The global oncology community is actually now talking about cures, realizes the immune system is crucial for this (as was first noted by the Society for Immunotherapy of Cancer in 2013), and is looking at cancer with a markedly increased sophistication in the search for necessary treatment algorithms for various tumors and tumor subtypes.

As with the rest of the oncology community, Provectus has challenges ahead, but PV-10 appears to be congruent with the mainstream more and more daily.

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Things May Get Worse Before They Get Better, Unless They Get Better Right Away

On the blog's Current News page I wrote about the tumors of patients who received and responded to treatment with Amgen's talimogene laherparepvec (T-Vec, or trade name Imylgic) that increased in size (i.e., following injection of IL drug T-Vec, the tumors appeared to progress) before they decreased in size or shrunk. See Progression Prior to Response (PPR) (March 17, 2016) and #3 under To Dos (March 16, 2016).

This transient tumor behavior of getting bigger before getting smaller (and hopefully going away) is referred to as pseudo-progression. This phenomenon was observed in patients suffering from glioblastoma multiforme (brain cancer) who received chemotherapy (e.g., temozolomide).

Some patients receiving immunotherapies like anti-CTLA-4 drug ipilimumab (Yervoy) as well as anti-PD-L1 drugs pembrolizumab (Keytruda) and nivolumab (Opdivo) also experienced pseudo-progression in clinical trials. Such transient behavior is with a delayed immune response. See, for example, Pseudoprogression and Immune-Related Response in Solid Tumors, Chiou et al., J Clin Oncol. 2015 Nov 1;33(31):3541-3.

BioVex, which designed T-Vec's pivotal Phase 3 trial, when it was called OncoVEX (GM-CSF), constructed it to facilitate some amount of time to elapse before assessment tumor response -- so as to not mischaracterize pseudo-progression as progression. Some clinical trials may employ so-called immune-related response criteria (irRC) to address pseudo-progression.

Pseudo-progression can occur by 12 weeks of imaging and maybe later.

Provectus' pivotal Phase 3 trial uses RECIST v. 1.1, which as I previously noted defines disease progression as an increase in overall lesion size of >20%. I also observed that half of the responding patients in T-Vec's Phase 3 trial experienced an increase in overall lesion size of ≥25% and/or developed at least one new lesion prior to ultimately achieving a response. T-Vec's trial used a modified WHO tumor assessment method. Provectus' CTO Dr. Eric Wachter, PhD's Phase 3 trial design seems to me to be a pretty down-the-middle-of-the-fairway approach, and a thoughtfully and carefully constructed one at that.

So, my comments about T-Vec, modified WHO vs. RECIST 1.1, pseudo-progression, event generation, etc. need to be taken into context, or better communicated by me.

Tumors injected with PV-10 do have a reaction: There can be some local inflammatory response, and occasionally there is ablation beyond the apparent tumor margin, but in general there's no pseudo-progression over the timeframe experienced by T-Vec, ipi, pembro, nivo, etc.

See, for example, Locoregional Disease Control in Metastatic Melanoma: Exploratory Analyses From Phase 2 Testing of Intralesional Rose Bengal, European Cancer Congress 2013, Abstract No. 3.755, Sep 2013.

One might remember Moffitt Cancer Center's Dr. Shari Pilon-Thomas' comments regarding the center's mechanism of action work: "Ironically, the original aim of the trial to assess tumor-infiltrating lymphocytes was thwarted when biopsies of patient tumors collected just 7-14 days after PV-10 injection no longer contained viable tumor tissue." {my bolded and underlined emphasis} (source: Provectus's April 2014 press release Induction of Systemic Immunity Following Treatment of Tumors with PV-10 Reported by Moffitt Cancer Center Researchers at American Association for Cancer Research Annual Meeting)

Takeaway: PV-10's tumor ablation effectiveness often is not only complete, but it is quickly complete. In the pivotal Phase 3 trial, it might occur before the first clinical assessment, and certainly/hopefully before the assessment to ascertain progression-free survival.

A cycle below is about one month or 4 weeks. A follow-up below is about 3 months or 12 weeks.

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"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

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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.

The Door

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Opaque as the Agency's process may appear to non-life sciences investors like me, and obviously highly generalized as my analogy below is, it's an understatement to say Provectus' past, present and future has been, is and will be more about the process (with current emphasis on the step of finally generating randomized clinical trial data). This is especially so for a molecule like PV-10 and Provectus' approach to treating cancer, the former being very novel and the latter being historically unsuccessful (i.e., treating the disease locally in order to defeat it locally and then [in so doing] systemically).

A door is built when a company achieves a consensus design for a pivotal Phase 3 trial with the FDA. The door is closed of course, but with its design and construction complete the drug company can commence a registration study in pursuit of the key the regulator holds to open it. A successful study that also leads to drug approval yields the key from the Agency to unlock the door, opening into the room of a market opportunity for the company to commercialize its therapeutic. Drugs fall down before they reach their doors' respective thresholds by failing their pivotal studies, and thus they're unable to get the key.

Unremarkably and yet, I suppose, obviously, designing and building the door, traveling the path to secure the key from the FDA, opening of the door, and entering the room are just parts of or steps in the Agency's process. Everyone does not follow the process all of the time. When they do, and if they are successful, the process works. The FDA's process could be observed as almost agnostic to the drug going through it.

1986. After a cursory review of the literature, the first I/O door that appears to have been designed, constructed, unlocked and opened was Interferon alpha (IFN-α) [1].

2010. The second I/O door built and unlocked could be for Provenge (sipuleucel-T) [2].

One could argue for other doors such as Bacillus Calmette-Guérin's (BCG) approval in 1990, Herceptin [trastuzumab] in 1998, Gardasil in 2006, and Xgeva [denosumab] in 2010.

2011. The third door might be for Bristol-Myers' anti-CTLA-4 agent Yervoy (ipilimumab). Pfizer's tremelimumab, a related compound, fell down before the threshold by failing its pivotal Phase 3 trial.

2014. The fourth and fifth doors then would be those for anti-PD-1 agents Keytruda (Merck U.S.' pembrolizumab) and Opdivo (Bristol's nivolumab).

Other similar doors may be designed, constructed and unlocked for companies entering pivotal trials of their anti-PD-1 or anti-PD-L1 agents. One also might consider Perjeta's (pertuzumab) approval in 2012.

2015. A sixth door has been designed and built for but currently remains unlocked to Amgen's talimogene laherparepvec (T-Vec).

April's 22-1 advisory committee vote in favor of the drug should encourage the FDA to give Amgen the key in or by October 27th (the drug's PDUFA date). This outcome, while probable, is not certain. Unlocking T-Vec's door, irrespective of the debate about the size of the room into which the opened door permits entry, could and should be a catalyst (in context) for PV-10. 

Provectus' CTO Dr. Eric Wachter, PhD designed and built PV-10's door last year and this year for melanoma (specifically, unresectable locally advanced cutaneous melanoma) by working with the FDA to achieve a consensus pivotal study design. In so doing he convinced the regulator the drug could be a viable treatment option for patients if the trial successfully meets its endpoints.

For Provectus unlocking T-Vec's door could substantially further discussion about or potentially lead to a license, co-development and/or collaboration deal with and/or an minority equity investment by Big Pharma. The issuance of the joint Pfizer-Provectus combination therapy patent allowed in April, more pivotal melanoma Phase 3 site activations, and/or the presentation/publication of Moffitt Cancer Center's PV-10 mechanism of action study also could contribute to the discussion or potentially lead to a deal or deals.

T-Vec and PV-10's doors are similar and different. While T-Vec's door is similar to those of Yervoy, Keytruda and Opdivo in that they have metastatic melanoma labels, PV-10's door possesses the different feature of treating patients at an earlier stage of the melanoma disease cycle. Its pivotal study embraces the potentially more profound outcome of being the local agent with the opportunity to prove that, delivered locally, PV-10 can forestall, prevent or stop the spread of the systemic disease that is cancer (melanoma).

[1] FDA-Approved Cancer Immunotherapies and CRI’s Impact, April 9, 2015, Alexandra Mulvey
[2] Issues Impacting Stakeholder Adoption of Immuno-Oncology, February 16, 2015, AJMC, Dr. Bruce Feinberg, DO

The Early Obsolescence of Checkpoint Inhibitors

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Take as a starting point Inman et al.’s 2007 article entitled Costimulation, coinhibition and cancer, and their statement therein: (underlined emphasis is mine):

“If sufficient co-stimulation is provided in the presence of adequate tumor-associated antigenic stimulation, the immune system will act against tumor antigen and, thus, destroy early tumors before they become fully established. Contrarily, if co-inhibitory signaling dominates, the immune system will be tolerized to tumor antigens, and the tumor will be permitted to grow unfettered and unmolested by the immune system. If neither co-stimulatory nor co-inhibitory signals dominate, the adaptive immune system may remain in a tenuous state of equilibrium, militating against tumor outgrowth with varying degrees of success.”

The essence of the authors’ view might be that the immune system is capable of decisively acting against cancer only in the situation where or circumstance that co-stimulation dominates co-inhibition. Take also as context to this starting point, however, that what we don’t know about the immune system probably dwarfs what we know about it.

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

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

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

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

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

Now consider Winograd et al.’s 2015 article entitled Induction of T cell immunity overcomes complete resistance to PD-1 and CTLA-4 blockade and improves survival in pancreatic carcinoma. In particular, note the underlined sentences (my emphasis) from the article’s abstract:

“Disabling the function of immune checkpoint molecules can unlock T cell immunity against cancer, yet despite remarkable clinical success with monoclonal antibodies (mAb) that block PD-1 or CTLA-4 resistance remains common and essentially unexplained. To date, pancreatic carcinoma is fully refractory to these antibodies. Here, using a genetically engineered mouse model of pancreatic ductal adenocarcinoma in which spontaneous immunity is minimal, we found that PD-L1 is prominent in the tumor microenvironment, a phenotype confirmed in patients; however, tumor PD-L1 was found to be independent of IFN-γin this model. Tumor T cells expressed PD-1 as prominently as T cells from chronically infected mice, but treatment with PD-1 mAb, with or without CTLA-4 mAb, failed in well-established tumors, recapitulating clinical results. Agonist CD40 mAb with chemotherapy induced T cell immunity and reversed the complete resistance of pancreatic tumors to PD-1 and CTLA-4. The combination of αCD40/chemotherapy plus PD-1 and/or CTLA-4 induced regression of subcutaneous tumors, improved overall survival, and confered curative protection from multiple rechallenges, consistent with immune memory not otherwise achievable. Combinatorial treatment nearly doubled survival of mice with spontaneous pancreatic cancers although no cures were observed. Our findings suggest that in pancreatic carcinoma, a non-immunogenic tumor, baseline refractoriness to checkpoint inhibitors can be rescued by the priming of a T cell response with αCD40/chemotherapy.”

CD40 is a co-stimulatory protein, while chemotherapy has been understood to act in a stimulatory fashion through the subsequent release of cancer antigens.

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

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

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

Dr. Weber

An interview of Moffitt Cancer Center's Dr. Jeffrey Weber, M.D., Ph.D. by OncLive's Andrew Roth, Expert Discusses Integration of PD-1 Inhibitors Into Clinical Practice, was published last week. I found several of Weber's answers to Roth's questions separately notable by themselves and germane to PV-10 (when viewed in the context of his involvement with the drug).

Dr. Weber's public positions on intralesional therapies and PV-10 are interesting, as has been his work with Provectus' drug when one considers his other clinical work. I have not been able to find disclosure statements for him that included Provectus—if you find any, let me know. Into November 2014 sample Weber disclosures included:

Click to enlarge. ESMO 2014-related (i.e., September)

Click to enlarge. November 6, 2014

Moffitt and Dr. Weber's work with PD-1s pembrolizumab and nivolumab are:

• Moffitt Cancer Center Plays Pivotal Role in FDA Approval of New Anti-PD-1 Inhibitor Keytruda for Metastatic Melanoma (Moffitt press release, September 2014): "Jeffrey S. Weber, M.D., Ph.D., director of the Donald A. Adam Comprehensive Melanoma Research Center of Excellence at Moffitt Cancer Center, was one of the lead investigators of the PD-1 clinical trial which led to the drug receiving breakthrough status from the FDA. “Pembrolizumab is the first PD-1 drug to be approved by the FDA, and it is a clearly effective drug that will prolong survival for many patients with metastatic melanoma.  This approval is a real advance, and a major milestone in the treatment of the disease,” Weber said."

• Bristol-Myers Squibb Receives Accelerated Approval of Opdivo (nivolumab) from the U.S. Food and Drug Administration (Bristol-Myers press release, December 2014): "“The approval of Opdivo gives patients and physicians an important new treatment option for a population where they were once very limited,” said Jeffrey S. Weber, MD, Ph.D., director of the Donald A. Adam Comprehensive Melanoma Research Center at Moffitt Cancer Center. “For the first time, a PD-1 blocking antibody has shown a response rate of 32% in a Phase 3 randomized clinical trial of patients with unresectable or metastatic melanoma, who have progressed following first line therapy.”"

Click to enlarge. Source link

Moffitt and Dr. Weber also have been involved in three other melanoma approvals, ipilimumab, vemurafenib, and the combination of dabrafenib and trametinib:

• (2011) "Researchers at several NCI-designated cancer centers were lead investigators in the pivotal phase III clinical trial that ultimately led to FDA approval in March 2011of ipilimumab as a treatment for advanced melanoma. These researchers included Dr. F. Stephen Hodi Exit Disclaimer of the Dana-Farber/Harvard Cancer Center, Dr. Jeffrey A. Sosman Exit Disclaimer of the Vanderbilt-Ingram Cancer Center, Dr. Jedd D. Wolchok Exit Disclaimer of the Memorial Sloan-Kettering Cancer Center, and Dr. Jeffrey S. Weber Exit Disclaimer of the Moffitt Cancer Center and Research Institute."

• FDA Approves Personalized Medicine Drug For Melanoma (Moffitt press release, August 2011): From Moffitt's website, "Jeffrey S. Weber, M.D., Ph.D., and others at Moffitt contributed significantly to the approval and testing of the melanoma drug Vemurafenib, including important laboratory work in developing an inhibitor to overcome resistance to the drug that has led to improved outcomes."

• Moffitt Cancer Center Instrumental in FDA Approval of Revolutionary Two-Drug Combo to Treat Advanced Melanoma (Moffitt press release, January 2014): "“Melanoma is the most aggressive type of skin cancer and the leading cause of death from skin disease,” said Jeffrey S. Weber, M.D., Ph.D., director of Moffitt’s Melanoma Research Center of Excellence. “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.”"

Of seven drugs the FDA has approved for melanoma since 2011, according to Moffitt and Dr. Weber, they have been instrumental or significantly participated in six approvals.

To date Dr. Weber has publicly associated himself (so to speak) with PV-10 two times, both around ASCO 2014 (June).

• He was senior author of Moffitt's ASCO abstract and poster entitled Assessment of immune and clinical efficacy after intralesional PV-10 in injected and uninjected metastatic melanoma lesions, which discussed some of the cancer center's clinical work. Moffitt's Dr. Amod Sarnaik, M.D., however, stood next to the poster and presumably spoke about it during relevant sessions, and

• Immediately following ASCO, Weber said "PV-10 might offer the perfect way to prime the immune system."

To add context to the above, however, he:

• Does not believe intralesional ("IL") therapies have a singular role in treating late-stage melanoma with heavy tumor burden and spread of the disease to visceral organs. See Debating Systemic Intralesional Therapies (April 16, 2014) on the blog's Archived News I, and

• Also described Amgen's IL agent tamilogene laherparepvec ("T-Vec") as (November 2014) "...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."

In the moment, as it relates to Provectus' upcoming pivotal Phase 3 trial for locally cutaneous advanced melanoma, the company has an initial pathway to licensure. When they finally start their trial, management finally would have advanced their drug candidate to the final clinical stage prior to approval (pending of course a positive outcome for the trial). A "fully FDA-approved" and fully operational Phase 3 protocol should be tantamount to a prospective drug label; that is, who to treat and how to treat them.

Returning to Dr. Weber's OncLive interview:

OncLive interview, Figure 1

Takeaway: He notes three approved drugs (ipi, pembro and nivo), and the IL agent (T-Vec) that has begun testing in combination with ipi and will be combined with pembro. Anti-CTLA-4 and PD-1 drugs do not sufficiently work singularly for late-stage patients. Combinations now are the order of the day for this patient population where drug permutations would be graded based on a combination of safety ("keep toxicity down") and efficacy ("boost the response rate). Combining two checkpoint inhibitors, or drugs that release the brakes of the immune system, does not make sense (you're further releasing the brake?) from safety, efficacy and cost perspectives. Combining a stimulatory agent (starting the engine) with an inhibitory one (i.e., a checkpoint blockade agent) makes more sense in order to garner a better grade.

OncLive interview, Figure 2

Takeaway: The role of chemotherapy is being diminished and presumably eventually eliminated as drugs are approved for different melanoma patient populations as safer and more effective alternatives to chemo. He notes three approved immunotherapies (ipi, pembro and nivo). IL-2, also an immunotherapy, was approved in 1998. If and when T-Vec is approved (for metastatic melanoma), it would be an alternative for certain patients. If and when PV-10 is approved (for locally advanced cutaneous melanoma), it would be an option for another segment of melanoma patients.

OncLive interview, Figure 3

Takeaway: I found this answer interesting because Provectus principal investigator and St. Luke's University Health Network medical oncologist Dr. Sanjiv Agarwala said at ECC 2013, "[d]iscussing the interest in the use of PV-10 by his surgical colleagues, Dr. Agarwala added other potential benefits of pre-surgical intralesional injection—turning unresectable lesions into resectable ones and stimulating the immune system to lower the odds of recurrence." Neoadjuvant therapy refers to treatment given prior to the primary one (i.e., in this context, surgery—turn an unresectable lesion into a resectable one so it may be removed with surgery or excision). PV-10 achieved a 71% objective response and 50% complete response in the subgroup of 28 patients from Provectus' melanoma Phase 2 trial who received PV-10 into all existing melanoma lesions (i.e., no un-injected lesions).

OncLive interview, Figure 4

Takeaway: I don't believe Moffitt has commented on progress it may have made in determining a biomarker for PV-10. At this year's J.P. Morgan Health Care Conference, Roche's Chief Financial Officer Dr. Alan Hippe, Ph.D. said 70% of the company's projects in development have a biomarker hypothesis, which underscores Roche's deal with Foundation Medicine. Provectus's upcoming pivotal Phase 3 trial would include patients with "indolent, low-burden, low bulk with normal LDH."

Should Dr. Weber lend his voice—appropriately and in context—to the process of approving PV-10, his could be an important one to the FDA, and one that could help frame the drug's initial and potential eventual roles in treating advanced melanoma in particular and melanoma in general.