The Untrigger

Updated below: 8/15/16.

I have written a lot about the so-called clinical trial math of Provectus' ongoing pivotal Phase 3 study entitled PV-10 Intralesional Injection vs Systemic Chemotherapy or Oncolytic Viral Therapy for Treatment of Locally Advanced Cutaneous Melanoma (official title). The company's CTO, board of directors member and a co-founder Dr. Eric Wachter, PhD discussed some of this math on Provectus' August 10th 2Q16 business update conference call.

Eric said the number (not the percentage) of disease progression events required to trigger the interim and full study analyses were 81 and 162, respectively. I discussed this as item 5. Clinical trial math under Quick: 2Q16 (August 9, 2016) on the blog's Current News page.

It was helpful and insightful, but disappointing, to hear Eric say the trial does not have a scheduled assessment (a prescribed time trigger):

"So, when we began designing the study several years ago, we looked at the issue of how to schedule an interim assessment. And while that was a rather uncommon idea, we looked at that very carefully. We even had discussions with FDA on that topic. And they were adamant that they were strongly opposed to any sort of effort to schedule an interim assessment. Our hypothesis at the time was that, for example, because the interim assessment and the final assessment are based on a number of progressions, they're modeled using standard statistical models. If there was a longer progression-free survival in the PV-10 arm than expected, there would not be the required number of progressions in that arm to add up to the required number of events."

As such, as I hear and read it, one should consider that there only is one trigger (a prescribed event trigger), stated on the trial's CT.gov page as "[a]n interim assessment of efficacy and safety will be performed by the IRC when 50% of the events required for the primary endpoint have occurred." As a number, rather than a percentage, this figure is 81.

Eric said on the call that "one of our crown jewels is our study protocols because they represent everything that we've invested in the company up to the point that that protocol is issued." He certainly is reluctant to show his jewels if he doesn't have to (although it is possible he may fondle them from time to time). He "teased" two sections of the Phase 3 trial protocol. First, section 4.9 (with my underlined emphasis):

"An interim assessment of efficacy and safety will be performed when the IRC--that's Independent Root [sp] Committee--will be performed by the IRC when 50 percent of the events required for the primary endpoint, that is 81 disease progressions as defined in the study protocol, have occurred. And so, that explains to you that there's a set number. It's designed at the beginning of the study, and that's the point when that number of progressions have occurred."

Second, section 4.10 (with my underlined emphasis):

"It doesn't matter if they're all in the PV-10 arm, if they're all in the comparator arm, which isn't possibly because there aren't enough patients in the comparator arm. We have to have enough progressions to hit that metric. Now, we had hoped, as I said, to have some sort of a mechanism in the study that would allow that to be triggered early if, for example, we're going along and we're not seeing progressions as we expected. And so, while we worked on that with the agency, as I said, they're adamant that that was not appropriate for a pivotal study. So, what we managed to compromise on was that in Section 4.10, which is captioned "Study Duration", that subjects will be monitored until survival--for survival until death, loss to follow up, withdrawal of consent, or study termination by the sponsor."

Rather than hash out or re-hash my work/writing about prescribed event and time triggers, the number of patients needed to be enrolled to hit 81 events, etc., I'd like to state (speculate) the following -- [I believe] there is a trigger Eric does not want to explicitly speak about or affirm, which could/would be an imbalance in the number of events between the treatment and control arms, which could/would cause a statistical and ethical dilemma for the study's IRC. What would an imbalance look like or comprise? In the extreme, or potentially actually, there would be no events in the PV-10 treatment arm, and events of whatever frequency or magnitude in the chemotherapy/oncolytic virus control arm. Takeaway: The pivotal trial does not have to reach 81 events for the interim analysis to be triggered.

In his own special way I believe Eric said this on the call (with my underlined emphasis):

"And so, we are able to monitor at the terminal end of the study, and if the clinical trial data monitoring committee determines that it's in the best interest to end the study, it could end before we had all of the progression events occurring. I doubt that'll happen. It will be a very unusual circumstance, but it would probably be positive for the drug because it would suggest that a large number of patients weren't progressing because of the majority of the patients in a two-to-one randomized study are from the PV-10 arm, and that probably would imply that the PV-10 patients weren't progressing. 

But, this is all speculation."

The statistical dilemma is having a treatment arm with no or very few events, and a control arm with many, many more (like 0 and 15, or 0 and 20). The ethical dilemma is a treatment arm that works and works very, very well (i.e., no disease progression), and a control arm that demonstrates what everyone already predicted (i.e., everybody progresses).

The question then would be, "how many events in total and across the two arms would be required for the IRC to recognize an imbalance, and thus trigger the interim analysis?" Twenty events in the control arm (and none in the treatment arm)? Thirty? A two-to-one study randomization then would suggest enrollment and treatment of 60 patients. Or 90.

Math, math, math.

Updated (8/15/16): My projection for enrollment in the pivotal melanoma Phase 3 trial is below (having adjusted only for 5 months of no enrollment as a result of the major amendment related to Amgen's intralesional (IL) drug Imlygic, and also differentiating enrollment rates between medical and surgical oncology sites). The study may generate enough events to highlight the imbalance between the two arms in 1Q16, where the idea is that most-to-all of the control arm patients generate events, and few-to-none of the treatment arm ones do.

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What proportion of events in each arm ("proportion"), and what number of events in each arm ("sample size") gets you to a sufficiently low p-value?

If 75-100% of the control arm generate events, and 0-25% of the treatment do too, who you got?! Using this calculator, which is a simple analysis, and may even be simplistic, may require upwards of 30 patients; however, this may be too low.

E.g., Sample 1: Proportion of Control Arm Events (Number of events generated in the control arm ÷ Number of control arm patients); Sample 2: Proportion of Treatment Arm Events (Number of events generated in the treatment arm ÷ Number of treatment arm patients)

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Generating Clinical Data

Image source

"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."

— Dr. Eric Wachter, PhD, Chief Technology Officer, Provectus Biopharmaceuticals, June 19, 2014 investor conference call 

"With an agent that is so promising in laboratory, it’s incumbent on us, the management of Provectus, to ensure that clinical trials are designed and executed to understand what this means in patients with melanoma and other cancers. 

As Chief Technology Officer, it’s my responsibility to carefully design the right studies to safely collect not just data, but the most appropriate data needed to understand any drug effect and detect any signal, hopefully, improvement in cancer patients. Each of our clinical studies: present, past and future, is designed with that purpose in mind." 

— Eric Wachter, November 5, 2015 3Q15 business update conference call

Evolving thoughts about Provectus' trials and "tribulations" in pursuit of generating more clinical data, randomized and otherwise.

Official title: PV-10 Intralesional Injection vs Systemic Chemotherapy for Treatment of Locally Advanced Cutaneous Melanoma Without Distant Metastases

• Crux: The initial pathway of approval for PV-10

• Hypotheses:

• Complete response of injected tumors is tantamount to elimination of disease symptoms

• PV-10 can forestall or prevent the spread of the disease from Stage III to Stage IV if all of it is treated

• Ideology: Focus on earlier treatment of cancer patients (i.e., < Stage III) (this will be a longer fight in order to change long-held beliefs and attitudes long-term)

• Comparison: PV-10 vs. dacarbazine (or temozolomide) (for approval as a single agent therapy for use in patients with Stage III disease)

• Process speculation:

• Demonstrate statistically significant progression-free survival (PFS) (primary endpoint) curve separation

• Collect qualitative and quantitative patient-reported outcome (PRO) data

• Undertake an interim data readout

• Submit for accelerated approval consideration

• Complete the Phase 3 trial as a post-marketing commitment in order to collect overall survival (OS) (secondary endpoint) data

• Question: The larger the difference between the treatment drug's treatment effect and the control drug's treatment effect, the smaller the number of patients required to achieve statistically significant curve clinical endpoint separation. If all control arm patients progress and no treatment arm patients progress -- how many patients are required?

Official title: A Phase 1b/2 Study of PV-10 Intralesional Injection in Combination With Systemic Immune Checkpoint Inhibition for Treatment of Metastatic Melanoma

• Crux: That PV-10 can work in combination with another drug or drug compound, proving orthogonality from both safety and efficacy perspectives

• Hypothesis: PV-10, together with a checkpoint inhibitor, can benefit patients (Stage IV) with disease inaccessible to PV-10 injection

• Ideology: Demonstrate a PV-10 solution for end-stage patients

• Comparison: Standard of care (SOC) (pembrolizumab) vs. SOC + PV-10 (for approval as a single agent for use in patients with Stage IV disease)

• Process speculation (partial process):

• Demonstrate safety and tolerability (i.e., frequency, duration, severity and attribution of adverse events and toxicities)

• Demonstrate efficacy via PFS (primary endpoint) and objective response rate (secondary endpoint)

• Populate electronic data room with preliminary initial data, and present some of this data

• Question: How good could this data be? It has to be in order to rise notably above the noise of the many combination therapies trials already being run.

The liver cancer study into which the current expanded Phase 1 study, which evolved from its Phase 1 study, will evolve

• Official title: ?

• Hypothesis: PV-10 can benefit patients with loco-regional hepatocellular carcinoma (HCC)

• Ideology: Demonstrate multi-indication viability

• Comparison:

• Asia (China, Singapore, Taiwan, South Korea): SOC (local ablation technology) vs. SOC + PV-10 (for approval as a single agent for use in patients with loco-regional HCC)

• U.S. & Western Europe: SOC (sorafenib) vs. SOC + PV-10 (for approval as a single agent for use in patients with loco-regional HCC)

• Process speculation (partial process):

• File and have accepted by the FDA a Phase 2 randomized control trial of sorafenib vs. sorafenib + PV-10

• File and have accepted by the CFDA (and other regional regulatory authorities) a Phase 1b of local ablation technology + PV-10

An incomplete thought

Click to enlarge. Updated 12/29/15

If one believes (as I do) that PV-10 is a paradigm shift in the treatment of cancer*, then is the Rose Bengal paradigm illustrated by the transition from systemic biological therapies of cancer to this (PV-10) local chemical therapy (having assumed systemic chemical ones are effectively now or soon-to-be completely history)?

Both "local" (via the tumor) and "chemical" (via physical chemistry) are critical constructs for this paradigm shift. As such, can the trials in progress and to be started -- Stage III melanoma Phase 3, Stage IV melanoma, cancers of the liver expanded Phase 1-Phase 1b/2 -- establish in a more widespread manner (widespread from the perspective of awareness) this transition, and thus this shift?


* Clinical value proposition:

• Safe and tissue sparing
• Locally and systemically effective
• Multi-indication viability
• Synergistic combinations
• Ease of physician use and supportive of patient compliance
• Easy to use, re-use, ship, store and handle
• Globally affordable

Why I'm Long Provectus Pharmaceuticals, September 24, 2013 (slightly edited below)

PV-10, a novel oncology compound being developed by Provectus Biopharmaceuticals, exemplifies innovation over incrementalism, meaningful over marginal, productized technology over hypothetical, and changing the world over accepting the status quo, with not an insignificant amount of serendipity over contrivance. In sum, these form the quintessential essence of a paradigm shift in the treatment of cancer.

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.

The FDA Response

The Agency's letter to Provectus has the look and feel of two different sets of views.

Key for me to the FDA's response regarding the Agency's denial of the company's breakthrough therapy designation ("BTD") application include:

"We have reviewed your request and while we have determined that treatment of “locally advanced cutaneous melanoma” meets the criteria for a serious or life-threatening disease or condition, the preliminary clinical evidence you submitted does not indicate that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints." {Bold emphasis is mine} 

There seems to be clear recognition by the FDA of the applicability of local/intralesional agent PV-10 for the treatment of locally advanced cutaneous melanoma, which the Agency deemed a serious or life-threatening disease or condition. That is substantive recognition.

"The preliminary clinical data provided in your request for Breakthrough Therapy designation are indicative of drug activity in the treatment of local, satellite or in-transit recurrence of malignant melanoma; however, the preliminary clinical data do not demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints." {Bold emphasis is mine} 

The FDA also seems to have recognized the drug works, notably in malignant melanoma. Again, that is substantive recognition.

Yet, in both letter sentences above, and here's where the divergence of opinion appears to manifest itself, the FDA qualified their positive recognitions of PV-10 by noting preliminary clinical data submitted by Provectus in seeking BTD did not demonstrate substantial improvement over existing therapies in one or more clinically significant endpoints, which they identify below as pain, infection and significant bleeding.

"This determination is based on the paucity of data on endpoints indicative of clinical benefit (e.g., pain, infection, significant bleeding) and our inability to determine the clinical significance of the reduction in the size in one to 10 target lesions in patients with locally advanced melanoma, who may have additional untreated cutaneous, subcutaneous, or visceral sites of disease." {Bold and bold underlined emphasis is mine} 

The FDA's choice of the word paucity is interesting and, I believe, nuanced: the presence of something only in small or insufficient quantities or amounts.

The Agency recognized the applicability of PV-10 to treat locally advanced cutaneous melanoma (which it also deemed a serious or life-threatening disease or condition). It recognized the drug worked. The FDA, however, said Provectus did not provide enough data -- from the 54 patient sub-group where all disease was followed and the 28 patient sub-group where all disease was treated -- regarding symptom control (e.g., pain, infection or significant bleeding) to warrant BTD. BTD's generalized two-fold criteria are (i) a serious condition and (ii) preliminary clinical evidence of substantial improvement over available therapy on a clinically significant endpoint(s). Robust complete response (which Eric believed was tantamount to symptom control) and some pain data from the aforementioned subgroups was not enough to establish the correlation between complete response and symptom control.

While the amount of data did not meet the FDA's threshold for BTD, the Agency agreed Provectus submitted appropriate data (albeit in small or insufficient quantities or amounts).

The company's metastatic melanoma Phase 2 trial data did not have as much information on pain, infection and significant bleeding as the FDA desired. This only was established at Provectus' December 16, 2013 meeting with the Agency:

"The Agency agreed with Provectus that treatment of cutaneous and subcutaneous tumors in patients with locally advanced cutaneous melanoma (i.e., recurrent, in-transit or satellite melanoma that has not yet spread from the skin to distant sites) could provide clinical benefit to such patients, particularly if the measured objective responses in patients' disease correlated to a demonstrated treatment effect on one or more symptoms of their disease (e.g., pain, infection or significant bleeding)."

Nothing we know today is any less positive than what we knew on Thursday. PV-10 works, and the Agency acknowledged it in writing. What we do know, however, is that BTD, at the moment, is not the appropriate program for the drug due to insufficient (not enough) data on pain, infection or significant bleeding.

What we need to know is what's next for PV-10's clinical development program to provide this data to the FDA. It would appear the FDA recognizes the company and drug can provide it.