"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).