Assessing Provectus' Pivotal Melanoma Phase 3 Trial, Part VII

The seventh in a series of blog posts and news items assessing the company's pivotal Phase 3 trial for unresectable locally advanced cutaneous melanoma (Stage III patients, and not metastatic [Stage IV] melanoma).

1. Win or lose: Will the trial succeed in meeting or fail to meet its primary and/or secondary endpoints?
2. Time-to-success or -failure: How long might it take for the trial to succeed or fail?
3. Good or bad process: Are there process steps and aspects thereof that may provide hints of potential future trial success or failure.

This blog news item, 3. Good or bad process: The consistency of melanoma patient outcomes from chemotherapy.

Blog post takeaways

• Stage 3 melanoma patients treated with systemic chemotherapy (dacarbazine or temozolomide) are not more likely to respond than Stage IV patients,

• A 30-year experience overview of dacarbazine in metastatic melanoma (Stage IV patients) noted an approximately reproducible 20% objective response rate (complete response + partial response), and

• Thus, Provectus' pivotal Phase 3 trial for locally advanced cutaneous melanoma (exclusively Stage III patients) should see high rates of disease progression (comparable to trials involving Stage IV melanoma patients) occur quickly in its control arm.

Prior analysis (categorized on the blog as Assessing Provectus' Pivotal Melanoma Phase 3 Trial, Parts I-VI, among other posts and news items) primarily utilized Middleton et al. (2000) — Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma (J Clin Oncol. 2000 Jun;18(11):2351). This work yielded chemo disease progression response rates (PD) of 65-70% and median progression-free survival (PFS) of 1.5-1.9 months in primarily Stage IV patients.

Shah et al. (Correspondence author: Chapman) (2010) — Phase II trial of neoadjuvant temozolomide in resectable melanoma patients (Ann Oncol. 2010 Aug;21(8):1718-22) — noted the following in a study of mostly Stage III patients (14 of 19; 5 Stage IV patients):

• 63% disease progression (12 of 19 patients),

• Of the 12 patients that had progression of disease, progression was detected at week 4 or 8 (a single cycle or less) in 11 of them. One patient with a mixed response received 4 weeks of a second cycle (less than a second cycle) before progression of disease was evident, and

• Most patients (12 of 19) only received a single cycle or less of chemo, where a cycle lasted 8 weeks. Six patients received 2 cycles. One patient, who had a complete response (CR), received 3 cycles.

The Shah et al. (inc. Chapman) study outcome is consistent with outcomes in earlier studies despite the earlier stage of disease and the aggressive treatment regimen.

In another study, Rietschel et al. (Correspondence author: Chapman) (2008) — Phase II Study of Extended-Dose Temozolomide in Patients With Melanoma (J Clin Oncol. 2008 May 10;26(14):2299-304) — noted the following in a study of both Stage III and IV patients (25 Stage III/IV M1a/IV M1b patients in one cohort, and 25 Stage IV M1c patients in a second):

• Objective response rates (CR + PR) in both cohorts were 12.5% (no CRs).

In Serrone et al. (2010) — Dacarbazine-based chemotherapy for metastatic melanoma: thirty-year experience overview (J Exp Clin Cancer Res. 2000 Mar;19(1):21-34) — the authors noted:

• 13 trials involving single agent dacarbazine for advanced melanoma,

• Objective response rates varying from 12-25%, and

• Observing, overall, an approximately reproducible 20% objective response rate with median response duration of 5 to 6 months [f/n 1] and complete response rates of 5%.

[f/n 1] Response duration refers to the durability of objective responses, CR and PR, and is not the same as PFS.

Previous entries in the series:

1. 3. Good or bad process: Patient enrollment. See Assessing Provectus' Pivotal Melanoma Phase 3 Trial, Part I (July 13, 2015) on the blog's Current News page,
2. 3. Good or bad process: Designing an interim analysis for efficacy into Provectus' pivotal melanoma Phase 3 trial. See July 16, 2015 blog post Assessing Provectus' Pivotal Melanoma Phase 3 Trial, Part II,
3. 3. Good or bad process: Patient crossover. See Assessing Provectus' Pivotal Melanoma Phase 3 Trial, Part III (July 20, 2015) on the blog's Current News page,
4. 2. Time-to-success or -failure: Triggering the interim analysis. See July 23, 2015 blog post Assessing Provectus' Pivotal Melanoma Phase 3 Trial, Part IV,
5. 3. Good or bad process: Patient-reported outcomes. See Assessing Provectus' Pivotal Melanoma Phase 3 Trial, Part V (July 24, 2015) on the blog's Current News page, and
6. 1. Win or lose: Predicting outcomes, (ii) 2. Time-to-success or -failure: An unusual response in one of the randomized controlled trial arms, and (iii) 3. Good or bad process: Multiple triggers. See August 4, 2015 blog post Assessing Provectus' Pivotal Melanoma Phase 3 Trial, Part VI.