The Efficacy and Safety of PRTX007-003 Combined With Pembrolizumab in Resectable Stage III Melanoma

Official title

A Phase 2 Study to Investigate the Activity of Neoadjuvant PRTX007 Combined With Pembrolizumab in Participants With Stage III Melanoma (INFLECTION-003)

Overview

This Phase 2, multi-center, single-arm study evaluates the safety, tolerability, and activity of neoadjuvant PRTX007 in combination with pembrolizumab in participants with resectable Stage III melanoma. Neoadjuvant immunotherapy has demonstrated improved clinical outcomes compared with adjuvant-only approaches, but there remains a need to enhance pathologic response rates without significant added toxicity. Participants will receive oral PRTX007, a Toll-like receptor 7 (TLR7) agonist prodrug, administered in combination with intravenous pembrolizumab prior to surgical resection. The primary objective is to determine the major pathologic response (MPR) rate following neoadjuvant therapy. Secondary objectives include evaluation of safety, pathologic complete response, event-free survival, overall survival, pharmacokinetics, and immune-related biomarkers. This study aims to determine whether the addition of PRTX007 to pembrolizumab improves antitumor immune responses and clinical outcomes in patients with Stage III melanoma.

Detailed description

This study investigates whether combining the TLR7 agonist PRTX007 with pembrolizumab enhances immune-mediated tumor response in the neoadjuvant setting for Stage III melanoma, with the goal of improving pathologic response rates and clinical outcomes while maintaining an acceptable safety profile.

Design This is a Phase 2, multi-center, open-label, single-arm study conducted in Australia. The study will enroll approximately 48 participants with resectable Stage III melanoma.

The study consists of two parts:

* Part A: 24 participants will be enrolled, including an initial dose-escalation safety run-in using a 3+3 design to evaluate tolerability and dose-limiting toxicities. * Part B: An additional 24 participants will be enrolled if sufficient activity is observed in Part A.

Treatment Plan

Participants will receive neoadjuvant therapy consisting of:

* PRTX007: Oral administration for 3 days on and 4 days off per week for 9 cycles (7-day cycles) * Pembrolizumab: 200 mg intravenous infusion every 3 weeks for 3 cycles Following completion of neoadjuvant therapy, participants will undergo definitive surgical resection.

Post-surgical treatment will be response-adapted:

* Participants achieving MPR may receive observation or pembrolizumab alone * Participants without MPR will receive adjuvant PRTX007 in combination with pembrolizumab

Interventions

• Drug PRTX007
  PRTX007 is an orally administered prodrug of PRX034, a Toll-like receptor 7 (TLR7) agonist designed to activate innate and adaptive immune responses. NEOADJUVANT REGIMEN * 600 mg orally once daily (safety run-in participants) or * 750 mg orally once daily (subsequent participants) * Administered 3 days on, 4 days off (7-day cycle) * Total of 9 cycles (9 weeks) ADJUVANT REGIMEN (IF NO MPR) * 750 mg orally once daily * Administered 3 days on, 4 days off * Total of 12 cycles (12 weeks)
• Drug Pembrolizumab
  Pembrolizumab is a programmed cell death protein-1 (PD-1) blocking antibody administered by intravenous infusion NEOADJUVANT REGIMEN * 200 mg IV every 3 weeks (Q3W) * Total of 3 cycles (9 weeks) ADJUVANT REGIMEN * 400 mg IV every 6 weeks (Q6W) for 7 cycles OR * 200 mg IV every 3 weeks (Q3W) for 14 cycles * Total duration: approximately 42 weeks

Primary outcome measures

• Major Pathologic Response (MPR) Rate [Time frame: At time of surgical resection (approximately 9 weeks after initiation of treatment)]

Secondary outcome measures (9)

• Incidence of Adverse Events (AEs), Serious Adverse Events (SAEs), Immune-Related AEs (irAEs), and Dose-Limiting Toxicities (DLTs) [Time frame: From first dose of study treatment through end of study (approximately up to 52 weeks)]
• Number of participants with abnormal physical examination findings, abnormal vital signs, abnormal Eastern Cooperative Oncology Group (ECOG) performance status, and abnormal clinical laboratory parameters [Time frame: Baseline through end of study (approximately up to 52 weeks)]
• Pathologic Complete Response (pCR) Rate [Time frame: At time of surgical resection (approximately 9 weeks after initiation of treatment)]
• Event-Free Survival (EFS) [Time frame: From first dose up to 1 year]
• Overall Survival (OS) [Time frame: From first dose through end of study (approximately up to 52 weeks or longer if followed)]
• Pharmacokinetics of PRTX007 [Time frame: During treatment period (multiple time points from baseline through approximately 9 weeks and selected later time points)]
• Changes in cytokine, chemokine and soluble PD-1/PD-L1 biomarkers [Time frame: Baseline through treatment period (up to approximately 9 weeks and selected later time points)]
• Changes in mRNA expression [Time frame: Baseline through treatment period (up to approximately 9 weeks and selected later time points)]
• Changes in immune cell activation and proliferation markers [Time frame: Baseline through treatment period (up to approximately 9 weeks and selected later time points)]

Eligibility criteria

Inclusion criteria

• Adults aged 18 years or older
• Histologically confirmed, resectable Stage III cutaneous melanoma.
• Candidate for curative-intent surgical resection
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Adequate organ function
• Able to provide written informed consent

Exclusion criteria

• Prior systemic therapy for melanoma, including immunotherapy
• Uveal melanoma or mucosal melanoma.
• Active autoimmune disease requiring systemic treatment
• Primary immunodeficiency or use of systemic immunosuppressive therapy
• Women who are pregnant or breastfeeding
• Recent treatment with another investigational therapy
• Any condition that, in the opinion of the investigator, would interfere with study participation or safety

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Australia · 5 centers

• Calvary Mater Newcastle — Waratah
• Gallipoli Medical Research — Greenslopes
• Princess Alexandra Hospital — Woolloongabba
• Peter MacCallum Cancer Centre — Melbourne
• One Clinical Research Pty Ltd — Nedlands

Identifiers

NCT: NCT07565285 · PRTX007-003

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗