A Phase 1a/1b Multicenter, Open-label Dose Escalation/Expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Evidence of Antitumor Activity of PLN-101095 as Monotherapy and in Combination With Pembrolizumab in Adult Participants With Advanced or Metastatic Solid Tumors Who Have Disease Progression While on Pembrolizumab

This is a Phase 1a/1b, dose-escalation/expansion, consecutive-cohort, open-label study to evaluate the safety, tolerability, PK, PD, and preliminary evidence of antitumor activity of PLN-101095 in combination with pembrolizumab (the study treatment regimen) in adult participants with advanced or metastatic solid tumors for which pembrolizumab is indicated but have documented disease progression (refractory \[primary resistance\]) or relapsed \[secondary resistance\]) after at least 3 months from the start of treatment with pembrolizumab. The study will consist of 2 main parts: * Part 1: Consecutive dose-escalation cohorts using a Bayesian optimal interval (BOIN) dose escalation design * Part 2: Dose-expansion cohorts using Simon's 2-stage design

Overview

PLN-101095 is an oral small-molecule inhibitor of integrins αvβ8 and αvβ1 being developed by Pliant Therapeutics for solid tumors resistant to immune checkpoint inhibitors (ICIs). A first‑in‑human, open‑label phase 1a/1b study (NCT06270706) is evaluating PLN-101095 as monotherapy lead‑in followed by combination with pembrolizumab in adults with advanced/metastatic solid tumors that progressed on prior pembrolizumab. As of March 17, 2025, interim data from the first three dose‑escalation cohorts reported early antitumor activity and acceptable tolerability, with ongoing enrollment and dose escalation. (cdek.pharmacy.purdue.edu)

Mechanism of action

PLN-101095 selectively inhibits integrins αvβ8 and αvβ1, which activate latent TGF‑β in the tumor microenvironment. By blocking TGF‑β activation, PLN-101095 aims to reduce immunosuppression and fibrosis, increase effector immune cell infiltration, and sensitize tumors to PD‑1 blockade. Preclinical data (SITC and AACR abstracts) showed that PLN‑101095 reduced tumor growth, decreased stromal/fibrotic markers, and enhanced responses to anti‑PD‑1 therapy across models, including EMT6 breast tumor, pancreatic ductal adenocarcinoma (PDA), and ex vivo human tumor tissues. (ir.pliantrx.com)

Clinical development

• Trial design: Phase 1a/1b, sequential BOIN dose‑escalation with 14‑day PLN‑101095 monotherapy lead‑in (250, 500, 1000 mg BID tested) followed by combination with pembrolizumab 200 mg Q3W; planned expansion cohorts using Simon’s two‑stage design. Target enrollment ~77 patients at U.S. sites. (cdek.pharmacy.purdue.edu)
• Status and cohorts: As of March 2025, data from cohorts 1–3 (through 1000 mg BID) were reported; the study continued enrolling and dose‑escalating. (ir.pliantrx.com)

Efficacy

Interim phase 1a/1b findings (first three cohorts; n=9 across six tumor types) reported the following in the 1000 mg BID cohort (cohort 3, n=6) for PLN‑101095 plus pembrolizumab: - Objective response rate: 50% (3/6 confirmed partial responses). - Tumor‑type details and depth of response: - NSCLC: confirmed PR, 74% tumor reduction at week 18 (initial PR at week 10). - Cholangiocarcinoma: confirmed PR, 48% reduction at week 42 (initial PR at week 34). - Melanoma: confirmed PR, 42% reduction at week 27 (initial PR at week 18). Patients were scanned at baseline, day 14, week 10, and every 8 weeks thereafter. Responses were ongoing at data cutoff. Note: small cohort size and early, noncomparative phase. (ir.pliantrx.com)

Safety

Across doses tested (250–1000 mg BID), PLN‑101095 was “generally well tolerated” in combination with pembrolizumab in this interim analysis. Reported aggregate safety (news summary referencing the company’s interim data) included, in cohort 3 (1000 mg BID, n=6): any‑grade TEAEs in 66.7%, grade ≥3 TEAEs in 33.3%, serious TEAEs in 33.3%, and discontinuation of PLN‑101095 due to TEAEs in 16.7%. Detailed event types and attribution were not provided in the public summary. (ir.pliantrx.com)

Notes and context

• Rationale: Targeting αvβ8/αvβ1 to limit TGF‑β activation is a mechanistically distinct approach to overcome ICI resistance; related scientific literature supports combining TGF‑β pathway blockade with PD‑1 inhibition to enhance antitumor immunity. (aacrjournals.org)
• IND cleared: FDA cleared the PLN‑101095 IND in February 2023; the phase 1 study initiated thereafter. (ir.pliantrx.com)

Further reading

• Phase 1 trial record (overview and design): NCT06270706 and an additional registry summary via Purdue CDEK: Trial NCT06270706. (ichgcp.net)
• Company interim data (March 17, 2025): Pliant Therapeutics press release. (ir.pliantrx.com)
• News summary with additional safety breakdown (cites the company release and trial listing): OncLive report. (onclive.com)
• Preclinical mechanistic data in PDA (AACR 2024 abstract): Cancer Research Abstract 6575. (aacrjournals.org)
• Program background and preclinical posters (SITC 2023): Pliant Oncology program page and SITC 2023 overview release. (pliantrx.com)

Disclaimer: Findings are from early, small cohorts of an ongoing phase 1 study; efficacy and safety profiles remain preliminary and subject to change with additional data. (ir.pliantrx.com)

Last updated: Oct 2025

Inclusion Criteria:

1. Has histologically or cytologically confirmed advanced solid tumor

2. Has an advanced or metastatic solid tumor (for which pembrolizumab is indicated) and have evidence of disease progression after treatment with pembrolizumab.

3. At least 1 measurable lesion, as defined by RECIST v1.1

4. Estimated survival of ≥3 months

5. No effective therapeutic options available (eg, has received standard of care or is intolerant of, refuses, or is not eligible for standard of care antineoplastic therapy)

Exclusion Criteria:

1. Any immune-related medical conditions that would put participants at greater risk when receiving pembrolizumab

2. Previous treatment with pembrolizumab \<21 days prior to the first dose of combination therapy of pembrolizumab and PLN-101095

3. Received an immunotherapy other than pembrolizumab in the last 4 weeks prior to the first dose of PLN-101095

4. Received radiotherapy (RT) within 1 week for palliative bone-directed therapy and 4 weeks for all other types, prior to the first dose of PLN-101095

5. Received chemotherapy or other targeted therapies within 2 weeks prior to the first dose of PLN-101095

6. Received a cell therapy within the last 12 months prior to the first dose of PLN-101095

7. Known active central nervous system (CNS) metastases (brain and/or leptomeningeal metastases)

8. Pregnant or lactating female participant