2321TiP - TEMPLE: Thiopurine enhanced mutations for PD-1/ligand-1 efficacy: A phase Ib/II clinical trial

Background

Immune checkpoint inhibitors (ICI) have revolutionized treatment of several cancer types. However, many patients fail to respond. A prerequisite for response is the presence of neoepitopes on cancer cells that trigger the immune system, and the likelihood hereof increases with the number of mutations in the cancer. The thiopurines 6-mercaptopurine (6MP) and 6-thioguanine (6TG) are prodrugs that are converted into cytotoxic metabolites that are incorporated into DNA and cause DNA-damage and mutations through futile DNA mismatch repair attempts. The TEMPLE project is a novel strategy for improving efficacy of ICI by applying an innovative thiopurine combination strategy to increase mutational burden and presence of neoepitopes. The TEMPLE project has been tested in a preclinical setting in an immune competent mouse model of inducible melanoma, where 6TG exposure increased the tumor mutational burden, reshaped the tumor microenvironment by increasing T and NK immune cells and making the tumors more responsive to ICI (PMID: 36545256).

Trial design

The TEMPLE study (NCT05276284) is an investigator-initiated single-center prospective phase 1b and 2 trial to determine the safety, tolerability and efficacy of Atezolizumab given in combination with thiopurines 6MP and 6TG in patients with metastatic solid tumors with an intermediate tumor mutational burden (5-10 mutations/megabase). Recommended phase II dose (RP2D) will be determined in a single armed, open label phase 1b trial with a dose-limiting toxicity (DLT) period of 4 weeks. The combination of thiopurines and Atezolizumab will be administered in 21-day cycles. Patients will be included in a modified 3+3 design. 3-18 patients are expected to be enrolled in the phase 1b study, depending on observed DLTs and the need for dose adjustments. Phase II will be an open label, single arm phase II trial enrolling additional patients up to a total of 27 patients treated at RP2D in a Simon's 2 stage design. Extensive exploratory analyses will include characterization of the tumor mutational and neoantigen landscape on serial biopsies using whole genome sequencing and RNA sequencing. The study was initiated in September 2022, and currently four patients have been included in the study.

Clinical trial identification

NCT05276284.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

300 doses of immune checkpoint inhibitor ‘atezolizumab’ are sponsored by Pharmaceutical company Roche as an unrestricted grant.

Disclosure

M. Hoejgaard: Financial Interests, Personal, Other, Advisory role for various diagnostic companies/investors: LingoMedical; Financial Interests, Personal, Stocks/Shares, stocks. Spanggaard: Financial Interests, Institutional, Local PI: Roche, Puma Biotechnology, MSD, Genentech, Incyte, AstraZeneca, Orion, Pfizer; Non-Financial Interests, Principal Investigator: Roche, Puma Biotechnology, MSD, Genentech, Incyte, AstraZeneca, Orion, Pfizer. K. Schmiegelow: Financial Interests, Advisory Board: Illumina, Jazz Pharmaceuticals, Servier; Financial Interests, Invited Speaker: Amgen, Medscape; Financial Interests, Funding: Servier, Novo Nordisk Foundation; Financial Interests, Personal, Stocks/Shares: Novo Nordisk. K.S. Rohrberg: Financial Interests, Personal, Invited Speaker: Bayer, Amgen, MSD, GSK; Financial Interests, Personal, Advisory Board: AbbVie; Financial Interests, Institutional, Coordinating PI: Lilly, Roche/Genentech, Bristol Myers Squibb, Symphogen, Pfizer, Novartis, Alligator Bioscience, Genmab, BioInvent, Monta Bioscience; Financial Interests, Institutional, Other: Bayer, Incyte, Puma Technology, Orion Clinical. All other authors have declared no conflicts of interest.