Study of the active ingredient AZD9574, either alone or in combination with other anticancer drugs, in patients with advanced solid tumors (CERTIS1)

Solid tumors include, among others, cancers of the ovaries, fallopian tubes, peritoneum, breast, pancreas, and prostate, as well as gliomas—tumors that originate in the brain itself. Some of these tumors have a mutation in one of the genes BRCA1, BRCA2, PALB2, RAD51C, or RAD51D. These genes contain the instructions for building proteins that are involved in repairing double-strand breaks in the genetic material (DNA). If the function of these genes is impaired, DNA damage can accumulate in the body’s cells over time, which may promote the development of cancer. AZD9574 is an investigational drug belonging to the class of PARP inhibitors. PARP is a protein (enzyme) involved in repairing damage to the genetic material. AZD9574 specifically targets the PARP1 form. By inhibiting PARP, the aim is to block another repair mechanism in cancer cells. Tumor cells in which certain other repair pathways are already disrupted can therefore no longer adequately repair damage to the genetic material and die (synthetic lethality).

The goal of the Phase 1/2 study is to investigate the safety and tolerability of the active ingredient AZD9574, as well as to examine how the active ingredient is absorbed, distributed, and metabolized in the body, and whether it demonstrates initial efficacy against the tumor. AZD9574 is also being studied in combination with temozolomide, a chemotherapy agent that damages DNA, as well as with trastuzumab deruxtecan and datopotamab deruxtecan, two antibody-drug conjugates in which an antibody recognizes a specific marker on the tumor cell (HER2 and TROP2, respectively) and is designed to deliver a cell-damaging drug to that site as precisely as possible. AZD9574 and temozolomide are taken by mouth (orally), while trastuzumab deruxtecan and datopotamab deruxtecan are administered as an infusion through a vein (intravenously). The Phase 1/2 trial has a modular design and consists of five parts: In Module 1, AZD9574 is tested alone; in Module 2, it is tested in combination with temozolomide for gliomas with an IDH1/2 mutation; in Module 3, it is tested either alone or in combination with temozolomide for various types of cancer; and in Module 4 and Module 5, respectively, AZD9574 is combined with trastuzumab deruxtecan or with datopotamab deruxtecan. Most modules begin with Part A, in which the dose is gradually increased; some are followed by Part B with additional cohorts. Patients are not randomly assigned but are allocated to study arms based on their disease (sequential design). The study is open-label, meaning that neither the study physicians nor the patients are blinded to which medication is being administered. The follow-up period for each patient is expected to last approximately three years, from the first administration of the study medication until the end of follow-up.

Eligible participants include patients aged 18 and older whose solid cancer is advanced, is progressing despite previous treatment (refractory), or has returned (recurrence), as well as patients whose tumor has already spread to other organs (metastatic). Depending on the study arm, additional tumor characteristics may be required in some cases. As a general rule, the disease must have progressed despite at least one prior treatment, or there must no longer be a satisfactory standard of care available.