PIKALO-1 Trial: Investigation of the mutation-selective PI3Ka inhibitor STX-478 in patients with advanced solid tumors

In healthy cells, the enzyme PI3Ka (phosphoinositide-3-kinase alpha) plays an important role in regulating cell growth and cell division. If the associated gene, PIK3CA, is altered by a mutation, it can lead to uncontrolled cell growth, which promotes the development and progression of cancer. Such PIK3CA mutations occur in various types of tumors, including hormone receptor-positive (HR-positive) breast cancer, as well as gynecological tumors such as uterine and ovarian cancer, and head and neck tumors. STX-478 is a novel, mutation-selective PI3Ka inhibitor that specifically inhibits the altered (mutated) form of the PI3Ka enzyme. The aim is to affect the unaltered (normal) form of the enzyme as little as possible. The drug has not yet been approved for the treatment of cancer.

The goal of this Phase 1/2 study is to investigate the safety and efficacy of the new active ingredient STX-478. The study is open-label (not blinded), meaning that both the study physicians and the patients know which drug is being administered. The study is divided into several parts. In the first part, researchers will determine which dosage of STX-478 is well tolerated and can be used safely. In this phase, patients with various solid tumors will receive STX-478 as a single-agent treatment (monotherapy). Subsequently, STX-478 will continue to be studied as a single-agent treatment, but now with a more targeted focus on specific tumor groups. The aim is to assess how well the treatment works for different types of cancer. In the second part, STX-478 will be combined with the anti-hormonal drug fulvestrant. This part of the study is intended for patients with HR-positive, HER2-negative, or HER2-low-expressing breast cancer with a PIK3CA mutation. In the third part, STX-478 will also be combined with anti-hormonal therapy and a CDK4/6 inhibitor. CDK4/6 inhibitors are drugs that block certain proteins that promote the growth of cancer cells. The goal is to investigate various combination therapies for hormone receptor-positive breast cancer. In another part of the study, researchers are also investigating how STX-478 is absorbed and processed by the body (pharmacokinetics) when used in combination with other medications. This includes, among other things, the combination with metformin, a medication used to treat diabetes mellitus. The study includes various patient groups (cohorts) that differ by tumor type and treatment combination, including cohorts for breast cancer, gynecological tumors, head and neck squamous cell carcinomas, and other solid tumors.

Women and men aged 18 and older are eligible to participate in the study if they have advanced or refractory solid tumor disease that has already metastasized or is locally advanced and inoperable. Another requirement is that the tumor must have a confirmed PIK3CA mutation. Before enrollment in the study, suitable tumor tissue must be available or able to be provided for testing. In addition, patients must be in sufficiently good general health (largely able to perform normal daily activities) and have adequate organ function. Patients who are ineligible include, among others, those with poorly controlled diabetes mellitus, those with symptomatic metastases in the brain or spinal cord, or those who have previously been treated with a PI3K, AKT, or mTOR inhibitor (with certain exceptions).