Study of LOXO-783 alone and in combination with other cancer therapies in patients with advanced breast cancer and other solid tumors harboring the PIK3CA H1047R mutation

Cancer cells often contain genetic changes (mutations) that can drive cell growth. The so-called PIK3CA H1047R mutation is common in hormone receptor-positive and HER2-negative breast cancer, but it also occurs in other types of cancer, such as colorectal, lung, and cervical cancer. The PIK3CA gene contains the blueprint for part of the enzyme phosphatidylinositol-3-kinase (PI3K). In the case of a so-called PIK3CA-H1047R mutation, this enzyme remains constantly active, continuously sending growth and survival signals to the cell, which drives cell growth and, consequently, tumor formation. At the same time, this mutation provides a target for targeted therapies that can halt cancer growth by specifically blocking this signaling pathway. LOXO-783 is a drug that specifically targets this enzyme and is designed to inhibit the overactive PI3K signaling pathway in cancer cells with this mutation. It is taken by mouth (orally) and is currently undergoing clinical trials (investigational drug). The goal of this Phase 1 study is to investigate the safety, side effects, and efficacy of the new drug LOXO-783, both as a single agent and in combination with other cancer therapies. The study is divided into several phases. First, LOXO-783 will be tested alone (Phase 1a), with the dose gradually increased to determine an appropriate and tolerable dose. In the second part of the study (Phase 1b), LOXO-783 will be combined with other cancer therapies or administered alone (study arms A–F). It will be combined with fulvestrant (administered as an intramuscular injection) or imlunestrant (administered as a tablet), both of which degrade the estrogen receptor in cancer cells and thereby inhibit the growth of hormone-dependent cancer cells, along with an aromatase inhibitor (anastrozole, exemestane, or letrozole, each as a tablet), which reduces the body’s own estrogen production; with the CDK4/6 inhibitor abemaciclib (as a tablet), which is intended to inhibit certain enzymes (cyclin-dependent kinases 4 and 6) and is thus intended to slow cell division, or with the chemotherapeutic agent paclitaxel from the taxane class (administered as an intravenous infusion), which disrupts cell division. Assignment is not random but sequential. Patients are assigned to specific treatment groups over the course of the study, often based on various interim results. Only within study arm F (LOXO-783 plus fulvestrant) are multiple dose levels assigned at random (randomized). The study is open-label, meaning it is not blinded. This means that both the patients and the study physicians know which medications are being administered. Participation lasts up to 36 months (3 years) and may continue longer if the disease does not progress during treatment. Eligible participants are patients 18 years of age or older with advanced breast cancer or another advanced solid tumor in which a PIK3CA H1047R mutation or, in certain cases, another activating PIK3CA alteration has been detected. Previous cancer treatments must be completed, and any significant side effects must have subsided. In some study arms, prior treatment with a CDK4/6 inhibitor is also required. Patients with colorectal cancer (colon or rectal cancer) are not eligible to participate. Additional eligibility criteria may apply for the various study arms.