Advanced Malignant Solid Neoplasm Clinical Trial
Official title:
Phase 2 Trial of the Combination of the BET Inhibitor, ZEN003694 (ZEN-3694), and the PARP Inhibitor Talazoparib, in Patients With Molecularly-Selected Solid Tumors (ComBET)
This phase II trial tests whether ZEN003694 (ZEN-3694) in combination with talazoparib works to shrink tumors in patients with solid tumors that are unlikely to be cured or controlled with treatment and that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). Another aim of this study is to find out if, and how, patients' genes influence their response to this specific drug combination. For this part of the study, investigators will run tests using samples of patients' tumor tissue and blood that will be collected during the study. ZEN-3694 is an inhibitor of a family of proteins called the bromodomain and extra-terminal (BET). It may prevent the growth of tumor cells that overproduce BET protein. Talazoparib is an inhibitor of PARP, an enzyme that helps repair deoxyribonucleic acid (DNA) when it becomes damaged. Blocking PARP may help keep cancer cells from repairing their damaged DNA, causing them to die. PARP inhibitors are a type of targeted therapy. Genes are pieces of the DNA code that individuals inherit from their parents. Some genes work to protect against cancer by correcting damage that can occur in the DNA when cells divide. BRCA1 and BRCA2 are two examples of these types of genes, and they are called tumor-suppressor genes. For example, if a person has a mutation in a BRCA1/2 gene they have a greatly increased risk of developing breast and ovarian cancer because their cells may no longer be able to completely repair damaged DNA. It is the accumulation of DNA damage which causes a cell to change into a cancerous cell. Other genes are also involved in this process, and these are called DNA damage repair genes. The KRAS mutation is a change in a protein in normal cells. Normally KRAS serves as an information hub for signals in the cell that lead to cell growth, but when there is a mutation in KRAS it signals too much and cells grow without being told to, which causes cancer. Combination therapy with ZEN-3694 and talazoparib may be effective at slowing or stopping tumor growth in patients with advanced cancer.
PRIMARY OBJECTIVE: I. To evaluate clinical response to the combination of BET bromodomain inhibitor ZEN-3694 (ZEN003694 [ZEN-3694]) and talazoparib using objective response rate (ORR) = (complete response [CR] + partial response [PR]). SECONDARY OBJECTIVES: I. To confirm the safety and toxicity profile of the combination of ZEN003694 (ZEN-3694) and talazoparib. II. To evaluate the clinical benefit rate (stable disease [SD] > 6 months [m]+CR+PR) and progression-free survival (PFS). III. To assess the pharmacodynamics of the combination of ZEN003694 (ZEN-3694) and talazoparib using pre- and on-treatment tumor biopsies. IV. To characterize pharmacodynamic changes of exploratory biomarkers to the combination of ZEN003694 (ZEN-3694) and talazoparib in pre- and on-treatment tumor biopsies. V. To assess putative predictive biomarkers of response and resistance to the combination of ZEN003694 (ZEN-3694) and talazoparib. OUTLINE: Patients receive ZEN-3694 orally (PO) once daily (QD) and talazoparib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo diagnostic imaging throughout the study and undergo blood sample collection and tumor biopsy while on study. After completion of study treatment, patients are followed up 30 days after administration of the last dose of study drug and then every 3 months for up to 2 years. ;
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