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.
Patients must have histologically confirmed malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective
Patients must have a tumor lesion that can be biopsied with 'low' or 'minimal' risk and at least one measurable disease site, as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1
Note: Tumor lesions that are situated in a previously irradiated area may or may not be considered measurable
Patients in cohorts 1, 2, and 4 should have at least one relevant mutation. Patients enrolled in cohorts 1-3 do not require that PARP inhibitor (i) be the immediate prior therapy to be eligible for the trial. Patients should sign a screening consent that will allow the review of local next generation sequencing (NGS) or equivalent Clinical Laboratory Improvement Amendment (CLIA)-certified assay results by MD Anderson's Precision Oncology Decision Support (PODS) team to ensure that the mutations are actionable. No variants of uncertain significance (VUS) will be allowed
Patients who are receiving any other investigational agents
History of allergic reactions attributed to compounds of similar chemical or biologic composition to ZEN003694 (ZEN-3694) or talazoparib
Patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A4 or P-gp, strong inhibitors of BCRP, sensitive substrates of CYP1A2, proton-pump-inhibitors (H2 antagonists are allowed), and herbal medications/preparations (vitamins are allowed) are ineligible. Strong inhibitors or inducers of CYP3A4 must be discontinued at least 7 days prior to the first dose of ZEN003694 (ZEN-3694). Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.
Patients with uncontrolled intercurrent illness
Single group
BET Bromodomain Inhibitor ZEN-3694
DrugGiven PO
Biopsy Procedure
Procedure/SurgeryUndergo tumor biopsy
Biospecimen Collection
Procedure/SurgeryUndergo blood sample collection
Diagnostic Imaging Testing
Procedure/SurgeryUndergo diagnostic imaging
Talazoparib
DrugGiven PO
Objective response rate (ORR)
Systemically assessed per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. ORR = complete response + partial response. Complete response is defined as the disappearance of all target or non-target lesions. Partial response is defined as at least a 30% decrease in the sum of the diameters of target or non-target lesions.
Duration of response
Assessed using RECIST v1.1.
Clinical benefit rate (CBR)
Assessed by radiographic disease assessments per RECIST v1.1. CBR = overall response + stable disease \> 6 months. Stable disease is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease.
Progression-free survival
Assessed by radiographic disease assessments per RECIST v1.1.
Overall survival
Assessed by radiographic disease assessments per RECIST v1.1.
Treatment-induced changes in phospho-protein signaling
Reverse phase proteomic array in pre- and on-treatment tumor biopsy samples conducted to assess treatment-induced changes in phospho-protein signaling, to correlate with treatment response and progression, and to assess changes in the levels of cytotoxic T lymphocyte precursor.
Correlation of single nucleotide variant (SNV) and copy number variant (CNV) profiles with treatment response
Whole exome sequencing conducted on pre-treatment biopsy and at progression to correlate SNV and CNV profiles with treatment response.
Gene expression profiling
Ribonucleic acid (RNA) sequencing conducted for gene expression profiling.
Correlate mutation profiles with tumor sequencing
Using circulating tumor deoxyribonucleic acid (ctDNA) for correlation.
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