Summary

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.

Objectives

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.

Eligibility

1. 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
2. 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
3. Patients in cohorts 1, 2, and 4 should have at least one relevant mutation. Patients enrolled in cohorts 1-3 do not require that PARPi 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 Act (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 in Cohort 1 must have (i) a germline or somatic mutation in BRCA1 or BRCA2; and (ii) must have received prior PARPi monotherapy or PARPi combination-therapy * Patients in Cohort 2 must have: (i) a germline or somatic mutation in any of the following deoxyribonucleic acid (DNA) damage response (DDR) genes: BARD1; FANCA; BRIP1; PALB2; RAD51; RAD51C; RAD51D, with no evidence of mutations in BRCA1 or BRCA2; and (ii) must have received prior PARPi monotherapy or PARPi combination therapy * Patients in Cohort 3 must be (i) patients who have had PR/CR on prior PARPi monotherapy or PARPi combination treatment; and (ii) patients with no evidence of BRCA1 or BRCA2 mutations or any of the relevant DDR aberrations listed in cohort 2. Patients with ovarian cancer should not have progressed on platinum-therapy within six months of therapy * Patients in Cohort 4 must have KRAS mutated advanced solid tumors. Prior treatments with KRAS inhibitors are permitted. Patients with KRAS G12C mutations must have already had KRAS G12C targeted therapy (e.g., sotorasib) previously
4. Patients must have received at least one line of systemic therapy in the advanced/metastatic setting. Subjects with diseases without known effective options, and subjects who have declined standard of care therapy prior to study introduction, are also eligible. Patients with ovarian cancer in cohort 3 should not have progressed on platinum within six months of therapy
5. Age >= 18 years * Because no dosing or adverse event data are currently available on the use of ZEN003694 (ZEN-3694) in combination with talazoparib in patients < 18 years of age, children are excluded from this study
6. Patients must be greater than 4 weeks (6 weeks for nitrosoureas or mitomycin C) beyond treatment with any chemotherapy or other investigational therapy including hormonal, biological, or targeted agents; or at least 5 half-lives from hormonal, biological, or targeted agents, whichever is shorter at the time of treatment initiation. Patients must have recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities =< grade 1) with the exception of alopecia or anorexia
7. Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
8. Absolute neutrophil count >= 1,500/mcL
9. Platelets >= 150,000/mcL
10. Hemoglobin >= 10.0 g/dL (no blood transfusion in the preceding 28 days)
11. Total bilirubin 1.5 x =< institutional upper limit of normal (ULN) OR direct bilirubin = ULN for subjects with total bilirubin levels > 1.5 x ULN
12. Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN
13. Creatinine 1.5 x institutional ULN OR glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2 for subjects with creatinine levels > 1.5 x institutional ULN, unless data exists supporting safe use at lower kidney function values, no lower than 30 mL/min/1.73 m^2
14. Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
15. Patients with evidence of chronic hepatitis B virus (HBV) infection must have an undetectable viral load while on suppressive therapy, if indicated
16. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
17. Patients with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to study enrollment, have discontinued corticosteroid treatment for these metastases for at least 2 weeks, and are neurologically stable. Patients with known symptomatic brain metastases requiring steroids are excluded. Of note, patients who required a single dose of corticosteroids on days receiving radiation treatment do not require a 2-week washout. Follow-up brain imaging after central nervous system (CNS)-directed therapy must show no evidence of progression and patient should be clinically stable for at least 1 month. This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability
18. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. However, patients with concurrent malignancy that is progressing or requiring active treatment are excluded
19. Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be of class 2B or better
20. The effects of the combination ZEN-3694 and talazoparib on the developing human fetus are unknown. For this reason, and because BET inhibitor agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 7 months after. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
21. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and for 7 months after completion of study drug administration
22. Women of child-bearing potential MUST have a negative serum or urine human chorionic gonadotropin (HCG) test unless prior tubal ligation (>/= 1 year before screening), total hysterectomy, or menopause (defined as 12 consecutive months of amenorrhea)
23. Ability to understand and the willingness to sign a written informed consent document

Treatment Sites in Georgia