This phase I trial tests the safety, side effects, and best dose of ZEN003694 in combination with binimetinib in treating patients with solid tumors that carry RAS alterations and that have spread to other places in the body (advanced/metastatic) or cannot be removed by surgery (unresectable). ZEN003694 is an oral medication with potential anticancer activity. It is an inhibitor of a family of proteins called bromodomain and extra-terminal (BET) which play important role during development and cellular growth. ZEN003694 may stop the growth of tumor cells that produce BET. Binimetinib is in a class of medications called kinase inhibitors. It works by blocking the action proteins called MEK1 and MEK2, that signal cancer cells to multiply. It may help keep cancer cells from growing and spreading. There is pre-clinical evidence that using ZEN003694 and binimetinib together may shrink or stabilize cancers studied in this trial. There are two parts of this study; dose escalation and dose expansion. In the dose escalation part of this study, different people will get different doses of the study drugs ZEN003694 and binimetinib. In the dose expansion part of this study, the highest dose with manageable side effects will be given to additional people. This will help to understand the side effects that may happen with this drug combination.
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of BET bromodomain inhibitor ZEN-3694 (ZEN003694 \[ZEN-3694\]) and binimetinib when given in combination in patients with advanced or metastatic solid tumors with rat sarcoma virus oncogene homolog (RAS) pathway alterations. (Part 1 \[Dose Escalation\]) II. To evaluate the safety and toxicity of ZEN003694 (ZEN-3694) and binimetinib when given in combination. (Part 2 \[Dose Expansion\]) SECONDARY OBJECTIVES: I. To determine the safety and tolerability of ZEN003694 (ZEN-3694) and binimetinib when given in combination in patients with advanced or metastatic solid tumors with RAS pathway alterations. (Part 1 \[Dose Escalation\]) II. To characterize the pharmacokinetics (PK) of ZEN003694 (ZEN-3694) when given in combination with binimetinib. (Part 1 \[Dose Escalation\]) III. To observe and record the preliminary antitumor activity of ZEN003694 (ZEN-3694) and binimetinib when given in combination. (Part 1 \[Dose Escalation\]) IV. To determine the effects of ZEN003694 (ZEN-3694) and binimetinib when given in combination on patient survival and other metrics of clinical activity. (Part 2 \[Dose Expansion\]) IVa. To evaluate objective response rate (ORR); IVb. To evaluate progression-free survival (PFS); IVc. To evaluate duration of response (DOR); IVd. To evaluate disease control rate (DCR) at 4 months. EXPLORATORY OBJECTIVES: I. To characterize the PK of the ZEN003694 (ZEN-3694) and binimetinib combination. (Part 2 \[Dose Expansion\]) II. To identify biomarkers of sensitivity and response to the ZEN003694 (ZEN-3694) and binimetinib combination. (Part 2 \[Dose Expansion\]) III. To determine histone H3 acetylated at lysine 27 (H3K27ac) levels via chromatin immunoprecipitation sequencing (ChIPseq) on tumor biopsy specimen. (Part 2 \[Dose Expansion\]) IV. To determine the open chromatin regions in response to the ZEN003694 (ZEN-3694) and binimetinib combination using assay for transposase-accessible chromatin sequencing (ATACseq). (Part 2 \[Dose Expansion\]) OUTLINE: This is a dose-escalation study of ZEN-3694 with fixed dose binimetinib followed by a dose expansion. Patients receive ZEN-3694 orally (PO) once daily (QD) and binimetinib PO twice daily (BID) on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. During the dose expansion phase, patients will have two mandatory biopsies - one before beginning the study and the second at day 15 of cycle 1. The study biopsy takes small pieces of cancer tissue from patient's body to look for markers (substances made by, on, or in tumor cells) related to how the study treatment works. Patients also undergo collection of blood samples at screening and on study and undergo computed tomography (CT) or magnetic resonance imaging (MRI) throughout the trial. After completion of study treatment, patients are followed up every 3 months for up to 2 years.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
42
Given PO
Given PO
Undergo biopsy
Undergo collection of blood samples
Undergo CT
Undergo MRI
Boston Medical Center
Boston, Massachusetts, United States
Dana-Farber Cancer Institute
Boston, Massachusetts, United States
University of Texas Medical Branch
Galveston, Texas, United States
M D Anderson Cancer Center
Houston, Texas, United States
Incidence of dose limiting toxicities (Part 1 [Dose Escalation])
Defined as the incidence of clinically significant adverse events or abnormal laboratory values thought to be at least possibly related to the study treatment occurring during the first cycle.
Time frame: Up to 28 days from treatment start date
Incidence of adverse events (Part 2 [Dose Expansion])
Including but not limited to treatment-emergent AEs, severe adverse events (SAEs), deaths, and clinical laboratory abnormalities, as assessed by the NCI CTCAE v5.0.
Time frame: Up to 30 days after last treatment dose
Incidence of adverse events (AEs) (Part 1 [Dose Escalation])
Toxicity will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0. Toxicity will be summarized by grade and type using descriptive statistics, including frequency and 95% confidence interval.
Time frame: Up to 30 days after last treatment dose
Pharmacokinetic (PK) parameters (Part 1 [Dose Escalation])
PK parameters will be estimated using non-compartmental method(s) and correlated with PD endpoints using non-parametric statistics.
Time frame: Days 2, 8, 15, and 16 of cycle 1
Overall response rate (ORR)
Defined as the percentage of participants who have a partial or complete response to the treatment. Descriptive statistics will be used to summarize ORR.
Time frame: Up to 2 years from treatment start date
Disease control rate (DCR)
Defined as the percentage of participants that have achieved complete response, partial response or stable disease after treatment. Descriptive statistics will be used to summarize DCR.
Time frame: Up to 4 months from treatment start date
Duration of response (DOR)
Defined as the length of time from treatment start date during the which the tumor does not grow. Kaplan-Meier method will be used to estimate DOR.
Time frame: Up to 2 years from treatment start date
Progression free survival (PFS)
Defined as the length of time during and after the study treatment during which the tumor does not grow. Kaplan-Meier method will be used to estimate PFS.
Time frame: Up to 2 years from treatment start date
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