This phase I/Ib trial is to find out the best dose, possible benefits and/or side effects of BET bromodomain inhibitor ZEN-3694 (ZEN003694) when given in combination with nivolumab with or without ipilimumab in treating patients with solid tumors. ZEN003694 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving ZEN003694 in combination with nivolumab with or without ipilimumab may shrink or stabilize solid tumors.
PRIMARY OBJECTIVE: I. To evaluate the safety/tolerability and recommended phase 2 dose (RP2D) of the BET inhibitor (BETi) ZEN003694 when combined with nivolumab with or without low dose ipilimumab in solid tumors. SECONDARY OBJECTIVES: I. To evaluate the efficacy of the triplet regimen in a cohort of patients with recurrent platinum-resistant BRCA wild type (wt) epithelial ovarian cancer. Ia. To observe and record anti-tumor activity. II. To evaluate the impact of BET inhibition on the tumor immune microenvironment (TIME). III. To explore predictors of response and resistance to therapy. IV. To characterize the pharmacokinetic (PK) profile of ZEN003694 and its active metabolite ZEN003791. EXPLORATORY OBJECTIVE: I. To correlate drug exposure with response and/or toxicity. OUTLINE: This is a dose-escalation study of ZEN003694 followed by a dose-expansion study. DOSE ESCALATION (DOUBLET TREATMENT): Patients receive nivolumab intravenously (IV) over 30 minutes on day 1 and ZEN003694 orally (PO) once daily (QD) on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo magnetic resonance imaging (MRI), a computed tomography (CT) scan, a positron emission tomography (PET) scan, and/or an x-ray as well as blood sample collection throughout the trial. Patients also undergo a biopsy during screening. DOES ESCALATION AND DOSE EXPANSION (TRIPLET TREATMENT): Patients receive nivolumab IV over 30 minutes on day 1, ipilimumab IV over 90 minutes on day 1, and ZEN003694 PO QD on days 1-21 or 1-28 of each cycle. Cycles repeat every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Beginning cycle 5, patients are no longer treated with ipilimumab, but receive nivolumab IV over 30 minutes on day 1 and ZEN003694 PO QD on days 1-21 or 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo MRI, a CT scan, a PET scan, and/or an x-ray as well as blood sample collection throughout the trial. Patients also undergo a biopsy during screening and on study. After completion of study treatment, patients are followed up for 30 days, then every 3 months for 1 year.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
66
Given PO
Undergo a biopsy
Undergo blood sample collection
Undergo a CT scan
Given IV
Undergo MRI
Given IV
Undergo a PET scan
Undergo x-ray
National Cancer Institute Developmental Therapeutics Clinic
Bethesda, Maryland, United States
ACTIVE_NOT_RECRUITINGNational Institutes of Health Clinical Center
Bethesda, Maryland, United States
ACTIVE_NOT_RECRUITINGMount Sinai Hospital
New York, New York, United States
ACTIVE_NOT_RECRUITINGMontefiore Medical Center-Einstein Campus
The Bronx, New York, United States
RECRUITINGMontefiore Medical Center-Weiler Hospital
The Bronx, New York, United States
RECRUITINGMontefiore Medical Center - Moses Campus
The Bronx, New York, United States
RECRUITINGCase Western Reserve University
Cleveland, Ohio, United States
SUSPENDEDOregon Health and Science University
Portland, Oregon, United States
RECRUITINGUniversity of Pittsburgh Cancer Institute (UPCI)
Pittsburgh, Pennsylvania, United States
RECRUITINGSafety and tolerability
Will calculate maximum tolerated dose and dose limiting toxicity with dose escalation using standard 3+3 design.
Time frame: Up to 1 cycle of treatment for doublet group (4 weeks) and up to 2 cycles for triplet group (6 weeks)
Phase 2 recommended dose for the combined regimens
Time frame: Up to 1 cycle of treatment for doublet group (4 weeks) and up to 2 cycles for triplet group (6 weeks)
Objective response rate (ORR)
Defined as partial or complete response to the combined regimens in the entire cohort and in the expansion cohort. Assessed by Response Evaluation Criteria in Solid Tumors version 1.1 (RECISTv1.1) only. All treatment decisions should be made by RECIST v1.1 only.
Time frame: Up to 1 year post-treatment
Progression-free survival
Time frame: Up to 1 year post-treatment
Overall survival
Time frame: Up to 1 year post-treatment
Incidence of adverse events
Will include grade 3 and 4 immune and non-immune events assessed by Common Terminology Criteria for Adverse Events version 5.0.
Time frame: Up to 1 year post-treatment
Clinical benefit
Defined as ORR and stable disease.
Time frame: Up to 1 year post-treatment
Whole exome sequencing
Will assess: a) CCNE1, MYC, BRD4 status b) MSI status and tumor mutational burden c) B2M mutation/deficiency and alteration in antigen processing/presentation machinery (MHC1) d) Alteration in other molecular pathways such as HRD/BRCA, PI3K.
Time frame: Up to 1 year post-treatment
Next generation sequencing ribonucleic acid sequencing
Will assess: a) Functional CCNE1, MYC, BRD4 gene expression status at baseline and at 4 weeks b) Alteration in tumor immune microenvironment and immune markers/signature like interferon-gamma signature.
Time frame: Up to 1 year post-treatment
PD-L1 expression in tumor cells and tumor-associated immune cells
Time frame: Up to 1 year post-treatment
Multiplex analysis of tumor infiltrating immune cells
Will assess immune cell subpopulations and their activation status.
Time frame: Up to 1 year post-treatment
Pharmacokinetic (PK) parameters
Individual PK parameters will be estimated, specifically maximum concentration, area under the concentration-time curve, half-life, apparent clearance, and apparent volume of distribution using non-compartmental methods. The PK variables will be tabulated and descriptive statistics (e.g., geometric means and coefficients of variation) calculated for each dose level. PK parameters will be reported descriptively for exploratory comparison with historical data.
Time frame: Pre dose, and then 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 h after dose on cycle 1, day 1; and pre dose and 1-3 hours post-dose on cycle 2, day 1
Phenotypic characteristics of peripheral blood mononuclear cells over treatment
Will compare these phenotypic characteristics to baseline to assess different immune cells subset and their activation status peripherally.
Time frame: At 4 weeks (cycle 2 day 1 of treatment)
Circulating tumor deoxyribonucleic acid
Assessed in plasma using TSO500 panel. Will assess: a) CCNE1, MYC, and BRD4 (if BRD4 became available) status at baseline and during treatment to assess if blood-based status is concordant with tissue based status and if the status changes during therapy b) Blood based molecular residual disease and tumor mutational burden.
Time frame: Up to 1 year post-treatment
Pro-inflammatory and anti-inflammatory cytokines analyses
Assessed in plasma.
Time frame: Up to 1 year post-treatment
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.