Studies
| Study First Submitted Date | 2023-04-06 |
| Study First Posted Date | 2023-04-07 |
| Last Update Posted Date | 2023-08-04 |
| Start Month Year | April 5, 2024 |
| Primary Completion Month Year | June 30, 2026 |
| Verification Month Year | July 2023 |
| Verification Date | 2023-07-31 |
| Last Update Posted Date | 2023-08-04 |
Detailed Descriptions
| Sequence: | 20786838 |
| Description | PRIMARY OBJECTIVE: I. To determine the safety and tolerability, maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of BET bromodomain inhibitor ZEN-3694 (ZEN003694 [ZEN-3694]) in combination with capecitabine in patients with solid tumors. SECONDARY OBJECTIVES: I. To observe and record anti-tumor activity of ZEN003694 (ZEN-3694) in combination with capecitabine. II. To determine the pharmacokinetics (PK) of ZEN003694 (ZEN-3694) in combination with capecitabine. III. To determine the pharmacodynamics (PD) of ZEN003694 (ZEN-3694) in combination with capecitabine (death receptor 5 [DR5] dynamics and apoptosis). IV. To identify molecular subpopulations particularly sensitized to bromodomain and extra-terminal motif inhibitor (BETi) and capecitabine. OUTLINE: This is a dose-escalation study of ZEN003694 and capecitabine, followed by a dose-expansion study. Patients receive ZEN003694 orally (PO) once daily (QD) and capecitabine PO twice daily (BID) 2 weeks on, 1 week off during each treatment cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) or magnetic resonance imaging (MRI), positron emission tomography (PET)/CT, and collection of blood samples throughout the trial. Patients may also undergo biopsies during screening and while on the study. After completion of study treatment, patients are followed up for safety 30 days after the last dose, and then every 3 months for 12 months. |
Facilities
| Sequence: | 200639392 |
| Status | Recruiting |
| Name | University of Pittsburgh Cancer Institute LAO |
| City | Pittsburgh |
| State | Pennsylvania |
| Zip | 15232 |
| Country | United States |
Facility Contacts
| Sequence: | 28190458 |
| Facility Id | 200639392 |
| Contact Type | primary |
| Name | Dennis Hsu |
| hsudj@upmc.edu | |
Facility Investigators
| Sequence: | 18382155 |
| Facility Id | 200639392 |
| Role | Principal Investigator |
| Name | Dennis Hsu |
Browse Interventions
| Sequence: | 96312549 | Sequence: | 96312550 | Sequence: | 96312551 | Sequence: | 96312552 | Sequence: | 96312553 |
| Mesh Term | Capecitabine | Mesh Term | Antimetabolites, Antineoplastic | Mesh Term | Antimetabolites | Mesh Term | Molecular Mechanisms of Pharmacological Action | Mesh Term | Antineoplastic Agents |
| Downcase Mesh Term | capecitabine | Downcase Mesh Term | antimetabolites, antineoplastic | Downcase Mesh Term | antimetabolites | Downcase Mesh Term | molecular mechanisms of pharmacological action | Downcase Mesh Term | antineoplastic agents |
| Mesh Type | mesh-list | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor |
Conditions
| Sequence: | 52337900 | Sequence: | 52337901 | Sequence: | 52337902 | Sequence: | 52337903 | Sequence: | 52337904 |
| Name | Metastatic Colorectal Carcinoma | Name | Metastatic Malignant Solid Neoplasm | Name | Stage IV Colorectal Cancer AJCC v8 | Name | Unresectable Colorectal Carcinoma | Name | Unresectable Malignant Solid Neoplasm |
| Downcase Name | metastatic colorectal carcinoma | Downcase Name | metastatic malignant solid neoplasm | Downcase Name | stage iv colorectal cancer ajcc v8 | Downcase Name | unresectable colorectal carcinoma | Downcase Name | unresectable malignant solid neoplasm |
Id Information
| Sequence: | 40277638 | Sequence: | 40277639 | Sequence: | 40277640 | Sequence: | 40277641 | Sequence: | 40277642 |
| Id Source | org_study_id | Id Source | secondary_id | Id Source | secondary_id | Id Source | secondary_id | Id Source | secondary_id |
| Id Value | NCI-2023-02652 | Id Value | NCI-2023-02652 | Id Value | 10579 | Id Value | 10579 | Id Value | UM1CA186690 |
| Id Type | Registry Identifier | Id Type | Other Identifier | Id Type | Other Identifier | Id Type | U.S. NIH Grant/Contract | ||
| Id Type Description | CTRP (Clinical Trial Reporting Program) | Id Type Description | University of Pittsburgh Cancer Institute LAO | Id Type Description | CTEP | ||||
| Id Link | https://reporter.nih.gov/quickSearch/UM1CA186690 |
Countries
| Sequence: | 42697255 |
| Name | United States |
| Removed | False |
Design Groups
| Sequence: | 55778761 |
| Group Type | Experimental |
| Title | Treatment (ZEN003694, capecitabine) |
| Description | Patients receive ZEN003694 PO QD and capecitabine PO BID 2 weeks on, 1 week off during each treatment cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT or MRI, PET/CT, and collection of blood samples throughout the trial. Patients may also undergo biopsies during screening and while on the study. |
Interventions
| Sequence: | 52648458 | Sequence: | 52648459 | Sequence: | 52648460 | Sequence: | 52648461 | Sequence: | 52648462 | Sequence: | 52648463 | Sequence: | 52648464 |
| Intervention Type | Drug | Intervention Type | Procedure | Intervention Type | Procedure | Intervention Type | Drug | Intervention Type | Procedure | Intervention Type | Procedure | Intervention Type | Procedure |
| Name | BET Bromodomain Inhibitor ZEN-3694 | Name | Biopsy | Name | Biospecimen Collection | Name | Capecitabine | Name | Computed Tomography | Name | Magnetic Resonance Imaging | Name | Positron Emission Tomography |
| Description | Given PO | Description | Undergo biopsy | Description | Undergo collection of blood samples | Description | Given PO | Description | Undergo CT and PET/CT | Description | Undergo MRI | Description | Undergo PET/CT |
Design Outcomes
| Sequence: | 177993909 | Sequence: | 177993910 | Sequence: | 177993911 | Sequence: | 177993912 | Sequence: | 177993913 | Sequence: | 177993914 | Sequence: | 177993915 | Sequence: | 177993916 | Sequence: | 177993917 |
| Outcome Type | primary | Outcome Type | primary | Outcome Type | primary | Outcome Type | secondary | Outcome Type | secondary | Outcome Type | secondary | Outcome Type | secondary | Outcome Type | secondary | Outcome Type | secondary |
| Measure | Incidence of adverse events | Measure | Maximum tolerated dose (MTD) | Measure | Recommended phase 2 dose (RP2D) | Measure | Anti-tumor activity of ZEN003694 (ZEN-3694) in combination with capecitabine | Measure | Progression free survival (PFS) | Measure | Objective overall response rate (ORR) | Measure | Pharmacokinetics (PK) of ZEN003694 (ZEN-3694) in combination with capecitabine | Measure | Pharmacodynamics (PD) of ZEN003694 (ZEN-3694) in combination with capecitabine | Measure | Molecular subpopulations particularly sensitized to BETi and capecitabine |
| Time Frame | Up to 30 days after last dose | Time Frame | Up to 30 days after last dose | Time Frame | Up to 12 months | Time Frame | Up to 12 months | Time Frame | Up to 12 months | Time Frame | Up to 12 months | Time Frame | Up to 12 months | Time Frame | Up to 12 months | Time Frame | Up to 12 months |
| Description | Adverse events and serious adverse events will be tabulated for each dose levels. As per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0, the term toxicity is defined as adverse events that are classified as either possibly, probably, or definitely related to study treatment. The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns. | Description | Defined as the highest dose level with no more than 1/6 dose-limiting toxicity. | Description | Will be determined based on the MTD and later cycle adverse event (AE) rates. | Description | Treatment response will be assessed for all patients based on Response Evaluation Criteria in Solid Tumors version 1.1: complete response (CR), partial response (PR), stable disease (SD), and progression of disease (PD). Clinical benefit rate is defined as the addition of CR, PR and SD. | Description | PFS will be estimated by the Kaplan-Meier method, along with 95% confidence regions. | Description | Defined as the addition of CR and PR. The probability of ORR and clinical benefit rate will be estimated with exact 95% binomial confidence intervals. | Description | Will determine the PK of ZEN003694 (ZEN-3694) in combination with capecitabine. Capecitabine PK will be evaluated in the absence and presence of ZEN003694 (ZEN-3694) and Cmax and area under curve (AUC) will be compared with a paired test. ZEN003694 (ZEN-3694) PK will be evaluated in the presence of capecitabine and Cmax and AUC will be compared descriptively with historical data. | Description | Will determine PD of ZEN003694 (ZEN-3694) in combination with capecitabine. Ribonucleic acid sequencing of death receptor 5 (DR5). DR5 is expected to be increased by the combination ZEN003694 (ZEN-3694) in combination with capecitabine. Pre-post comparisons will be made within patients enrolled on the expansion cohort using a non-parametric paired test, at a significance level (alpha) of 0.05. Apoptosis by Pharmacodynamic Assay Development and Implementation Section (PADIS) lab. Panel 3 is priority, but other panels will be evaluated with remaining lysate. Apoptosis is expected to be increased by the combination ZEN003694 (ZEN-3694) in combination with capecitabine. Pre-post comparisons will be made within patients enrolled on the expansion cohort using a non-parametric paired test, at a significance level (alpha) of 0.05. | Description | Will identify molecular subpopulations particularly sensitized to BETi and capecitabine. Based on WES of archival tissue, we will evaluate descriptively any mutations in genes relevant to DNA damage repair, signaling and (fluoropyrimidine) metabolism, any relations with peculiar response and/or toxicity. |
Browse Conditions
| Sequence: | 194120975 | Sequence: | 194120976 | Sequence: | 194120977 | Sequence: | 194120978 | Sequence: | 194120979 | Sequence: | 194120980 | Sequence: | 194120981 | Sequence: | 194120982 | Sequence: | 194120983 | Sequence: | 194120984 | Sequence: | 194120985 | Sequence: | 194120986 | Sequence: | 194120987 | Sequence: | 194120988 |
| Mesh Term | Carcinoma | Mesh Term | Neoplasms | Mesh Term | Colorectal Neoplasms | Mesh Term | Neoplasms, Glandular and Epithelial | Mesh Term | Neoplasms by Histologic Type | Mesh Term | Intestinal Neoplasms | Mesh Term | Gastrointestinal Neoplasms | Mesh Term | Digestive System Neoplasms | Mesh Term | Neoplasms by Site | Mesh Term | Digestive System Diseases | Mesh Term | Gastrointestinal Diseases | Mesh Term | Colonic Diseases | Mesh Term | Intestinal Diseases | Mesh Term | Rectal Diseases |
| Downcase Mesh Term | carcinoma | Downcase Mesh Term | neoplasms | Downcase Mesh Term | colorectal neoplasms | Downcase Mesh Term | neoplasms, glandular and epithelial | Downcase Mesh Term | neoplasms by histologic type | Downcase Mesh Term | intestinal neoplasms | Downcase Mesh Term | gastrointestinal neoplasms | Downcase Mesh Term | digestive system neoplasms | Downcase Mesh Term | neoplasms by site | Downcase Mesh Term | digestive system diseases | Downcase Mesh Term | gastrointestinal diseases | Downcase Mesh Term | colonic diseases | Downcase Mesh Term | intestinal diseases | Downcase Mesh Term | rectal diseases |
| Mesh Type | mesh-list | Mesh Type | mesh-list | Mesh Type | mesh-list | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor |
Sponsors
| Sequence: | 48475285 |
| Agency Class | NIH |
| Lead Or Collaborator | lead |
| Name | National Cancer Institute (NCI) |
Overall Officials
| Sequence: | 29373841 |
| Role | Principal Investigator |
| Name | Dennis Hsu |
| Affiliation | University of Pittsburgh Cancer Institute LAO |
Design Group Interventions
| Sequence: | 68374852 | Sequence: | 68374853 | Sequence: | 68374854 | Sequence: | 68374855 | Sequence: | 68374856 | Sequence: | 68374857 | Sequence: | 68374858 |
| Design Group Id | 55778761 | Design Group Id | 55778761 | Design Group Id | 55778761 | Design Group Id | 55778761 | Design Group Id | 55778761 | Design Group Id | 55778761 | Design Group Id | 55778761 |
| Intervention Id | 52648458 | Intervention Id | 52648459 | Intervention Id | 52648460 | Intervention Id | 52648461 | Intervention Id | 52648462 | Intervention Id | 52648463 | Intervention Id | 52648464 |
Eligibilities
| Sequence: | 30861911 |
| Gender | All |
| Minimum Age | 18 Years |
| Maximum Age | N/A |
| Healthy Volunteers | No |
| Criteria | Inclusion Criteria: Dose Escalation additional criteria: Patients must have histologically confirmed cancer that is metastatic or unresectable and must have progressed on standard therapies which would have included fluorouracil (5-FU) or capecitabine Dose Escalation additional criteria specifically for colorectal cancer (CRC) patients: Willingness and ability to undergo a pre-treatment biopsy Dose Expansion additional criteria: Patients must have histologically confirmed CRC that is metastatic or unresectable and must have progressed on standard therapies which would have included 5-FU or capecitabine Dose Expansion additional criteria: Willingness and ability to undergo pre- and on- treatment biopsies Patients must have measurable disease Age >= 18 years. Because no dosing or adverse event data are currently available on the use of ZEN003694 (ZEN-3694) in combination with capecitabine in patients < 18 years of age, children are excluded from this study Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (Karnofsky >= 60%) Availability of archival tumor tissue at the time of patient enrollment for molecular profiling studies Prior to study dosing, previous systemic therapy must have been completed for at least five half-lives or 2 weeks, whichever is shorter Absolute neutrophil count >= 1,000/mcL Platelets >= 100,000/mcL Total bilirubin =< 1.5 institutional upper limit of normal (ULN) Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN Glomerular filtration rate (GFR) >= 50 mL/min/1.73 m^2 Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated 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 Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression 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 Patients should be New York Heart Association Functional Classification of class 2B or better The effects of ZEN003694 (ZEN-3694) and capecitabine on the developing human fetus are unknown. For this reason and because BET inhibitors 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 and for the duration of study participation. Women of child-bearing potential and 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 6 months after completion of ZEN003694 (ZEN-3694) and capecitabine administration Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants Exclusion Criteria: Previous treatment with BET inhibitors History of inability to tolerate capecitabine at the projected treatment dose on this trial Use of oral Factor Xa inhibitors (i.e., rivaroxaban, apixaban, betrixaban, edoxaban otamixaban, letaxaban, eribaxaban) and Factor IIa inhibitors (i.e., dabigatran). Low molecular weight heparin is allowed Treatment for HIV, hepatitis B or hepatitis C only if this interferes with the current treatment (e.g. through drug-drug interactions) Gastrointestinal pathology or history that adversely impacts the ability to take or absorb oral medication Hepatic tumor burden > 30% or peritoneal carcinomatosis Untreated/uncontrolled central nervous system (CNS) disease Known dihydropyrimidine dehydrogenase (DPD) deficiency Severe intercurrent illness or comorbidity Inability to comply with the protocol and/or not willing or who will not be available for follow-up assessments Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia and neuropathy up to and including grade 2 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 other agents used in study Patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A4 are ineligible. Strong inhibitors of CYP3A4 must be discontinued at least 7 days, and inducers 14 days prior to the first dose of ZEN003694 and capecitabine. Substrates of CYP1A2 with narrow therapeutic window must be avoided while taking ZEN003694 Pregnant women are excluded from this study because ZEN003694 (ZEN-3694) is an agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with ZEN003694 (ZEN-3694), breastfeeding should be discontinued if the mother is treated with ZEN003694 (ZEN-3694). These potential risks may also apply to other agents used in this study |
| Adult | True |
| Child | False |
| Older Adult | True |
Calculated Values
| Sequence: | 253917480 |
| Number Of Facilities | 1 |
| Registered In Calendar Year | 2023 |
| Were Results Reported | False |
| Has Us Facility | True |
| Has Single Facility | True |
| Minimum Age Num | 18 |
| Minimum Age Unit | Years |
| Number Of Primary Outcomes To Measure | 3 |
| Number Of Secondary Outcomes To Measure | 6 |
Designs
| Sequence: | 30607737 |
| Allocation | N/A |
| Intervention Model | Single Group Assignment |
| Observational Model | |
| Primary Purpose | Treatment |
| Time Perspective | |
| Masking | None (Open Label) |
Intervention Other Names
| Sequence: | 26751661 | Sequence: | 26751662 | Sequence: | 26751663 | Sequence: | 26751664 | Sequence: | 26751665 | Sequence: | 26751666 | Sequence: | 26751667 | Sequence: | 26751668 | Sequence: | 26751669 | Sequence: | 26751670 | Sequence: | 26751671 | Sequence: | 26751672 | Sequence: | 26751673 | Sequence: | 26751674 | Sequence: | 26751675 | Sequence: | 26751676 | Sequence: | 26751677 | Sequence: | 26751678 | Sequence: | 26751679 | Sequence: | 26751680 | Sequence: | 26751681 | Sequence: | 26751682 | Sequence: | 26751683 | Sequence: | 26751684 | Sequence: | 26751685 | Sequence: | 26751686 | Sequence: | 26751687 | Sequence: | 26751688 | Sequence: | 26751689 | Sequence: | 26751690 | Sequence: | 26751691 | Sequence: | 26751692 | Sequence: | 26751693 | Sequence: | 26751694 | Sequence: | 26751695 | Sequence: | 26751696 | Sequence: | 26751697 | Sequence: | 26751698 | Sequence: | 26751699 |
| Intervention Id | 52648458 | Intervention Id | 52648458 | Intervention Id | 52648458 | Intervention Id | 52648458 | Intervention Id | 52648459 | Intervention Id | 52648459 | Intervention Id | 52648460 | Intervention Id | 52648460 | Intervention Id | 52648460 | Intervention Id | 52648461 | Intervention Id | 52648461 | Intervention Id | 52648462 | Intervention Id | 52648462 | Intervention Id | 52648462 | Intervention Id | 52648462 | Intervention Id | 52648462 | Intervention Id | 52648462 | Intervention Id | 52648462 | Intervention Id | 52648462 | Intervention Id | 52648462 | Intervention Id | 52648463 | Intervention Id | 52648463 | Intervention Id | 52648463 | Intervention Id | 52648463 | Intervention Id | 52648463 | Intervention Id | 52648463 | Intervention Id | 52648463 | Intervention Id | 52648463 | Intervention Id | 52648463 | Intervention Id | 52648463 | Intervention Id | 52648463 | Intervention Id | 52648464 | Intervention Id | 52648464 | Intervention Id | 52648464 | Intervention Id | 52648464 | Intervention Id | 52648464 | Intervention Id | 52648464 | Intervention Id | 52648464 | Intervention Id | 52648464 |
| Name | BETi ZEN-3694 | Name | ZEN 3694 | Name | ZEN-3694 | Name | ZEN003694 | Name | BIOPSY_TYPE | Name | Bx | Name | Biological Sample Collection | Name | Biospecimen Collected | Name | Specimen Collection | Name | Ro 09-1978/000 | Name | Xeloda | Name | CAT | Name | CAT Scan | Name | Computed Axial Tomography | Name | Computerized Axial Tomography | Name | Computerized axial tomography (procedure) | Name | Computerized Tomography | Name | CT | Name | CT Scan | Name | tomography | Name | Magnetic Resonance | Name | Magnetic resonance imaging (procedure) | Name | Magnetic Resonance Imaging Scan | Name | Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance | Name | MR | Name | MR Imaging | Name | MRI | Name | MRI Scan | Name | NMR Imaging | Name | NMRI | Name | Nuclear Magnetic Resonance Imaging | Name | Medical Imaging, Positron Emission Tomography | Name | PET | Name | PET Scan | Name | Positron emission tomography (procedure) | Name | Positron Emission Tomography Scan | Name | Positron-Emission Tomography | Name | proton magnetic resonance spectroscopic imaging | Name | PT |
Responsible Parties
| Sequence: | 28974271 |
| Responsible Party Type | Sponsor |