Study Stopped
Other - Pending amendment.
Testing the Combination of ZEN003694 and Nivolumab With or Without Ipilimumab in Solid Tumors
Phase I/Ib Trial Evaluating the Safety and Efficacy of BET Inhibitor, ZEN003694 With PD-1 Inhibitor, Nivolumab With or Without CTLA-4 Inhibitor, Ipilimumab in Solid Tumors
4 other identifiers
interventional
66
1 country
9
Brief Summary
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_1
Started Feb 2022
Longer than P75 for phase_1
9 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
April 9, 2021
CompletedFirst Posted
Study publicly available on registry
April 12, 2021
CompletedStudy Start
First participant enrolled
February 2, 2022
CompletedPrimary Completion
Last participant's last visit for primary outcome
September 1, 2028
ExpectedStudy Completion
Last participant's last visit for all outcomes
September 1, 2028
May 13, 2026
February 1, 2026
6.6 years
April 9, 2021
May 12, 2026
Conditions
Outcome Measures
Primary Outcomes (2)
Safety and tolerability
Will calculate maximum tolerated dose and dose limiting toxicity with dose escalation using standard 3+3 design.
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
Up to 1 cycle of treatment for doublet group (4 weeks) and up to 2 cycles for triplet group (6 weeks)
Secondary Outcomes (13)
Objective response rate (ORR)
Up to 1 year post-treatment
Progression-free survival
Up to 1 year post-treatment
Overall survival
Up to 1 year post-treatment
Incidence of adverse events
Up to 1 year post-treatment
Clinical benefit
Up to 1 year post-treatment
- +8 more secondary outcomes
Study Arms (2)
Doublet treatment (ZEN003694, nivolumab)
EXPERIMENTALPatients receive nivolumab IV over 30 minutes on day 1 and ZEN003694 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 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.
Triplet treatment (nivolumab, ZEN003694, ipilimumab)
EXPERIMENTALPatients 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.
Interventions
Given PO
Undergo MRI
Given IV
Undergo a PET scan
Undergo x-ray
Undergo a CT scan
Undergo a biopsy
Undergo blood sample collection
Given IV
Eligibility Criteria
You may qualify if:
- Patients must have histologically confirmed metastatic or recurrent solid tumor malignancy for which standard curative or palliative measures do not exist or are no longer effective
- Dose escalation/phase I: Metastatic or recurrent solid tumors with measurable or evaluable disease
- Dose expansion exploratory cohorts (nivolumab + ipilimumab + ZEN003694): Recurrent BRCAwt epithelial ovarian carcinoma patients who have progressed or recurred within \< 6 months from prior platinum-based therapy
- Dose escalation and expansion exploratory cohorts: Patients must have measurable and biopsiable disease (at least two lesions) per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1. For patients in the dose escalation with evaluable disease, biopsy is mandated if feasible
- No more than 5 lines of prior therapy for the dose escalation and expansion phases
- In the expansion cohorts, up to 2 prior lines in the platinum-resistant setting is allowed
- Patients with primary refractory ovarian cancer (who progressed while on primary 1L platinum therapy) will be excluded in the dose expansion cohorts but allowed in the dose escalation cohort
- Patients who have had chemotherapy or radiotherapy more than 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study and who have recovered from adverse events due to agents administered more than 4 weeks earlier are eligible; for oral therapies, a patient is eligible after 5 half-lives of the drug. Prior palliative (limited field) radiation therapy is permitted, if all of the following criteria are met:
- Palliative radiation must have been completed at least 4 weeks before starting study treatment
- Repeat imaging demonstrates no new sites of bone metastases
- Irradiated sites of metastasis should not be selected as target lesions
- Patients must have recovered to meet all eligibility criteria
- Age \>= 18 years. Because no dosing or adverse event (AE) data are currently available on the use of nivolumab in combination with ZEN003694 +/- ipilimumab in patients \< 18 years of age, children are excluded from this study
- Eastern Cooperative Oncology Group (ECOG) performance status =\< 1 (Karnofsky \>= 80%)
- Leukocytes \>= 2,000/mcL
- +12 more criteria
You may not qualify if:
- Patients with sarcoma or non-epithelial histology
- Patients with known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to the first dose of study intervention
- Prior therapy with PD-1, PD-L1, or CTLA-4 inhibitors, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways. Prior anti-PD-1/PD-L1 in microsatellite instability-high (MSI-H) tumors is allowed in the dose escalation cohort if no grade 2 or more toxicities developed during that therapy requiring stopping immune checkpoint inhibition. Patients who have received prior vaccine therapy are eligible
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab, ipilimumab, and/or ZEN003694, including severe hypersensitivity reactions to any monoclonal antibody
- Patients who are receiving any other investigational agents
- Patients with human immunodeficiency virus (HIV) infection may be enrolled on this study provided: (a) they are on a stable regimen of highly active anti-retroviral therapy (HAART) with no medications otherwise prohibited by this protocol (e.g. drug-drug interactions,), e.g. medications cannot be CYP3A4 inducers or inhibitors and cannot interact with ZEN003694), and (b) they require no concurrent antibiotics or antifungals for the prevention of opportunistic infections, and (c) they have a CD4 count above 250 cell/mcL and an undetectable viral load on standard polymerase chain reaction (PCR)-based tests within 1 month of initiation of study treatment
- Other patients with clinically significant immunosuppression, e.g. organ transplant patients, are not eligible. If clarification is needed, this may be discussed with the medical monitor. Patients should be excluded if they have a positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV RNA) indicating acute or chronic infection. Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids, should be excluded. These include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded because of the risk of recurrence or exacerbation of disease. Patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible. Patients with rheumatoid arthritis and other arthropathies, Sjögren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible
- Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses =\< 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. Patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic corticosteroids are permitted, even if =\< 10 mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted
- Patients who have had evidence of active or acute diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction and abdominal carcinomatosis which are known risk factors for bowel perforation should be evaluated for the potential need for additional treatment before coming on study
- Patients with known immune impairment who may be unable to respond to anti-CTLA-4 antibody
- Bowel obstruction or any condition precluding oral intake. No gastric tube for venting purposes. No significant gastrointestinal disease or fistula
- Known active hepatitis infections or active infections require IV systemic antibiotics
- Patients receiving any medications or substances that are inhibitors or inducers of CYP3A4 or that receive fluoxetine (moderate CYP2C19 inhibitor with a metabolite that potentially causes CYP3A4 inhibition) are ineligible. 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
- Patients with psychiatric illness/social situations that would limit compliance with study requirements
- +3 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (9)
National Cancer Institute Developmental Therapeutics Clinic
Bethesda, Maryland, 20892, United States
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892, United States
Mount Sinai Hospital
New York, New York, 10029, United States
Montefiore Medical Center-Einstein Campus
The Bronx, New York, 10461, United States
Montefiore Medical Center-Weiler Hospital
The Bronx, New York, 10461, United States
Montefiore Medical Center - Moses Campus
The Bronx, New York, 10467, United States
Case Western Reserve University
Cleveland, Ohio, 44106, United States
Oregon Health and Science University
Portland, Oregon, 97239, United States
University of Pittsburgh Cancer Institute (UPCI)
Pittsburgh, Pennsylvania, 15232, United States
Related Publications (1)
Feng Y, Mahdi H, Piekarz R, Beumer JH, Synold TW. An LC-MS/MS method for determination of the bromodomain inhibitor ZEN-3694 and its metabolite ZEN-3791 in human plasma. Bioanalysis. 2024;16(8):227-238. doi: 10.4155/bio-2023-0252. Epub 2024 Mar 18.
PMID: 38497709DERIVED
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Haider S Mahdi
University of Pittsburgh Cancer Institute LAO
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- NON RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- SEQUENTIAL
- Sponsor Type
- NIH
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
April 9, 2021
First Posted
April 12, 2021
Study Start
February 2, 2022
Primary Completion (Estimated)
September 1, 2028
Study Completion (Estimated)
September 1, 2028
Last Updated
May 13, 2026
Record last verified: 2026-02
Data Sharing
- IPD Sharing
- Will share
NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.