ZEN003694 + Nivolumab/Ipilimumab for Cancer
Recruiting in Palo Alto (17 mi)
+5 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: National Cancer Institute (NCI)
Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers
Disqualifiers: Sarcoma, CNS metastases, Autoimmune, others
No Placebo Group
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?
This trial is testing a new drug combination to treat solid tumors, especially in patients whose cancer doesn't respond to usual treatments. The drugs work by blocking tumor growth and boosting the immune system to fight the cancer. The goal is to find the best dose and see if the treatment can shrink or stabilize the tumors.
Will I have to stop taking my current medications?
The trial does not specify if you must stop taking your current medications. However, you cannot take medications that are inhibitors or inducers of CYP3A4, or fluoxetine, as these can interact with the trial drugs. It's important to discuss your current medications with the trial team to ensure there are no interactions.
What data supports the effectiveness of the drug combination ZEN003694, Nivolumab, and Ipilimumab for cancer?
The combination of nivolumab (Opdivo) and ipilimumab (Yervoy) has shown long-term effectiveness in treating advanced non-small cell lung cancer (NSCLC), with better results than chemotherapy, according to the CheckMate 227 trial. This suggests that these drugs can be effective in treating certain types of cancer.12345
Is the combination of ZEN003694, Nivolumab, and Ipilimumab safe for humans?
The combination of Nivolumab and Ipilimumab has been associated with increased risk of immune-related side effects, such as heart problems and other toxicities, especially when used together. These side effects can occur within the first few weeks of treatment, and more studies are needed to fully understand their safety profile.678910
What makes the drug combination of ZEN003694, Nivolumab, and Ipilimumab unique for cancer treatment?
This drug combination is unique because it combines ZEN003694, a novel agent, with Nivolumab and Ipilimumab, which are immune checkpoint inhibitors that help the immune system recognize and attack cancer cells. This approach may offer a new way to enhance the body's immune response against cancer, potentially improving outcomes compared to traditional chemotherapy.2341112
Eligibility Criteria
Adults with advanced solid tumors that have not responded to standard treatments may join this trial. They should have a good performance status, adequate organ function, and measurable disease that can be biopsied. Excluded are those with certain allergies, uncontrolled illnesses, severe heart conditions, active infections like HIV or hepatitis, recent immunosuppressive treatment, prior therapy targeting immune checkpoints or pregnant/breastfeeding women.Inclusion Criteria
I have someone legally authorized to make decisions for me due to my impaired decision-making capacity.
You have a low number of white blood cells.
I am fully active and can carry on all pre-disease activities without restriction.
See 11 more
Exclusion Criteria
You are currently taking any other experimental drugs.
I cannot eat or drink due to a blockage or condition.
I have not had any other type of cancer, except under certain conditions.
See 15 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
1 visit (in-person)
Dose Escalation (Doublet Treatment)
Patients receive nivolumab IV and ZEN003694 PO daily. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
28 days per cycle
1 visit per cycle (in-person)
Dose Escalation and Dose Expansion (Triplet Treatment)
Patients receive nivolumab IV, ipilimumab IV, and ZEN003694 PO daily for up to 4 cycles. Beginning cycle 5, treatment continues with nivolumab and ZEN003694 only.
4 cycles of 28 days each, then continuation
1 visit per cycle (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment completion.
1 year
Every 3 months
Treatment Details
Interventions
- Ipilimumab (Checkpoint Inhibitor)
- Nivolumab (Checkpoint Inhibitor)
- ZEN003694 (BET Bromodomain Inhibitor)
Trial OverviewThe trial is testing the combination of ZEN003694 (a drug blocking enzymes for cell growth) with Nivolumab and possibly Ipilimumab (both boost the immune system to fight cancer). It aims to determine the best dose and assess potential benefits or side effects in shrinking or stabilizing solid tumors.
Participant Groups
2Treatment groups
Experimental Treatment
Group I: Triplet treatment (nivolumab, ZEN003694, ipilimumab)Experimental Treatment9 Interventions
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 of each cycle. Treatment repeats 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 1-28 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.
Group II: Doublet treatment (ZEN003694, nivolumab)Experimental Treatment8 Interventions
Patients 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.
Ipilimumab is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as Yervoy for:
- Advanced melanoma
- Stage III unresectable melanoma
- Stage IV metastatic melanoma
🇪🇺 Approved in European Union as Yervoy for:
- Advanced melanoma
- Stage III unresectable melanoma
- Stage IV metastatic melanoma
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of Pittsburgh Cancer Institute LAOPittsburgh, PA
Oregon Health and Science UniversityPortland, OR
University of Pittsburgh Cancer Institute (UPCI)Pittsburgh, PA
National Cancer Institute Developmental Therapeutics ClinicBethesda, MD
More Trial Locations
Loading ...
Who Is Running the Clinical Trial?
National Cancer Institute (NCI)Lead Sponsor
References
High TMB Predicts Immunotherapy Benefit. [2019]The first data from the phase III CheckMate-227 trial of ipilimumab plus nivolumab for the treatment of non-small cell lung cancer suggests that the two drugs boost progression-free survival in patients with a high tumor mutation burden. After 1 year, progression-free survival was 43% for patients treated with the checkpoint inhibitor combination, compared with 13% for patients treated with chemotherapy.
Nivolumab and pembrolizumab: Monoclonal antibodies against programmed cell death-1 (PD-1) that are interchangeable. [2022]Nivolumab (Opdivo, Bristol Meyer Squibb, New York, NY) and pembrolizumab (Keytruda, Merck, Kenilworth, NJ) are the first two US Food and Drug Administration (FDA)-approved monoclonal antibodies targeting programmed death-1 (PD-1). Nivolumab and pembrolizumab work by interfering with the interaction between PD-1 and programmed death ligand-1 (PD-L1), whose unimpeded interaction downregulates T cells allowing cancer cells to evade immune surveillance. These drugs have earned a series of FDA approvals for melanoma, non-small cell lung cancer (NSCLC), head and neck squamous cell cancer (HNSCC), urothelial cancer, classical Hodgkin lymphoma, and renal cell cancer. In this review we will summarize the data for efficacy and toxicity for these two agents. We conclude that they represent two valuable but interchangeable alternatives to target their approved indications. We will discuss how this can help global payers seeking to contain the cost of cancer therapeutics that continues to spiral out of control.
Nivolumab/Ipilimumab Combo Yields Durable Efficacy in Advanced NSCLC. [2021]Frontline treatment with nivolumab (Opdivo) plus ipilimumab (Yervoy) induced durable and long-term efficacy, compared with chemotherapy, in patients with advanced non-small cell lung cancer (NSCLC) and tumor PD-L1 expression greater than 1% or less than 1%, according to updated results from part 1 of the phase 3 CheckMate 227 (NCT02477826)trial presented at the 2020 American Society of Clinical Oncology Virtual Scientific Program.
Antitumor activity of nivolumab on hemodialysis after renal allograft rejection. [2023]Nivolumab (Opdivo™) is a novel IgG4 subclass programmed death-1 (PD-1) inhibiting antibody that has demonstrated breakthrough-designation anti-tumor activity. To date, clinical trials of nivolumab and other checkpoint inhibitors have generally excluded patients with solid organ transplantation and patients with concurrent immunosuppression. However, organ transplant recipients are at high-risk of development of malignancy as a result of suppressed immune surveillance of cancer.
Nivolumab plus ipilimumab in non-small-cell lung cancer. [2019]Nivolumab and ipilimumab, two therapeutic immune checkpoint inhibitor antibodies that block PD-1 and CTLA-4, respectively, have indications in cancer as single agents and in combination. In this Review, we examine the potential role of dual immune checkpoint inhibition with nivolumab plus ipilimumab in the management of patients with previously untreated advanced non-small-cell lung cancer, based on results from the Phase III CheckMate 227 study. Immunotherapies with indications in the first-line treatment of non-small-cell lung cancer include pembrolizumab alone and combined with chemotherapy, and atezolizumab combined with bevacizumab and chemotherapy. CheckMate 227 is the first Phase III study evaluating first-line chemotherapy-sparing combination immunotherapy and including tumor mutational burden as a biomarker for patient selection.
Real-world efficacy and toxicity of combined nivolumab and ipilimumab in patients with metastatic melanoma. [2019]There is limited real-world data on the efficacy and safety of combination programmed cell death protein-1 (PD-1) inhibitor, nivolumab and the cytotoxic T-lymphocyte antigen (CTLA-4) inhibitor ipilimumab.
Adverse Events of Cabozantinib Plus Nivolumab Versus Ipilimumab Plus Nivolumab. [2023]Recently, many agents and combinations for metastatic and advanced renal cell carcinoma have been approved. This study aims to highlight the comprehensive differences in adverse events (AEs) between cabozantinib (CAB) plus nivolumab (NIVO) and ipilimumab (IPI) plus NIVO based on a real-world big dataset.
Immunotherapy-associated complete heart block in a patient with NSCLC: A case report and literature review. [2021]The role for PD-1/PD-L1 and CTLA-4 targeted immunotherapy is well outlined in the treatment of metastatic NSCLC. Increased survival benefit supports the use of these medications and the development of next-generation agents with improved efficacy and favorable side-effect profiles. The prevalence of immunotherapy-associated cardiotoxicity (IAC) has grown significantly over the past two years as awareness of this toxicity class has emerged. High-grade conduction disorders comprise a subset of cardiotoxicities with a high case fatality rate. We presented a case of suspected combination ipilimumab-nivolumab associated 3rd degree heart block. The onset of this event was 16 days after immunotherapy initiation. A literature review has suggested that over 75% of cases of cardiotoxicity are observed within the first 6 weeks. We present findings from an interrogation of the FDA Adverse Event Reporting System (FAERS) and provide clinical guidance for the early identification of high-risk patients.
Safety of First-Line Nivolumab Plus Ipilimumab in Patients With Metastatic NSCLC: A Pooled Analysis of CheckMate 227, CheckMate 568, and CheckMate 817. [2023]We characterized the safety of first-line nivolumab plus ipilimumab (NIVO+IPI) in a large patient population with metastatic NSCLC and efficacy outcomes after NIVO+IPI discontinuation owing to treatment-related adverse events (TRAEs).
Retrospective Side Effect Profiling of the Metastatic Melanoma Combination Therapy Ipilimumab-Nivolumab Using Adverse Event Data. [2022]Recent studies suggest that combining nivolumab with ipilimumab is a more effective treatment for melanoma patients, compared to using ipilimumab or nivolumab alone. However, treatment with these immunotherapeutic agents is frequently associated with increased risk of toxicity, and (auto-) immune-related adverse events. The precise pathophysiologic mechanisms of these events are not yet clear, and evidence from clinical trials and translational studies remains limited. Our retrospective analysis of ~7700 metastatic melanoma patients treated with ipilimumab and/or nivolumab from the FDA Adverse Event Reporting System (FAERS) demonstrates that the identified immune-related reactions are specific to ipilimumab and/or nivolumab, and that when the two agents are administered together, their safety profile combines reactions from each drug alone. While more prospective studies are needed to characterize the safety of ipilimumab and nivolumab, the present work constitutes perhaps the first effort to examine the safety of these drugs and their combination based on computational evidence from real world post marketing data.
Nivolumab: a review in advanced squamous non-small cell lung cancer. [2022]Nivolumab (Opdivo(®); Nivolumab BMS™) was the first programmed death (PD)-1 immune checkpoint inhibitor to be approved for use in advanced, squamous non-small cell lung cancer (NSCLC) following prior chemotherapy. In the pivotal CheckMate 017 trial, intravenous nivolumab 3 mg/kg every 2 weeks was associated with significantly better overall survival and progression-free survival and a significantly higher overall response rate than intravenous docetaxel in the second-line treatment of advanced, squamous NSCLC. Nivolumab was also better tolerated than docetaxel in CheckMate 017, and its adverse event profile (which included immune-mediated adverse events) was manageable. In conclusion, nivolumab represents an important advance in previously-treated, advanced, squamous NSCLC.
Nivolumab: a review of its use in patients with malignant melanoma. [2021]Nivolumab (Opdivo(®)) is a fully human monoclonal antibody against programmed death receptor-1, a negative regulatory checkpoint molecule with a role in immunosuppression. The drug is administered intravenously and is approved for the treatment of unresectable malignant melanoma in Japan. The potential for intravenous nivolumab to be used in the treatment of advanced malignancies such as melanoma was initially demonstrated in phase I dose-ranging trials. Subsequently, in a noncomparative, open-label, phase II trial, almost one-quarter of Japanese patients with previously treated stage III/IV melanoma (recurrent or unresectable) achieved a partial tumour response with intravenous nivolumab 2 mg/kg every 3 weeks. The clinical benefit of the drug was durable, with patients surviving free from progression for a median of 172 days and median overall survival not yet reached. Nivolumab had an acceptable tolerability profile in this trial, with fewer than 18 % of patients experiencing grade 3 or 4 adverse events related to the drug, the most common of which was increased γ-glutamyl transferase. Thus, nivolumab is an emerging, promising option for the treatment of malignant melanoma.