ZEN003694 + Nivolumab/Ipilimumab for Cancer

Recruiting at 11 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Sarcoma, CNS metastases, Autoimmune, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 6

66 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new approach to treating solid tumors using a combination of drugs. It tests the effectiveness of ZEN003694, a drug that may slow tumor growth, alongside two immunotherapy drugs, nivolumab (Opdivo) and ipilimumab (Yervoy), which help the immune system attack cancer. Researchers aim to determine the best dose and assess any benefits or side effects. Individuals with solid tumors unresponsive to standard treatments might be suitable candidates for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Past studies have used the drugs nivolumab and ipilimumab together to treat various cancers. These drugs are usually well-tolerated, with common side effects like tiredness and skin rash. More serious side effects can occur but are less common. The FDA has approved this combination for certain cancers, indicating that its safety is well understood.

ZEN003694 is a newer drug still under investigation. Early research shows it might cause mild to moderate side effects, such as nausea and tiredness. However, its full safety profile is still being explored. This trial is in an early stage, focusing on finding a safe dose and understanding the side effects, so researchers are still collecting safety information.

Participants will help researchers learn more about the safety of ZEN003694 when used with nivolumab and ipilimumab. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine innovative approaches to target cancer. Unlike standard treatments that often focus on a single pathway, the combination of ZEN003694, Nivolumab, and Ipilimumab acts on multiple fronts. ZEN003694 is a BET inhibitor, which disrupts cancer cell growth by affecting gene expression. Nivolumab and Ipilimumab are immune checkpoint inhibitors that help the immune system recognize and attack cancer cells more effectively. This multi-pronged approach could enhance treatment efficacy and offer new hope for patients who may not respond to existing therapies.

What evidence suggests that this trial's treatments could be effective for solid tumors?

Research has shown that using nivolumab and ipilimumab together can significantly improve survival rates for people with advanced cancers. Studies have found that this combination can lower the risk of death by 28% in patients with renal cell carcinoma, a type of kidney cancer. In this trial, one group of participants will receive a triplet treatment of nivolumab, ipilimumab, and ZEN003694. ZEN003694 aims to stop tumors from growing by blocking certain enzymes that cancer cells need. Although limited human data exists on ZEN003694, researchers are exploring its potential to work well with immunotherapy drugs like nivolumab. Another group in this trial will receive a doublet treatment of ZEN003694 and nivolumab. Combining these treatments might help stabilize or shrink solid tumors by boosting the body's immune response against cancer. Early signs suggest that these combinations could offer promising benefits for people with solid tumors. ^{1 2 6 7 8}

Who Is on the Research Team?

Haider Mahdi, MD

Principal Investigator

University of Pittsburgh Cancer Institute LAO

Are You a Good Fit for This Trial?

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.

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Ipilimumab
• Nivolumab
• ZEN003694

Trial Overview

The 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.

How Is the Trial Designed?

Group I: Triplet treatment (nivolumab, ZEN003694, ipilimumab) Experimental Treatment 9 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 or 1-28 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 1-21 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.

Group II: Doublet treatment (ZEN003694, nivolumab) Experimental Treatment 8 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

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a study of 45 patients with metastatic melanoma treated with the combination of nivolumab and ipilimumab, the disease control rate was 54% and the objective response rate was 29%, indicating moderate efficacy in a real-world setting.

The treatment had a high toxicity profile, with 88% of patients experiencing adverse events, and 44% discontinuing treatment due to these events, highlighting the need for careful monitoring and management of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world efficacy and toxicity of combined nivolumab and ipilimumab in patients with metastatic melanoma. Parakh, S., Randhawa, M., Nguyen, B., et al.[2019]

Nivolumab, an immune checkpoint inhibitor, significantly improved overall survival and progression-free survival compared to docetaxel in patients with advanced squamous non-small cell lung cancer (NSCLC) in the CheckMate 017 trial.

Nivolumab was better tolerated than docetaxel, with manageable adverse effects, making it a promising treatment option for patients who have already undergone chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab: a review in advanced squamous non-small cell lung cancer. Keating, GM.[2022]

Nivolumab, an anti-PD-1 antibody, was administered to a 63-year-old female patient with metastatic melanoma after renal transplantation, highlighting the potential for anti-tumor activity in high-risk patients, despite the challenges of concurrent immunosuppression.

The patient experienced acute renal allograft rejection and renal failure shortly after starting nivolumab, indicating significant risks associated with this treatment in transplant recipients, but she later showed a positive clinical response after re-challenging with nivolumab while on hemodialysis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor activity of nivolumab on hemodialysis after renal allograft rejection. Ong, M., Ibrahim, AM., Bourassa-Blanchette, S., et al.[2023]

Nivolumab plus ipilimumab showed durable and long-term efficacy in treating advanced non-small cell lung cancer (NSCLC) compared to chemotherapy, regardless of tumor PD-L1 expression levels.

These findings are based on updated results from part 1 of the phase 3 CheckMate 227 trial, indicating that this combination therapy could be a more effective frontline treatment option for NSCLC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab/Ipilimumab Combo Yields Durable Efficacy in Advanced NSCLC. Kahl, KL.[2021]

Nivolumab and pembrolizumab are FDA-approved monoclonal antibodies that target PD-1, helping to enhance T cell activity against cancer by blocking the PD-1/PD-L1 interaction, which allows cancer cells to escape immune detection.

Both drugs have shown efficacy across multiple cancer types, including melanoma and non-small cell lung cancer, and are considered interchangeable options for treating these conditions, which may help manage the rising costs of cancer therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab and pembrolizumab: Monoclonal antibodies against programmed cell death-1 (PD-1) that are interchangeable. Prasad, V., Kaestner, V.[2022]

Immunotherapy targeting PD-1/PD-L1 and CTLA-4 has shown increased survival benefits in treating metastatic non-small cell lung cancer (NSCLC), but it is also associated with significant cardiotoxicity, particularly high-grade conduction disorders like 3rd degree heart block.

A case study highlighted a patient who developed 3rd degree heart block 16 days after starting combination therapy with ipilimumab and nivolumab, emphasizing that over 75% of immunotherapy-related cardiotoxicity cases occur within the first 6 weeks, which underscores the need for early identification and monitoring of high-risk patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunotherapy-associated complete heart block in a patient with NSCLC: A case report and literature review. Vartanov, A., Kalotra, A., Varughese, J., et al.[2021]

The combination of nivolumab and ipilimumab has shown promise as a first-line treatment for previously untreated advanced non-small-cell lung cancer, as demonstrated in the Phase III CheckMate 227 study.

This study is significant because it is the first to evaluate a chemotherapy-sparing approach using dual immune checkpoint inhibition, while also considering tumor mutational burden as a biomarker for selecting suitable patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus ipilimumab in non-small-cell lung cancer. Reck, M., Borghaei, H., O'Byrne, KJ.[2019]

Combining nivolumab and ipilimumab shows improved effectiveness in treating metastatic melanoma compared to using either drug alone, based on a retrospective analysis of approximately 7700 patients.

The combination therapy presents a safety profile that includes immune-related adverse events from both drugs, indicating that while the combination is effective, it also carries a heightened risk of toxicity that needs further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retrospective Side Effect Profiling of the Metastatic Melanoma Combination Therapy Ipilimumab-Nivolumab Using Adverse Event Data. Soldatos, TG., Dimitrakopoulou-Strauss, A., Larribere, L., et al.[2022]

The phase III CheckMate-227 trial indicates that the combination of ipilimumab and nivolumab significantly improves progression-free survival in non-small cell lung cancer patients with a high tumor mutation burden, with 43% of patients remaining progression-free after 1 year.

In contrast, only 13% of patients treated with chemotherapy experienced progression-free survival, highlighting the potential efficacy of the checkpoint inhibitor combination over traditional chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High TMB Predicts Immunotherapy Benefit. [2019]

In a study of 1255 patients with metastatic non-small cell lung cancer (NSCLC), first-line treatment with nivolumab plus ipilimumab (NIVO+IPI) showed a high incidence of treatment-related adverse events (TRAEs), with 78% experiencing any-grade TRAEs and 34% experiencing severe (grade 3 or 4) TRAEs, but the treatment was generally well tolerated.

Patients who discontinued NIVO+IPI due to TRAEs still had a favorable long-term survival rate, with a 3-year overall survival of 50%, indicating that stopping treatment because of side effects did not negatively impact their long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of First-Line Nivolumab Plus Ipilimumab in Patients With Metastatic NSCLC: A Pooled Analysis of CheckMate 227, CheckMate 568, and CheckMate 817. Paz-Ares, LG., Ciuleanu, TE., Pluzanski, A., et al.[2023]

Nivolumab, a monoclonal antibody targeting the programmed death receptor-1, has shown promising efficacy in treating advanced malignant melanoma, with nearly 25% of patients achieving a partial tumor response in a phase II trial involving previously treated stage III/IV patients.

The treatment demonstrated a durable clinical benefit, with a median progression-free survival of 172 days and an acceptable safety profile, as less than 18% of patients experienced severe adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab: a review of its use in patients with malignant melanoma. Deeks, ED.[2021]

In a real-world analysis of adverse events from two combination therapies for advanced renal cell carcinoma, cabozantinib (CAB) plus nivolumab (NIVO) showed higher incidence rates of seven types of toxicities compared to ipilimumab (IPI) plus NIVO.

Conversely, IPI + NIVO was associated with higher rates of three types of toxicities and had a greater incidence of serious adverse events, suggesting that both therapies have distinct safety profiles that can guide treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events of Cabozantinib Plus Nivolumab Versus Ipilimumab Plus Nivolumab. Blas, L., Shiota, M., Tsukahara, S., et al.[2023]

Citations

1.

clinicaltrials.gov

clinicaltrials.gov/study/NCT04840589

Study Details | NCT04840589 | Testing the Combination of ...

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 ...

2.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC11216518/

An LC–MS/MS method for determination of the ...

ZEN-3694's potential as a combination agent in advanced and metastatic tumors that are resistant to other therapies will be evaluated, hence the ...

3.

cancer.gov

cancer.gov/research/participate/clinical-trials/intervention/ipilimumab?pn=1

Clinical Trials Using Ipilimumab - NCI

NCI supports clinical trials that test new and more effective ways to treat cancer. Find clinical trials studying ipilimumab.

4.

apps.dtic.mil

apps.dtic.mil/sti/trecms/pdf/AD1223417.pdf

2023 W81XWH-18-1-0256 (OC170443) Final ... - DTIC

In this trial, we have enrolled 8 patients in the doublet combination (nivolumab combined with BET inhibitor, ZEN3694). Of them, 4 patients had ...

5.

targetedonc.com

targetedonc.com/view/hbi-8000-plus-nivolumab-is-safe-active-in-melanoma

HBI-8000 Plus Nivolumab Is Safe, Active in Melanoma

The overall response rate for the 38 patients evaluable for efficacy was 65.8%. This included 6 (15.8%) complete responses and 19 (50%) partial ...

6.

opdivohcp.com

opdivohcp.com/safety/nsclc/opdivo

OPDIVO® (nivolumab) Safety Profile for Previously Treated ...

View the selected safety profile for OPDIVO® (nivolumab) treatment in previously treated metastatic NSCLC. Please see Indications and Important Safety ...

7.

apps.dtic.mil

apps.dtic.mil/sti/trecms/pdf/AD1166804.pdf

Phase I/Ib Trial Evaluating the Safety and Efficacy of BET ...

Phase I/Ib trial evaluating the safety and efficacy of BET inhibitor, ZEN003694 with PD-1 inhibitor, nivolumab with or without CTLA-A inhibitor, ipilimumab in.

8.

cancer.gov

cancer.gov/research/participate/clinical-trials/intervention/bet-bromodomain-inhibitor-zen-3694?pn=1

Clinical Trials Using BET Bromodomain Inhibitor ZEN-3694

NCI supports clinical trials that test new and more effective ways to treat cancer. Find clinical trials studying bet bromodomain inhibitor zen-3694.