ZEN003694 + Nivolumab/Ipilimumab for Cancer

Recruiting at 5 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

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. ^{1 2 3 4 5}

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. ^{6 7 8 9 10}

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. ^{2 3 4 11 12}

Research Team

Haider Mahdi, MD

Principal Investigator

University of Pittsburgh Cancer Institute LAO

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.

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

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
• 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.

Participant Groups

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 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 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+

Findings from Research

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]

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]

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, 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]

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]

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]

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]

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]

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]

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]

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, 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]

References

1. United States pubmed.ncbi.nlm.nih.gov

High TMB Predicts Immunotherapy Benefit. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

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

3. United States pubmed.ncbi.nlm.nih.gov

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

4. England pubmed.ncbi.nlm.nih.gov

Antitumor activity of nivolumab on hemodialysis after renal allograft rejection. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Nivolumab plus ipilimumab in non-small-cell lung cancer. [2019]

6. Australia pubmed.ncbi.nlm.nih.gov

Real-world efficacy and toxicity of combined nivolumab and ipilimumab in patients with metastatic melanoma. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

Adverse Events of Cabozantinib Plus Nivolumab Versus Ipilimumab Plus Nivolumab. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Immunotherapy-associated complete heart block in a patient with NSCLC: A case report and literature review. [2021]

9. United States 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. [2023]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Retrospective Side Effect Profiling of the Metastatic Melanoma Combination Therapy Ipilimumab-Nivolumab Using Adverse Event Data. [2022]

11. New Zealand pubmed.ncbi.nlm.nih.gov

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

12. New Zealand pubmed.ncbi.nlm.nih.gov

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