Triple Combination Immunotherapy for Lung Cancer

Not currently recruiting at 1 trial location

Overseen By Daniel Morgensztern

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Washington University School of Medicine

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: EGFR mutation, ALK rearrangement, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 21

Duration: 9 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of three drugs to evaluate their effectiveness in treating non-small cell lung cancer. The goal is to determine if this triple therapy (immunotherapy) can benefit individuals whose cancer has previously been treated with other immune therapies. The trial seeks participants diagnosed with metastatic non-small cell lung cancer, who have undergone certain prior treatments, and possess specific tumor characteristics. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Do I need to stop my current medications to join the trial?

The trial requires that you stop taking certain medications that interact with the study drugs, such as strong inhibitors or inducers of specific enzymes and transporters, at least 4 weeks or 5 half-lives before starting the trial. If you're on any of these medications, you may need to stop them before participating.

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

Research shows that zimberelimab, domvanalimab, and etrumadenant are being tested for safety in people with non-small cell lung cancer. Previous studies have found that these drugs work well together. Each targets the immune system differently, potentially increasing their effectiveness as a team.

Regarding safety, these treatments have been tested both individually and with other drugs. Although detailed safety results for this specific combination are not widely available, earlier studies have generally found these drugs to be well-tolerated. Most reported side effects include tiredness, nausea, and skin rash, while serious side effects are less common.

This trial is in phase 2, indicating that the treatment has already passed initial safety tests in earlier stages. This suggests it is considered safe enough for testing in a larger group. However, the goal remains to continue monitoring its safety and effectiveness. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the triple combination of Domvanalimab, Etrumadenant, and Zimberelimab for lung cancer because it targets the disease in a novel way. Unlike traditional treatments like chemotherapy or PD-1 inhibitors that primarily focus on killing cancer cells directly or blocking PD-1 pathways, this combination therapy enhances the body's immune response in multiple ways. Domvanalimab is an anti-TIGIT antibody, Etrumadenant targets the adenosine signaling pathway, and Zimberelimab is a PD-1 inhibitor, together potentially offering a more robust attack on cancer cells. This multi-pronged approach could lead to better outcomes, especially for patients with higher levels of PD-L1 expression, offering hope for more effective and personalized cancer treatment.

What evidence suggests that this trial's treatments could be effective for non-small cell lung cancer?

Research shows that the combination of zimberelimab, domvanalimab, and etrumadenant may help treat non-small cell lung cancer (NSCLC). In this trial, participants will receive this combination therapy, which blocks the ways cancer cells hide from the immune system. Previous studies have found that domvanalimab and etrumadenant can boost the effects of zimberelimab, possibly strengthening the immune system's response to cancer. In patients who have already tried other immune therapies, these drugs have shown some success in shrinking tumors. This combination targets several methods cancer uses to avoid immune attacks, making it a potentially powerful treatment for NSCLC. ^{1 2 3 4 6}

Who Is on the Research Team?

Daniel Morgensztern

Principal Investigator

Washington University School of Medicine

Are You a Good Fit for This Trial?

This trial is for adults with non-small cell lung cancer who've had previous treatments including immune checkpoint blockers. They must have at least one measurable tumor and cannot have more than two prior therapies in the metastatic setting. Participants need normal organ function, no severe psychiatric issues or substance abuse, not be pregnant/breastfeeding, and can't have certain other cancers or active autoimmune diseases.

Inclusion Criteria

We don't know how the study drugs might affect a developing baby in the womb.

My bone marrow and organs are functioning normally.

My cancer shows PD-L1 expression of 1% or more.

Exclusion Criteria

Pregnant and/or breastfeeding

I have not received any live vaccines in the last 28 days.

You have had allergic reactions to similar drugs as zimberelimab, domvanalimab, etrumadenant, or other drugs used in the study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive zimberelimab, domvanalimab, and etrumadenant in 21-day cycles

9 months

21-day cycles with visits on Day 1

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

What Are the Treatments Tested in This Trial?

Interventions

• Domvanalimab
• Etrumadenant
• Zimberelimab

Trial Overview The study tests a combination of three drugs: Zimberelimab, Domvanalimab, and Etrumadenant on patients with non-small cell lung cancer who didn't respond well to previous treatments. It explores how these drugs work together since they target different aspects of the immune system's ability to fight cancer.

How Is the Trial Designed?

Group I: Cohort B: Zimberelimab + Domvanalimab + Etrumadenant Experimental Treatment 3 Interventions

* Patients will be treated on 21-day cycles with 360 mg zimberelimab intravenously on Day 1, 15 mg/kg domvanalimab intravenously on Day 1, and 150 mg etrumadenant orally daily on Days 1 to 21. * Cohort B participants are those that have PD-L1 ≥ 50%.

Group II: Cohort A: Zimberelimab + Domvanalimab + Etrumadenant Experimental Treatment 3 Interventions

* Patients will be treated on 21-day cycles with 360 mg zimberelimab intravenously on Day 1, 15 mg/kg domvanalimab intravenously on Day 1, and 150 mg etrumadenant orally daily on Days 1 to 21. * Cohort A participants are those that have PD-L1 1-49%

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

Arcus Biosciences, Inc.

Industry Sponsor

Trials

44

Recruited

7,500+

Published Research Related to This Trial

The combination of PD-1/PD-L1 and CTLA-4 inhibitors significantly improves objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) in patients with advanced lung cancer, based on a review of six studies.

While the incidence of severe adverse events (grade ≥3) was lower than in control groups, it was still notable, indicating that while the treatment is generally tolerable, monitoring for side effects remains important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of PD-1/PD-L1 plus CTLA-4 antibodies ± other therapies in lung cancer: a systematic review and meta-analysis. Shen, X., Huang, S., Xiao, H., et al.[2023]

The phase III POSEIDON trial demonstrated that a three-drug regimen combining the CTLA4 inhibitor tremelimumab, the PD-L1 inhibitor durvalumab, and chemotherapy significantly improves progression-free survival and overall survival in patients with metastatic non-small cell lung cancer compared to chemotherapy alone.

This study suggests that targeting multiple immune pathways with this combination therapy may enhance treatment effectiveness for lung cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Three-Drug Regimen Bests Chemo in NSCLC. [2022]

The combination of platinum-based chemotherapy and immunotherapy is now the standard treatment for patients with metastatic non-small-cell lung cancer, regardless of their programmed death ligand 1 tumor proportion score.

Clinical trials have shown that this combination therapy can lead to improved and long-lasting responses by enhancing the immune system's ability to attack tumors and reducing the immunosuppressive environment that hinders immune detection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combining Immunotherapy and Chemotherapy for Non-Small Cell Lung Cancer. Judd, J., Borghaei, H.[2020]

In a meta-analysis of 16 clinical trials involving 6208 patients with non-small cell lung cancer, the overall incidence of immune-related adverse events (irAEs) was found to be 22%, with a higher rate of severe irAEs (4%) associated with PD-1 inhibitors compared to PD-L1 inhibitors.

The most common organ-specific irAEs occurred in the endocrine system, skin, pulmonary tract, and gastrointestinal tract, with pneumonitis being the leading cause of death among the 14 patients (0.34%) who died due to irAEs, highlighting the importance of monitoring and managing these side effects during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune-related adverse events associated with programmed cell death protein-1 and programmed cell death ligand 1 inhibitors for non-small cell lung cancer: a PRISMA systematic review and meta-analysis. Sun, X., Roudi, R., Dai, T., et al.[2020]

In a study of 184 patients with non-small cell lung cancer treated with immune checkpoint inhibitors, 26.6% developed immune-related adverse events (IRAEs), with certain factors like statin use and previous corticosteroid therapy increasing the risk of IRAEs.

Interestingly, patients who experienced IRAEs had significantly better progression-free survival (41 weeks vs. 9 weeks) and overall survival (89 weeks vs. 28 weeks), suggesting that the occurrence of IRAEs may be linked to improved treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predictors of immune-related adverse events and outcomes in patients with NSCLC treated with immune-checkpoint inhibitors. Serino, M., Freitas, C., Martins, M., et al.[2022]

Patients with metastatic non-small-cell lung cancer who developed immune-mediated adverse events (imAEs) while treated with durvalumab showed significantly improved overall survival compared to those without imAEs, indicating a potential link between imAE development and treatment efficacy.

A predictive model was created using machine learning to identify patients at higher risk of developing imAEs, which could help tailor treatment strategies and enhance patient outcomes in immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association between immune-mediated adverse events and efficacy in metastatic non-small-cell lung cancer patients treated with durvalumab and tremelimumab. Dey, A., Austin, M., Kluger, HM., et al.[2022]

In a study involving 51 patients with advanced non-small-cell lung cancer (NSCLC) who had previously undergone multiple treatments, the combination of pembrolizumab and ipilimumab demonstrated an objective response rate of 30%, indicating some level of antitumor activity.

While the combination therapy showed potential benefits, it also resulted in significant toxicity, with 64% of patients experiencing treatment-related adverse events, highlighting the need for careful monitoring and management of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in combination with ipilimumab as second-line or later therapy for advanced non-small-cell lung cancer: KEYNOTE-021 cohorts D and H. Gubens, MA., Sequist, LV., Stevenson, JP., et al.[2020]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04791839

Study Details | NCT04791839 | Safety and Efficacy of ... ... Efficacy of Zimberelimab (AB122) in Combination With Domvanalimab (AB154) ... Etrumadenant (AB928) in Patients With Previously Treated Non-Small Cell Lung Cancer.

2. cancertherapyadvisor.com cancertherapyadvisor.com/home/cancer-topics/lung-cancer/zimberelimab-domvanalimab-etrumadenant-metastatic-nsclc/

Zimberelimab, Domvanalimab, and Etrumadenant for ... Researchers are evaluating zimberelimab, domvanalimab, and etrumadenant in patients with previously treated, metastatic NSCLC.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT04262856

NCT04262856 | Study to Evaluate Monotherapy and ... This randomized phase 2 open-label study will evaluate the safety and efficacy of zimberelimab (AB122) monotherapy, domvanalimab (AB154) in combination with ...

4. clinical-lung-cancer.com clinical-lung-cancer.com/article/S1525-7304(23)00267-X/abstract

A Phase III Randomized Study of Domvanalimab and ... The STAR-121 (NCT05502237) phase III, global, randomized, open-label study will investigate first-line domvanalimab (anti-TIGIT) and zimberelimab (anti–PD-1) ...

5. clin.larvol.com clin.larvol.com/trial-detail/NCT04791839

Safety and Efficacy of Zimberelimab (AB122) in ... Safety and efficacy of Zimberelimab (AB122) in combination with Domvanalimab (AB154) and Etrumadenant (AB928) in patients with previously treated non-small ...

6. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2020-04927

Study to Evaluate Monotherapy and Combination ... This randomized phase 2 open-label study will evaluate the safety and efficacy of zimberelimab (AB122) monotherapy, domvanalimab (AB154) in combination with ...