Triple Drug Therapy for Non-Small Cell Lung Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: H. Lee Moffitt Cancer Center and Research Institute

Must not be taking: Anticancer agents, Immunosuppressive drugs

Disqualifiers: Active infections, Autoimmune disease, Cardiovascular diseases, 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: 12

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether a combination of three drugs—nivolumab (Opdivo), ipilimumab (Yervoy), and nintedanib—can effectively treat non-small cell lung cancer, a common lung cancer type. Researchers aim to determine if this drug combination is both effective and safe. The trial includes different groups for individuals who haven't received previous treatments and those who have tried immunotherapy before. Individuals with advanced non-small cell lung cancer, who have exhausted curative options, might be a good fit for this study. As a Phase 1, Phase 2 trial, this research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group.

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

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot use other anticancer agents, investigational drugs, or certain immunosuppressive medications before starting the trial treatment.

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

Research has shown that the combination of nivolumab, ipilimumab, and nintedanib is generally safe and well-tolerated. Studies have found that the side effects of this combination are manageable, meaning they are not severe and can be controlled. For instance, one study noted that patients experienced expected and mild side effects. These findings are encouraging because they indicate that the treatment can be safely administered to patients with non-small cell lung cancer.

Nivolumab and ipilimumab, when used together, have effectively treated various cancers, including lung cancer. They have been used for some time, so doctors understand their effects on patients. Nintedanib has also been tested and is known to work well with nivolumab and ipilimumab.

Overall, evidence suggests that this drug combination is safe for clinical trial participation. Participants receive close monitoring to manage any side effects that might occur. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this triple drug therapy because it combines three powerful agents—Ipilimumab, Nintedanib, and Nivolumab—to tackle non-small cell lung cancer in a novel way. Unlike traditional treatments like chemotherapy and radiation, which often target rapidly dividing cells in general, this combination includes two immunotherapy drugs, Nivolumab and Ipilimumab, that boost the body’s immune system to fight cancer cells more effectively. Nintedanib adds another layer by inhibiting enzymes that help tumors grow new blood vessels, potentially starving the tumors. This multi-pronged approach aims to improve response rates and offers hope for both newly diagnosed patients and those who have already undergone other immunotherapies.

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

Research has shown that using nivolumab, ipilimumab, and nintedanib together may be promising for treating non-small cell lung cancer (NSCLC). In this trial, participants will receive this combination therapy. Studies have found that nivolumab and ipilimumab can improve five-year survival rates for patients with advanced NSCLC, increasing survival from 7% to much higher levels. Adding nintedanib, which helps stop blood vessels from growing in tumors, reportedly boosts the effectiveness of this treatment. One study noted that this combination of three drugs had manageable side effects and worked well for both newly diagnosed and previously treated patients. Overall, early findings suggest this combination could be a helpful option for NSCLC patients. ^{1 2 5 6 7}

Who Is on the Research Team?

Jhanelle E. Gray, M.D.

Principal Investigator

H. Lee Moffitt Cancer Center and Research Institute

Are You a Good Fit for This Trial?

Adults with advanced non-small cell lung cancer (NSCLC) who are treatment-naive or have had prior immunotherapy can join this trial. They should have a measurable tumor, be in good physical condition (ECOG score 0-1), and expect to live at least another 3-6 months. Women must not be pregnant and participants must agree to use contraception.

Inclusion Criteria

You have at least one visible tumor that can be measured using specific criteria.

My organs and bone marrow are functioning well.

I have tissue samples from previous biopsies or surgeries.

Exclusion Criteria

I do not have stomach or intestine problems that affect medication absorption.

I do not have any serious illnesses or conditions that could make this study unsafe for me.

I am not currently using any other cancer treatments not listed in the study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Treatment

Dose escalation to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of nivolumab, ipilimumab, and nintedanib

Up to 12 months

Bi-weekly visits for nivolumab, every 6 weeks for ipilimumab

Phase 2 Treatment

Participants receive nivolumab, ipilimumab, and nintedanib at RP2D, with separate arms for treatment-naïve and treatment non-naïve patients

Up to 36 months

Bi-weekly visits for nivolumab, every 6 weeks for ipilimumab

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 36 months

What Are the Treatments Tested in This Trial?

Interventions

• Ipilimumab
• Nintedanib
• Nivolumab

Trial Overview The study is testing the safety and effectiveness of combining three drugs: Nivolumab, Ipilimumab, and Nintedanib for NSCLC treatment. It's structured in phases to first determine safe dosages (Phase I) then assess how well the drug combination works (Phase II).

How Is the Trial Designed?

Group I: Phase 1 Nintedanib Dose Escalation 100-200 mg QD to BID Experimental Treatment 3 Interventions

Nivolumab + Ipilimumab + Nintedanib dose escalation. Participants were given the following: Nivolumab: 3 mg/kg IV Q2 weeks. Ipilimumab: 1 mg/kg Q6 weeks. Nintedanib Level -1: 100 mg by mouth (PO) once a day (QD) Days 1-14 (Daily dose =100 mg). Nintedanib Level 0:150 mg by mouth (PO) once a day (QD) Days 1-14 (Daily dose =150 mg) Nintedanib Level 1: 100 mg PO twice daily (BID) Days 2-28 (Daily dose = 200 mg). Nintedanib Level 2: 150 mg PO BID Days 1-14 (Daily dose = 300 mg). Nintedanib Level 3: 200 mg PO BID Days 1-14 (Daily dose = 400 mg).

Group II: Phase 2 - Arm A Nintedanib 100-200 mg BID Treatment-naïve Active Control 3 Interventions

Arm A: Treatment-naïve defined as newly diagnosed or treatment-naïve patients, with a target overall response rate (ORR) of 50%. Participants were given the following: Nivolumab + Ipilimumab + Nintedanib at RP2D. Nivolumab: Intravenous nivolumab every 2 weeks. Ipilimumab: Intravenous ipilimumab every 6 weeks. Nintedanib: Nintedanib 100-200 mg capsules by mouth twice daily for two-week cycles.

Group III: Phase 2 - Arm B Nintedanib 100-200 mg BID Treatment Non-naïve Active Control 3 Interventions

Arm B: Treatment Non-naïve defined as patients who have been previously exposed to immunotherapy, such as anti-PD-1, anti-PD-L1 or anti-CTLA-4, with a target ORR of 20%. Participants were given the following: Nivolumab + Ipilimumab + Nintedanib at RP2D. Nivolumab: Intravenous nivolumab every 2 weeks. Ipilimumab: Intravenous ipilimumab every 6 weeks. Nintedanib: Nintedanib 100-200 mg capsules by mouth twice daily for two-week cycles.

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?

H. Lee Moffitt Cancer Center and Research Institute

Lead Sponsor

Trials

576

Recruited

145,000+

Published Research Related to This Trial

In the Asian subpopulation with advanced non-small cell lung cancer (NSCLC) and PD-L1 expression ≥1%, patients treated with nivolumab plus ipilimumab showed significantly improved overall survival (OS) and progression-free survival (PFS) compared to those receiving chemotherapy, with a 3-year OS rate of 53% versus 37%.

The safety profile of nivolumab plus ipilimumab was manageable, with grade 3-4 treatment-related adverse events occurring in 40% of patients, similar to the 36% in the chemotherapy group, indicating no new safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line nivolumab + ipilimumab in advanced NSCLC: CheckMate 227 subpopulation analyses in Asian patients. O'Byrne, KJ., Lee, KH., Kim, SW., et al.[2022]

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]

Ipilimumab has shown a positive impact on overall survival in patients with stage IV melanoma, with long-term follow-up indicating its effectiveness compared to conventional treatments.

While 84.8% of patients experience drug-related adverse events, most are mild to moderate; however, severe reactions can occur, necessitating careful monitoring and management, especially when combined with other therapies like vemurafenib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CTLA-4 blockade with ipilimumab: biology, safety, efficacy, and future considerations. Camacho, LH.[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, used as a first-line treatment for non-small cell lung cancer, shows promise in improving patient survival rates.

Combining nivolumab with platinum-doublet chemotherapy did not enhance survival benefits and may increase toxicity, indicating a need for careful consideration when using these treatments together.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab May Work as First-Line NSCLC Therapy. [2018]

Nivolumab plus ipilimumab (N+I) and nivolumab plus ipilimumab with chemotherapy (N+I+chemotherapy) improve overall survival and progression-free survival for patients with metastatic non-small cell lung cancer (NSCLC), but both treatments are not cost-effective compared to chemotherapy alone, with high incremental cost-effectiveness ratios (ICERs) of $239,072 and $838,198 per quality-adjusted life year (QALY) respectively.

The cost-effectiveness analysis showed that N+I had a very low probability (2.6%) of being considered cost-effective at a willingness-to-pay threshold of $150,000 per QALY, indicating that while these treatments may improve survival, they come at a significant financial burden to the healthcare system.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost-Effectiveness of Nivolumab Plus Ipilimumab With and Without Chemotherapy for Advanced Non-Small Cell Lung Cancer. Yang, SC., Kunst, N., Gross, CP., et al.[2022]

Ipilimumab is an FDA-approved monoclonal antibody that activates T-cells to treat advanced melanoma, showing a clear survival benefit in Phase III studies with ongoing investigations for other solid tumors.

While ipilimumab can cause immune-related adverse events (irAEs) in 60% of patients, most of these side effects are reversible with proper management, highlighting the importance of monitoring and early intervention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emerging options for the treatment of melanoma - focus on ipilimumab. Roddie, C., Peggs, KS.[2020]

In a pooled analysis of 1332 patients with advanced non-small-cell lung cancer (NSCLC), the combination of nivolumab and ipilimumab showed a median overall survival (OS) of 18.6 months and a 3-year OS rate of 35%, indicating significant long-term survival benefits compared to traditional chemotherapy.

The study found that patients who responded to treatment at 6 months had markedly better survival rates, with a 3-year OS of 66% for responders, highlighting the importance of early response in predicting long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term survival with first-line nivolumab plus ipilimumab in patients with advanced non-small-cell lung cancer: a pooled analysis. Borghaei, H., Ciuleanu, TE., Lee, JS., et al.[2023]

In a phase 2 trial involving 117 patients with advanced, refractory squamous non-small-cell lung cancer, nivolumab demonstrated a 14.5% objective response rate, indicating its potential effectiveness as a treatment option.

The safety profile of nivolumab was manageable, with 17% of patients experiencing severe treatment-related adverse events, suggesting that while there are risks, the benefits may outweigh them for patients with limited treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Rizvi, NA., Mazières, J., Planchard, D., et al.[2022]

In a phase 3 clinical trial involving 252 patients with advanced squamous non-small cell lung cancer (NSCLC), the combination of nivolumab and ipilimumab did not significantly improve overall survival compared to nivolumab alone, with median survival times of 10 months and 11 months respectively.

While the combination treatment showed a slightly better progression-free survival (IA-PFS) of 3.8 months compared to 2.9 months for nivolumab alone, the difference was not statistically significant, and both treatments had similar response rates and adverse event profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab Plus Ipilimumab vs Nivolumab for Previously Treated Patients With Stage IV Squamous Cell Lung Cancer: The Lung-MAP S1400I Phase 3 Randomized Clinical Trial. Gettinger, SN., Redman, MW., Bazhenova, L., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03377023

Phase I/II Study of Nivolumab and Ipilimumab Combined ... The main purpose of this study is to see if the combination of nivolumab, ipilimumab and nintedanib is effective in people with non- small cell lung cancer.

2. opdivohcp.com opdivohcp.com/efficacy/nsclc

Efficacy Data for Non-Small Cell Lung Cancer (NSCLC) - Opdivo Find OPDIVO® (nivolumab) efficacy information for the treatment of non-small cell lung cancers. Please see Indications and Important Safety Information.

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.9102

The final analysis of a phase I/II study of nivolumab ... The combination of nivolumab, ipilimumab and nintedanib had a manageable toxicity profile and demonstrated promising antitumor activity in both TN and IP ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9937094/

Five-Year Survival Outcomes With Nivolumab Plus Ipilimumab ... Patients with metastatic non–small-cell lung cancer (mNSCLC) have historically had a 5-year survival rate of only 7%, but more recently, immune check point ...

5. opdivohcp.com opdivohcp.com/efficacy/nsclc/opdivo-yervoy

OPDIVO® (nivolumab) + YERVOY® (ipilimumab) Efficacy ... Five-year survival outcomes with nivolumab plus ipilimumab versus chemotherapy as first-line treatment for metastatic non-small cell lung cancer in CheckMate ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5933620/

Nivolumab in the treatment of metastatic squamous non- ... The ICIs have been shown to be effective in a range of hematological and solid tumors, including melanomas, non-small cell lung cancer (NSCLC), renal cell ...

7. jto.org jto.org/article/S1556-0864(21)02599-5/fulltext

MA13.02 Phase II Study of Nivolumab and Ipilimumab ... The combination of nivolumab, ipilimumab and nintedanib was well tolerated and demonstrated antitumor activity despite tumor progression on prior ICI therapy.