Triple Immunotherapy for Advanced Cancer

Recruiting at 21 trial locations

Overseen By Incyte Corporation Call Center (US)

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Incyte Corporation

Must not be taking: LAG-3, TIM-3 agents

Disqualifiers: Autoimmune disease, Active infections, HIV, others

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

Compensation: Varies

Number of Visits: 16

61 Participants Needed

Trial Summary

What is the purpose of this trial?

The study will determine Recommended Phase 2 Dose for all study drugs, based on the safety and tolerability of the following combinations: INCAGN02385 + INCAGN02390 and INCAGN02385 + INCAGN02390 + INCMGA00012.

Will I have to stop taking my current medications?

The trial requires that participants stop taking anticancer medications or investigational drugs within certain timeframes before starting the study treatment. Specifically, you must stop these medications at least 28 days or 5 half-lives (whichever is longer) before the first dose. Other medications, like systemic corticosteroids and antibiotics, also have specific restrictions.

What data supports the effectiveness of the drug Retifanlimab in the treatment of advanced cancer?

Retifanlimab has shown effectiveness in treating Merkel cell carcinoma, a type of skin cancer, by blocking a protein that helps cancer cells hide from the immune system. This suggests it might also help in treating other advanced cancers when used in combination with other drugs. ^{1 2 3 4 5}

What safety data exists for Retifanlimab (Zynyz) in humans?

Retifanlimab, also known as Zynyz, has been approved for treating a type of skin cancer called Merkel cell carcinoma. While specific safety data for triple immunotherapy isn't provided, Retifanlimab is a type of immunotherapy, and similar treatments can cause immune-related side effects, which are often manageable with early diagnosis and treatment. ^{2 6 7 8 9}

How is the drug Retifanlimab unique for treating advanced cancer?

Retifanlimab is unique because it is a programmed cell death 1 receptor-blocking antibody that has been developed for treating solid tumors, both alone and in combination with other agents, and it recently received accelerated approval for treating Merkel cell carcinoma, highlighting its potential in advanced cancer therapy. ^{2 5 10 11 12}

Eligibility Criteria

This trial is for adults with advanced solid tumors that have not responded to standard treatments or who cannot tolerate them. It includes those with untreated metastatic melanoma (Cohort B) and those whose melanoma failed anti-PD-(L)1 therapy (Cohort A). Participants must be in good physical condition, willing to prevent pregnancy, and have no history of severe reactions to the study drugs.

Inclusion Criteria

My cancer has spread, and standard treatments or immunotherapy haven't worked or aren't suitable for me.

My melanoma cannot be surgically removed and didn't respond to previous anti-PD-(L)1 therapy.

I have melanoma that has not been treated and cannot be surgically removed.

Exclusion Criteria

I haven't taken any cancer drugs or experimental medications recently.

I have an active hepatitis B or C infection.

You have been diagnosed with HIV.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Treatment

Participants receive combination therapy to confirm safety of INCAGN02385 + INCAGN02390 and INCAGN02385 + INCAGN02390 + INCMGA00012

Approximately 24 months

Every 8 weeks for first 12 months, and every 12 weeks thereafter

Phase 2 Treatment

Participants receive combination therapy to determine preliminary efficacy and proof of concept for the combination of INCAGN02385 + INCAGN02390 + INCMGA00012

Approximately 24 months

Every 8 weeks for first 12 months, and every 12 weeks thereafter

Follow-up

Participants are monitored for safety and effectiveness after treatment

28 days after end of study

Treatment Details

Interventions

• INCAGN02385
• INCAGN02390
• INCMGA00012

Trial Overview The trial is testing combinations of three drugs: INCMGA00012 (Anti-PD-1), INCAGN02385 (Anti-LAG-3), and INCAGN02390 (Anti-TIM-3). The goal is to find the safest and most tolerable doses for these drug combinations in treating select advanced cancers.

Participant Groups

Group I: Phase 2 Cohort B Experimental Treatment 3 Interventions

Phase 2 will determine preliminary efficacy and proof of concept for the combination of INCAGN02385 + INCAGN02390 + INCMGA00012. INCAGN02385 will be administered first intravenously followed by INCAGN02390 and INCMGA00012

Group II: Phase 2 Cohort A Experimental Treatment 3 Interventions

Phase 2 will determine preliminary efficacy and proof of concept for the combination of INCAGN02385 + INCAGN02390 + INCMGA00012. INCAGN02385 will be administered first intravenously followed by INCAGN02390 and INCMGA00012

Group III: Phase 1 Part 4 Experimental Treatment 3 Interventions

Part 1 will confirm the safety of INCAGN02385 + INCAGN02390 + INCMGA00012 in combination.

Group IV: Phase 1 Part 3 Experimental Treatment 3 Interventions

Part 1 will confirm the safety of INCAGN02385 + INCAGN02390 + INCMGA00012 when used in combination.

Group V: Phase 1 Part 2 Experimental Treatment 3 Interventions

Part 2 will confirm the safety of the triple combination of INCAGN02385 + INCAGN02390 + INCMGA00012, following confirmation of the safety of the doublet in Part 1. INCAGN02385 will be administered first intravenously followed by INCAGN02390 and INCMGA00012.

Group VI: Phase 1 Part 1 Experimental Treatment 2 Interventions

Part 1 will confirm the safety of INCAGN02385 and INCAGN02390 when used in combination. INCAGN02385 will be administered first intravenously followed by INCAGN02390.

Who Is Running the Clinical Trial?

Incyte Corporation

Lead Sponsor

Trials

408

Recruited

66,800+

Steven Stein

Incyte Corporation

Chief Medical Officer since 2015

MD from University of Witwatersrand

Hervé Hoppenot

Incyte Corporation

Chief Executive Officer since 2014

MBA from ESSEC Business School

Findings from Research

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]

Retifanlimab is a programmed cell death 1 (PD-1) receptor-blocking antibody developed for treating solid tumors, showing promise both alone and in combination with other therapies.

It has received accelerated approval for adults with metastatic or recurrent locally advanced Merkel cell carcinoma, marking a significant milestone in its development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retifanlimab: First Approval. Kang, C.[2023]

Relatlimab, when used in combination with nivolumab, is an approved first-line treatment for metastatic or unresectable melanoma, enhancing the immune response against cancer cells.

The review highlights the mechanism of action and safety profile of this combination therapy, emphasizing its clinical efficacy based on recent studies and ongoing trials, making it a significant option for dermatologists treating melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relatlimab-nivolumab: A practical overview for dermatologists. Mullick, N., Nambudiri, VE.[2023]

In a phase III trial, the combination of the LAG3 immune checkpoint inhibitor relatlimab with the PD-1 inhibitor nivolumab significantly improved progression-free survival for melanoma patients, more than doubling the time without disease progression.

The combination therapy was associated with relatively manageable side effects, suggesting it could be a safe and effective addition to current melanoma treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

LAG3-PD-1 Combo Impresses in Melanoma. [2021]

The combination of lenvatinib, a multikinase inhibitor, and pembrolizumab, a PD-1 inhibitor, shows promising antitumor activity and durable responses in various solid tumors, as indicated by preliminary results from the LEAP clinical trial program.

This combination therapy has a manageable safety profile, suggesting it could be a valuable new treatment option for solid cancers that currently have limited therapeutic alternatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The LEAP program: lenvatinib plus pembrolizumab for the treatment of advanced solid tumors. Taylor, MH., Schmidt, EV., Dutcus, C., et al.[2021]

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]

Nivolumab, administered at 3 mg/kg with or without a peptide vaccine, was well tolerated and demonstrated a 25% response rate in patients with advanced melanoma, regardless of prior ipilimumab treatment.

The study suggests that nivolumab can induce long-lasting responses, with some patients responding for up to 140 weeks, and highlights the potential for combining or sequencing nivolumab with ipilimumab for better treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. Weber, JS., Kudchadkar, RR., Yu, B., et al.[2022]

Axitinib combined with immune checkpoint inhibitors (ICI) like pembrolizumab or avelumab is now approved for treating advanced renal cell carcinoma, but distinguishing between adverse events (AEs) caused by each treatment is crucial for optimizing therapy.

Experts identified specific AEs such as diarrhea, hepatic toxicity, fatigue, and cardiovascular issues that require unique management strategies when using axitinib-ICI combinations, emphasizing the need for careful clinical monitoring and tailored treatment approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Axitinib plus immune checkpoint inhibitor: evidence- and expert-based consensus recommendation for treatment optimisation and management of related adverse events. Grünwald, V., Voss, MH., Rini, BI., et al.[2021]

The combination of ramucirumab and durvalumab was found to have manageable safety, with grade ≥3 treatment-related adverse events occurring in 32.1% of NSCLC, 37.9% of gastric/GEJ, and 42.9% of HCC patients, indicating that while there are risks, they are within acceptable limits for further study.

The treatment showed preliminary efficacy with an objective response rate of 11% for NSCLC and HCC, and 21% for gastric/GEJ, with better outcomes observed in patients with high PD-L1 expression, suggesting that this combination may be particularly beneficial for certain patient populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ramucirumab and durvalumab for previously treated, advanced non-small-cell lung cancer, gastric/gastro-oesophageal junction adenocarcinoma, or hepatocellular carcinoma: An open-label, phase Ia/b study (JVDJ). Bang, YJ., Golan, T., Dahan, L., et al.[2023]

In a clinical trial involving 55 patients with advanced solid tumors, the PD-1 inhibitor dostarlimab was found to be well tolerated in both doublet and triplet combination therapies, with no new safety concerns arising.

The triplet combinations showed higher disease control rates compared to doublets, with preliminary antitumor activity observed in various combinations, indicating potential for improved efficacy in treating advanced cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

IOLite: phase 1b trial of doublet/triplet combinations of dostarlimab with niraparib, carboplatin-paclitaxel, with or without bevacizumab in patients with advanced cancer. Yap, TA., Bessudo, A., Hamilton, E., et al.[2022]

In a phase 2 trial involving 142 patients with untreated advanced melanoma, the combination of nivolumab and ipilimumab resulted in a 2-year overall survival rate of 63.8%, compared to 53.6% for those receiving ipilimumab alone, suggesting improved survival outcomes with the combination therapy.

However, the combination treatment was associated with a higher incidence of severe side effects, with 54% of patients experiencing grade 3-4 adverse events compared to 20% in the ipilimumab-only group, indicating a trade-off between efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Hodi, FS., Chesney, J., Pavlick, AC., et al.[2022]

References

1. England 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. [2022]

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

Retifanlimab: First Approval. [2023]

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

Relatlimab-nivolumab: A practical overview for dermatologists. [2023]

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

LAG3-PD-1 Combo Impresses in Melanoma. [2021]

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

The LEAP program: lenvatinib plus pembrolizumab for the treatment of advanced solid tumors. [2021]

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

Emerging options for the treatment of melanoma - focus on ipilimumab. [2020]

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

Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. [2022]

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

Axitinib plus immune checkpoint inhibitor: evidence- and expert-based consensus recommendation for treatment optimisation and management of related adverse events. [2021]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Vemurafenib Induced Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): A Disproportionality Analysis in FAERS Database. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Ramucirumab and durvalumab for previously treated, advanced non-small-cell lung cancer, gastric/gastro-oesophageal junction adenocarcinoma, or hepatocellular carcinoma: An open-label, phase Ia/b study (JVDJ). [2023]

11. England pubmed.ncbi.nlm.nih.gov

IOLite: phase 1b trial of doublet/triplet combinations of dostarlimab with niraparib, carboplatin-paclitaxel, with or without bevacizumab in patients with advanced cancer. [2022]

12. England pubmed.ncbi.nlm.nih.gov

Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. [2022]