Combination Immunotherapy + VSV-IFNβ-NIS for Solid Tumors

Not currently recruiting at 1 trial location

Overseen By Lihong He

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Vyriad, Inc.

Must not be taking: Corticosteroids, Chemotherapy

Disqualifiers: EGFR mutations, ALK translocations, Serious infection, 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: 2

Duration: Up to 2 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments for individuals with certain solid tumors unresponsive to previous therapies. The focus is on combining a virus-based treatment, VSV-IFNβ-NIS, with pembrolizumab (also known as KEYTRUDA, an immune checkpoint inhibitor) to determine if it safely combats cancer in conditions like non-small cell lung cancer (NSCLC) and neuroendocrine carcinoma (NEC). Participants should have a type of solid tumor that has continued to grow despite treatment with PD-1/PD-L1 inhibitors, a form of immune therapy. The study aims to identify the safest and most effective dose of this new treatment combination. As a Phase 1 trial, the research seeks to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, it mentions that prior therapies like chemotherapy or immunotherapy should not have been received within a certain timeframe before starting the study treatment. It's best to discuss your specific medications with the trial team.

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

Research has shown that the combination of VSV-IFNβ-NIS and pembrolizumab has generally been well-tolerated in past studies. Patients safely received doses up to 1.7 × 10¹¹ TCID50, suggesting that the treatment might be well-tolerated at the doses used in this study.

Pembrolizumab is an approved medication for several cancers, including non-small cell lung cancer (NSCLC), supporting its safety. It has been widely studied and is generally considered safe, though it can cause some immune-related side effects.

For the combination of VSV-IFNβ-NIS with ipilimumab and nivolumab, research indicates that this mix can be used safely, as shown in several studies. Nivolumab and ipilimumab are also approved treatments with established safety records, though they can cause immune-related side effects.

In summary, both treatment combinations in this trial have shown promising safety profiles in past research. However, participants might still experience some side effects, as with any medical treatment. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine innovative viral therapy with existing immunotherapy strategies. VSV-IFNβ-NIS is a genetically engineered virus that can selectively infect and destroy cancer cells while boosting the immune response with interferon beta. When used alongside pembrolizumab, ipilimumab, or nivolumab, which are known checkpoint inhibitors, this combination has the potential to enhance the body's ability to recognize and attack cancer cells. This approach is distinct from standard treatments that primarily focus on either chemotherapy or single-agent immunotherapy, offering a promising new avenue for tackling difficult-to-treat cancers like neuroendocrine carcinoma, non-small cell lung cancer, and renal cell carcinoma.

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

Studies have shown that pembrolizumab, a drug that boosts the immune system, can help treat certain cancers by enabling the body to attack cancer cells more effectively. However, some cancers, such as non-small cell lung cancer (NSCLC) and neuroendocrine carcinoma (NEC), may not respond well to pembrolizumab alone. In this trial, some participants will receive a combination of pembrolizumab with VSV-IFNβ-NIS, a virus designed to enhance the immune system's ability to fight cancer, which might prove more effective. Early findings suggest that this combination could be more effective, particularly for cancers that are difficult to treat with pembrolizumab alone. For kidney cancer, another arm of this trial will combine VSV-IFNβ-NIS with ipilimumab and nivolumab, two other immune-boosting drugs, which has shown promise in early studies. This approach could offer new hope for treating these challenging cancers. ^{1 2 6 7 8}

Who Is on the Research Team?

Alex Adjei, MD, PhD

Principal Investigator

The Cleveland Clinic

Patrick McGarrah, MD

Principal Investigator

Mayo Clinic

Are You a Good Fit for This Trial?

This trial is for adults with advanced or metastatic non-small cell lung cancer (NSCLC) or neuroendocrine carcinoma (NEC) that worsened on PD-1/PD-L1 inhibitor therapy. They should have a life expectancy over 3 months, no active brain cancer involvement, good organ function, and be willing to provide tissue samples. Pregnant women, those with certain autoimmune diseases or unresolved treatment toxicities, and individuals with other serious health risks are excluded.

Inclusion Criteria

You are expected to live for more than 3 months without receiving cancer treatment.

Willingness to provide biological samples required for the duration of the study including a fresh tumor biopsy sample

You have been diagnosed with advanced or metastatic lung cancer that has not responded to treatment with a specific kind of medication.

Exclusion Criteria

You have had a lung condition that needed steroids in the past, or you currently have a lung condition.

You have a serious autoimmune disease that is currently active and could harm your organs.

Your disease is in an advanced stage, as confirmed by medical tests and markers.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Safety Run-in/Dose Escalation

Safety run-in to identify the optimal dose of VSV-IFNβ-NIS in combination with pembrolizumab, following a 3+3 design

21 days

1 visit (in-person) every 21 days

Treatment

Participants receive VSV-IFNβ-NIS in combination with checkpoint inhibitors, with efficacy evaluations every 9 weeks

Up to 2 years

1 visit (in-person) every 21 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

What Are the Treatments Tested in This Trial?

Interventions

• Pembrolizumab
• VSV-IFNβ-NIS

Trial Overview

The study tests different doses of VSV-IFNβ-NIS combined with pembrolizumab to find the safest and most effective dose for treating solid tumors including NSCLC and NEC. It starts by testing safety in small groups using a '3+3 design' before expanding to more patients once the optimal dose is found.

How Is the Trial Designed?

Group I: Safety Run-in Dose Level 2 Experimental Treatment 2 Interventions

Patients with pembrolizumab refractory Neuroendocrine Carcinoma (NEC) or non small cell lung cancer (NSCLC) will receive a single IV dose of 1.0e11 TCID50 VSV-IFNβ-NIS in combination with Pembrolizumab at standard labeled dose administered on day 8, then every 21 days, up to 2 years.

Group II: Safety Run-in Dose Level 1 Experimental Treatment 2 Interventions

Patients with pembrolizumab refractory solid tumors will receive a single IV dose of 5e10 TCID50 VSV-IFNβ-NIS in combination with Pembrolizumab at standard labeled dose administered on day 1, then every 21 days, up to 2 years.

Group III: Expansion Renal Cell Carcinoma (RCC) Part E Experimental Treatment 2 Interventions

Arm Description: Renal Cell Carcinoma (RCC) will receive a single IV dose of VSV-IFNβ-NIS on Day 4 in combination with ipilumumab + nivolumab at standard labeled dose administered on Day 1 then every 21 days for a total of 4 Cycles. Nivo Single agent will be administered every 28 days starting with Cycle 5 for a total treatment period of up to 2 years.

Group IV: Expansion Part D Experimental Treatment 2 Interventions

Patients with non small cell lung cancer (NSCLC) or Neuroendocrine Carcinoma (NEC) will receive a single IV dose of VSV-IFNβ-NIS on Day 4 in combination with ipilumumab + nivolumab at standard labeled dose administered on Day 1 then every 21 days up to 2 years.

Group V: Expansion NSCLC arm Experimental Treatment 2 Interventions

Patients with pembrolizumab refractory non small cell lung cancer (NSCLC) will receive a single IV dose of 1.0e11 TCID50 VSV-IFNβ-NIS in combination with Pembrolizumab at standard labeled dose administered on day 8, then every 21 days, up to 2 years.

Group VI: Expansion NEC Experimental Treatment 2 Interventions

Patients with pembrolizumab refractory Neuroendocrine Carcinoma (NEC) will receive a single IV dose of 1.0e11 TCID50 VSV-IFNβ-NIS in combination with Pembrolizumab at standard labeled dose administered on day 8, then every 21 days, up to 2 years.

Pembrolizumab is already approved in United States, European Union, United Kingdom for the following indications:

Approved in United States as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in European Union as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in United Kingdom as KEYTRUDA for:

• Untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1

Who Is Running the Clinical Trial?

Vyriad, Inc.

Lead Sponsor

Trials

6

Recruited

290+

Mayo Clinic

Collaborator

Trials

3,427

Recruited

3,221,000+

Published Research Related to This Trial

Pembrolizumab, a PD-1 inhibitor, has demonstrated clinical effectiveness in treating various solid tumors, particularly in patients with PD-L1-positive non-small-cell lung cancer and unresectable/metastatic melanoma.

Early-phase trials and ongoing studies are focused on further confirming the clinical benefits of pembrolizumab in thoracic malignancies, highlighting its potential as a significant treatment option in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. Karim, S., Leighl, N.[2017]

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]

In a study of 24 patients with advanced non-small cell lung cancer (NSCLC) treated with pembrolizumab, the objective response rate was 45.8%, indicating that nearly half of the patients experienced a reduction in tumor size after treatment.

Pembrolizumab showed promising results even in PD-L1-negative patients, with a major pathological response of 75% and a pathological complete response of 50% in those who underwent surgery, suggesting its potential effectiveness across different patient profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of pembrolizumab for the treatment of advanced non-small cell lung cancer: a retrospective, single-centre, single-arm study. Guo, T., Ding, Y., Chen, L., et al.[2022]

The combination of vibostolimab and pembrolizumab is well tolerated by patients, indicating a favorable safety profile for this treatment regimen.

This combination therapy demonstrates antitumor activity, suggesting it may be an effective option for cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An Anti-TIGIT Antibody with a PD-1 Inhibitor Shows Promise in Solid Tumors. [2022]

Pembrolizumab, an immune checkpoint inhibitor, can cause pneumonitis in 1%-5% of patients, and this case report highlights an atypical presentation of this side effect in a patient with metastatic squamous cell carcinoma.

The patient was successfully treated with steroid therapy after ruling out other potential causes, leading to complete resolution of the pneumonitis, emphasizing the importance of recognizing and managing atypical cases of checkpoint inhibitor-pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. Jeon, WJ., Nguyen, J., Castillo, DR., et al.[2023]

Pembrolizumab, a PD-1 inhibitor used in cancer treatment, can lead to rare but serious immune-related adverse events, including type 1 diabetes mellitus, occurring in about 0.2% of cases.

A review of 42 cases revealed that patients may develop diabetic ketoacidosis during treatment, highlighting the need for blood glucose monitoring and awareness of this potential side effect among clinicians.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. Clotman, K., Janssens, K., Specenier, P., et al.[2022]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating advanced melanoma, showing an overall response rate of 24% in a trial of 89 patients, with 86% of responses lasting at least 6 months.

While there are potential immune-mediated side effects, the benefits of prolonged tumor response durations were deemed to outweigh these risks, marking an improvement over existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. Chuk, MK., Chang, JT., Theoret, MR., et al.[2021]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating unresectable or metastatic melanoma based on two clinical trials involving 1,374 patients, showing significant improvements in overall survival compared to ipilimumab, with hazard ratios indicating a reduced risk of death.

Patients receiving pembrolizumab also experienced significant improvements in progression-free survival, although some immune-mediated adverse reactions like hypothyroidism and pneumonitis were noted, highlighting the importance of monitoring for side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma. Barone, A., Hazarika, M., Theoret, MR., et al.[2022]

In a study of 56 melanoma patients, those who received prior treatment with pegylated interferon alpha (PEG-IFN-α) showed significantly improved efficacy from subsequent adjuvant pembrolizumab therapy, with a hazard ratio of 0.37 indicating a lower risk of recurrence.

Patients treated with prior PEG-IFN-α had a longer recurrence-free survival (RFS) of 8.5 months compared to 4.5 months for those without prior treatment, suggesting that PEG-IFN-α enhances the effectiveness of PD-1 blockade in melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prior Therapy With Pegylated-Interferon Alfa-2b Improves the Efficacy of Adjuvant Pembrolizumab in Resectable Advanced Melanoma. Jia, DD., Niu, Y., Zhu, H., et al.[2021]

Pembrolizumab, an immunotherapy for advanced non-small-cell lung cancer (NSCLC), significantly improves progression-free and overall survival compared to traditional chemotherapy, with fewer side effects, particularly in patients with high PD-L1 expression (≥50%).

In combination with pemetrexed and carboplatin, pembrolizumab also enhances treatment effectiveness and maintains manageable toxicity, leading to a shift in first-line treatment strategies for advanced NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab as first-line therapy for metastatic non-small-cell lung cancer. Reck, M.[2018]

Pembrolizumab is a monoclonal antibody that blocks the PD-1/PD-L1 interaction, which is crucial for preventing the immune system from attacking tumors, making it a key player in cancer immunotherapy.

It has been approved by the FDA for treating patients with advanced melanoma who have not responded to previous treatments, highlighting its efficacy in managing difficult cases of this aggressive cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New developments in the management of advanced melanoma - role of pembrolizumab. Improta, G., Leone, I., Donia, M., et al.[2020]

Citations

1.

clinicaltrials.gov

clinicaltrials.gov/study/NCT03647163

NCT03647163 | Ph I/II Trial of Systemic VSV-IFNβ-NIS in ...

Patients with pembrolizumab refractory non small cell lung cancer (NSCLC) will receive a single IV dose of 1.0e11 TCID50 VSV-IFNβ-NIS in combination with ...

2.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/40157574/

the phase III 3475A-D77 trial

Subcutaneous versus intravenous pembrolizumab, in combination with chemotherapy, for treatment of metastatic non-small-cell lung cancer: the phase III 3475A-D77 ...

3.

trialx.com

trialx.com/clinical-trials/listings/264052/ph-iii-trial-of-systemic-vsv-ifn-nis-in-combination-with-checkpoint-inhibitor-therapy-in-patients-with-select-solid-tumors/?&geo_lat=41.4847&geo_lng=-81.8018&radius=10&place=Lakewood&user_country=United%20States

Ph I/II Trial of Systemic VSV-IFNβ-NIS in Combination With ...

The safety run-in portion of this study is designed to identify the optimal dose of VSV-IFNβ-NIS in combination with pembrolizumab in patients ...

4.

clinicaltrials.gov

clinicaltrials.gov/study/NCT02142738

NCT02142738 | Study of Pembrolizumab (MK-3475) ...

This is a study to assess the efficacy and safety of pembrolizumab (MK-3475/SCH 900475) compared to standard of care (SOC) platinum-based chemotherapies.

5.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC10338510/

PMC - PubMed Central

Treatment with pembrolizumab alone and pembrolizumab plus chemotherapy was ineffective in advanced, progressive EP-PDNECs. Clinical trial ...

6.

clinicaltrials.gov

clinicaltrials.gov/study/NCT02142738

NCT02142738 | Study of Pembrolizumab (MK-3475) ...

This is a study to assess the efficacy and safety of pembrolizumab (MK-3475/SCH 900475) compared to standard of care (SOC) platinum-based chemotherapies.

7.

ascopubs.org

ascopubs.org/doi/10.1200/JCO.2023.41.4_suppl.TPS657

Phase 1/2 trial of vesicular stomatitis virus expressing ...

This is a phase 1-2 safety run-in study designed to determine the safety of VSV-IFNβ-NIS in combination with a single agent ICI, pembrolizumab, followed by ...

8.

withpower.com

withpower.com/trial/phase-2-squamous-cell-carcinoma-of-head-and-neck-3-2019-61393

Combination Immunotherapy + VSV-IFNβ-NIS for Solid ...

Pembrolizumab has shown effectiveness in treating various solid tumors, including non-small-cell lung cancer and melanoma, by improving survival rates and ...