Combination Immunotherapy + VSV-IFNβ-NIS for Solid Tumors

Recruiting in Palo Alto (17 mi)

+1 other location

Overseen by Alex Adjei, MD, PhD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Vyriad, Inc.

Must not be taking: Corticosteroids, Chemotherapy

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

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial tests a combination of a virus-based therapy and an immune-boosting drug for patients with hard-to-treat cancers. The treatment works by making cancer cells more visible to the immune system and keeping the immune system active against them.

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.

What data supports the effectiveness of the drug pembrolizumab in treating solid tumors?

Pembrolizumab has shown effectiveness in treating various solid tumors, including non-small-cell lung cancer and melanoma, by improving survival rates and reducing recurrence when used alone or in combination with other therapies. ^{1 2 3 4 5}

Is the combination immunotherapy with Pembrolizumab generally safe for humans?

Pembrolizumab, used in cancer treatment, can cause side effects like pneumonitis (lung inflammation) in 1%-5% of patients and rare cases of type 1 diabetes. Common side effects include fatigue, cough, and nausea, while immune-related issues can affect the lungs, liver, and thyroid. ^{1 6 7 8 9}

What makes the combination immunotherapy with Pembrolizumab and VSV-IFNβ-NIS unique for treating solid tumors?

This treatment is unique because it combines Pembrolizumab, a PD-1 inhibitor that helps the immune system attack cancer cells, with VSV-IFNβ-NIS, a virus engineered to selectively infect and kill cancer cells while sparing normal cells. This dual approach aims to enhance the immune response against tumors more effectively than using Pembrolizumab alone. ^{1 4 9 10 11}

Research Team

Patrick McGarrah, MD

Principal Investigator

Mayo Clinic

Alex Adjei, MD, PhD

Principal Investigator

The Cleveland Clinic

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Pembrolizumab (Checkpoint Inhibitor)
• VSV-IFNβ-NIS (Virus Therapy)

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.

Participant Groups

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.

Who Is Running the Clinical Trial?

Vyriad, Inc.

Lead Sponsor

Trials

6

Recruited

290+

Mayo Clinic

Collaborator

Trials

3,427

Recruited

3,221,000+

Dr. Gianrico Farrugia

Mayo Clinic

Chief Executive Officer since 2019

MD from University of Malta Medical School

Dr. Richard Afable

Mayo Clinic

Chief Medical Officer

MD from Loyola Stritch School of Medicine

Findings from Research

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]

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]

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]

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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. [2017]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Prior Therapy With Pegylated-Interferon Alfa-2b Improves the Efficacy of Adjuvant Pembrolizumab in Resectable Advanced Melanoma. [2021]

3. England pubmed.ncbi.nlm.nih.gov

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

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

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

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

New developments in the management of advanced melanoma - role of pembrolizumab. [2020]

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

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. [2022]

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

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. [2021]

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

FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. [2023]

10. China 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. [2022]

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

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