Pembrolizumab + sEphB4 for Cancer

Overseen By Jon Cogan, MS

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Vasgene Therapeutics, Inc

Must be taking: Pembrolizumab

Must not be taking: Immunosuppressants, Steroids

Disqualifiers: HIV, Hepatitis, Active TB, 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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 9

Duration: Ongoing as long as participants respond and remain clinically stable

38 Participants Needed

Trial Summary

What is the purpose of this trial?

sEphB-HSA may prevent tumor cells from multiplying and blocks several compounds that promote the growth of blood vessels that bring nutrients to the tumor. The purpose of this study is to evaluate the combination of Pembrolizumab + sEphB4-HSA in the population of patients with previously untreated advanced (metastatic or recurrent) urothelial carcinoma who are chemotherapy ineligible or who refuse chemotherapy.

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, if you are on systemic steroid therapy or other immunosuppressive treatments, you must stop them at least 7 days before starting the trial.

What data supports the effectiveness of the drug Pembrolizumab + sEphB4-HSA for cancer?

Pembrolizumab, a part of the treatment, has shown effectiveness in improving survival and response rates in various cancers, such as non-small-cell lung cancer and melanoma, when used in combination with other drugs. This suggests potential benefits when combined with sEphB4-HSA, although specific data for this combination is not available. ^{1 2 3 4 5}

Is Pembrolizumab + sEphB4 generally safe for humans?

Immune checkpoint inhibitors like Pembrolizumab are generally well tolerated, but more than 80% of patients may experience immune-related side effects, which can include joint and muscle issues. ^{6 7 8 9 10}

What makes the drug Pembrolizumab + sEphB4-HSA unique for cancer treatment?

Pembrolizumab + sEphB4-HSA is unique because it combines an immune checkpoint inhibitor (Pembrolizumab) that helps the immune system attack cancer cells with sEphB4-HSA, which may target specific pathways involved in cancer growth. This combination could offer a novel approach compared to standard treatments that typically involve chemotherapy or single-agent immunotherapy. ^{1 4 11 12 13}

Research Team

Sarmad Sadeghi, MD

Principal Investigator

University of Southern California

Eligibility Criteria

This trial is for adults with advanced urothelial carcinoma who haven't been treated yet and can't have or don't want chemotherapy. They should be in good health overall, able to consent, and not have certain other medical conditions like active brain metastases, immune deficiencies, uncontrolled high blood pressure, or recent live vaccines.

Inclusion Criteria

My cancer can be measured and tracked using scans.

Be willing and able to provide written informed consent/assent for the trial

I am fully active or restricted in physically strenuous activity but can do light work.

Exclusion Criteria

Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment

I have a history of active tuberculosis.

I have been diagnosed with HIV.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Pembrolizumab + sEphB4-HSA through intravenous infusion. Pembrolizumab is administered on Day 1 of each 3-week cycle, and sEphB4-HSA is administered on Day 1, 8, and 15 of each 3-week cycle.

Ongoing as long as participants respond and remain clinically stable

3 visits per 3-week cycle (in-person)

Safety Follow-up

Participants are monitored for safety 30 days after the last dose of treatment.

30 days

Follow-up

Participants are monitored for progression-free survival and overall survival every 6 weeks, and survival follow-up every 12 weeks.

Average of 60 months

Every 6 weeks (follow-up), every 12 weeks (survival follow-up)

Treatment Details

Interventions

• Pembrolizumab + sEphB4-HSA

Trial Overview The study tests a combination of Pembrolizumab (an immunotherapy drug) and sEphB4-HSA (a protein that may stop tumor growth), focusing on patients with untreated advanced urothelial carcinoma ineligible for or refusing chemotherapy.

Participant Groups

Group I: Combination Therapy Experimental Treatment 1 Intervention

All study participants will receive Pembrolizumab + sEphB4-HSA through a needle in a vein in their arm for an hour in an outpatient clinic. Pembrolizumab will be given at Day 1 of each 3 week cycle. The study drug (sEphB4-HSA) will be given at Day 1, 8, and 15 of each 3 week cycle.

Pembrolizumab + sEphB4-HSA is already approved in United States, European Union for the following indications:

Approved in United States as Pembrolizumab for:

• Melanoma
• Non-small cell lung cancer
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Gastric cancer
• Esophageal cancer
• Cervical cancer
• Endometrial cancer

Approved in European Union as Pembrolizumab for:

• Melanoma
• Non-small cell lung cancer
• Urothelial carcinoma
• Head and neck squamous cell carcinoma
• Renal cell carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Gastric cancer
• Esophageal cancer
• Cervical cancer
• Endometrial cancer

Who Is Running the Clinical Trial?

Vasgene Therapeutics, Inc

Lead Sponsor

Trials

9

Recruited

1,000+

Findings from Research

In the KEYNOTE-189 study involving 616 patients with metastatic non-squamous non-small-cell lung cancer, the combination of pembrolizumab and pemetrexed-platinum significantly maintained quality of life (GHS/QOL) scores compared to placebo, with a notable improvement at week 21.

Patients receiving pembrolizumab also experienced a longer median time to deterioration in symptoms like cough and chest pain, although this result was not statistically significant, indicating potential benefits in symptom management with this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-reported outcomes following pembrolizumab or placebo plus pemetrexed and platinum in patients with previously untreated, metastatic, non-squamous non-small-cell lung cancer (KEYNOTE-189): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Garassino, MC., Gadgeel, S., Esteban, E., et al.[2020]

In the KEYNOTE-407 study involving 1107 patients with untreated metastatic squamous non-small-cell lung cancer, the addition of pembrolizumab to chemotherapy significantly improved overall survival and quality of life without increasing severe toxicity.

Patients receiving pembrolizumab reported better health-related quality of life scores at weeks 9 and 18 compared to those receiving placebo, indicating that pembrolizumab enhances patient well-being while maintaining effective cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health-Related Quality of Life With Carboplatin-Paclitaxel or nab-Paclitaxel With or Without Pembrolizumab in Patients With Metastatic Squamous Non-Small-Cell Lung Cancer. Mazieres, J., Kowalski, D., Luft, A., et al.[2020]

The first-in-human study of MK-4830, a novel IgG4 monoclonal antibody targeting the ILT4 receptor, showed it was well tolerated with no dose-limiting toxicities among 84 patients with advanced solid tumors.

In combination with pembrolizumab, MK-4830 demonstrated promising antitumor activity, with 11 out of 34 patients achieving objective responses, including some who had previously progressed on other therapies, suggesting enhanced effectiveness in certain tumor microenvironments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-in-Class Anti-immunoglobulin-like Transcript 4 Myeloid-Specific Antibody MK-4830 Abrogates a PD-1 Resistance Mechanism in Patients with Advanced Solid Tumors. Siu, LL., Wang, D., Hilton, J., 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 is a monoclonal antibody that effectively blocks the PD-1 receptor on T cells, enhancing their ability to attack cancer cells, particularly in melanoma patients.

In a Phase I study involving 411 patients, pembrolizumab demonstrated high durable response rates with minimal toxicity, indicating its potential as a safe and effective treatment option for melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab joins the anti-PD-1 armamentarium in the treatment of melanoma. Hersey, P., Gowrishankar, K.[2017]

In a study analyzing data from 1,524 patients with spondylarthritis (SpA) and 4,006 with rheumatoid arthritis (RA), TNF antagonists showed significantly better drug survival rates in SpA, with a hazard ratio of 0.66 indicating lower discontinuation rates compared to RA.

Patients with SpA experienced fewer adverse events (17%) compared to those with RA (26%), suggesting a better safety profile for TNF antagonists in treating SpA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Survival of TNF antagonists in spondylarthritis is better than in rheumatoid arthritis. Data from the Spanish registry BIOBADASER. Carmona, L., Gómez-Reino, JJ.[2022]

The study involving 298 healthy subjects demonstrated that the pharmacokinetic (PK) profiles of the candidate biosimilar AVT04 are similar to those of the reference products (RP) ustekinumab, with all primary PK parameters meeting the bioequivalence criteria.

Safety and immunogenicity profiles were comparable among AVT04 and both EU- and US-approved ustekinumab, indicating that AVT04 is a safe alternative, although the study was not designed to detect minor differences.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized, double-blind, 3-arm, parallel study assessing the pharmacokinetics, safety, tolerability and immunogenicity of AVT04, an ustekinumab candidate biosimilar, in healthy adults. Wynne, C., Hamilton, P., McLendon, K., et al.[2023]

Immune checkpoint inhibitors, while generally well tolerated, can lead to immune-related adverse events in over 80% of patients, including rheumatic and musculoskeletal issues that are not well characterized.

In a case study of a patient with psoriatic arthritis, treatment with apremilast, a small oral molecule that inhibits phosphodiesterase 4, was explored, highlighting a potential therapeutic option for managing this challenging condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Psoriatic arthritis induced by anti-PD1 and treated with apremilast: a case report and review of the literature. Nigro, O., Pinotti, G., Gueli, R., et al.[2021]

In a systematic review of 10 RCTs and 51 observational studies, infliximab was associated with a higher risk of treatment discontinuation and serious infections compared to abatacept, adalimumab, and etanercept in patients with rheumatoid arthritis (RA).

The safety profile of targeted immunomodulators generally favored abatacept, adalimumab, and etanercept over infliximab, although there was insufficient evidence to compare other TIMs or assess safety outcomes in non-RA populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative Risk of Harm Associated With the Use of Targeted Immunomodulators: A Systematic Review. Desai, RJ., Thaler, KJ., Mahlknecht, P., et al.[2022]

The BIOBADASER III registry, initiated in December 2015, includes data from 2,664 patients with rheumatic diseases treated with biological or synthetic drugs, focusing on tracking adverse events and treatment effectiveness.

In the first year, the most common adverse events reported were infections and infestations, highlighting the need for ongoing monitoring of safety in patients undergoing long-term treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Objectives and methodology of BIOBADASER phase iii. Sanchez-Piedra, C., Hernández Miguel, MV., Manero, J., et al.[2021]

In a phase II trial involving 51 patients with advanced hepatocellular carcinoma (HCC) who had not received prior systemic therapy, pembrolizumab demonstrated a 16% objective response rate, indicating its potential effectiveness in this patient population.

The treatment showed a median overall survival of 17 months and a median duration of response of 16 months, with a safety profile that included grade ≥3 treatment-related adverse events in 16% of patients, suggesting it is tolerable for use in advanced HCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab Monotherapy for Previously Untreated Advanced Hepatocellular Carcinoma: Data from the Open-Label, Phase II KEYNOTE-224 Trial. Verset, G., Borbath, I., Karwal, M., et al.[2023]

In a real-life study of 121 patients with advanced non-squamous non-small cell lung cancer, the combination of pembrolizumab and chemotherapy resulted in a median progression-free survival of 9 months and overall survival of 20.6 months, demonstrating its efficacy as a first-line treatment.

The treatment was generally well-tolerated, with manageable side effects; however, 17.5% of patients experienced grade 3-4 adverse events, and there were two treatment-related deaths, indicating the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus pemetrexed-carboplatin combination in first-line treatment of advanced non-squamous non-small cell lung cancer: a multicenter real-life study (CAP29). Renaud, E., Ricordel, C., Corre, R., et al.[2023]

Pembrolizumab (Keytruda) is an approved treatment for metastatic or locally advanced esophageal and gastroesophageal junction cancer, indicating its efficacy in targeting these specific cancer types.

It is used in combination with platinum- and fluoropyrimidine-based chemotherapy, suggesting a synergistic approach to enhance treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab Approved for Esophageal or Gastroesophageal Cancer. Aschenbrenner, DS.[2023]

References

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

Patient-reported outcomes following pembrolizumab or placebo plus pemetrexed and platinum in patients with previously untreated, metastatic, non-squamous non-small-cell lung cancer (KEYNOTE-189): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. [2020]

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

Health-Related Quality of Life With Carboplatin-Paclitaxel or nab-Paclitaxel With or Without Pembrolizumab in Patients With Metastatic Squamous Non-Small-Cell Lung Cancer. [2020]

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

First-in-Class Anti-immunoglobulin-like Transcript 4 Myeloid-Specific Antibody MK-4830 Abrogates a PD-1 Resistance Mechanism in Patients with Advanced Solid Tumors. [2023]

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

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

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

Pembrolizumab joins the anti-PD-1 armamentarium in the treatment of melanoma. [2017]

6. England pubmed.ncbi.nlm.nih.gov

Survival of TNF antagonists in spondylarthritis is better than in rheumatoid arthritis. Data from the Spanish registry BIOBADASER. [2022]

7. England pubmed.ncbi.nlm.nih.gov

A randomized, double-blind, 3-arm, parallel study assessing the pharmacokinetics, safety, tolerability and immunogenicity of AVT04, an ustekinumab candidate biosimilar, in healthy adults. [2023]

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

Psoriatic arthritis induced by anti-PD1 and treated with apremilast: a case report and review of the literature. [2021]

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

Comparative Risk of Harm Associated With the Use of Targeted Immunomodulators: A Systematic Review. [2022]

10. Spain pubmed.ncbi.nlm.nih.gov

Objectives and methodology of BIOBADASER phase iii. [2021]

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

Pembrolizumab Monotherapy for Previously Untreated Advanced Hepatocellular Carcinoma: Data from the Open-Label, Phase II KEYNOTE-224 Trial. [2023]

12. China pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus pemetrexed-carboplatin combination in first-line treatment of advanced non-squamous non-small cell lung cancer: a multicenter real-life study (CAP29). [2023]

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

Pembrolizumab Approved for Esophageal or Gastroesophageal Cancer. [2023]