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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination treatment for individuals with advanced bladder cancer who have not received prior treatment and cannot or will not undergo chemotherapy. The treatment includes Pembrolizumab, which helps the immune system attack cancer, and sEphB4-HSA, which may inhibit tumor growth by blocking essential nutrients. Participants should have advanced bladder cancer that has either spread or recurred and should be unable or unwilling to take chemotherapy. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering a chance to contribute to significant advancements in cancer care.

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.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research shows that the combination of pembrolizumab and sEphB4-HSA is generally safe and well-tolerated. Studies indicate that this combination has a safety profile similar to previous findings, with no new overlapping side effects. In some trials, sEphB4-HSA did not cause any severe side effects, the most serious ones.

This suggests that the treatment is relatively safe for people. Notably, sEphB4-HSA has been tested in various cancers, showing promising results without major safety concerns. Pembrolizumab, a commonly used cancer treatment, further supports the safety of this combination. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about the combination of Pembrolizumab and sEphB4-HSA because it introduces a unique approach to cancer treatment. While Pembrolizumab is an established immunotherapy that helps the immune system target cancer cells, the addition of sEphB4-HSA offers a new mechanism of action by potentially blocking pathways that tumors use to grow and spread. This dual action could enhance the effectiveness of the treatment compared to standard options, offering hope for better cancer control. Plus, the regimen is administered intravenously on a timely schedule, which might optimize the therapeutic effects.

What evidence suggests that Pembrolizumab + sEphB4-HSA might be an effective treatment for urothelial carcinoma?

Research has shown that using pembrolizumab with sEphB4-HSA may help treat advanced bladder cancer. In one study, 37% of patients experienced a reduction or disappearance of their cancer. Another study found a 24% response rate, with some patients, especially those without HPV and with certain markers, achieving good results. All participants in this trial will receive this treatment combination, which is generally well-tolerated and usually doesn't cause severe side effects for most people. These findings suggest that this treatment could help control cancer growth in patients who can't or choose not to undergo chemotherapy. ^{1 2 3 4 6}

Who Is on the Research Team?

Sarmad Sadeghi, MD

Principal Investigator

University of Southern California

Are You a Good Fit for This Trial?

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.

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

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

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 for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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) 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]

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]

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]

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 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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11235133/

Improved efficacy of pembrolizumab combined with soluble ... Results: Twenty-five patients were enrolled. Median follow up was 40.4 months (range 9.8 – 40.4). There were 6 responders (ORR 24%). There were ...

2. oncotarget.com oncotarget.com/news/pr/improved-efficacy-of-pembrolizumab-when-combined-with-sephb-hsa-in-hpv-negative-ephrinb-positive-hnscc/

Improved Efficacy of Pembrolizumab When Combined With ... The combination of sEphB4-HSA and pembrolizumab has a favorable toxicity profile and favorable activity particularly among HPV-negative EphrinB2 positive ...

3. urotoday.com urotoday.com/conference-highlights/esmo-2021/esmo-2021-bladder-cancer/132176-esmo-2021-phase-ii-trial-of-pembrolizumab-p-in-combination-with-sephb4-hsa-b4-in-previously-treated-metastatic-urothelial-carcinoma-muc.html

ESMO 2021: Phase II Trial of Pembrolizumab (P) in ... The combination of sEphB4-HSA and pembrolizumab demonstrated impressive activity. The ORR was 37% in the overall cohort with a complete response ...

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.6_suppl.084

A phase II study of sEphB4-HSA in metastatic castration- ... A phase I clinical trial of sEphB4-HSA led to response or stable disease in 56% of patients, with no grade 4 or 5 related adverse events.

5. annalsofoncology.org annalsofoncology.org/article/S0923-7534(21)02261-4/fulltext

651O Phase II trial of pembrolizumab (P) in combination ... B4 + P is well tolerated and may have synergistic efficacy in mUC. B2 was expressed in the majority of pts and predicted for improved tx outcome.

6. sciencedirect.com sciencedirect.com/science/article/pii/S155876732200180X

A Phase II Study of sEphB4-HSA in Metastatic Castration- ... Therapy with sEphB4-HSA has demonstrated efficacy in other solid tumors: in urothelial cancer, where it yields a 38% response rate when given in combination ...