sEphB4-HSA + Pembrolizumab for Cancer
Recruiting in Palo Alto (17 mi)
+8 other locations
Overseen BySarmad Sadeghi, MD
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: University of Southern California
Must not be taking: Immunosuppressants, Steroids
Disqualifiers: Active TB, CNS metastases, others
Stay on your current meds
No Placebo Group
Prior Safety Data
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?This is a multi-cohort single arm phase II/screening trial of the combination of a fusion protein that binds EphrinB2 and blocks interaction with cell surface EphB receptors (sEphB4-HSA) in combination with an anti-PD1 antibody (MK-7435 / Pembrolizumab) for treatment of patients with specific solid tumors. There will be four cohorts in this trial:
1. Cohort A, phase II 2nd line trial of sEphB4-HSA and pembrolizumab for platinum refractory metastatic urothelial carcinoma.
2. Cohort B, phase II 3rd line trial of sEphB4-HSA and pembrolizumab for platinum refractory metastatic urothelial carcinoma.
3. Cohort C, phase II neoadjuvant trial of sEphB4-HSA and pembrolizumab for locally advanced muscle invasive urothelial carcinoma.
4. Cohort D, phase II neoadjuvant trial of sEphB4-HSA and pembrolizumab for locally advanced prostate cancer.
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, you cannot participate if you are on systemic steroid therapy or any form of immunosuppressive therapy within 7 days before the trial starts. It's best to discuss your specific medications with the trial team.
What data supports the effectiveness of the drug Pembrolizumab (Keytruda) for cancer treatment?
Pembrolizumab has been approved for treating several types of cancer, including esophageal, gastroesophageal, and endometrial cancers, and has shown high response rates in melanoma patients. It works by helping the immune system attack cancer cells more effectively.
12345Is the combination of sEphB4-HSA and Pembrolizumab generally safe for humans?
Pembrolizumab, also known as Keytruda, has been shown to be generally safe in humans, with common side effects including fatigue, rash, itching, and diarrhea. However, it can also cause less common immune-related side effects like inflammation of the lungs (pneumonitis), thyroid issues, and liver inflammation (hepatitis). In nonhuman primate studies, no significant toxic effects were observed.
45678What makes the drug sEphB4-HSA + Pembrolizumab unique for cancer treatment?
The combination of sEphB4-HSA and pembrolizumab is unique because it combines a recombinant protein that targets the EphB4 receptor, potentially affecting tumor blood supply, with pembrolizumab, an immune checkpoint inhibitor that helps the immune system attack cancer cells. This dual approach may offer a novel mechanism of action compared to standard treatments.
123910Eligibility Criteria
This trial is for adults with certain advanced solid tumors, specifically metastatic or recurrent urothelial carcinoma that's resistant to platinum-based treatment, and locally advanced prostate cancer. Participants must have adequate organ function, no recent other treatments or surgeries, and agree to use contraception. Those with active pneumonitis, uncontrolled hypertension, known psychiatric disorders affecting cooperation, prior anti-PD-1/PD-L1 therapy or sEphB4-HSA are excluded.Inclusion Criteria
My bladder cancer is at a stage where surgery to remove it is planned and considered potentially curative.
My liver function tests are within the required range.
I am fully active or restricted in physically strenuous activity but can do light work.
My kidney function, measured by creatinine clearance or GFR, is adequate.
Exclusion Criteria
I have been diagnosed with HIV.
I have an immune system disorder or have been on steroids or other immune-weakening medicines in the last week.
I have an active tuberculosis infection.
I have been treated with specific immune therapy drugs before.
I have or had lung inflammation not caused by an infection.
I have not received a live vaccine within the last 30 days.
I do not have severe heart issues, uncontrolled diabetes, or severe lung problems that required hospitalization in the last 6 months.
Participant Groups
The trial tests a combination of sEphB4-HSA (a fusion protein blocking cell surface receptors) and Pembrolizumab (an anti-PD1 antibody) on four cohorts: two for second and third-line treatment of urothelial carcinoma after platinum failure; one as neoadjuvant for muscle invasive urothelial carcinoma; another as neoadjuvant for prostate cancer.
1Treatment groups
Experimental Treatment
Group I: Treatment (EphB4-HSA and pembrolizumab)Experimental Treatment5 Interventions
Patients receive recombinant EphB4-HSA fusion protein IV over 60 minutes on days 1, 8, and 15 and pembrolizumab IV over 30 minutes on day 1. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.
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
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
University of Virginia Cancer CenterCharlottesville, VA
UC Davis Comprehensive Cancer CenterSacramento, CA
Levine Cancer Institute-Carolinas Medical CenterCharlotte, NC
USC / Norris Comprehensive Cancer CenterLos Angeles, CA
More Trial Locations
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Who is running the clinical trial?
University of Southern CaliforniaLead Sponsor
National Cancer Institute (NCI)Collaborator
References
Pembrolizumab Approved for Esophageal or Gastroesophageal Cancer. [2023]Pembrolizumab (Keytruda) has been approved to treat metastatic or locally advanced esophageal or gastroesophageal junction cancer. It is used in combination with platinum- and fluoropyrimidine-based chemotherapy.
Pembrolizumab joins the anti-PD-1 armamentarium in the treatment of melanoma. [2017]Pembrolizumab (MK-3475) is a monoclonal antibody that binds to the PD-1 receptor on T cells and prevents binding to its ligands PD-L1 and PD-L2. Blocking this receptor frees T cells from the inhibitory effects of PD-L1 and allows them to mediate antitumor effects against cancer cells. In a large Phase I study of 411 patients with melanoma, high durable response rates over a range of doses and schedules have been shown with very little toxicity. A Phase III study of pembrolizumab comparing two schedules of administration with the current standard treatment with the anti-CTLA-4 monoclonal antibody is in progress. Combinations with other checkpoint inhibitors as well as other anticancer agents are also being evaluated. Approval of pembrolizumab for the treatment of melanoma is expected.
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]In this first-in-human study (NCT03564691) in advanced solid tumors, we investigated a novel first-in-class human IgG4 monoclonal antibody targeting the immunoglobulin-like transcript 4 (ILT4) receptor, MK-4830, as monotherapy and in combination with pembrolizumab.
New Approved Use for Keytruda. [2022]Pembrolizumab (Keytruda) is now approved as a single agent to treat advanced endometrial carcinoma that is microsatellite instability-high or mismatch repair deficient in those whose disease has progressed following prior systemic therapy in any setting and who are not candidates for curative surgery or radiation.
Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. [2022]Pembrolizumab (Keytruda; Merck Sharp & Dohme) is a humanized IgG4 monoclonal antibody used in cancer immunotherapy. It targets the programmed cell death-1 (PD-1) receptor, which is important in maintaining self-tolerance. However, immune checkpoint blockade is associated with a risk for immune-related adverse events (irAEs) potentially affecting the endocrine organs. Type 1 diabetes mellitus is a rare irAE of PD-1 inhibitors, occurring in 0.2% of cases.
Biophysical and Immunological Characterization and In Vivo Pharmacokinetics and Toxicology in Nonhuman Primates of the Anti-PD-1 Antibody Pembrolizumab. [2021]The programmed cell death 1 (PD-1) pathway represents a major immune checkpoint, which may be engaged by cells in the tumor microenvironment to overcome active T-cell immune surveillance. Pembrolizumab (Keytruda®, MK-3475) is a potent and highly selective humanized mAb of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This blockade enhances the functional activity of T cells to facilitate tumor regression and ultimately immune rejection. Pembrolizumab binds to human and cynomolgus monkey PD-1 with picomolar affinity and blocks the binding of human and cynomolgus monkey PD-1 to PD-L1 and PD-L2 with comparable potency. Pembrolizumab binds both the C'D and FG loops of PD-1. Pembrolizumab overcomes human and cynomolgus monkey PD-L1-mediated immune suppression in T-cell cultures by enhancing IL2 production following staphylococcal enterotoxin B stimulation of healthy donor and cancer patient cells, and IFNγ production in human primary tumor histoculture. Ex vivo and in vitro studies with human and primate T cells show that pembrolizumab enhances antigen-specific T-cell IFNγ and IL2 production. Pembrolizumab does not mediate FcR or complement-driven effector function against PD-1-expressing cells. Pembrolizumab displays dose-dependent clearance and half-life in cynomolgus monkey pharmacokinetic and toxicokinetic studies typical for human IgG4 antibodies. In nonhuman primate toxicology studies, no findings of toxicologic significance were observed. The preclinical data for pembrolizumab are consistent with the clinical anticancer activity and safety that has been demonstrated in human clinical trials.
Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. [2023]Pembrolizumab (Keytruda) is a monoclonal antibody against the programmed cell death-1 (PD-1) receptor on lymphocytes, which is one of the immune checkpoint inhibitors (ICIs) approved for multiple solid and hematologic malignancies. Although ICIs have proven to be more effective and less toxic compared to chemotherapy, there are reports of adverse side effects with ICIs. For example, pneumonitis is a potentially lethal side effect occurring in 1%-5% of patients who received ICIs in clinical trials, and there are case reports with clinical and radiological features of checkpoint inhibitor-pneumonitis (CIP).
Pembrolizumab in the management of metastatic melanoma. [2020]Pembrolizumab is a humanized IgG4 anti-PD-1 antibody that plays a major role in the treatment of advanced melanoma. Through blockade of PD-1, it leads to an increase in effector T-cell activity in the tumor microenvironment. Clinical trial outcomes for pembrolizumab in addition to pharmacokinetics, pharmacodynamics and safety of the compound are discussed in this article. Phase I trials have demonstrated safety and efficacy of pembrolizumab in advanced, pretreated melanoma patients. When compared with chemotherapy in a Phase II trial of ipilimumab-refractory patients, those treated with pembrolizumab showed superior progression-free survival. In addition, in the pivotal Phase III trial pembrolizumab improved overall survival compared with ipilimumab in patients naive to immune checkpoint inhibition. Pembrolizumab is well tolerated and has a favorable safety profile. Common adverse events are fatigue, rash, itching and diarrhea. Less frequent immune-related adverse events include hypothyroidism, colitis, hepatitis and pneumonitis.
Immune-mediated necrotizing myopathy with pembrolizumab: a specific neuromuscular entity. [2022]Pembrolizumab is a humanized monoclonal antibody that binds to the programmed cell-death protein-1 (PD-1) on immune T-cells, thus blocking PD-1 activity. Pembrolizumab is indicated for the treatment of advanced melanoma, metastatic non-small-cell lung cancer, and head and neck squamous cell carcinoma. However, it is associated with immune-related adverse events.
Safety and Efficacy of Pembrolizumab With Chemoradiotherapy in Locally Advanced Head and Neck Squamous Cell Carcinoma: A Phase IB Study. [2022]Pembrolizumab is a humanized monoclonal antibody that blocks interaction between programmed death receptor-1 (PD-1) and its ligands (PD-L1, PD-L2). Although pembrolizumab is approved for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), its role in the management of locally advanced (LA) disease is not defined. We report a phase IB study evaluating the safety and efficacy of adding pembrolizumab to cisplatin-based chemoradiotherapy in patients with LA HNSCC.