Multicohort Phase II Trial of sEphB4-HSA+Pembrolizumab in Solid Tumors

Phase 2

Recruiting

• Conditions: Urothelial Carcinoma; Stage IV Bladder Urothelial Carcinoma; Prostate Cancer
• Interventions: Procedure: Computed Tomography; Other: Laboratory Biomarker Analysis; Biological: Pembrolizumab; Procedure: Positron Emission Tomography; Biological: Recombinant EphB4-HSA Fusion Protein

• Registration Number: NCT02717156
• Lead Sponsor: University of Southern California

Brief Summary

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.

Detailed Description

PRIMARY OBJECTIVES:

I. To describe the toxicity associated with the Pembrolizumab-sEphB4-HSA combination in patients with solid tumors (all Cohorts).

II. To identify a signal of activity for each of 4 cohorts of patients:

1. To measure the overall survival (OS) in patients with urothelial carcinoma who have previously been treated with one line of platinum-based therapy in advanced/metastatic setting (Cohort A).

2. To measure the overall survival (OS) in patients with urothelial carcinoma who have previously been treated with at least two lines of therapy, of which at least one is platinum-based, in advanced/metastatic setting (Cohort B).

3. To measure the pathologic complete response (pCR) rate in patients with newly diagnosed urothelial carcinoma of the bladder (platinum eligible and ineligible) treated in neoadjuvant setting prior to radical cystectomy (Cohort C).

4. To measure the PSA response rate in patients with newly diagnosed prostate cancer in neoadjuvant setting prior to radical prostatectomy (Cohort D).

SECONDARY OBJECTIVES:

I. To measure the progression-free survival (PFS) in Cohorts A and B

II. To measure the disease-free survival (DFS) in Cohorts C and D

III. To measure the objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 in Cohorts A and B

IV. To measure the pathologic response rate in newly diagnosed prostate cancer patients in neoadjuvant setting prior to radical prostatectomy in Cohort D

TERTIARY OBJECTIVES:

I. To examine programmed cell death 1 (PD-1), programmed cell death 1 ligand 1 (PD-L1), programmed cell death 1 ligand 2 (PD-L2) and EPH receptor B4 (EphB4) expression by tumor cells (TC) as well as immune cells (IC)- macrophages and T cells- in tumor tissue and correlate them with ORR, PFS and OS.

II. To examine the tumor tissue T cell frequency (counts), tumor tissue T cell clonality using T cell receptor (TCR) sequencing, and peripheral blood T cell clonality, pre-treatment and post-treatment and correlate these with ORR, PFS and OS.

III. To measure the phenotype of lymphocytes and myeloid derived suppressor cells (MDSC), in pre and post-treatment blood samples and correlate these with ORR, PFS and OS; an extra blood sample for future studies will also be collected and banked.

IV. To examine peripheral blood circulating tumor cells (CTCs) for enumeration and molecular analysis in pre and post-treatment blood samples, and correlate these with ORR, PFS and OS.

V. To collect and bank tumor tissue. VI. To examine the role of adding positron emission tomography (PET) to a contrast computed tomography (CT) for evaluation of response to treatment.

OUTLINE:

Patients receive recombinant EphB4-HSA fusion protein intravenously (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.

After completion of study treatment, patients are followed up at 30 days and then every 6-12 weeks.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2016-03-17
• Study First Submitted QC: 2016-03-17
• Study First Posted: 2016-03-23
• Study Start: 2016-11-21
• Status Verified: 2024-02
• Last Update Submitted: 2024-02-14
• Last Update Posted: 2024-02-15
• Primary Completion: 2025-11-21
• Study Completion: 2026-11-21

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 170

Inclusion Criteria

Not provided

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Exclusion Criteria

• Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment
• Has a known history of active TB (bacillus tuberculosis)
• Hypersensitivity to pembrolizumab or any of its excipients
• Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 or who has not recovered (ie, =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier
• Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (ie, =< grade 1 or at baseline) from adverse events due to a previously administered agent; Note: subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study; Note: if subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
• Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs); replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc) is not considered a form of systemic treatment
• Has known history of, or any evidence of active, non-infectious pneumonitis
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, or sEsphB4-HSA
• Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
• Has known active Hepatitis B (eg, hepatitis B surface antigen [HBsAg] reactive) or Hepatitis C (eg, hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
• Has New York Heart Association (NYHA) class 3 or 4, myocardial infarction, acute coronary syndrome, diabetes mellitus with ketoacidosis or chronic obstructive pulmonary disease (COPD) requiring hospitalization in the preceding 6 months; or any other intercurrent medical condition that contraindicates treatment with sEphB4HSA or pembrolizumab (MK-3475) or places the patient at undue risk for treatment related complications
• Has received a live vaccine within 30 days of planned start of study therapy; Note: seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (eg, flu-mist) are live attenuated vaccines, and are not allowed
• Uncontrolled hypertension is excluded- systolic blood pressure >140mmHg or diastolic >90mmHg. Patients experiencing white coat hypertension in the office, may be considered eligible if blood pressure log at home is within acceptable limits AND upon review and agreement from the Sponsor.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (EphB4-HSA and pembrolizumab)	Laboratory Biomarker Analysis	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.
Treatment (EphB4-HSA and pembrolizumab)	Positron Emission Tomography	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.
Treatment (EphB4-HSA and pembrolizumab)	Computed Tomography	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.
Treatment (EphB4-HSA and pembrolizumab)	Recombinant EphB4-HSA Fusion Protein	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.
Treatment (EphB4-HSA and pembrolizumab)	Pembrolizumab	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.

Primary Outcome Measures

Name	Time	Method
Incidence of toxicities and adverse events classified according to the Common Terminology Criteria for Adverse Events v4.03	Up to 30 days	All observed toxicities will be summarized in terms of type (organ affected or laboratory determination, severity, and time of onset. Tables will be created to summarize these toxicities and side effects, overall and by course. The proportion of patients who are eligible to begin the 3rd planned cycle will be calculated, using the number of eligible patients who began treatment as the denominator; 95% confidence intervals will be constructed.

Secondary Outcome Measures

Name	Time	Method
OR defined as complete response or partial response according to RECIST v 1.1	Up to 3 years	The proportion of patients who experience an overall objective response (CR or PR will be calculated as the ratio of the number of eligible patients who experienced the response, divided by the total number of eligible patients who began treatment; 95% confidence intervals will be constructed.

Trial Locations

Locations (9)

Comprehensive Cancer Centers of Nevada; 🇺🇸 Las Vegas, Nevada, United States

USC / Norris Comprehensive Cancer Center; 🇺🇸 Los Angeles, California, United States

USC Norris Oncology/Hematology - Newport Beach; 🇺🇸 Newport Beach, California, United States

University of Virginia Cancer Center; 🇺🇸 Charlottesville, Virginia, United States

City of Hope; 🇺🇸 Duarte, California, United States

LAC+USC Medical Center; 🇺🇸 Los Angeles, California, United States

UC Davis Comprehensive Cancer Center; 🇺🇸 Sacramento, California, United States

Levine Cancer Institute-Carolinas Medical Center; 🇺🇸 Charlotte, North Carolina, United States

University of Kansas Cancer Center; 🇺🇸 Kansas City, Kansas, United States