Modular Trial of sEphB4-HSA in EphrinB2-High Solid Tumors

NCT ID: NCT06493552

Last Updated: 2025-04-03

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 700 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-03-15
• Study Completion Date: 2034-08-31

Brief Summary

Patients with solid tumors that have high expression levels of EphrinB2 are treated with regimens that include EphrinB2 inhibitor, sEphB4-HSA. The primary objective of this study is to demonstrate additive therapeutic benefit for sEphB4-HSA. The secondary objectives are to determine whether the sEphB4-HSA containing regimen is safe and whether the oncological endpoints of importance in each cohort improve as a result of treatment with sEphB4-HSA containing regimen relative to a predefined threshold or to a control arm in the cohort where available. Treatment continues until progression of disease or unacceptable toxicities arise.

Detailed Description

The investigators hypothesize that the inhibition of EphrinB2 overcomes the negative prognostic impact of this biomarker and improves the treatment outcomes. It is further hypothesized that this higher level of activity is attributable to the synergistic immune-stimulatory effect of sEphB4-HSA when combined with pembrolizumab.

Cohort A is designed to treat patients with MIBC whose tumors express EphrinB2. Patients in this cohort will be randomized to receive sEphB4-HSA + Pembrolizumab or Gemcitabine-Cisplatin (GC) regimen per standard of care of 4 cycle. Patients ineligible for cisplatin-based chemotherapy or refusing such chemotherapy will be able to receive pembrolizumab alone for 4 cycles based on PURE-01 data showing comparable response rate to chemotherapy with GC regimen.

Cohort B will study the combination of sEphB4-HSA + Pembrolizumab in previously treated mUC, in EphrinB2-high subgroup, a group that in previous studies demonstrated a 52% response rate. In the multi-institutional retrospective series reported by the study team, the expected response rate for anti-PD-L1/PD-1 antibodies is 12% among tumors with high EphrinB2 expression. This represents more than 4-fold improvement in efficacy of immunotherapy if EphrinB2 is inhibited with a mild toxicity profile for the combination. In contrast, EV + Pembrolizumab while effective, has a significant and at times prohibitive toxicity profile. It is also unclear whether EV + Pembrolizumab can deliver the published results in patients with high EphrinB2 expression. Therefore, Cohort B is designed to explore this question.

Upon study entry, participants in either Cohort will be randomly assigned to either sEphB4-HSA + Pembrolizumab or Standard of Care (Control). Study interventions will be administered according to the protocol and participants will be monitored and assessed for safety and efficacy at designated times throughout the study.

Conditions

Muscle-Invasive Bladder Carcinoma; Metastatic Urothelial Carcinoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

sEphB4-HSA + Pembrolizumab in MIBC

sEphB4-HSA shall be started at a dose of 10mg/kg using actual body weight and administered IV over 60 minutes on days 1 and 8 of each cycle as outlined under section 7.1.3.

Trial treatment may be administered up to 3 days before or after the scheduled Day 1 of each cycle due to administrative reasons. All trial treatments will be administered on an outpatient basis unless the patient has been admitted for another reason and meets all criteria for further therapy.

Pembrolizumab dose, schedule, delays, and discontinuation of therapy shall be determined by the treating physician in accordance with product label(s), standard of care and institutional policies.

Treatment will continue until the prespecified number of cycle of therapy are completed or until progression of disease or unacceptable toxicities where specified by the protocol for specific cohort(s).

Group Type: EXPERIMENTAL

SEphB4-HSA

Intervention Type: DRUG

A recombinant protein comprised of the soluble form of human receptor EphB4 fused to human serum albumin.

Pembrolizumab

Intervention Type: DRUG

Antibody to human PD-1.

Gemcitabine-Cisplatin (GC) or Pembrolizumab Alone in MIBC

Dose modification, delays and discontinuation of therapy shall be determined by the treating physician in accordance with product label(s), standard of care and institutional policies.

Group Type: ACTIVE_COMPARATOR

Pembrolizumab

Intervention Type: DRUG

Antibody to human PD-1.

Gemcitabine

Intervention Type: DRUG

A chemotherapy drug used to treat various types of cancer.

Cisplatin

Intervention Type: DRUG

A type of chemotherapy drug called an alkylating agent used to treat various types of cancer.

sEphB4-HSA + Pembrolizumab in Naive mUC

sEphB4-HSA shall be started at a dose of 10mg/kg using actual body weight and administered IV over 60 minutes on days 1 and 8 of each cycle as outlined under section 7.1.3.

Trial treatment may be administered up to 3 days before or after the scheduled Day 1 of each cycle due to administrative reasons. All trial treatments will be administered on an outpatient basis unless the patient has been admitted for another reason and meets all criteria for further therapy.

Pembrolizumab dose, schedule, delays, and discontinuation of therapy shall be determined by the treating physician in accordance with product label(s), standard of care and institutional policies.

Treatment will continue until the prespecified number of cycle of therapy are completed or until progression of disease or unacceptable toxicities where specified by the protocol for specific cohort(s).

Group Type: EXPERIMENTAL

SEphB4-HSA

Intervention Type: DRUG

A recombinant protein comprised of the soluble form of human receptor EphB4 fused to human serum albumin.

Pembrolizumab

Intervention Type: DRUG

Antibody to human PD-1.

Enfortumab Vedotin (EV) + Pembrolizumab in Naive mUC

Dose modification, delays and discontinuation of therapy shall be determined by the treating physician in accordance with product label(s), standard of care and institutional policies.

Group Type: ACTIVE_COMPARATOR

Pembrolizumab

Intervention Type: DRUG

Antibody to human PD-1.

Enfortumab vedotin

Intervention Type: DRUG

Nectin-4-directed antibody and microtubule inhibitor conjugate.

Interventions

SEphB4-HSA

A recombinant protein comprised of the soluble form of human receptor EphB4 fused to human serum albumin.

Intervention Type: DRUG

Pembrolizumab

Antibody to human PD-1.

Intervention Type: DRUG

Gemcitabine

A chemotherapy drug used to treat various types of cancer.

Intervention Type: DRUG

Cisplatin

A type of chemotherapy drug called an alkylating agent used to treat various types of cancer.

Intervention Type: DRUG

Enfortumab vedotin

Nectin-4-directed antibody and microtubule inhibitor conjugate.

Intervention Type: DRUG

Other Intervention Names

sB4HSA; Keytruda; GEM, Gemzar; CIS; EV, Padcev

Eligibility Criteria

Inclusion Criteria

• Willing and able to provide informed consent.
• Men and women 18 years of age, or older.
• Must provide the cell block or a minimum of 15 slides from the diagnostic biopsy or archival tissue.
• Tumor tissue must be submitted for molecular profile through a commercial service such as Tempus, CARIS, Foundation One, etc. This must include a PD-L1 assay.
• Tumor must express EphrinB2 as assessed by USC Norris Core Lab.
• Zubrod performance status of less than or equal to 1.
• Women of childbearing potential must use method(s) of contraception. The individual methods of contraception should be determined in consultation with the treating physician or investigator.
• Women of childbearing potential are eligible if serum pregnancy test obtained during screening is negative. Women are also eligible if one of the following criteria is met:

• Have undergone a documented hysterectomy and/or bilateral oophorectomy; OR
• Have medically confirmed ovarian failure; OR
• Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; OR
• A serum follicle stimulating hormone (FSH) level within the laboratory's reference range for postmenopausal women.
• Women must not be breastfeeding.
• Men who are sexually active with women of childbearing potential must agree to use 2 contraceptive methods with a failure rate of less than 1% per year.

o NOTE: Contraception should be continued using two highly effective methods for a period of 120 days after the last dose of treatment.

• Adequate organ function as defined below using baseline laboratory requirements obtained within 14 days prior to randomization:

• Measured or calculated creatinine clearance (CrCl) greater than or equal to 30 mL/min using the Cockcroft-Gault formula using actual weight (NOT ideal or adjusted weights).
• WBC ≥2000/uL
• Neutrophils ≥1500/uL
• Platelets ≥100x103/uL
• Hemoglobin ≥9g/dL
• AST ≤3 x ULN
• ALT ≤3 x ULN
• Bilirubin ≤1.5 x ULN

• Urothelial carcinoma, variant components and differentiations allowed. Pure small cell not allowed.
• cT2 to cT4a N0M0, by TURBT or imaging.
• No systemic therapy for cancer in the previous 12 months.
• Choice of treatment if randomized to the control arm must be declared prior to randomization. If cisplatin ineligible or refusing, pembrolizumab must be approved by patient's insurance prior to randomization.

• Urothelial carcinoma, variant components and differentiations allowed. Pure small cell not allowed.
• Tumor must be Nectin4 non-amplified- testing performed during pre-screening assessment.
• No systemic therapy for cancer in the previous 12 months.
• Measurable disease as defined by RECIST1.1 criteria

Exclusion Criteria

• Patients with known symptomatic brain metastases requiring systemic corticosteroids. Patients with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to the start of study medication, have discontinued corticosteroid treatment for these metastases for at least 4 weeks and are neurologically stable. Mild neurological deficit is allowed, if it does not interfere with the ability to judge the safety on the trial.
• History of or active autoimmune disorders (including but not limited to: Crohn's Disease, rheumatoid arthritis, scleroderma, systemic lupus erythematosus, Grave's disease) and other conditions that compromise or impair the immune system.
• Known active bacterial, fungal or viral infection including hepatitis B (HBV), hepatitis C (HCV), known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) -related illness. Routine testing is not required; however, treating physicians may use their discretion to determine whether testing is necessary.
• Uncontrolled adrenal insufficiency.
• Any known active chronic liver disease.
• Concurrent or active second malignancy requiring systemic therapy is excluded.
• Known medical condition (eg, a condition associated with diarrhea or acute diverticulitis) that, in the investigator's opinion, would increase the risk associated with study participation or study drug administration or interfere with the interpretation of safety results.
• Major surgery less than 6 weeks prior to the first dose of study drug. Minor surgery less than 4 weeks prior to the first dose of study drug. Insertion of vascular access device ≥ 7 days prior to 1st dose of study drug is allowed.
• History of severe hypersensitivity reaction to any monoclonal antibody.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Vasgene Therapeutics, Inc

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Sarmad Sadeghi, MD

Role: PRINCIPAL_INVESTIGATOR

University of Southern California

Locations

Sarcoma Oncology Center

Santa Monica, California, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Jon Cogan, MS

Role: CONTACT

info@vasgene.com

323-221-7818

Facility Contacts

Victoria Chua

Role: primary

vchua@sarcomaoncology.com

310-552-9999

Other Identifiers

B2-001

Identifier Type: -

Identifier Source: org_study_id