A Modular, Open Label, Randomized Phase II/III Trial to Assess Efficacy of Combining sEphB4-HSA (EphrinB2 Inhibitor) With Immunotherapy Regimens in Patients With EphrinB2-High Solid Tumors
Trial Snapshot
- Phase
- Phase 2
- Status
- Recruiting
- Sponsor
- Vasgene Therapeutics, Inc
- Enrollment
- 700
- Locations
- 1
- Primary Endpoint
- Improved Radiographic Objective Response Rate (ORR) in sEphB4+Pembro vs. Control in mUC
Study Overview
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •General Inclusion Criteria for Both Arms
- •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
- •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
- •Module A Inclusion Criteria
- •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.
- •Module B inclusion Criteria
- •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.
Arms & Interventions
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).
Intervention: SEphB4-HSA (Drug)
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).
Intervention: Pembrolizumab (Drug)
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.
Intervention: Pembrolizumab (Drug)
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.
Intervention: Gemcitabine (Drug)
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.
Intervention: Cisplatin (Drug)
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).
Intervention: SEphB4-HSA (Drug)
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).
Intervention: Pembrolizumab (Drug)
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.
Intervention: Pembrolizumab (Drug)
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.
Intervention: Enfortumab vedotin (Drug)
Outcomes
Primary Outcomes
Improved Radiographic Objective Response Rate (ORR) in sEphB4+Pembro vs. Control in mUC
Time Frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months
Using RECIST 1.1 on CT or MR imaging of chest, MR imaging of Chest, Abdomen and Pelvis every 6 weeks for the first 3 months and then every 12 weeks.
Improved pathological response (pCR) in sEphB4-HSA+Pembro vs. Standard of Care for MIBC
Time Frame: Through study completion, an average of 6 months
Pathologic complete response (pCR), a binary outcome. pCR is defined as absence of the muscle invasive component of the tumor in the radical cystectomy specimen by pathologic review. CIS (pTis), pT1, and pTa are considered to be pCR. All patients with pCR must have pN0/M0. Patients don't have pCR due to refusal of radical cystectomy, dropout prior to radical cystectomry, or pathologic evaluation results are inconclusive or unknown will be classified as non-responders in the ITT.
Improved Overall Survival (OS) in sEphB4-HSA+Pembro vs. Standard of Care for MIBC
Time Frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months
Overall survival (OS) defined as period from randomization to death from any cause. OS will be censored at the last follow-up if patients are known to be alive. OS is a time to event variable of the primary interest.
Non-inferior Overall Survival (OS) of sEphB4+Pembro vs. Control in mUC
Time Frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months
Overall survival (OS) defined as period from randomization to death from any cause. OS will be censored at the last follow-up if patients are known to be alive. OS is a time to event variable of the primary interest.
Secondary Outcomes
- Improved Disease Free Survival and/or Event Free Survival in sEphB4 vs. control for MIBC arm.(From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months)
- Improved toxicity of EphB4-HSA + Pembro in MIBC vs. control(From start of study intervention until one week after cessation of study intervention, assessed up to 60 months)
- Improved toxicity of sEphB4-HSA + Pembro in mUC vs. control(From start of study intervention until one week after cessation of study intervention, assessed up to 60 months)
- Improved Duration of Response and/or Progression Free Survival in sEphB4 vs. control for mUC arm.(From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months)