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Recombinant EphB4-HSA Fusion Protein and Pembrolizumab in Treating Patients with Metastatic or Recurrent Urothelial Cancer That Is Refractory to Certain Chemotherapy Drugs

Trial Status: Active

This phase II trial studies how well recombinant EphB4-HSA fusion protein and pembrolizumab work in treating patients with urothelial (bladder) cancer that has spread from the primary site to other places in the body or has come back and does not respond to certain chemotherapy drugs. Combinations of biological substances in recombinant EphB4-HSA fusion protein may be able to carry tumor-killing substances directly to urothelial cancer cells. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving recombinant EphB4-HSA fusion protein and pembrolizumab together may be a better treatment for patients with urothelial cancer.

Inclusion Criteria

  • Advanced (metastatic or recurrent) pathologically proven urothelial carcinoma with progression of disease after front line platinum containing regimen are candidates for this trial
  • Be willing and able to provide written informed consent/assent for the trial
  • Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale
  • Absolute neutrophil count (ANC) >= 1,500/mcL (within 10 days of treatment initiation)
  • Platelets >= 100,000/mcL (within 10 days of treatment initiation)
  • Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment)
  • Measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 30mL/min using Cockcroft-Gault formula (within 10 days of treatment initiation)
  • Serum total bilirubin =< 1.5 X upper limit of normal (ULN) or direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN (within 10 days of treatment initiation)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN or =< 5 X ULN for subjects with liver metastases (within 10 days of treatment initiation)
  • Albumin >= 2.5 mg/dL (within 10 days of treatment initiation)
  • International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants (within 10 days of treatment initiation)
  • Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants (within 10 days of treatment initiation)
  • Recovered to grade 1 from the effects (excluding alopecia) of any prior therapy for their malignancies
  • Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
  • Female subjects of childbearing potential must be willing to adequate method of contraception as outlined, for the course of the study through 120 days after the last dose of study medication; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year * Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
  • Male subjects of childbearing potential must agree to use an adequate method of contraception as outlined, starting with the first dose of study therapy through 120 days after the last dose of study therapy * Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
  • CRITERIA SPECIFIC TO 2ND LINE AND 3RD LINE AND BEYOND COHORTS
  • Advanced (metastatic or recurrent) pathologically proven urothelial carcinoma which is refractory to platinum based due to disease progression on a platinum containing regimen; patients progressing within 12 months of their last dose of platinum-based neoadjuvant or adjuvant chemotherapy will be considered platinum refractory
  • Have measurable disease based on RECIST 1.1
  • Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion; newly-obtained is defined as a specimen obtained up to 12 weeks (84 days) after discontinuation of previous systemic therapy and prior to initiation of treatment on day 1 on this study; subjects for whom newly obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement from the sponsor; * Will request an OPTIONAL core biopsy from an accessible metastatic site after a minimum of 2 cycles of treatment AND prior to progression of disease to help the investigators better understand the activity of these drugs in tumor tissue * In addition, we will request an OPTIONAL collection of any surgical specimens obtained per standard of care during the study; for instance, specimens from palliative cystectomy or metastesectomy while patient is undergoing therapy on this study
  • CRITERIA SPECIFIC TO THE NEOADJUVANT COHORT
  • Must have tumor stage >= T2 AND =< T3, N0, M0 (American Joint Committee on Cancer [AJCC] 8th edition) urothelial carcinoma of the bladder deemed resectable and planned for radical cystectomy with curative intent
  • Must have TURBT specimen obtained within 6 weeks prior to the first day of treatment on the study and the specimen must include muscle
  • TURBT specimen must be received by the study coordinator prior to initiation of treatment; a cell block or 15 unstained slides is required
  • Prior intravesical therapy is allowed; however, patients who have received prior systemic therapy within 12 months enrollment are excluded

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 an active infection requiring systemic therapy
  • Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
  • 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)
  • Major systemic infection requiring antibiotics 72 hours or less prior to first dose of study drug
  • 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
  • Any other condition, including mental illness or substance abuse, deemed by the investigator to be likely to interfere with a patient's ability to sign informed consent, cooperate and participate in the study, or interferes with the interpretation of the results
  • Any active bleeding in the last =< 4 weeks or have an otherwise known bleeding diathesis
  • 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

California

Duarte
City of Hope Comprehensive Cancer Center
Status: ACTIVE
Contact: Valerie Mira
Phone: 626-218-0171
Email: vmira@coh.org
Los Angeles
Los Angeles County-USC Medical Center
Status: ACTIVE
Contact: Cheryl Kefauver
Phone: 323-865-0459
USC / Norris Comprehensive Cancer Center
Status: ACTIVE
Contact: Cheryl Kefauver
Phone: 323-865-0459
Newport Beach
USC Norris Oncology / Hematology-Newport Beach
Status: ACTIVE
Contact: Kristy Marie Massopust
Phone: 949-474-5733
Sacramento
University of California Davis Comprehensive Cancer Center
Status: ACTIVE
Contact: Mamta Parikh
Phone: 916-734-3772

Kansas

Kansas City
University of Kansas Cancer Center
Status: ACTIVE
Contact: Rahul A. Parikh
Phone: 913-588-1897

Nevada

Las Vegas
Comprehensive Cancer Centers of Nevada - Central Valley
Status: ACTIVE
Contact: Nicholas J. Vogelzang
Phone: 702-968-3880

North Carolina

Charlotte
Carolinas Medical Center / Levine Cancer Institute
Status: ACTIVE
Contact: Earle Frederick Burgess
Phone: 980-442-2000
Levine Cancer Institute-Ballantyne
Status: ACTIVE
Contact: Earle Frederick Burgess
Phone: 980-442-2000
Gastonia
Levine Cancer Institute-Gaston
Status: ACTIVE
Contact: Earle Frederick Burgess

Virginia

Charlottesville
University of Virginia Cancer Center
Status: ACTIVE
Contact: Michael E Devitt
Phone: 434-297-7782

PRIMARY OBJECTIVES:

I. To determine the feasibility of using pembrolizumab-recombinant EphB4-HSA fusion protein (sEphB4-HSA) combination in patients with urothelial carcinoma.

II. To estimate the overall survival (OS) in patients previously treated platinum refractory patients.

III. To estimate the pathologic response rate and overall survival (OS) in newly diagnosed platinum eligible and ineligible patients treated in neoadjuvant setting prior to radical cystectomy.

SECONDARY OBJECTIVES:

I. To estimate the progression-free survival (PFS) in both previously treated and previously untreated patients.

II. To estimate the objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 in previously treated patients.

CORRELATIVE 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.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
USC / Norris Comprehensive Cancer Center

Principal Investigator
Sarmad Sadeghi

  • Primary ID 4B-15-11
  • Secondary IDs NCI-2016-00147
  • Clinicaltrials.gov ID NCT02717156