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

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ClinicalTrials.gov Identifier: NCT02717156
Recruitment Status : Recruiting
First Posted : March 23, 2016
Last Update Posted : June 15, 2022
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Stage IV Bladder Urothelial Carcinoma Prostate Cancer Urothelial Carcinoma Procedure: Computed Tomography Other: Laboratory Biomarker Analysis Biological: Pembrolizumab Procedure: Positron Emission Tomography Biological: Recombinant EphB4-HSA Fusion Protein Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 170 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Trial of sEphB4-HSA in Combination With Anti PD1 Antibody Pembrolizumab (MK-3475) for Solid Tumors
Actual Study Start Date : November 21, 2016
Estimated Primary Completion Date : November 21, 2023
Estimated Study Completion Date : November 21, 2024


Arm Intervention/treatment
Experimental: Treatment (EphB4-HSA and 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.
Procedure: Computed Tomography
Correlative studies
Other Names:
  • CAT
  • CAT Scan
  • Computerized Axial Tomography
  • Computerized Tomography
  • CT
  • CT SCAN
  • tomography

Other: Laboratory Biomarker Analysis
Correlative studies

Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475

Procedure: Positron Emission Tomography
Correlative studies
Other Names:
  • Medical Imaging, Positron Emission Tomography
  • PET
  • PET SCAN
  • Positron Emission Tomography Scan
  • Positron-Emission Tomography
  • proton magnetic resonance spectroscopic imaging

Biological: Recombinant EphB4-HSA Fusion Protein
Given IV
Other Name: sEphB4-HSA




Primary Outcome Measures :
  1. Incidence of toxicities and adverse events classified according to the Common Terminology Criteria for Adverse Events v4.03 [ Time Frame: 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 :
  1. OR defined as complete response or partial response according to RECIST v 1.1 [ Time Frame: 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria (for all Cohorts):

  • 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
  • Platelets >= 100,000/mcL
  • 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 for subject with creatinine levels > 1.5 X institutional upper limit of normal (ULN)
  • Serum total bilirubin =< 1.5 X ULN or direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN
  • 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
  • Albumin >= 2.5 mg/dL
  • 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
  • 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
  • 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; 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 use adequate method of birth control or be surgically sterile, or abstain from heterosexual activity 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
  • Male subjects must agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy

Criteria specific to 2nd line and 3rd line and beyond cohorts (Cohorts A and B):

  • 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 for 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; an optional core biopsy will be requested from an accessible metastatic site after 2 cycles of treatment and prior to progression of disease to help the investigators better understand the activity of these drugs in tumor tissue.

Criteria specific to the neoadjuvant urothelial cohort (Cohort C):

  • Must have tumor stage ≥T2 AND ≤T4a, N0, M0 (AJCC 8th edition) urothelial carcinoma of the bladder deemed resectable and planned for radical cystectomy with curative intent. T4 due to infiltration of the prostate is allowed.
  • Must have TURBT specimen obtained within 12 weeks prior to the first day of treatment on the study and the specimen must include muscle. Subjects for whom a TURBT specimen within 12 weeks of C1D1 cannot be provided, but an older specimen is available (e.g. unlikely to be able to obtain adequate specimen or subject safety concern) may submit an archived specimen only upon written agreement from the Sponsor.
  • Prior intravesical therapy is allowed. However, patients who have received prior systemic therapy within 12 months enrollment are excluded.

Criteria specific to the neoadjuvant prostate cohort (Cohort D):

  • Must have biopsy proven prostate cancer (Gleason Score ≥7, and PSA >4.0 ng/mL- rare cases can be reviewed and approved with a written agreement from the Sponsor) amenable to radical prostatectomy.
  • Must have appropriate staging imaging showing no evidence of distant metastatic disease. Choice of imaging is per treating physician- some acceptable imaging examples include MRI of pelvis, CT of abdomen and pelvis, bone scan, Axumin PET CT, and PSMA PET CT. For Cohort D, the imaging studies may be considered valid for enrollment beyond the 28 days at the discretion of the treating physician and no longer than 90 days.

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02717156


Contacts
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Contact: Cheryl Kefauver, RN 323-865-0459 Cheryl.Kefauver@med.usc.edu

Locations
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United States, California
City of Hope Recruiting
Duarte, California, United States, 91010
Contact: Valerie Mira    626-218-0171    vmira@coh.org   
Contact: Tina Moore    626-218-5282    timoore@coh.org   
Principal Investigator: Tanya Dorff, MD         
LAC+USC Medical Center Recruiting
Los Angeles, California, United States, 90033
Contact: Cheryl Kefauver, RN    323-865-0459    Cheryl.Kefauver@med.usc.edu   
Principal Investigator: Sarmad Sadeghi, MD         
USC / Norris Comprehensive Cancer Center Recruiting
Los Angeles, California, United States, 90033
Contact: Cheryl Kefauver, RN    323-865-0459    Cheryl.Kefauver@med.usc.edu   
Principal Investigator: Sarmad Sadeghi         
USC Norris Oncology/Hematology - Newport Beach Recruiting
Newport Beach, California, United States, 92663
Contact: Kristy Massopust    949-474-5733    Massopust_K@med.usc.edu   
Sub-Investigator: Greg Angstreich, MD         
UC Davis Comprehensive Cancer Center Recruiting
Sacramento, California, United States, 95817
Contact: Andrew J Buck    916-734-3772    ajbuck@ucdavis.edu   
Principal Investigator: Mamta Parikh, MD         
United States, Kansas
University of Kansas Cancer Center Recruiting
Kansas City, Kansas, United States, 66205
Contact: Jane Ledesma    913-588-0545    jledesma2@kumc.edu   
Contact: Christina Hopkins    913-588-2566    chopkins2@kumc.edu   
Principal Investigator: Rahul Parikh, MD         
United States, Nevada
Comprehensive Cancer Centers of Nevada Recruiting
Las Vegas, Nevada, United States, 89169
Contact: Melissa Vicuna, RN    702-952-3400    melissa.vicuna@usoncology.com   
Contact: Christina Shirley, RN    702-952-3438    christina.shirley@usoncology.com   
Principal Investigator: Nicholas Vogelzang, MD         
United States, North Carolina
Levine Cancer Institute-Carolinas Medical Center Recruiting
Charlotte, North Carolina, United States, 28277
Contact: Melani Terry    704-863-2318    Melani.Terry@atriumhealth.org   
Contact: Lorretta Cecil    980-442-5218    Lorretta.Cecil@atriumhealth.org   
Principal Investigator: Earle Burgess, MD         
United States, Virginia
University of Virginia Cancer Center Recruiting
Charlottesville, Virginia, United States, 22908
Contact: Jennifer Drake    434-243-7064    JD4CX@hscmail.mcc.virginia.edu   
Principal Investigator: Michael Devitt, MD         
Sponsors and Collaborators
University of Southern California
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Sarmad Sadeghi, MD University of Southern California
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Responsible Party: University of Southern California
ClinicalTrials.gov Identifier: NCT02717156    
Other Study ID Numbers: 4B-15-11
NCI-2016-00147 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
4B-15-11 ( Other Identifier: USC / Norris Comprehensive Cancer Center )
P30CA014089 ( U.S. NIH Grant/Contract )
First Posted: March 23, 2016    Key Record Dates
Last Update Posted: June 15, 2022
Last Verified: June 2022

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Transitional Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents