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Recombinant EphB4-HSA Fusion Protein and Pembrolizumab, MK-3475

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ClinicalTrials.gov Identifier: NCT03049618
Recruitment Status : Recruiting
First Posted : February 10, 2017
Last Update Posted : April 3, 2018
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
University of Southern California

Brief Summary:
This phase IIa trial studies how well recombinant EphB4-HSA fusion protein and pembrolizumab work in treating patients with non-small cell lung cancer that has spread to other places in the body or head and neck squamous cell cancer that has come back or spread to other places in the body. Recombinant EphB4-HSA fusion protein may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of cancer cells to grow and spread. Giving recombinant EphB4-HSA fusion protein and pembrolizumab may work better in treating patients with non-small cell lung or head and neck squamous cell cancer.

Condition or disease Intervention/treatment Phase
ALK Gene Mutation BRAF Gene Mutation EGFR Gene Mutation Head and Neck Squamous Cell Carcinoma Metastatic Head and Neck Carcinoma Recurrent Head and Neck Carcinoma Recurrent Non-Small Cell Lung Carcinoma ROS1 Gene Mutation Stage III Non-Small Cell Lung Cancer Stage IIIA Non-Small Cell Lung Cancer Stage IIIB Non-Small Cell Lung Cancer Stage IV Non-Small Cell Lung Cancer Other: Laboratory Biomarker Analysis Biological: Pembrolizumab Biological: Recombinant EphB4-HSA Fusion Protein Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. Determine the response rate of the combination of pembrolizumab and recombinant EphB4-HSA fusion protein (sEphB4-HSA) as combination therapy.

SECONDARY OBJECTIVES:

I. Determine the biomarkers of response. II. Determine the unique toxicities of the combination of pembrolizumab and sEphB4-HSA.

OUTLINE:

Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1 and recombinant EphB4-HSA fusion protein IV over 30 minutes on days 1, 8, and 15. Courses repeat every 3 weeks for up to 24 months in the absence of disease progression or unacceptable toxicity.

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


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase IIa Trial of sEphB4-HSA in Combination With Anti PD-1 Antibody (Pembrolizumab, MK3475) in Patients With Non-small Cell Lung and Head/Neck Cancer
Actual Study Start Date : March 10, 2017
Estimated Primary Completion Date : March 10, 2019
Estimated Study Completion Date : March 10, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Treatment (pembrolizumab, sEphB4-HSA)
Patients receive pembrolizumab IV over 30 minutes on day 1 and recombinant EphB4-HSA fusion protein IV over 30 minutes on days 1, 8, and 15. Courses repeat every 3 weeks for up to 24 months in the absence of disease progression or unacceptable toxicity.
Other: Laboratory Biomarker Analysis
Correlative studies

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

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




Primary Outcome Measures :
  1. Overall response rate (ORR) [ Time Frame: Up to 5 years ]
    Will be calculated based on the evaluable population of patients who received at least 1 dose of therapy. Will be analyzed in groupings of patients according to biomarkers of interest including (a) PD-L1 expression on archival tissue and current peripheral blood CTCs, (b) peripheral blood T cell subset analysis, (c) quantitative T-cell tumor infiltration, and (d) genomic complexity and (e) integrin expression pattern in tumor blood vessels.


Secondary Outcome Measures :
  1. Duration of response [ Time Frame: Up to 5 years ]
    Duration of response is measured from date of first confirmed response until date of disease progression.

  2. Incidence of adverse events assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 5 years ]
    Adverse events will be tabulated for the duration of the trial and reported in tabular format.

  3. Overall survival (OS) [ Time Frame: Up to 5 years ]
    Will be determined according to the method of Kaplan and Meier and analyzed for each cohort. Will be analyzed in groupings of patients according to biomarkers of interest including (a) PD-L1 expression on archival tissue and current peripheral blood CTCs, (b) peripheral blood T cell subset analysis, (c) quantitative T-cell tumor infiltration, and (d) genomic complexity and (e) integrin expression pattern in tumor blood vessels.

  4. Progression free survival (PFS) [ Time Frame: Up to 5 years ]
    Will be determined according to the method of Kaplan and Meier and analyzed for each cohort. Will be analyzed in groupings of patients according to biomarkers of interest including (a) PD-L1 expression on archival tissue and current peripheral blood CTCs, (b) peripheral blood T cell subset analysis, (c) quantitative T-cell tumor infiltration, and (d) genomic complexity and (e) integrin expression pattern in tumor blood vessels.


Other Outcome Measures:
  1. Biomarker analysis of PD-1 and PD-L1 assessed by archived tumor tissue by immunohistochemical testing [ Time Frame: Up to 5 years ]
    The impact of treatment on the levels of PD-L1 expression, T-cell subsets and tumor infiltrating lymphocytes will be compared in archival and post treatment biopsy specimens.



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:

  • One of the following:

    • Locally advanced or metastatic non-small cell lung cancer that has progressed after at least 1 line of platinum based chemotherapy

      • Patients may have received up to 2 prior lines of chemotherapy
      • Patients with actionable alterations in EGFR/ALK/ROS1/BRAF must also have progressed after treatment with a tyrosine kinase inhibitor appropriate for their genetic alteration
      • Untreated patients who refuse 1st line platinum based chemotherapy are also eligible
    • Squamous cell carcinoma of the head and neck whose disease has progressed after at least 1 line of platinum based chemotherapy

      • Patients may have received up to 2 prior lines of chemotherapy
      • Untreated patients who refuse 1st line platinum based chemotherapy are also eligible
      • Patients who relapse within 6 months of adjuvant cisplatin based concurrent chemoradiation, or neoadjuvant cisplatin based therapy can be considered eligible without an additional course of platinum chemotherapy for relapsed disease
      • Patients may have either locally recurrent or distant metastatic disease
  • Be willing and able to provide written informed consent/assent for the trial
  • Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
  • Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion after 2 cycles of therapy
  • 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)
  • Serum creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine levels > 1.5 x institutional 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
  • 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 use an adequate method of contraception for the course of the study through 120 days after the last dose of study medication

    • 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, 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

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 (i.e., =< 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 (i.e., =< 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; known brain metastases are considered active, if any of the following criteria is applicable:

    • Brain imaging during screening demonstrates progression of existing metastases and/or appearance of new lesions compared to brain imaging performed at least 4 weeks earlier
    • Neurological symptoms attributed to brain metastases have not returned to baseline
    • Steroids were used for brain metastases within 28 days of randomization
  • 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, anti-PD-L2, or anti cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways
  • Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
  • Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
  • 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 (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed

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): NCT03049618


Contacts
Contact: Gina Tse, RN 323-865-0514 Gina.Tse@med.usc.edu
Contact: Laurie Laurie 323-409-4357 laurie.deoliveira@med.usc.edu

Locations
United States, California
USC / Norris Comprehensive Cancer Center Recruiting
Los Angeles, California, United States, 90033
Contact: Jorge J. Nieva    323-865-0421    jorge.nieva@med.usc.edu   
Principal Investigator: Jorge J. Nieva         
Sponsors and Collaborators
University of Southern California
National Cancer Institute (NCI)
Investigators
Principal Investigator: Jorge Nieva, MD University of Southern California

Responsible Party: University of Southern California
ClinicalTrials.gov Identifier: NCT03049618     History of Changes
Other Study ID Numbers: 0S-16-8
NCI-2017-00189 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
0S-16-8 ( Other Identifier: USC / Norris Comprehensive Cancer Center )
P30CA014089 ( U.S. NIH Grant/Contract )
First Posted: February 10, 2017    Key Record Dates
Last Update Posted: April 3, 2018
Last Verified: March 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Carcinoma
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Carcinoma, Squamous Cell
Head and Neck Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Neoplasms, Squamous Cell
Pembrolizumab
Antineoplastic Agents