Clinical Trials /

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

NCT03049618

Description:

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.

Related Conditions:
  • Head and Neck Squamous Cell Carcinoma
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Recombinant EphB4-HSA Fusion Protein and Pembrolizumab, MK-3475
  • 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

Clinical Trial IDs

  • ORG STUDY ID: 0S-16-8
  • SECONDARY ID: NCI-2017-00189
  • SECONDARY ID: 0S-16-8
  • SECONDARY ID: P30CA014089
  • NCT ID: NCT03049618

Conditions

  • 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

Interventions

DrugSynonymsArms
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (pembrolizumab, sEphB4-HSA)
Recombinant EphB4-HSA Fusion ProteinsEphB4-HSATreatment (pembrolizumab, sEphB4-HSA)

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (pembrolizumab, sEphB4-HSA)ExperimentalPatients 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.
  • Pembrolizumab
  • Recombinant EphB4-HSA Fusion Protein

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate (ORR)
Time Frame:Up to 5 years
Safety Issue:
Description: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

Measure:Duration of response
Time Frame:Up to 5 years
Safety Issue:
Description:Duration of response is measured from date of first confirmed response until date of disease progression.
Measure:Incidence of adverse events assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
Time Frame:Up to 5 years
Safety Issue:
Description:Adverse events will be tabulated for the duration of the trial and reported in tabular format.
Measure:Overall survival (OS)
Time Frame:Up to 5 years
Safety Issue:
Description: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.
Measure:Progression free survival (PFS)
Time Frame:Up to 5 years
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Southern California

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