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Ramucirumab and Pembrolizumab for the Treatment of EGFR Mutant Recurrent or Metastatic Non-small Cell Lung Cancer

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ClinicalTrials.gov Identifier: NCT04120454
Recruitment Status : Recruiting
First Posted : October 9, 2019
Last Update Posted : October 9, 2020
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Erin Bertino, Ohio State University Comprehensive Cancer Center

Brief Summary:
This phase II trial studies how well ramucirumab and pembrolizumab work in treating EGFR mutant non-small cell lung cancer that has come back (recurrent) or spread to other places in the body (metastatic). Ramucirumab may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. 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 ramucirumab and pembrolizumab may work better in treating EGFR mutant non-small cell lung cancer compared to pembrolizumab alone.

Condition or disease Intervention/treatment Phase
Metastatic Lung Non-Small Cell Carcinoma Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Cancer AJCC v8 Stage IVA Lung Cancer AJCC v8 Stage IVB Lung Cancer AJCC v8 Biological: Pembrolizumab Biological: Ramucirumab Phase 2

Detailed Description:

PRIMARY OBJECTIVE:

I. To evaluate response rate of the combination of ramucirumab and pembrolizumab in EGFR mutant non-small cell lung cancer (NSCLC).

SECONDARY OBJECTIVE:

I. To evaluate safety, tolerability, and survival for patients receiving pembrolizumab and ramucirumab.

EXPLORATORY OBJECTIVE:

I. To characterize predictive immunologic biomarkers of response in tissue and peripheral blood of patients receiving ramucirumab and pembrolizumab combination therapy.

OUTLINE:

Patients receive ramucirumab intravenously (IV) over 60 minutes and pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 35 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, every 3 months for 1 year, and then every 6 months for 1 year.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 34 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Investigator-Sponsored Phase 2 Single Arm Trial of Ramucirumab and Pembrolizumab in Patients With EGFR Mutant Non-Small Cell Lung Cancer
Actual Study Start Date : March 16, 2020
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : December 31, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Treatment (ramucirumab, pembrolizumab)
Patients receive ramucirumab IV over 60 minutes and pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 35 cycles in the absence of disease progression or unacceptable toxicity.
Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475

Biological: Ramucirumab
Given IV
Other Names:
  • anti-VEGFR-2 fully human monoclonal antibody IMC-1121B
  • Cyramza
  • IMC-1121B
  • LY3009806
  • Monoclonal Antibody HGS-ETR2




Primary Outcome Measures :
  1. Overall response rate [ Time Frame: Up to 2 years ]
    Response rate will be evaluated with computed tomography (CT) scans every 2 cycles and tumor measurements using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Immune RECIST (iRECIST) will also be assessed.


Secondary Outcome Measures :
  1. Incidence of adverse events [ Time Frame: Up to 2 years ]
    Common Terminology Criteria for Adverse Events version 4.0 will be used for adverse event grading. Attributions of causality will be assessed by the primary treating physician. Frequency and severity of adverse events and tolerability of the regimen will be collected and summarized by descriptive statistics for each of the disease cohorts.

  2. Clinical benefit rate (complete response + partial response + stable disease) [ Time Frame: Up to 2 years ]
    Clinical benefit rate will be evaluated with CT scans every 2 cycles and tumor measurements using RECIST 1.1 criteria. iRECIST will also be assessed.

  3. Progression-free survival [ Time Frame: From the date of study registration to the date of progressive disease, assessed up to 2 years ]
    Kaplan-Meier curves will be calculated to estimate progression-free survival.

  4. Overall survival [ Time Frame: From the date of study registration to the date of death, assessed up to 2 years ]
    Kaplan-Meier curves will be calculated to estimate overall survival.


Other Outcome Measures:
  1. Tumor immunoprofile [ Time Frame: Baseline ]
    Measured by immunohistochemistry, including tumor infiltrating lymphocytes and T cell receptor (TCR) immunosequencing (immunoSEQ) and relationship to clinical outcomes, including response rate. TCR immunoSEQ data will be summarized for each patient for T-cell clonality difference, descriptive statistics and confidence interval will be obtained across patients.

  2. Circulating immune cell profiles in response to treatment and in relation to clinical response [ Time Frame: Up to 2 years ]
    Measured using 10-color 65 marker multiplex Clinical Laboratory Improvement Act-certified IMMUNOME flow cytometry profile on peripheral blood samples. For immune cell subpopulation data by flow cytometry, will identify differences between the paired peripheral blood mononuclear cell samples from the same patients.

  3. Change in circulating VEGF levels [ Time Frame: Baseline up to 2 years ]
    Will evaluate correlation with clinical response. A bivariate plot will be used to describe the relationship between response rate and peak VEGF via enzyme-linked immunosorbent assay over time.



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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:

  • Histologically confirmed recurrent or metastatic non-small cell carcinoma of the lung with sensitizing EGFR mutations. Exon 20 resistance mutations will not be permitted but uncommon sensitizing mutations are allowed
  • Prior systemic anticancer therapy: neo/adjuvant therapy or prior therapy for locally advanced disease will be permitted if interval between last therapy and recurrent disease is at least 6 months. Patients with prior exposure to PD/PD-L1 inhibitors will be excluded. Limit of 2 prior EGFR tyrosine kinase inhibitors (TKIs) (erlotinib, gefitinib, afatinib, dacomitinib or osimertinib). Patients who develop progressive disease after erlotinib, gefitinib, afatinib, or dacomitinib must either receive osimertintib (T790M positive) or be T790M negative. Prior chemotherapy for metastatic disease is permitted only if TKI was the most recent therapy received
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Evaluation of ECOG is to be performed within 7 days prior to the date of allocation/randomization
  • Absolute neutrophil count (ANC) >= 1500/uL (within 10 days prior to the start of study treatment)
  • Platelets >= 100 000/uL (within 10 days prior to the start of study treatment)
  • Hemoglobin >= 9.0 g/dL or >= 5.6 mmol/L (within 10 days prior to the start of study treatment)

    • Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks
  • Creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance >= 40 mL/min for participant with creatinine levels > 1.5 x institutional ULN (within 10 days prior to the start of study treatment)

    • Creatinine clearance (CrCl) should be calculated per institutional standard
    • Glomerular filtration rate (GFR) can also be used in place of creatinine or CrCl
  • Urine protein =< 1+ on dipstick or routine urinalysis (UA) (within 10 days prior to the start of study treatment)

    • If urine dipstick or routine analysis is >= 2+, a 24-hour urine collection for protein must demonstrate < 1000 mg of protein in 24 hours to allow participation in this protocol
  • Total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for participants with total bilirubin levels > 1.5 x ULN (within 10 days prior to the start of study treatment)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x ULN (=< 5 x ULN for participants with liver metastases) (within 10 days prior to the start of study treatment)
  • International normalized ratio (INR) OR prothrombin time (PT) =< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or activated partial thromboplastin time (aPTT) is within therapeutic range of intended use of anticoagulants (within 10 days prior to the start of study treatment)

    • Patients on full-dose anticoagulation must be on a stable dose (minimum duration 14 days) of oral anticoagulant or low molecular weight heparin (LMWH). If receiving warfarin, the patient must have an INR =< 3.0. For heparin and LMWH there should be no active bleeding (that is, no bleeding within 14 days prior to first dose of protocol therapy) or pathological condition present that carries a high risk of bleeding (for example, tumor involving major vessels or known varices)
  • Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants (within 10 days prior to the start of study treatment)

    • Patients on full-dose anticoagulation must be on a stable dose (minimum duration 14 days) of oral anticoagulant or low molecular weight heparin (LMWH). If receiving warfarin, the patient must have an INR =< 3.0. For heparin and LMWH there should be no active bleeding (that is, no bleeding within 14 days prior to first dose of protocol therapy) or pathological condition present that carries a high risk of bleeding (for example, tumor involving major vessels or known varices)
  • Because the teratogenicity of ramucirumab is not known, patients who are sexually active, must be either postmenopausal, surgically sterile, or using effective contraception (hormonal or barrier methods)

    • A male participant must agree to use a contraception during the treatment period and for at least 3 months after the last dose of study treatment and refrain from donating sperm during this period
    • A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:

      • Not a woman of childbearing potential (WOCBP) OR
      • A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 3 months after the last dose of study treatment
  • For female patients of childbearing potential, a negative serum pregnancy test within 72 hours prior to first dose of protocol therapy is required

Exclusion Criteria:

  • 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 (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
  • Known active chronic infections ? human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), known active hepatitis B or C. Known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (defined as hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected) infection

    • Note: no testing for hepatitis B and hepatitis C is required unless mandated by local health authority
  • Cirrhosis (Child-Pugh B or worse) or cirrhosis with history of hepatic encephalopathy or clinically meaningful ascites resulting from cirrhosis. Clinically meaningful ascites is defined as ascites from cirrhosis requiring diuretics or paracentesis
  • Prior exposure to ramucirumab
  • Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX-40, CD137)
  • Any grade 3-4 gastrointestinal (GI) bleeding within 3 months prior to first dose of protocol therapy
  • History of deep vein thrombosis (DVT), pulmonary embolism (PE), or any other significant thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis are not considered ?significant?) during the 3 months prior to first dose of protocol therapy
  • Patients receiving chronic antiplatelet therapy, including aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs, including ibuprofen, naproxen, and others), dipyridamole or clopidogrel, or similar agents. Once-daily aspirin use (maximum dose 325 mg/day) is permitted
  • Untreated central nervous system (CNS) metastases. Patients with treated brain metastases are eligible if they were clinically stable with regard to neurologic function, off steroids after cranial irradiation (whole brain radiation therapy, focal radiation therapy, and stereotactic radiosurgery) ending at least 2 weeks prior to randomization, or after surgical resection performed at least 28 days prior to randomization. The patient must have no evidence of grade >= 1 CNS hemorrhage based on pretreatment magnetic resonance imaging (MRI) or IV contrast computed tomography (CT) scan (performed within 21 days before randomization)
  • Hemoptysis (defined as bright red blood or >= 1/2 teaspoon) within 2 months prior to first dose of protocol therapy or with radiographic evidence of intratumor cavitation or has radiologically documented evidence of major blood vessel invasion or encasement by cancer
  • Uncontrolled or poorly-controlled hypertension (> 160 mmHg systolic or > 100 mmHg diastolic for > 4 weeks) despite standard medical management
  • Any arterial thromboembolic events, including but not limited to myocardial infarction, transient ischemic attack, cerebrovascular accident, or unstable angina, within 6 months prior to first dose of protocol therapy
  • Major surgery within 28 days or device placement within 7 days prior to the first dose of protocol therapy. Patient has elective or planned major surgery to be performed during the course of the clinical trial
  • Serious or non-healing wound, ulcer, or bone fracture within 28 days of study treatment
  • Prior history of GI perforation/fistula (within 6 months of first dose of protocol therapy) or risk factors for perforation
  • Small cell or mixed (small cell/non-small cell) lung cancer
  • Pregnancy or breastfeeding
  • Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed
  • History of (non-infectious) pneumonitis that required steroids or has current pneumonitis
  • History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject?s participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
  • Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
  • Severe hypersensitivity (>= grade 3) to pembrolizumab and/or any of its excipients
  • Active infection requiring systemic therapy
  • Known history of active TB (Bacillus tuberculosis)

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): NCT04120454


Contacts
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Contact: The Ohio State University Comprehensive Cancer Center 1-800-293-5066 OSUCCCClinicaltrial@osumc.edu
Contact: Carly Pilcher carly.pilcher@osumc.edu

Locations
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United States, Ohio
Ohio State University Comprehensive Cancer Center Recruiting
Columbus, Ohio, United States, 43210
Contact: Erin M. Bertino, MD    614-293-8000    Erin.Bertino@osumc.edu   
Principal Investigator: Erin M. Bertino, MD         
Sponsors and Collaborators
Ohio State University Comprehensive Cancer Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Erin M Bertino, M.D. Ohio State University Comprehensive Cancer Center
Additional Information:
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Responsible Party: Erin Bertino, Principal Investigator, Ohio State University Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT04120454    
Other Study ID Numbers: OSU-19132
NCI-2019-05348 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
P30CA016058 ( U.S. NIH Grant/Contract )
First Posted: October 9, 2019    Key Record Dates
Last Update Posted: October 9, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
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
Antineoplastic Agents, Immunological
Pembrolizumab
Ramucirumab
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Lexatumumab
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents