Clinical Trials /

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

NCT04120454

Description:

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.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Ramucirumab and Pembrolizumab for the Treatment of EGFR Mutant Recurrent or Metastatic Non-small Cell Lung Cancer
  • Official Title: An Investigator-Sponsored Phase 2 Single Arm Trial of Ramucirumab and Pembrolizumab in Patients With EGFR Mutant Non-Small Cell Lung Cancer

Clinical Trial IDs

  • ORG STUDY ID: OSU-19132
  • SECONDARY ID: NCI-2019-05348
  • SECONDARY ID: P30CA016058
  • NCT ID: NCT04120454

Conditions

  • 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

Interventions

DrugSynonymsArms
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (ramucirumab, pembrolizumab)
Ramucirumabanti-VEGFR-2 fully human monoclonal antibody IMC-1121B, Cyramza, IMC-1121B, LY3009806, Monoclonal Antibody HGS-ETR2Treatment (ramucirumab, pembrolizumab)

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (ramucirumab, pembrolizumab)ExperimentalPatients 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.
  • Pembrolizumab
  • Ramucirumab

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

Primary Outcome Measures

Measure:Overall response rate
Time Frame:Up to 2 years
Safety Issue:
Description: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

Measure:Incidence of adverse events
Time Frame:Up to 2 years
Safety Issue:
Description: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.
Measure:Clinical benefit rate (complete response + partial response + stable disease)
Time Frame:Up to 2 years
Safety Issue:
Description: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.
Measure:Progression-free survival
Time Frame:From the date of study registration to the date of progressive disease, assessed up to 2 years
Safety Issue:
Description:Kaplan-Meier curves will be calculated to estimate progression-free survival.
Measure:Overall survival
Time Frame:From the date of study registration to the date of death, assessed up to 2 years
Safety Issue:
Description:Kaplan-Meier curves will be calculated to estimate overall survival.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Ohio State University Comprehensive Cancer Center

Last Updated