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Ramucirumab and Pembrolizumab Versus Standard of Care in Treating Patients With Stage IV or Recurrent Non-small Cell Lung Cancer (A Lung-MAP Non-Match Treatment Trial)

NCT03971474

Description:

This phase II Lung-MAP non-Match treatment trial studies how well ramucirumab and pembrolizumab work versus standard of care in treating patients with non-small cell lung cancer that is stage IV or has come back. Immunotherapy with monoclonal antibodies, such as ramucirumab and pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in standard of care chemotherapy for non-small cell lung cancer, such as docetaxel, gemcitabine hydrochloride, and pemetrexed, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ramucirumab and pembrolizumab together may work better in treating patients with non-small lung cancer compared to standard of care.

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

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Ramucirumab and Pembrolizumab Versus Standard of Care in Treating Patients With Stage IV or Recurrent Non-small Cell Lung Cancer (A Lung-MAP Non-Match Treatment Trial)
  • Official Title: A Phase II Randomized Study of Ramucirumab Plus MK3475 (Pembrolizumab) Versus Standard of Care for Patients Previously Treated With Immunotherapy for Stage IV or Recurrent Non-Small Cell Lung Cancer (Lung-MAP Non-Matched Sub-Study)

Clinical Trial IDs

  • ORG STUDY ID: S1800A
  • SECONDARY ID: NCI-2019-00703
  • SECONDARY ID: S1800A
  • SECONDARY ID: S1800A
  • SECONDARY ID: U10CA180888
  • NCT ID: NCT03971474

Conditions

  • 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
DocetaxelDocecad, RP56976, Taxotere, Taxotere Injection ConcentrateArm A (docetaxel, gemcitabine, ramucirumab, pemetrexed)
GemcitabinedFdC, dFdCyd, DifluorodeoxycytidineArm A (docetaxel, gemcitabine, ramucirumab, pemetrexed)
Gemcitabine HydrochloridedFdCyd, Difluorodeoxycytidine Hydrochloride, Gemzar, LY-188011, LY188011Arm A (docetaxel, gemcitabine, ramucirumab, pemetrexed)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Arm B (ramucirumab, pembrolizumab)
PemetrexedMTA, Multitargeted AntifolateArm A (docetaxel, gemcitabine, ramucirumab, pemetrexed)
Pemetrexed DisodiumAlimta, LY231514, N-[4-[2-(2-Amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic Acid Disodium SaltArm A (docetaxel, gemcitabine, ramucirumab, pemetrexed)
Ramucirumabanti-VEGFR-2 fully human monoclonal antibody IMC-1121B, Cyramza, IMC-1121B, LY3009806, Monoclonal Antibody HGS-ETR2Arm A (docetaxel, gemcitabine, ramucirumab, pemetrexed)

Purpose

This phase II Lung-MAP non-Match treatment trial studies how well ramucirumab and pembrolizumab work versus standard of care in treating patients with non-small cell lung cancer that is stage IV or has come back. Immunotherapy with monoclonal antibodies, such as ramucirumab and pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in standard of care chemotherapy for non-small cell lung cancer, such as docetaxel, gemcitabine hydrochloride, and pemetrexed, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ramucirumab and pembrolizumab together may work better in treating patients with non-small lung cancer compared to standard of care.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To compare overall survival between patients previously treated with platinum-based
      chemotherapy and immunotherapy for stage IV or recurrent non-small cell lung cancer
      randomized to ramucirumab and MK-3475 (pembrolizumab) versus standard of care (SoC).

      SECONDARY OBJECTIVES:

      I. To compare response rates between the arms, including complete response (CR) and partial
      response (PR) (confirmed and unconfirmed).

      II. To compare the disease control rate (CR, PR, confirmed and unconfirmed and stable disease
      [SD]).

      III. To evaluate the duration of response (DoR) among responders within each arm.

      IV. To evaluate the frequency and severity of toxicities within each arm. V. To compare
      investigator assessed-progression-free survival (IA-PFS) between the arms.

      VI. To evaluate the clinical outcomes (overall survival [OS], IA-PFS, response) by
      randomization stratification factors by comparing outcomes within the ramucirumab and MK-3475
      (pembrolizumab) arm, performing a sub-group analysis of the arms, and by evaluating an
      interaction between the factors and treatment arm.

      TRANSLATIONAL MEDICINE OBJECTIVES:

      I. To evaluate if PD-L1 expression levels are associated with clinical outcomes (OS, IA-PFS,
      and response).

      II. To evaluate if tumor mutation burden (TMB) as determined by the Foundation Medicine Inc
      (FMI) Foundation One panel is associated with clinical outcomes.

      III. To collect, process, and bank cell-free (circulating cell-free deoxyribonucleic acid
      [cfDNA]) at baseline and progression for future development of a proposal to evaluate
      comprehensive next-generation sequencing of circulating tumor DNA (ctDNA).

      IV. To establish a tissue/blood repository to pursue future studies.

      OUTLINE: Patients are randomized to 1 of 2 arms.

      ARM A: Patients may receive docetaxel intravenously (IV) over 10-30 minutes on day 1,
      gemcitabine hydrochloride IV over 30 minutes on days 1 and 8, pemetrexed IV over 10 minutes
      on day 1 (non-squamous NSCLC patients only), or ramucirumab IV over 60 minutes combined with
      docetaxel IV over 10-30 minutes on day 1. Cycles repeat every 21 days in the absence of
      disease progression or unacceptable toxicity.

      ARM B: Patients receive ramucirumab IV over 60 minutes on day 1. Cycles repeat every 21 days
      in the absence of disease progression or unacceptable toxicity. Patients also receive
      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 (prior to disease progression), patients are followed up
      every 3 months for the first year, and then every 6 months for up to 3 years from date of
      randomization. After completion of study treatment (after disease progression), patients are
      followed up every 6 months for 2 years, then at the end of year 3 from the date of
      randomization.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (docetaxel, gemcitabine, ramucirumab, pemetrexed)Active ComparatorPatients receive docetaxel IV over 10-30 minutes on day 1 and gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 or ramucirumab IV over 60 minutes and docetaxel IV over 10-30 minutes on day 1. Patients with non-squamous NSCLC receiving docetaxel and gemcitabine hydrochloride, also receive pemetrexed IV over 10 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Docetaxel
  • Gemcitabine
  • Gemcitabine Hydrochloride
  • Pemetrexed
  • Pemetrexed Disodium
  • Ramucirumab
Arm B (ramucirumab, pembrolizumab)ExperimentalPatients receive ramucirumab IV over 60 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also receive 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:

          -  Patients must have been assigned to S1800A by the Southwest Oncology Group (SWOG)
             Statistics and Data Management Center (SDMC). Patients who were screened under S1400
             (legacy screening/pre-screening study) must have had prior PD-L1 testing by the Dako
             22C3 PharmDx immunohistochemistry (IHC) assay, and must have results available for
             stratification purposes

          -  Patients must not have EGFR sensitizing mutations, EGFR T790M mutation, ALK gene
             fusion, ROS 1 gene rearrangement, and BRAF V600E mutation unless they have progressed
             following all standard of care targeted therapy

          -  Patients must not have an active autoimmune disease that has required systemic
             treatment in past two 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) is not considered a form of systemic treatment and is allowed

          -  Patients must not have any history of primary immunodeficiency

          -  Patients must not have experienced the following:

               -  Any grade 3 or worse immune-related adverse event (irAE). Exception: asymptomatic
                  nonbullous/nonexfoliative rash

               -  Any unresolved grade 2 irAE

               -  Any toxicity that led to permanent discontinuation of prior anti-PD-1/PD-L1
                  immunotherapy

                    -  Exception to the above: Toxicities of any grade that requires replacement
                       therapy and has stabilized on therapy (e.g., thyroxine, insulin, or
                       physiologic corticosteroid replacement therapy for adrenal or pituitary
                       insufficiency) are allowed

          -  Patients must not have any history of organ transplant that requires use of
             immunosuppressives

          -  Patients must not have clinical signs or symptoms of active tuberculosis infection

          -  Patients must not have history of (non-infectious) pneumonitis that required steroids
             or current pneumonitis/interstitial lung disease

          -  Patients must not have had a serious or nonhealing wound, ulcer, or bone fracture
             within 28 days prior to sub-study randomization

          -  Patients must not have a history of gastrointestinal perforation or fistula within six
             months prior to sub-study randomization

          -  Patients must not have grade 3-4 gastrointestinal bleeding (defined by National Cancer
             Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version [v] 5)
             within three months prior to sub-study randomization

          -  Patients must not have any known allergy or reaction to any component of the
             investigational and standard of care formulations

          -  Patients must not have any grade III/IV cardiac disease as defined by the New York
             Heart Association criteria (i.e., patients with cardiac disease resulting in marked
             limitation of physical activity or resulting in inability to carry on any physical
             activity without discomfort), unstable angina pectoris, and myocardial infarction
             within six months prior to sub-study randomization, or serious uncontrolled cardiac
             arrhythmia

          -  Patients must not have experienced any arterial thromboembolic events, including but
             not limited to myocardial infarction, transient ischemic attack, cerebrovascular
             accident, or unstable angina, within six months prior to sub-study randomization

          -  Patients must not have documented evidence of acute hepatitis or have an active or
             uncontrolled infection

          -  Patients with known human immunodeficiency virus (HIV) infection are eligible,
             provided they are on effective anti-retroviral therapy and have undetectable viral
             load at their most recent viral load test and within 6 months prior to randomization

          -  Patients with evidence of chronic hepatitis B virus (HBV) infection are eligible
             provided viral load is undetectable on suppressive therapy, if indicated

          -  Patients with a history of hepatitis C virus (HCV) infection must have been treated
             and cured. For patients with HCV infection who are currently on treatment, they are
             eligible if they have an undetectable HCV viral load

          -  Patients must not have undergone major surgery within 28 days prior to sub-study
             randomization, or subcutaneous venous access device placement within 7 days prior to
             randomization. Any patient with postoperative bleeding complications or wound
             complications from a surgical procedure performed in the last two months should be
             excluded. The patient must not have elective or planned major surgery to be performed
             during the course of the clinical trial

          -  Patients must not have gross hemoptysis within two months of sub-study randomization
             (defined as bright red blood or >= 1/2 teaspoon) or with radiographic evidence of
             intratumor cavitation or has radiologically documented evidence of major blood vessel
             invasion or encasement by cancer

          -  No other prior malignancy is allowed except for the following: adequately treated
             basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated
             stage I or II cancer from which the patient is currently in complete remission, or any
             other cancer from which the patient has been disease free for five years

          -  Patients must not have been diagnosed with venous thrombosis less than 3 months prior
             to randomization. Patients with venous thrombosis diagnosed more than 3 months prior
             to randomization must be on stable doses of anticoagulants

          -  Patients must not have any of following:

               -  Cirrhosis at a level of Child-Pugh B (or worse);

               -  Cirrhosis (any degree) and a history of hepatic encephalopathy; or

               -  Clinically meaningful ascites resulting from cirrhosis. Clinically meaningful
                  ascites is defined as ascites from cirrhosis requiring diuretics or paracentesis

          -  Patients must have received exactly one line of anti-PD-1 or anti-PD-L1 therapy for at
             least 84 days as their most recent line of therapy, either alone or in combination
             with platinum-based chemotherapy. Patients must have experienced disease progression
             during or after this regimen. Patients whose most recent line of therapy was anti-PD-1
             or anti-PD-L1 monotherapy must have also experienced disease progression during or
             after prior platinum-based chemotherapy

          -  Patients must not have received any prior systemic therapy (systemic chemotherapy,
             immunotherapy or investigational drug) within 21 days prior to substudy randomization.
             Patients must have recovered (=< grade 1) from any side effects of prior therapy,
             except for alopecia. Patients must not have received any radiation therapy within 14
             days prior to sub-study randomization

          -  Patients must not have received nitrosoureas or mitomycin-c within 42 days prior to
             sub-study randomization

          -  Patients must not have received systemic treatment with corticosteroids (> 10 mg daily
             prednisone or equivalent) or other immunosuppressive medications within seven days
             prior to sub-study randomization. Inhaled or topical steroids, and adrenal replacement
             doses =< 10 mg daily prednisone or equivalent are permitted in the absence of active
             autoimmune disease

          -  Patients must not have received a live attenuated vaccination within 28 days prior to
             sub-study randomization

          -  Patients must not be planning to receive any concurrent chemotherapy, immunotherapy,
             biologic or hormonal therapy for cancer treatment while receiving treatment on this
             study. Concurrent use of hormones for non-cancer-related conditions (e.g., insulin for
             diabetes and hormone replacement therapy) is acceptable

          -  Patients must not be receiving chronic antiplatelet therapy, including aspirin,
             nonsteroidal anti-inflammatory drugs (NSAIDs, including ibuprofen, naproxen, and
             others), dipyridamole or clopidogrel, or similar agents within 7 days prior to
             randomization. Once-daily aspirin use (maximum dose 325 mg/day) is permitted

          -  Patient must not have received radiotherapy within 14 days before the first dose of
             study treatment or received lung radiation therapy of > 30 Gy within 6 months before
             the first dose of study treatment

               -  Note: Participants must have recovered from all radiation-related toxicities to
                  grade 1 or less, not require corticosteroids, and not have had radiation
                  pneumonitis

          -  Patients must have measurable disease documented by computed tomography (CT) or
             magnetic resonance imaging (MRI). The CT from a combined positron emission tomography
             (PET)/CT may be used to document only non-measurable disease unless it is of
             diagnostic quality. Measurable disease must be assessed within 28 days prior to
             substudy randomization. Pleural effusions, ascites and laboratory parameters are not
             acceptable as the only evidence of disease. Non-measurable disease must be assessed
             within 42 days prior to sub-study randomization. All disease must be assessed and
             documented on the Baseline Tumor Assessment Form. Patients whose only measurable
             disease is within a previous radiation therapy port must demonstrate clearly
             progressive disease (in the opinion of the treating investigator) prior to sub-study
             randomization. CT and MRI scans must be submitted for central review via transfer of
             images and data (TRIAD)

          -  Patients must have a CT or MRI scan of the brain to evaluate for central nervous
             system (CNS) disease within 42 days prior to sub-study randomization. Patient must not
             have leptomeningeal disease, spinal cord compression or brain metastases unless: (1)
             metastases have been locally treated and have remained clinically controlled and
             asymptomatic for at least 14 days following treatment, and prior to sub-study
             randomization, AND (2) patient has no residual neurological dysfunction and has been
             off corticosteroids for at least seven days prior to sub-study randomization

          -  Absolute neutrophil count (ANC) >= 1,500/mcl (obtained within 28 days prior to
             sub-study randomization)

          -  Platelet count >= 100,000 mcl (obtained within 28 days prior to sub-study
             randomization)

          -  Hemoglobin >= 9 g/dL (obtained within 28 days prior to sub-study randomization)

          -  Serum bilirubin =< institutional upper limit of normal (IULN) within 28 days prior to
             sub-study randomization. For patients with liver metastases, bilirubin must be =< 5 x
             IULN; and either

          -  Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) =< 2 x IULN within
             28 days prior to sub-study randomization (if both ALT and AST are done, both must be <
             2 IULN). For patients with liver metastases, either ALT or AST must be =< 5 x IULN (if
             both ALT and AST are done, both must be =< 5 x IULN)

          -  Serum creatinine =< the IULN OR calculated creatinine clearance >= 50 mL/min using the
             Cockcroft-Gault formula. This specimen must have been drawn and processed within 28
             days prior to sub-study randomization

          -  Patients? urinary protein must be =< 1+ on dipstick or routine urinalysis (UA). If
             urine dipstick or routine analysis indicated proteinuria >= 2+, then a 24-hour urine
             is to be collected and demonstrate < 1000 mg of protein in 24 hours to allow
             participation in the study

          -  Patients must not have a history of uncontrolled or poorly-controlled hypertension
             (defined as >= 150 / >= 90 mm Hg for > 4 weeks) despite standard medical management

          -  International normalized ratio (INR) =< 1.5 (documented within 28 calendar days prior
             to randomization)

          -  Partial thromboplastin time (PTT) =< 5 seconds above the institutional upper limit of
             normal (IULN) (unless receiving anticoagulation therapy) (documented within 28
             calendar days prior to randomization)

          -  Patients receiving warfarin must be switched to low molecular weight heparin and have
             achieved stable coagulation profile 14 days prior to randomization. If receiving
             warfarin, the patient must have an INR =< 3.0. For heparin and low molecular weight
             heparin (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)

          -  Patients must have Zubrod performance status 0-1 documented within 28 days prior to
             sub-study randomization

          -  Pre-study history and physical exam must be obtained within 28 days prior to substudy
             randomization

          -  Patients must not be pregnant or nursing. Women/men of reproductive potential must
             have agreed to use an effective contraceptive method during the study and 4 months
             after study completion. A woman is considered to be of "reproductive potential" if she
             has had menses at any time in the preceding 12 consecutive months. In addition to
             routine contraceptive methods, "effective contraception" also includes heterosexual
             celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy
             prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal
             ligation. However, if at any point a previously celibate patient chooses to become
             heterosexually active during the time period for use of contraceptive measures
             outlined in the protocol, he/she is responsible for beginning contraceptive measures
             during the study and 4 months after study completion

          -  Patients must agree to have blood specimens submitted for circulating tumor DNA
             (ctDNA)

          -  Patients must also be offered participation in banking and in the correlative studies
             for collection and future use of specimens

          -  As a part of the Oncology Patient Enrollment Network (OPEN) registration process the
             treating institution's identity is provided in order to ensure that the current
             (within 365 days) date of institutional review board approval for this study has been
             entered in the system

          -  Patients with impaired decision-making capacity are eligible as long as their
             neurological or psychological condition does not preclude their safe participation in
             the study (e.g., tracking pill consumption and reporting adverse events to the
             investigator)

          -  Patients must be informed of the investigational nature of this study and must sign
             and give written informed consent in accordance with institutional and federal
             guidelines
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall survival (OS)
Time Frame:Up to 3 years
Safety Issue:
Description:Will be compared between patients previously treated with platinum-based chemotherapy and immunotherapy for stage IV or recurrent non-small cell lung cancer randomized to ramucirumab and MK-3475 (pembrolizumab) versus standard of care (SoC). Will be estimated using the method of Kaplan-Meier.

Secondary Outcome Measures

Measure:Investigator assessed-progression-free survival (IA-PFS)
Time Frame:From date of sub-study registration to date of first documentation of progression assessed by central review or symptomatic deterioration, or death due to any cause, assessed up to 3 years
Safety Issue:
Description:Will be estimated using the method of Kaplan-Meier. Median and landmark time-point estimates will be based on the Kaplan-Meier estimates. The average hazard ratio (HR) will be estimated using a Cox proportional hazards model. An assessment of the proportional hazards assumption will be performed and an assessment of the time-dependent HR will be done.
Measure:Duration of response (DOR)
Time Frame:From date of first documentation of response (CR or PR), or death due to any cause among patients who achieve a response (CR or PR), assessed up to 3 years
Safety Issue:
Description:Will be estimated using the method of Kaplan-Meier. Median and landmark time-point estimates will be based on the Kaplan-Meier estimates. The average HR will be estimated using a Cox proportional hazards model. An assessment of the proportional hazards assumption will be performed and an assessment of the time-dependent HR will be done.
Measure:Response rates (RR)
Time Frame:Up to 3 years
Safety Issue:
Description:Binary proportions will be summarized with associated confidence intervals. Will be compared with toxicities using a chi-squared test at the 1-sided 0.05 level.
Measure:Incidence of adverse events
Time Frame:Up to 3 years
Safety Issue:
Description:Will be assessed using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Binary proportions will be summarized with associated confidence intervals. Will be compared with RR using a chi-squared test at the 1-sided 0.05 level.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Southwest Oncology Group

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