Clinical Trials /

Pembrolizumab With or Without Chemotherapy Before Surgery in Treating Patients With Stage I-IIIA Non-Small Cell Lung Cancer

NCT04061590

Description:

This phase II trial studies how well pembrolizumab with or without chemotherapy works when given before surgery in treating patients with stage I-IIIA non-small cell lung cancer. Immunotherapy with pembrolizumab, may induce changes in body?s immune system and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as cisplatin 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 pembrolizumab with or without chemotherapy may shrink the cancer prior to surgery and decrease the likelihood of the cancer returning following surgery.

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

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab With or Without Chemotherapy Before Surgery in Treating Patients With Stage I-IIIA Non-Small Cell Lung Cancer
  • Official Title: A Phase 2 Study of Neoadjuvant Pembrolizumab-Based Combination Immunotherapy in the Treatment of Early Stage Non-Small Cell Lung Cancer

Clinical Trial IDs

  • ORG STUDY ID: 19702
  • SECONDARY ID: NCI-2019-04763
  • NCT ID: NCT04061590

Conditions

  • Lung Non-Small Cell Carcinoma
  • Stage I Lung Cancer AJCC v8
  • Stage IA1 Lung Cancer AJCC v8
  • Stage IA2 Lung Cancer AJCC v8
  • Stage IA3 Lung Cancer AJCC v8
  • Stage IB Lung Cancer AJCC v8
  • Stage II Lung Cancer AJCC v8
  • Stage IIA Lung Cancer AJCC v8
  • Stage IIB Lung Cancer AJCC v8
  • Stage IIIA Lung Cancer AJCC v8

Interventions

DrugSynonymsArms
CisplatinAbiplatin, Blastolem, Briplatin, CDDP, Cis-diammine-dichloroplatinum, Cis-diamminedichloridoplatinum, Cis-diamminedichloro Platinum (II), Cis-diamminedichloroplatinum, Cis-dichloroammine Platinum (II), Cis-platinous Diamine Dichloride, Cis-platinum, Cis-platinum II, Cis-platinum II Diamine Dichloride, Cismaplat, Cisplatina, Cisplatinum, Cisplatyl, Citoplatino, Citosin, Cysplatyna, DDP, Lederplatin, Metaplatin, Neoplatin, Peyrone''s Chloride, Peyrone''s Salt, Placis, Plastistil, Platamine, Platiblastin, Platiblastin-S, Platinex, Platinol, Platinol- AQ, Platinol-AQ, Platinol-AQ VHA Plus, Platinoxan, Platinum, Platinum Diamminodichloride, Platiran, Platistin, PlatosinCohort B (pembrolizumab, cisplatin pemetrexed)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Cohort A (pembrolizumab)
PemetrexedMTA, Multitargeted AntifolateCohort B (pembrolizumab, cisplatin pemetrexed)
Pemetrexed DisodiumAlimta, Almita, 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 SaltCohort B (pembrolizumab, cisplatin pemetrexed)

Purpose

This phase II trial studies how well pembrolizumab with or without chemotherapy works when given before surgery in treating patients with stage I-IIIA non-small cell lung cancer. Immunotherapy with pembrolizumab, may induce changes in body?s immune system and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as cisplatin 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 pembrolizumab with or without chemotherapy may shrink the cancer prior to surgery and decrease the likelihood of the cancer returning following surgery.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the impact of neoadjuvant pembrolizumab-based combination therapy on the
      composition, phenotype, and function of tumor-infiltrating immune cells (TIICs) in patients
      with early stage non-small cell lung cancer (NSCLC).

      SECONDARY OBJECTIVES:

      I. To determine the safety and tolerability of neoadjuvant pembrolizumab alone and in
      combination with chemotherapy as measured by the National Cancer Institute (NCI) Common
      Terminology Criteria for Adverse Events (CTCAE) 5.0.

      II. To determine the clinical efficacy of neoadjuvant pembrolizumab alone and in combination
      with chemotherapy.

      EXPLORATORY OBJECTIVES:

      I. To explore the relationship between changes in TIICs and clinical efficacy in patients
      with early stage NSCLC treated with neoadjuvant pembrolizumab-based combination therapy.

      II. To characterize changes in the frequency and number of circulating immune cells induced
      by neoadjuvant pembrolizumab-based combination therapy in patients with early stage NSCLC.

      III. To determine the impact of neoadjuvant pembrolizumab-based combination therapy on the
      composition and phenotype of the tumor microenvironment (including tumor and stromal cells)
      in patients with NSCLC.

      III. To determine the change in T cell repertoire within the tumor and blood induced by
      neoadjuvant pembrolizumab-based combination therapy in patients with early stage NSCLC.

      IV. To explore molecular profiles to identify potentially predictive biomarkers for patients
      with early stage NSCLC treated with immunotherapy.

      OUTLINE: Patients are assigned to 1 of 2 cohorts.

      COHORT A: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1.
      Treatment repeats every 21 days for up to 2 cycles in the absence of disease progression or
      unacceptable toxicity. Patients then undergo surgery within 4 weeks following study
      treatment.

      COHORT B: Patients receive pembrolizumab IV over 30 minutes and chemotherapy
      (cisplatin/pemetrexed) IV on day 1. Treatment repeats every 21 days for up to 2 cycles in the
      absence of disease progression or unacceptable toxicity. Patients then undergo surgery within
      4 weeks following study treatment.

      After completion of study treatment, patients are followed up every 3 months for up to 2
      years.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort A (pembrolizumab)ExperimentalPatients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo surgery within 4 weeks following study treatment.
  • Pembrolizumab
Cohort B (pembrolizumab, cisplatin pemetrexed)ExperimentalPatients receive pembrolizumab IV over 30 minutes and chemotherapy (cisplatin/pemetrexed) IV on day 1. Treatment repeats every 21 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo surgery within 4 weeks following study treatment.
  • Cisplatin
  • Pembrolizumab
  • Pemetrexed
  • Pemetrexed Disodium

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically or cytologically confirmed NSCLC, performed on a biopsy that occurred
             within the last 60 days

          -  Computed tomography (CT) within the last 30 days showing radiographic stage I to IIIa
             lung cancer (mediastinal staging biopsy is allowed but not required) by the American
             Joint Committee on Cancer (AJCC) 8th edition

          -  Documentation that the patient is a candidate for surgical resection of their lung
             cancer by an American Board of Thoracic Surgery-certified surgeon

          -  Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as
             assessed by the investigator

          -  Adequate tissue specimens for correlative biomarker analysis. The patient should be
             willing to provide tissue from a newly obtained core or excisional biopsy of a tumor
             lesion. Newly-obtained is defined as a specimen obtained up to 8 weeks (56 days) prior
             to initiation of treatment on day 1. Patients for whom newly-obtained samples cannot
             be provided (e.g. inaccessible or patient safety concern) may submit an archived
             specimen only upon agreement from the principal investigator

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

          -  Resolution of all acute toxic effects of prior chemotherapy, radiotherapy or surgical
             procedures to NCI CTCAE version (v)5.0 grade 1

          -  Be willing and able to provide written informed consent for the trial

          -  Absolute neutrophil count (ANC) >= 1500 cells/ microlitre(uL) (within 10 days prior to
             the start of trial treatment)

          -  Platelets >= 100 000 cells/uL (within 10 days prior to the start of trial treatment)

          -  Hemoglobin >= 9.0 g/dL or >= 5.6 mmol/L (criteria must be met without erythropoietin
             dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks)
             (within 10 days prior to the start of trial treatment)

          -  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) >= 30 mL/min for patients with creatinine levels > 1.5 x
             institutional ULN (within 10 days prior to the start of trial treatment)

          -  Total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for patients with total
             bilirubin levels > 1.5 x ULN (within 10 days prior to the start of trial treatment)

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and
             alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
             ULN (=< 5 x ULN for patients with liver metastases) (within 10 days prior to the start
             of trial treatment)

          -  International normalized ratio (INR) OR prothrombin time (PT) =< 1.5 x ULN unless
             patient is receiving anticoagulant therapy as long as PT or partial thromboplastin
             time (PTT) is within therapeutic range of intended use of anticoagulants (within 10
             days prior to the start of trial treatment)

          -  Activated partial thromboplastin time (aPTT)/PTT =< 1.5 x ULN unless patient is
             receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is
             within therapeutic range of intended use of anticoagulants (within 10 days prior to
             the start of trial treatment)

          -  Female patients of childbearing potential must have a negative urine or serum
             pregnancy test within 72 hours prior to receiving the first dose of trial medication.
             If the urine test is positive or cannot be confirmed as negative, a serum pregnancy
             test will be required

          -  Male and female patients of childbearing potential must be willing to use an adequate
             method of contraception as outlined, for the course of the trial through 120 days
             after the last dose of trial drug

               -  Note: Abstinence is acceptable if this is the usual lifestyle and preferred
                  contraception for the patient

          -  Be willing to provide newly obtained tissue (core biopsy of tumor) for PD-L1 biomarker
             analysis and, based on the adequacy of the tissue sample quality for assessment of
             PD-L1 status, received permission for enrollment from the core laboratory. Repeat
             samples may be required if adequate tissue is not provided. Newly obtained biopsy
             specimens are preferable to archived samples, and formalin-fixed paraffin-embedded
             (FFPE) block specimens are preferred to slides. A post-treatment biopsy after
             pembrolizumab treatment is desirable if patient agrees

               -  Collection of an archived tissue sample will also be requested available) to
                  support evaluation of the clinical utility of PD-L1 assessment in newly obtained
                  versus (vs.) archived tissue samples; however, a patient will not be precluded
                  from participating in the study if an archived tissue sample is not available for
                  collection or is otherwise insufficient for analysis

        Exclusion Criteria:

          -  Is ineligible for an operation based on medical or oncologic contraindications to
             surgery

          -  Is currently participating in or has participated in a trial of an investigational
             agent or has used an investigational device within 4 weeks prior to the first dose of
             trial treatment

               -  Note: Patients who have entered the follow-up phase of an investigational trial
                  may participate as long as it has been 4 weeks after the last dose of the
                  previous investigational agent

          -  Has any component of small cell tumor in the specimen, e.g. mixed NSCLC/small cell

          -  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)

          -  Has severe hypersensitivity >= grade 3) to pembrolizumab and/or any of its excipients

          -  Has a history of (non-infectious) pneumonitis / interstitial lung disease that
             required treatment with steroids or has current pneumonitis / interstitial lung
             disease that requires steroids

          -  Has a known history of human immunodeficiency virus (HIV) infection

               -  Note: No HIV testing is required unless mandated by local health authority

          -  Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg]
             reactive) or known active hepatitis C virus (HCV) (defined as 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

          -  Has a known history of active tuberculosis (TB; Mycobacterium tuberculosis)

          -  Has received prior radiotherapy within 2 weeks of start of trial treatment. Patients
             must have recovered from all radiation-related toxicities, not require
             corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted
             for palliative radiation (=< 2 weeks of radiotherapy) to non-central nervous system
             (CNS) disease

          -  Has received a live vaccine within 30 days prior to the first dose of trial 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-Gurin (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

          -  Has evidence of clinically significant interstitial lung disease

          -  Has an active second malignancy, i.e. patient known to have potentially fatal cancer
             present for which he/she may be (but not necessarily) currently receiving treatment.
             Patients with a history of malignancy that has been completely treated, with no
             evidence of that cancer currently, are permitted to enroll in the trial if curative
             therapy has been completed, such as 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 a diagnosis of immunodeficiency or is receiving systemic steroid therapy (in
             dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
             immunosuppressive therapy within 7 days prior to the first dose of trial treatment

          -  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 (e.g., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment

          -  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 patient?s
             participation for the full duration of the trial, or is not in the best interest of
             the patient to participate, in the opinion of the treating investigator, including
             dialysis

          -  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 screening visit through 120 days
             after the last dose of trial treatment

          -  Has had an allogeneic tissue/solid organ transplant

        ADDITIONAL EXCLUSION CRITERIA For Arm B

          -  Has squamous cell carcinoma. Adenosquamous and adenocarcinoma with squamous features
             disease allowed

          -  Creatinine clearance < 45 ml/min as calculated by institutional standard

          -  Is taking any herbal/complementary oral or IV medicine within 4 weeks of first dose of
             treatment
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Proportion of patients with a >= 2-fold increase in the number of tumor-infiltrating immune cells (TIICs) in post- versus (vs.) pre-pembrolizumab treatment tumor specimens
Time Frame:Up to 2 years
Safety Issue:
Description:Will be summarized by descriptive statistics (median and range).

Secondary Outcome Measures

Measure:Incidence of adverse events (AEs)
Time Frame:Up to 2 years
Safety Issue:
Description:Will be assessed by reported AEs using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Measure:Disease response
Time Frame:Up to 2 years
Safety Issue:
Description:Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Reported using descriptive statistics (n, percentage and 95% confidence interval).
Measure:Clinical benefit rate
Time Frame:Up to 2 years
Safety Issue:
Description:Assessed by RECIST 1.1. Reported using descriptive statistics (n, percentage and 95% confidence interval).
Measure:Pathologic response in resected tumor
Time Frame:Up to 2 years
Safety Issue:
Description:Reported using descriptive statistics (n, percentage and 95% confidence interval).
Measure:Progression-free survival (PFS)
Time Frame:At 12 and 24 months
Safety Issue:
Description:Reported using descriptive statistics (n, percentage and 95% confidence interval). Median PFS following surgical resection will be reported using the Kaplan-Meier estimate.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University of California, San Francisco

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