Clinical Trials /

Pembrolizumab With and Without Radiotherapy for Non-Small Cell Lung Cancer

NCT03217071

Description:

This is a randomized single-institution, phase II, open-label clinical trial of neoadjuvant pembrolizumab with or without low-dose stereotactic radiation therapy (SRT) in stage I-IIIA non-small lung cancer (NSCLC) patients who are planned to undergo surgical resection of their lung cancer.

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

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab With and Without Radiotherapy for Non-Small Cell Lung Cancer
  • Official Title: PembroX: Enhancing the Immunogenicity of Non-Small Cell Lung Cancer With Pembrolizumab +/- Stereotactic Radiotherapy Delivered in the Preoperative Window, A Randomized Phase II Study With Correlative Biomarkers

Clinical Trial IDs

  • ORG STUDY ID: CC# 166520
  • NCT ID: NCT03217071

Conditions

  • Non Small Cell Lung Cancer

Interventions

DrugSynonymsArms
PembrolizumabKeytrudaPembrolizumab

Purpose

This is a randomized single-institution, phase II, open-label clinical trial of neoadjuvant pembrolizumab with or without low-dose stereotactic radiation therapy (SRT) in stage I-IIIA non-small lung cancer (NSCLC) patients who are planned to undergo surgical resection of their lung cancer.

Detailed Description

      Two consecutive run-in cohorts will administer pembrolizumab or pembrolizumab with SRT of 12
      Gy to the lateral aspect of the primary tumor. Patients will receive pembrolizumab for 2
      cycles prior to surgery or SRT and surgery. Surgical resection of all involved areas of tumor
      will occur within 6 weeks of the last administration of pembrolizumab. It should be noted
      that surgery is expected to occur within a much shorter window and 6 weeks would represent
      the greatest allowable amount of delay.

      If during the run-in, only the pembrolizumab-alone cohort meets pre-specified safety
      parameters, subsequently enrolled patients will enter a larger expansion cohort, with
      treatment given according to that cohort only. If during the run-in both cohorts meet
      pre-specified safety parameters, subsequently enrolled patients will enter the expansion
      cohort and be randomized between preoperative pembrolizumab versus pembrolizumab with SRT of
      12 Gy.
    

Trial Arms

NameTypeDescriptionInterventions
PembrolizumabExperimentalPatients will receive 200mg pembrolizumab on Day 1 of each 3 week cycle, for 2 cycles, prior to surgery. Pembrolizumab will be administered via IV infusion for 30 minutes. Surgery will occur no later than 6 weeks following the last dose of pembrolizumab.
  • Pembrolizumab
Pembrolizumab + RadiationExperimentalPatients will receive 200mg pembrolizumab on Day 1 of each 3 week cycle, for 2 cycles. Pembrolizumab will be administered via IV infusion for 30 minutes.Within the week (7 days +/- 3 days) following administration of the second cycle, a single 12 Gy dose of stereotactic radiation therapy (SRT) will be delivered to 50% of the primary tumor only. Definitive surgical resection will occur no later than 6 weeks following the last dose of pembrolizumab.
  • Pembrolizumab

Eligibility Criteria

        Diagnosis/Condition for Entry into the Trial

          1. Histologically or cytologically confirmed non-small cell lung cancer, performed on a
             biopsy that occurred within the last 60 days.

          2. PET-CT within the last 30 days showing radiographic stage I to IIIa lung cancer
             (mediastinal staging biopsy is allowed but not required).

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

          4. Measurable disease as defined by RECIST v1.1.

          5. 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 6 weeks (42 days) prior
             to initiation of treatment on Day 1. Subjects for whom newly-obtained samples cannot
             be provided (e.g. inaccessible or subject safety concern) may submit an archived
             specimen only upon agreement from the Principal Investigator.

          6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

          7. Resolution of all acute toxic effects of prior chemotherapy, radiotherapy or surgical
             procedures to NCI CTCAE Version 4.0 grade 1.

        Inclusion Criteria:

          1. Be willing and able to provide written informed consent/assent for the trial.

          2. Be at least 18 years of age on day of signing informed consent.

          3. Demonstrate adequate organ function as defined below. All screening labs should be
             performed within 10 days of treatment initiation.

             System Laboratory Value Hematological Absolute neutrophil count (ANC) greater than or
             equal to 1,500 /mcL Platelets greater than or equal to 100,000 / mcL Hemoglobin
             greater than or equal to 9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency
             (within 7 days of assessment)

             Renal Serum creatinine OR Measured or calculated creatinine clearance (GFR can also be
             used in place of creatinine or CrCl) less than or equal to 1.5 X upper limit of normal
             (ULN) OR

             Greater than or equal to 60 mL/min for subject with creatinine levels greater than 1.5
             X institutional ULN Hepatic Serum total bilirubin Less than or equal to 1.5 X ULN AST
             (SGOT) and ALT (SGPT) Less than or equal to 2.5 X ULN

             Coagulation International Normalized Ratio (INR) or Prothrombin Time (PT)

             Activated Partial Thromboplastin Time (aPTT) Less than or equal to 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 Less than or equal to 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

             Creatinine clearance should be calculated per institutional standard.

          4. 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.

          5. 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.

          6. 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:

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

          2. Has known history of, or any evidence of active, non-infectious pneumonitis that
             required steroids, or current pneumonitis.

          3. Has evidence of interstitial lung disease.

          4. 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.

          5. 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.

          6. 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.

          7. Has a known history of active TB (Bacillus Tuberculosis)

          8. Hypersensitivity to pembrolizumab or any of its excipients.

          9. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study
             Day 1 or who has not recovered (i.e., Less than or equal to Grade 1 or at baseline)
             from adverse events due to agents administered more than 4 weeks earlier.

         10. 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., less than or equal
             to Grade 1 or at baseline) from adverse events due to a previously administered agent.

               -  Note: Subjects with less than or equal to 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.

         11. 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.

         12. Has an active infection requiring systemic therapy.

         13. 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.

         14. Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.

         15. 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.

         16. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.

         17. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

         18. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
             [qualitative] is detected).

         19. 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:Change in number of infiltrating CD3+ T cells/ μm2
Time Frame:Over the duration of the study, which is estimated to be approximately 25 months.
Safety Issue:
Description:The primary endpoint for this study is the change in number of infiltrating CD3+ T cells/ μm2 in the lung cancer tissue from before and after pembrolizumab +/- SRT, based on quantification using immunohistochemistry (IHC) and image analysis. This endpoint was selected as a marker of T cell proliferation and activation. It is expected that immunologic activation would be reflected by the presence of this biomarker. The purpose of this study is to determine whether neoadjuvant pembrolizumab +/- SRT is sufficient to produce a two-fold change in the CD3+ T cell population, comparing pre-treatment biopsy tissue to post-treatment resection specimens.

Secondary Outcome Measures

Measure:Overall Survival
Time Frame:1 year from the initiation of therapy.
Safety Issue:
Description:1 year overall survival rate
Measure:Relapse Free Survival
Time Frame:1 year from the initiation of therapy.
Safety Issue:
Description:1 year relapse free survival
Measure:Distant Metastases
Time Frame:1 year from the initiation of therapy.
Safety Issue:
Description:1 year rate of distant metastases
Measure:Progression to Unresectability
Time Frame:Over the duration of the study, which is estimated to be approximately 25 months.
Safety Issue:
Description:Rate of progression to unresectability following the preoperative program
Measure:Incidence of Treatment-Related Adverse Events (AEs)
Time Frame:Over the duration of the study, which is estimated to be approximately 25 months.
Safety Issue:
Description:According to CTCAE v. 4, including immune-related AEs

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Sue Yom

Trial Keywords

  • non small cell lung cancer, resectable

Last Updated