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

This study is currently recruiting participants.
Verified August 2017 by Sue Yom, University of California, San Francisco
Sponsor:
ClinicalTrials.gov Identifier:
NCT03217071
First Posted: July 13, 2017
Last Update Posted: August 30, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Sue Yom, University of California, San Francisco
  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.

Condition Intervention Phase
Non Small Cell Lung Cancer Drug: Pembrolizumab Radiation: stereotactic radiation therapy (SRT) Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Sue Yom, University of California, San Francisco:

Primary Outcome Measures:
  • 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. ]
    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:
  • Overall Survival [ Time Frame: 1 year from the initiation of therapy. ]
    1 year overall survival rate

  • Relapse Free Survival [ Time Frame: 1 year from the initiation of therapy. ]
    1 year relapse free survival

  • Distant Metastases [ Time Frame: 1 year from the initiation of therapy. ]
    1 year rate of distant metastases

  • Progression to Unresectability [ Time Frame: Over the duration of the study, which is estimated to be approximately 25 months. ]
    Rate of progression to unresectability following the preoperative program

  • Incidence of Treatment-Related Adverse Events (AEs) [ Time Frame: Over the duration of the study, which is estimated to be approximately 25 months. ]
    According to CTCAE v. 4, including immune-related AEs


Estimated Enrollment: 40
Actual Study Start Date: August 28, 2017
Estimated Study Completion Date: September 1, 2021
Estimated Primary Completion Date: September 1, 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Pembrolizumab
Patients 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.
Drug: Pembrolizumab
All study participants will receive pembrolizumab every 3 weeks, for 2 cycles.
Other Name: Keytruda
Experimental: Pembrolizumab + Radiation
Patients 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.
Drug: Pembrolizumab
All study participants will receive pembrolizumab every 3 weeks, for 2 cycles.
Other Name: Keytruda
Radiation: stereotactic radiation therapy (SRT)
Patients in Cohort 2 of the Safety run-in and patients in the expansion cohort who are randomized to the 'pembrolizumab +radiation arm' will receive one dose of SRT within 1 week (+/- 3 days) following the second administration of pembrolizumab.

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.

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
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): NCT03217071


Contacts
Contact: Clinical Trials Office - UCSF Cancer Center 877-827-3222 cancertrials@ucsf.edu

Locations
United States, California
Helen Diller Family Comprehensive Center, UCSF Recruiting
San Francisco, California, United States, 94115
Contact: Clinical Trials Office    877-827-3222    cancertrials@ucsf.edu   
Principal Investigator: Sue Yom, M.D.         
Sponsors and Collaborators
Sue Yom
Merck Sharp & Dohme Corp.
Investigators
Principal Investigator: Sue Yom, MD University of California, San Francisco
  More Information

Responsible Party: Sue Yom, Associate Professor, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT03217071     History of Changes
Other Study ID Numbers: CC# 166520
First Submitted: July 10, 2017
First Posted: July 13, 2017
Last Update Posted: August 30, 2017
Last Verified: August 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Sue Yom, University of California, San Francisco:
non small cell lung cancer, resectable

Additional relevant MeSH terms:
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Pembrolizumab
Antineoplastic Agents