Pembrolizumab Alone or Sequentially Following Single Fraction Non-ablative Radiation to One of the Target Lesions, in Previously Treated Patients With Stage IV NSCLC

A Phase II Trial of Pembrolizumab Sequentially Following Single Fraction Non-ablative Radiation to One of the Target Lesions, in Previously Treated Patients With Stage IV NSCLC

This study looks at patients with advanced lung cancer. Participants in this study will be randomized into two groups. The first group will have radiation plus a drug (pembrolizumab). The second group will have only the drug (pembrolizumab). Tumors of participants will be measured to see if the addition of radiation changes the growth of the tumor compared to the drug alone.

Study Overview

• Status: Completed
• Conditions: Stage IV Non-Small Cell Lung Cancer
• Intervention / Treatment: Drug: Pembrolizumab; Radiation: Single Fraction Radiation Therapy

Detailed Description

This is a Phase 2 randomized two arm phase II trial of pembrolizumab alone or sequentially following focal radiation to one of the target lesions, in previously treated patients with stage IV Non-Small Cell Lung Cancer (NSCLC). The primary goal of this trial is to compare the efficacy of focal radiation (RT) to an index lesion as a way of enhancing the anti-tumor immune response to pembrolizumab to that of pembrolizumab alone. The primary efficacy endpoint is overall RECIST-defined response outside the radiation field. To accomplish this goal 66 patients will be randomized 2:1 (stratified by histology (squamous versus non-squamous) and refractory versus non-refractory disease) to radiation plus pembrolizumab or pembrolizumab only, respectively.

Primary Objective: To determine the tumor responses outside the radiation field (abscopal effect) after radiation followed by pembrolizumab in metastatic NSCLC.

Secondary Objectives:

1. To determine the progression-free and overall survival in patients with NSCLC receiving pembrolizumab, who receive Single Fraction Radiation Therapy (SFRT)
2. To determine the safety and toxicity of the combination of SFRT and pembrolizumab
3. To examine potential predictive biomarkers in tumor samples and peripheral blood in patients treated with pembrolizumab and SFRT
4. To determine the local control of SFRT in the radiated lesion, when SFRT is given with pembrolizumab
5. To evaluate the induction of a T-cell response in patients with metastatic NSCLC treated with radiation and the effect of radiation

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44118
      • Cleveland Clinic, Case Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Be willing and able to provide written informed consent/assent for the trial.
• Have measurable disease based on RECIST 1.1.
• 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 Sponsor and primary investigator.
• Have a performance status of ≤1 ECOG Performance Scale.

• Demonstrate adequate organ function

  • Absolute neutrophil count (ANC) ≥ 1,500/mcL
  • Platelets ≥ 100,000/mcL
  • Hemoglobin ≥ 9g/dL
  • Serum creatinine or measured ≤1.5 times the upper limit of normal (ULN) or measured or calculated creatinine clearance ≥ 60 mL/min for subjects with creatinine levels >1.5 times the institutional ULN
  • Serum total bilirubin ≤ 1.5 X ULN or direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN
  • AST (SGOT) and ALT (SGPT) ≤ 2.5 times ULN or ≤ 5 times ULN for subjects with liver metastases
  • Albumin ≥ 2.5 mg/dL
• Have one measurable lesion of at least 1 cm outside the planned radiation field (defined as not receiving direct beam from any of the treatment portals).
• 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.
• Female subjects of childbearing potential must be willing to use an adequate method of contraception - 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

• Male subjects of childbearing potential must agree to use an adequate method of contraception- 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:

• 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.
• 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.
• Has a known history of active TB (Bacillus Tuberculosis)
• Hypersensitivity to pembrolizumab or any of its excipients.
• Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.

• 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., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.

  • Note: Subjects with ≤ 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.
• Patient who have previously received radiation overlapping with the current planned radiation treatment fields are ineligible. Overlap is defined as any tissue falling within the direct path of both prior and current planned radiation fields.
• Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
• Patients with active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are clinically stable for at least 4 weeks and, have no evidence of new or enlarging brain metastases and also are off steroids 3 days prior to dosing with study medication. Stable brain metastases by this definition should be established prior to the first dose of pembrolizumab.
• Has had prior chemotherapy, within 2 weeks prior to study treatment. Patients on targeted therapy (tyrosine kinase inhibitor) may go on the study after 5 days off therapy.

• Patients who have not recovered (i.e., ≤ Grade 2 or at baseline) from adverse events due to a previously administered agent.

  --Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy. 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.

• Has history of (non-infectious) pneumonitis that required steroids, evidence of interstitial lung disease or active, non-infectious pneumonitis.
• 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 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.
• 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 pre-screening or screening visit through 120 days after the last dose of trial treatment.
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
• Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
• Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C.

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Single Fraction Radiation Therapy (SFRT) + pembrolizumab; 200mg Pembrolizumab by IV infusion on day 1 of each 3 week cycle. 8Gy will be given in a single fraction on the first day of treatment	Drug: Pembrolizumab; 200mg Pembrolizumab by IV infusion; Radiation: Single Fraction Radiation Therapy; 8Gy radiation therapy will be given in a single fraction on the first day of treatment; Other Names: RT; SFRT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with each response as measured by RECIST 1.1	The Best Overall Response is the best response recorded from the start of the treatment until disease progression (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The anti-tumor activity will be evaluated as an efficacy endpoints based on radiographic (CT or PET/CT). RECIST 1.1 will be applied for evaluation of tumor response.	From first visit to disease progression, up to 24 months after beginning treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Median time of progression free survival	Progression free survival, PFS is defined as the time from initiation of study drug post-SFRT, until the first documented, confirmed progression of disease. PFS will also be measured and report from the initiation of study drug, pre-SFRT.	From first visit to disease progression, up to 24 months after beginning treatment
Median time of overall survival	Overall Survival, OS will be measure from the initiation of study therapy	From first visit to disease progression, up to 24 months after beginning treatment
Number of patients with local control of disease with SFRT	Local Control with SFRT: The target lesion selected for SFRT will be followed for local control. For the purpose of the study, local control will be defined as a complete response, partial response, or stable disease within the planning target volume.	From first visit to disease progression, up to 24 months after beginning treatment
Duration of local control of disease with SFRT	Local Control with SFRT: The target lesion selected for SFRT will be followed for local control. For the purpose of the study, local control will be defined as a complete response, partial response, or stable disease within the planning target volume. The duration of local control will be measured from the time of SBRT treatment fraction.	From first visit to disease progression, up to 24 months after beginning treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with pneumonitis	For patients receiving SFRT to lung lesions, the development of grade 3 or greater pneumonitis that is probably or definitely attributable to either SFRT or pembrolizumab within the follow-up period will be monitored	From first visit to 30 days after disease progression, up to 25 months after beginning treatment
Changes in PD-L1	From first visit to disease progression, up to 24 months after beginning treatment	From first visit to 30 days post treatment, up to 25 months

Collaborators and Investigators

• Sponsor: Case Comprehensive Cancer Center
• Investigators: Principal Investigator: Nathan Pennell, MD, PhD, Cleveland Clinic, Case Comprehensive Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): June 7, 2017
• Primary Completion (Actual): February 26, 2022
• Study Completion (Actual): March 10, 2023

Study Registration Dates

• First Submitted: January 14, 2016
• First Submitted That Met QC Criteria: January 14, 2016
• First Posted (Estimated): January 18, 2016

Study Record Updates

• Last Update Posted (Estimated): February 1, 2024
• Last Update Submitted That Met QC Criteria: January 31, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Lung Cancer; pembrolizumab; RT; focal radiation
• Additional Relevant MeSH Terms: Skin Diseases; Erythema; Skin Diseases, Vesiculobullous; Erythema Multiforme; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Pembrolizumab
• Other Study ID Numbers: CASE1516

Drug and device information, study documents

• 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.: No