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

Stage IV Non-Small Cell Lung Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02658097
• Other study ID #: CASE1516
• Status: Completed
• Phase: Phase 2
• Start date: June 7, 2017
• Est. completion date: March 10, 2023

Study information

• Verified date: May 2024
• Source: Case Comprehensive Cancer Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The goal of this clinical trial is to determine if low single palliative dose radiation to the lung cancer will improve your immune response against the tumor and if sequential treatment with pembrolizumab (the study drug) would offer superior results compared to pembrolizumab alone in participants with non-small cell lung cancer.

The purpose of this research is also to study whether there are any changes present in the DNA, RNA, and proteins of a participant's tumor or the blood cells that may contribute to a response to the study treatment or progression of cancer. This research may help researchers in the future to learn more about the causes, risks, treatments, or prevention of cancers or other health problems.

Participants will consent to a screening period, a core or treatment phase, and a post-study observation phase. During the screening phase, participants will undergo a series of tests to determine if they are eligible for the study. The core study period, or treatment period, will start with a single dose of radiation and then continue for the first eight treatments of pembrolizumab, approximately 24-28 weeks. Participants will have a new biopsy taken after two treatments of the study drug. Following the 24-28 week treatment cycle, if the cancer is responding to treatment, the participant's physician will continue to treat with pembrolizumab as a standard treatment. Following treatment, the post-study observation phase will monitor participant response to drugs and outcomes.

Description:

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.

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 13
• Est. completion date: March 10, 2023
• Est. primary completion date: February 26, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Erythema Multiforme
• Stage IV Non-Small Cell Lung Cancer

Intervention

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

Locations

Country	Name	City	State
United States	Cleveland Clinic, Case Comprehensive Cancer Center	Cleveland	Ohio

Sponsors (1)

Lead Sponsor	Collaborator
Case Comprehensive Cancer Center

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	Changes in PD-L1	From first visit to disease progression, up to 25 months after beginning treatment. Median (95% CI) overall survival by PD-L1 status in months.	From first visit to 30 days post treatment, up to 25 months
Primary	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. RECIST 1.1 criteria are as follows: Complete Response (CR) is defined as the disappearance of all lesions and pathologic lymph nodes; Partial Response (PR) is = 30% decrease in sum of diameters with no new lesions, no progression of non-target lesions; Stable disease(SD) is defined as no PR - no progressive disease; and Progressive Disease (PD) is defined as = 20% increase compared to smallest sum of diameters in study or progression of non-target lesions or new lesions.	From first visit to disease progression, up to 24 months after beginning treatment
Secondary	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
Secondary	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
Secondary	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
Secondary	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