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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02658097

Enrollment

Registered

2016-01-18

Start date

2017-06-07

Completion date

2023-03-10

Last updated

2024-05-03

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Stage IV Non-Small Cell Lung Cancer

Keywords

Lung Cancer, pembrolizumab, focal radiation, RT

Brief 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.

Detailed 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

Interventions

DRUGPembrolizumab

200mg Pembrolizumab by IV infusion

RADIATIONSingle Fraction Radiation Therapy

8Gy radiation therapy will be given in a single fraction on the first day of treatment

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
Number of Patients With Each Response as Measured by RECIST 1.1	From first visit to disease progression, up to 24 months after beginning treatment	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.

Secondary

Measure	Time frame	Description
Median Time of Progression Free Survival	From first visit to disease progression, up to 24 months after beginning treatment	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.
Median Time of Overall Survival	From first visit to disease progression, up to 24 months after beginning treatment	Overall Survival, OS will be measure from the initiation of study therapy
Number of Patients With Local Control of Disease With SFRT	From first visit to disease progression, up to 24 months after beginning treatment	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.
Duration of Local Control of Disease With SFRT	From first visit to disease progression, up to 24 months after beginning treatment	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.

Other

Measure	Time frame	Description
Number of Patients With Pneumonitis	From first visit to 30 days after disease progression, up to 25 months after beginning treatment	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
Changes in PD-L1	From first visit to 30 days post treatment, up to 25 months	From first visit to disease progression, up to 25 months after beginning treatment. Median (95% CI) overall survival by PD-L1 status in months.

Countries

United States

Participant flow

Participants by arm

Arm	Count
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 Pembrolizumab: 200mg Pembrolizumab by IV infusion Single Fraction Radiation Therapy: 8Gy radiation therapy will be given in a single fraction on the first day of treatment	13
Total	13

Baseline characteristics

Characteristic	Single Fraction Radiation Therapy (SFRT) + Pembrolizumab
Age, Customized 40-49 years of age	0 Participants
Age, Customized 50-59 years of age	2 Participants
Age, Customized 60-69 years of age	3 Participants
Age, Customized 70-79 years of age	7 Participants
Age, Customized 80-89 years of age	1 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	11 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	2 Participants
Former Smoker Former Smoker	13 Participants
Former Smoker Non-smoker	0 Participants
Prior Treatment 1 prior treatment	8 Participants
Prior Treatment 2 prior treatments	3 Participants
Prior Treatment 3 prior treatments	2 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	0 Participants
Race (NIH/OMB) Black or African American	3 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants
Race (NIH/OMB) White	9 Participants
Region of Enrollment United States	13 participants
Sex: Female, Male Female	10 Participants
Sex: Female, Male Male	3 Participants
Sites of Metastatic Disease Bone site	5 number of sites
Sites of Metastatic Disease Lung site	1 number of sites
Sites of Metastatic Disease Lymph Nodes site	8 number of sites
Sites of Other Metastatic Disease Adrenal Gland site	5 number of sites
Sites of Other Metastatic Disease Contralateral lung site	7 number of sites
Sites of Other Metastatic Disease Kidney site	1 number of sites
Sites of Other Metastatic Disease L supreaspinatus muscle site	2 number of sites
Sites of Other Metastatic Disease Mediastinal LN site	3 number of sites
Sites of Other Metastatic Disease Pleura site	2 number of sites
Sites of Other Metastatic Disease Retoperitoneal LNs site	2 number of sites
Sites of Other Metastatic Disease Rib site	1 number of sites
Types of prior treatments Carboplatin/Abraxane	1 number of prior treatments
Types of prior treatments Carboplatin/Pemetrexed	5 number of prior treatments
Types of prior treatments Cisplatin/Alimta	1 number of prior treatments
Types of prior treatments ETOPOSIDE / CARBOPLATIN 21 DAY	1 number of prior treatments
Types of prior treatments Maintenance Pemetrexed	4 number of prior treatments
Types of prior treatments Pemetrexed + Bevacizumab	1 number of prior treatments
Types of prior treatments Rucaparib	2 number of prior treatments
Types of prior treatments SBRT	1 number of prior treatments

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	9 / 13
other Total, other adverse events	10 / 13
serious Total, serious adverse events	5 / 13

Outcome results

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.