NSCLC Stage IV
Conditions
Keywords
Lung, Immunotherapy, Fraction non-ablative radiation, untreated patients, metastatic
Brief summary
The purpose of this study is to test if low dose radiation, which is routinely used in treating patients with lung cancer for symptom control, can improve the results from the standard treatment with pembrolizumab and chemotherapy. In this study, only individuals who have NSCLC that is advanced (Stage IV), or has come back (recurred), will be able to participate.
Detailed description
This is a phase II open-label trial of pembrolizumab sequentially following upfront non-ablative focal therapy to up to five distinct metastatic subsites in de novo stage IV Non-Small Cell Lung Cancer (NSCLC). The primary goal of this trial is to evaluate the efficacy defined by time to progression or death with upfront non-ablative focal radiation (RT) to index lesions as a way of enhancing the anti-tumor immune response to pembrolizumab. Adult patients with metastatic NSCLC, with at least 2 measurable lesions and those Patients with metastatic NSCLC who are previously untreated are eligible for the study if they meet all inclusion criteria, and do not satisfy any exclusion criteria. Participants will receive standard of care immunotherapy of Pembrolizumab in addition to non-ablative radiation. The intervention is the low dose fractionation, 4Gy x 5, in the upfront treatment of de novo stage IV NSCLC in up to five distinct subsites of metastatic NSCLC.
Interventions
DRUGPembrolizumab
Pembrolizumab 200mg solution administered intravenously every 3 weeks for 6 cycles followed by maintenance therapy until progression of disease or unacceptable toxicity (standard of care). Administered alongside chemotherapy.
RADIATIONRadiation
One-time, up-front radiation delivered at up to five metastatic subsites at a 4 Gy x 5 radiation dose fractionation schedule. Radiation will be delivered within five days before or after initiation of first cycle of pembrolizumab treatment. Radiation modality and technique will be determined at the discretion of the treating radiation oncologist.
DRUGChemotherapy
Administered alongside pembrolizumab every 3 weeks for 6 cycles per institutional standard of care. For non-squamous, the standard chemotherapy option of choice is carboplatin and pemetrexed. For squamous cell carcinoma, the chemotherapy used would be carboplatin and paclitaxel or nab-paclitaxel
Sponsors
NYU Langone Health
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
1. Be willing and able to provide written informed consent/assent for the trial. 2. Histologically documented, metastatic NSCLC with no previous systemic therapy 3. At least 2 distinct measurable metastatic sites, which are 1 cm or larger; patients can have radiation to multiple measurable disease sites as clinically indicated, however, there must be at least 1 measurable non-radiated target lesion for response assessment. 4. Agreeable to provide archival tissue for correlative studies; if no archival tissue available may obtain an exemption by the study team. 5. Be at least 18 years of age on day of signing informed consent. 6. Have measurable disease based on RECIST 1.1. 7. Have a performance status of ≤1 ECOG Performance Scale. 8. Demonstrate adequate organ function as defined in Table 2, all screening labs should be performed within 10 days of treatment initiation 9. 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). 10. 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. 11. Female subjects of childbearing potential must be willing to use an adequate method of contraception as outlined in Section - 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. 12. Male subjects of childbearing potential must agree to use an adequate method of contraception as outlined in Section- 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 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. 2. 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. 3. Has a known history of active TB (Bacillus Tuberculosis) 4. Hypersensitivity to pembrolizumab or any of its excipients. 5. Has had prior chemotherapy, immunotherapy or targeted small molecule therapy within 6 months prior to study Day 1. 6. Patient who have previously received radiation overlapping, as determined by the treating radiation oncologist, with the current planned radiation treatment fields are ineligible. 7. Patient's treated with whole brain radiation therapy are ineligible. 8. 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. 9. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases (with SRS and/or neurosurgery) may participate provided they are clinically stable and, have no evidence of new or enlarging brain metastases and also are off steroids 3 days prior to dosing with study medication. 10. 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 (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. 11. Has history of autoimmune disorders, (non-infectious) pneumonitis that required steroids, evidence of interstitial lung disease or active, non-infectious pneumonitis. 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. Patients with prior history of chemoradiation for lung cancer 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent of Participants With a Best Overall Response of Complete Response (CR) or Partial Response (PR) by End of Treatment Cycle 4 | Up to Week 12 (End of Cycle 4 - each cycle is 21 days) | Defined as the best response recorded from the start of the study treatment until the end of treatment Cycle 4, either Complete Response or Partial Response. A CR is defined as the disappearance of all target lesions (TLs) and reduction in the short axis measurement of all pathologic lymph nodes to ≤10 mm. A PR is defined as at least a 30% decrease in the sum of the longest diameter (SLD) of TLs, taking as reference the baseline SLD. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) at Final Follow-Up | From enrollment until the first documented and confirmed progression of disease, death, date last follow-up, or end of study; assessed up to 81 weeks | PFS is defined as the time from initiation of study drug post-radiation, until the first documented, confirmed progression of disease or death. |
| Overall Survival (OS) at Final Follow-Up | From enrollment until the first documented and confirmed progression of disease, death, date last follow-up, or end of study; assessed up to 81 weeks | OS is defined as the time (in weeks) to death from the start of drug therapy. |
| Percentage of Participants With an Objective Response | Week 52 | An objective response (Complete Response or Partial Response) is defined as lasting continuously for 6 months and starting any time within 12 months of initiating therapy. A CR is defined as the disappearance of all target lesions and reduction in the short axis measurement of all pathologic lymph nodes to ≤10 mm. A PR is defined as at least a 30% decrease in the sum of the longest diameter (SLD) of TLs, taking as reference the baseline SLD. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Untreated Patients With Stage IV NSCLC Participants will receive radiation in concert with starting chemotherapy with pembrolizumab for up to 6 cycles (18 weeks), followed by continued treatment with pembrolizumab (standard of care). Patients will be followed for 1 year following the completion of the core study period of 6 cycles.
Pembrolizumab: Pembrolizumab 200mg solution administered intravenously every 3 weeks for 6 cycles followed by maintenance therapy until progression of disease or unacceptable toxicity (standard of care). Administered alongside chemotherapy.
Radiation: One-time, up-front radiation delivered at up to five metastatic subsites at a 4 Gy x 5 radiation dose fractionation schedule. Radiation will be delivered within five days before or after initiation of first cycle of pembrolizumab treatment. Radiation modality and technique will be determined at the discretion of the treating radiation oncologist.
Chemotherapy: Administered alongside pembrolizumab every 3 weeks for 6 cycles per institutional standard of care. For non-squamous, the standard chemotherapy option of choice is carboplatin and pemetrexed. For squamous cell carcinoma, the chemotherapy used would be carboplatin and paclitaxel or nab-paclitaxel | 14 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Eligibility criteria not met | 3 |
| Overall Study | Physician Decision | 2 |
Baseline characteristics
| Characteristic | Untreated Patients With Stage IV NSCLC |
|---|---|
| Age, Continuous | 80 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 4 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 | 8 Participants |
| Region of Enrollment United States | 14 participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 4 / 14 |
| other Total, other adverse events | 13 / 14 |
| serious Total, serious adverse events | 9 / 14 |
Outcome results
Primary
Percent of Participants With a Best Overall Response of Complete Response (CR) or Partial Response (PR) by End of Treatment Cycle 4
Defined as the best response recorded from the start of the study treatment until the end of treatment Cycle 4, either Complete Response or Partial Response. A CR is defined as the disappearance of all target lesions (TLs) and reduction in the short axis measurement of all pathologic lymph nodes to ≤10 mm. A PR is defined as at least a 30% decrease in the sum of the longest diameter (SLD) of TLs, taking as reference the baseline SLD.
Time frame: Up to Week 12 (End of Cycle 4 - each cycle is 21 days)
Population: 1 participant did not start treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Untreated Patients With Stage IV NSCLC | Percent of Participants With a Best Overall Response of Complete Response (CR) or Partial Response (PR) by End of Treatment Cycle 4 | 30.77 percentage of participants |
Secondary
Overall Survival (OS) at Final Follow-Up
OS is defined as the time (in weeks) to death from the start of drug therapy.
Time frame: From enrollment until the first documented and confirmed progression of disease, death, date last follow-up, or end of study; assessed up to 81 weeks
Population: 1 participant did not start treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Untreated Patients With Stage IV NSCLC | Overall Survival (OS) at Final Follow-Up | 51.57 weeks |
Secondary
Percentage of Participants With an Objective Response
An objective response (Complete Response or Partial Response) is defined as lasting continuously for 6 months and starting any time within 12 months of initiating therapy. A CR is defined as the disappearance of all target lesions and reduction in the short axis measurement of all pathologic lymph nodes to ≤10 mm. A PR is defined as at least a 30% decrease in the sum of the longest diameter (SLD) of TLs, taking as reference the baseline SLD.
Time frame: Week 52
Population: 1 participant did not start treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Untreated Patients With Stage IV NSCLC | Percentage of Participants With an Objective Response | 38.46 percentage of participants |
Secondary
Progression-Free Survival (PFS) at Final Follow-Up
PFS is defined as the time from initiation of study drug post-radiation, until the first documented, confirmed progression of disease or death.
Time frame: From enrollment until the first documented and confirmed progression of disease, death, date last follow-up, or end of study; assessed up to 81 weeks
Population: 1 participant did not start treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Untreated Patients With Stage IV NSCLC | Progression-Free Survival (PFS) at Final Follow-Up | 42.86 weeks |