Stage IV Non-Small Cell Lung Cancer
Conditions
Brief summary
This phase II trial studies how well radical-dose image guided radiation therapy works in treating patients with non-small cell lung cancer that has spread to other places in the body who are undergoing immunotherapy. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving radical-dose image guided radiation therapy to patients with non-small cell lung cancer may help to improve response to immunotherapy anti-cancer treatment.
Detailed description
PRIMARY OBJECTIVES: I. Determine if progression-free survival at 24 weeks with this treatment combination is improved compared to historical controls who received immunotherapy without radiation therapy. SECONDARY OBJECTIVES: I. Assess acute (0-6 months) and late (\> 6 months) grade 3-5 toxicity. II. Assess overall survival. III. Correlate circulating tumor deoxyribonucleic acid (DNA) (ratio of post-radiation therapy \[RT\] to pre-RT level) with radiographic response. IV. Correlate immune markers in peripheral blood with radiographic response. TERTIARY OBJECTIVES: I. Analyze progression-free survival with immune-related response criteria. II. Measure time to discontinuation of study immunotherapy agent. III. Assess patterns of progression. OUTLINE: Patients are assigned to 1 of 2 arms. ARM I: Patients undergo radical-dose image guided radiation therapy daily for up to 10 days (within 2 weeks) while undergoing standard of care immunotherapy. Arm II: Patients who decline to undergo radiation therapy receive standard of care immunotherapy. After completion of study treatment, patients are followed up at 30 days and every 6 months thereafter.
Interventions
RADIATIONImage-guided Radiation Therapy
Ablative treatment as 50 Gy in 5 or 10 fractions. Non-ablative treatment as 27 Gy in 3 fractions, or 40 Gy in 10 fractions.
DRUGImmunotherapy (physician's choice for standard of care immunotherapy)
Continue regular medical care immunotherapy. Other than being an anti-PD-1 or anti-PD-L1 immunotherapy, the agent, dose, and schedule is not specified by protocol.
Sponsors
Varian Medical Systems
Stanford University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Has stage IV non-small cell lung cancer, or initially stage I-III disease with distant metastatic recurrence 2. Age ≥ 18 3. Has been receiving anti-PD-1 or anti-PD-L1 immunotherapy for at least four weeks (refer to section 4.2.1) 4. Has had restaging imaging after initiation of immunotherapy, at least 4 weeks after pre-immunotherapy baseline imaging. CT or PET/CT of at least chest/upper abdomen must be performed within 4 weeks prior to registration. For patients with history of brain metastases, brain MRI or CT is required within 4 weeks of registration; for other patients brain MRI or CT is required within 12 weeks of registration. Diagnostic PET/CT performed as part of radiation simulation can be used as the restaging imaging. 5. Most recent imaging shows measurable disease as defined by RECIST 1.1 6. Evaluation by a Stanford medical oncologist must show: 1. The patient is expected to continue on immunotherapy for at least three more months 2. Imaging must show response, stable disease, or modest progression 3. If there is modest progression, the patient must be clinically stable in terms of performance status and overall disease-related symptoms 7. Has at least one extracranial tumor safely treatable with radical-dose radiation therapy and that has not been previously treated with radiation 8. ECOG performance status 0-2 9. Has the ability to understand and the willingness to sign a written informed consent document.
Exclusion criteria
* Untreated brain metastases, if not planned to be treated in this course of radiation therapy * Pregnancy or women of childbearing potential not willing/able to use contraception during protocol treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | 24 weeks from study entry | Defined as percentage of participants without disease progression or death at 24 weeks from date of study entry, assessed per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Complete Response (CR): Disappearance of all target lesions Partial Response (PR): ≥30% decrease in the sum of the longest diameter of target lesions Overall Response (OR): CR + PR |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Circulating Tumor Deoxyribonucleic Acid Levels as Measured Using CAncer Personalized Profiling by Deep Sequencing | Baseline (pre-treatment) | Will correlate with radiographic response. Plasma biomarkers (e.g. cell free deoxyribonucleic acid level) will be summarized using medians and interquartile ranges; changes in biomarkers will be assessed using the Wilcoxon signed rank test. Correlation of biomarkers with radiographic response will be evaluated using a Wilcoxon rank sum test on patients with and without the event of interest. If feasible, these analyses will be supplemented by more formal analyses with the Cox model. |
| Change in Immune Marker Levels as Measured From Peripheral Blood Using Flow Cytometry Performed by the Human Immune Monitoring Core at Stanford University | Pre-radiation (up to 14 days before RT) and post-radiation (up to 14 days after completion of RT) | Change in immune marker levels was measured using flow cytometry performed by the Human Immune Monitoring Core at Stanford University. These changes will correlate with radiographic response. |
| Number of Participants With Acute (0-6 Months) and Late (> 6 Months) Grade 3-5 Toxicity | Up to 4 years after study entry | This outcome measured the number of participants who experienced Grade 3-5 acute (0-6 months) and late (\>6 months) toxicities, assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 4, through up to 4 years after study entry. |
| Overall Survival | Time from study entry to death, assessed up to 4 years after study entry | The electronic medical record was monitored for patient deaths. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Tumor Response (Including Abscopal Responses) | Up to 4 years | Number of participants who experienced a tumor response, including abscopal responses, following image-guided radiation therapy. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. |
| Progression Free Survival | Pre-radiation (up to 14 days before RT) and post-radiation (up to 14 days after completion of RT) | Evaluated with immune-related Response Criteria. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. |
| Time to Discontinuation of Study Immunotherapy Agent | Up to 4 years | Time to discontinuation of study immunotherapy agent was measured. |
Countries
United States
Participant flow
Pre-assignment details
Although the 'Immunotherapy Alone (Regular Medical Care)' arm was included in the study design, no participants were enrolled or assigned to this arm
Participants by arm
| Arm | Count |
|---|---|
| Immunotherapy Plus Image-guided Radiation Therapy Patients undergo radical-dose image guided radiation therapy daily for up to 10 days (within 2 weeks) while continuing their prior treatment with the treating physician's choice of regular medical care immunotherapy.
Image-guided Radiation Therapy: Ablative treatment as 50 Gy in 5 or 10 fractions.
Non-ablative treatment as 27 Gy in 3 fractions, or 40 Gy in 10 fractions.
Immunotherapy (physician's choice for standard of care immunotherapy): Continue regular medical care immunotherapy. Other than being an anti-PD-1 or anti-PD-L1 immunotherapy, the agent, dose, and schedule is not specified by protocol. | 44 |
| Immunotherapy Alone (Regular Medical Care) Patients who decline to undergo radiation therapy will continue their prior treatment with the treating physician's choice of regular medical care immunotherapy.
Immunotherapy (physician's choice for standard of care immunotherapy): Continue regular medical care immunotherapy. Other than being an anti-PD-1 or anti-PD-L1 immunotherapy, the agent, dose, and schedule is not specified by protocol. | 0 |
| Total | 44 |
Baseline characteristics
| Characteristic | Immunotherapy Plus Image-guided Radiation Therapy | Total |
|---|---|---|
| Age, Customized 30-39 years | 2 Participants | 2 Participants |
| Age, Customized 40-49 years | 3 Participants | 3 Participants |
| Age, Customized 50-59 years | 4 Participants | 4 Participants |
| Age, Customized 60-69 years | 10 Participants | 10 Participants |
| Age, Customized 70-79 years | 18 Participants | 18 Participants |
| Age, Customized 80-89 years | 7 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 43 Participants | 43 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 15 Participants | 15 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 26 Participants | 26 Participants |
| Region of Enrollment United States | 44 participants | 44 participants |
| Sex: Female, Male Female | 19 Participants | 19 Participants |
| Sex: Female, Male Male | 25 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 44 |
| other Total, other adverse events | 32 / 44 |
| serious Total, serious adverse events | 6 / 44 |
Outcome results
Primary
Progression-free Survival
Defined as percentage of participants without disease progression or death at 24 weeks from date of study entry, assessed per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Complete Response (CR): Disappearance of all target lesions Partial Response (PR): ≥30% decrease in the sum of the longest diameter of target lesions Overall Response (OR): CR + PR
Time frame: 24 weeks from study entry
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Immunotherapy Plus Image-guided Radiation Therapy | Progression-free Survival | 26 Participants |
p-value: 0.0007Exact binomial test
Secondary
Change in Circulating Tumor Deoxyribonucleic Acid Levels as Measured Using CAncer Personalized Profiling by Deep Sequencing
Will correlate with radiographic response. Plasma biomarkers (e.g. cell free deoxyribonucleic acid level) will be summarized using medians and interquartile ranges; changes in biomarkers will be assessed using the Wilcoxon signed rank test. Correlation of biomarkers with radiographic response will be evaluated using a Wilcoxon rank sum test on patients with and without the event of interest. If feasible, these analyses will be supplemented by more formal analyses with the Cox model.
Time frame: Baseline (pre-treatment)
Population: Blood samples were collected for this outcome measure, however, no laboratory analysis was conducted due to lack of funding. No future analyses are planned.
Secondary
Change in Immune Marker Levels as Measured From Peripheral Blood Using Flow Cytometry Performed by the Human Immune Monitoring Core at Stanford University
Change in immune marker levels was measured using flow cytometry performed by the Human Immune Monitoring Core at Stanford University. These changes will correlate with radiographic response.
Time frame: Pre-radiation (up to 14 days before RT) and post-radiation (up to 14 days after completion of RT)
Population: Peripheral blood samples were collected at the pre-specified time points, but immune marker levels were not analyzed due to lack of funding for laboratory processing. No future analyses are planned.
Secondary
Number of Participants With Acute (0-6 Months) and Late (> 6 Months) Grade 3-5 Toxicity
This outcome measured the number of participants who experienced Grade 3-5 acute (0-6 months) and late (\>6 months) toxicities, assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 4, through up to 4 years after study entry.
Time frame: Up to 4 years after study entry
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Immunotherapy Plus Image-guided Radiation Therapy | Number of Participants With Acute (0-6 Months) and Late (> 6 Months) Grade 3-5 Toxicity | 4 Participants |
Secondary
Overall Survival
The electronic medical record was monitored for patient deaths.
Time frame: Time from study entry to death, assessed up to 4 years after study entry
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Immunotherapy Plus Image-guided Radiation Therapy | Overall Survival | 27.4 months |
Other Pre-specified
Number of Participants With Tumor Response (Including Abscopal Responses)
Number of participants who experienced a tumor response, including abscopal responses, following image-guided radiation therapy. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: Up to 4 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Immunotherapy Plus Image-guided Radiation Therapy | Number of Participants With Tumor Response (Including Abscopal Responses) | 26 Participants |
Other Pre-specified
Progression Free Survival
Evaluated with immune-related Response Criteria. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: Pre-radiation (up to 14 days before RT) and post-radiation (up to 14 days after completion of RT)
Population: Imaging data were collected for assessment of progression-free survival using immune-related response criteria (iRRC); however, these data were not analyzed because the outcome was deemed not scientifically relevant at the time of final analysis. No future analyses are planned.
Other Pre-specified
Time to Discontinuation of Study Immunotherapy Agent
Time to discontinuation of study immunotherapy agent was measured.
Time frame: Up to 4 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Immunotherapy Plus Image-guided Radiation Therapy | Time to Discontinuation of Study Immunotherapy Agent | 6.1 Months |