Metastatic Kidney Carcinoma, Recurrent Lung Non-Small Cell Carcinoma, Stage IV Cutaneous Melanoma AJCC v6 and v7, Stage IV Lung Non-Small Cell Cancer AJCC v7, Stage IV Renal Cell Cancer AJCC v7
Conditions
Keywords
Kidney, Lung, Melanoma, Skin
Brief summary
This phase II trial studies how well image guided hypofractionated radiation therapy works with nelfinavir mesylate, pembrolizumab, nivolumab, and atezolizumab in treating patients with melanoma, lung cancer, or kidney cancer that has spread (advanced). Hypofractionated radiation therapy delivers higher doses of radiation therapy over a shorter period of time and may kill more tumor cells and have fewer side effects. Nelfinavir mesylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as pembrolizumab, nivolumab and atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving hypofractionated radiation therapy, nelfinavir mesylate, pembrolizumab, nivolumab and atezolizumab may work better in treating patients with melanoma, lung, or kidney cancer.
Detailed description
OUTLINE: Beginning 7-14 days prior to start of pembrolizumab, nivolumab, or atezolizumab, patients receive nelfinavir mesylate orally (PO) twice daily (BID) on days 1-7 or 1-14 (dependent upon when treatment is started) up to 11-12 weeks. Patients also receive pembrolizumab, nivolumab or atezolizumab intravenously (IV) over 30-60 minutes on day 1. Cycles repeat every 21-28 days in the absence of disease progression or unacceptable toxicity. Patients then undergo hypofractionated radiation therapy over 3-14 days starting after cycle 1 and before cycle 3 of pembrolizumab, nivolumab or atezolizumab. After completion of study treatment, patients are followed up at 30 days and then every 6 months for up to 2 years.
Interventions
DRUGAtezolizumab
Given IV
RADIATIONHypofractionated Radiation Therapy
Undergo hypofractionated radiation therapy
OTHERLaboratory Biomarker Analysis
Correlative studies
DRUGNelfinavir Mesylate
Given PO
BIOLOGICALNivolumab
Given IV
BIOLOGICALPembrolizumab
Given IV
Sponsors
National Cancer Institute (NCI)
University of Washington
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Disease eligibility and stage * Histologically confirmed diagnosis of melanoma, non-small cell lung cancer (NSCLC), or renal carcinoma * Previously treated or previously untreated stage IV melanoma, stage IV or recurrent lung cancer, and metastatic renal cancer by American Joint Committee on Cancer (AJCC) staging criteria * Presence of a lesion that is suitable for hypofractionated radiotherapy * Subjects must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria independent of the lesion to be irradiated. Prior checkpoint inhibitor immunotherapy or chemotherapy is allowed as long as the last dose was received \> 14 days prior to enrollment * Eastern Cooperative Oncology Group (ECOG) 0-2 * Acceptable marrow function and hematologic indices for PD1/PDL1 immune checkpoint inhibitor and nelfinavir as per standard of care * Ability to understand and the willingness to sign a written informed consent document
Exclusion criteria
* Subjects who have had immunotherapy, chemotherapy, or radiation therapy within 14 days (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier * Subjects may not be receiving other investigational agents * Patients with untreated/active brain metastases as documented by computed tomography (CT) or magnetic resonance imaging (MRI) within 2 months of study enrollment; by active brain metastases - we mean - actively symptomatic brain metastases requiring steroids * Allergy or intolerance to nelfinavir or selected PD1/PDL1 immune checkpoint inhibitor * Patients requiring steroids or other immunosuppressive therapy; low-dose or topical steroids are allowable if being used as replacement therapy * Patients receiving anti-retroviral therapy or other agents that are contra-indicated with nelfinavir due to drug-drug interactions\* * Pregnant or lactating patients * Prior radiation that precludes delivery of hypofractionated radiotherapy * \*For a study regarding the safety and efficacy of high dose nelfinavir on patients with Kaposi's Sarcoma (KS),
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Response Rate | Up to 6 months after initiating treatment | Will be determined by immune-related Response Evaluation Criteria in Solid Tumor 1.1. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT Scan: 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 |
|---|---|---|
| Overall Survival | From start of study treatment to death due to any cause, assessed up to 2 years | Any long term data in the medical record that showed survival was use to measure overall survival. |
| Progression-free Survival | From start of treatment to progression by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, symptomatic deterioration, or death due to any cause, assessed up to 2 years | No RECIST measurable progression over the course of 2 years post-treatment. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions |
| Number of Adverse Events | Adverse events were assessed up to 6 months from start of study treatment and All Cause Mortality was assessed upto 2 years from start of study treatment. | Will be assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. All adverse events that were attributable to study intervention in 20 participants, and counted the frequency of severity levels in the participants. |
| Immune Correlative Studies: Changes in T-cell Repertoire | Up to 6 months | Changes in T-cell receptor diversity |
Countries
United States
Participant flow
Pre-assignment details
We consented 21 patients but 1 patient was not eligible. Therefore, there are only 20 patients in the number of participants.
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Nelfinavir, Immunotherapy, Radiation Therapy) Beginning 7-14 days prior to start of pembrolizumab, nivolumab, or atezolizumab, patients receive nelfinavir mesylate PO BID on days 1-7 or 1-14 (dependent upon when treatment is started) up to 11-12 weeks. Patients also receive pembrolizumab, nivolumab or atezolizumab IV over 30-60 minutes on day 1. Cycles repeat every 21-28 days in the absence of disease progression or unacceptable toxicity. Patients then undergo hypofractionated radiation therapy over 3-14 days starting after cycle 1 and before cycle 3 of pembrolizumab, nivolumab or atezolizumab. The study will exclude irradiation of liver metastases as an added precaution.
Atezolizumab: Given IV
Hypofractionated Radiation Therapy: Undergo hypofractionated radiation therapy
Laboratory Biomarker Analysis: Correlative studies
Nelfinavir Mesylate: Given PO
Nivolumab: Given IV
Pembrolizumab: Given IV | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 7 |
| Overall Study | Progression | 7 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Treatment (Nelfinavir, Immunotherapy, Radiation Therapy) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 8 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 2 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 | 15 Participants |
| Region of Enrollment United States | 20 participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 12 / 20 |
| other Total, other adverse events | 20 / 20 |
| serious Total, serious adverse events | 10 / 20 |
Outcome results
Primary
Response Rate
Will be determined by immune-related Response Evaluation Criteria in Solid Tumor 1.1. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT Scan: 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 6 months after initiating treatment
Population: All patients starting trial therapy
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Nelfinavir, Immunotherapy, Radiation Therapy) | Response Rate | 2 Participants |
Secondary
Immune Correlative Studies: Changes in T-cell Repertoire
Changes in T-cell receptor diversity
Time frame: Up to 6 months
Population: Bio-specimens have been collected and stored, and cannot be analyzed by a processing team due to COVID-19 staffing limitations.
Secondary
Number of Adverse Events
Will be assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. All adverse events that were attributable to study intervention in 20 participants, and counted the frequency of severity levels in the participants.
Time frame: Adverse events were assessed up to 6 months from start of study treatment and All Cause Mortality was assessed upto 2 years from start of study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment (Nelfinavir, Immunotherapy, Radiation Therapy) | Number of Adverse Events | Percentage of mild adverse events | 59 Percentage of adverse events |
| Treatment (Nelfinavir, Immunotherapy, Radiation Therapy) | Number of Adverse Events | Percentage of Moderate Adverse Events | 23 Percentage of adverse events |
| Treatment (Nelfinavir, Immunotherapy, Radiation Therapy) | Number of Adverse Events | Percentage of Severe Adverse Events | 14.5 Percentage of adverse events |
| Treatment (Nelfinavir, Immunotherapy, Radiation Therapy) | Number of Adverse Events | Percentage of Life-Threatening Adverse Events | 3.5 Percentage of adverse events |
Secondary
Overall Survival
Any long term data in the medical record that showed survival was use to measure overall survival.
Time frame: From start of study treatment to death due to any cause, assessed up to 2 years
Population: 2 Patients were lost to follow-up before 2 year mark, 1 patient passed away during treatment due to Myocardial infarction, so they were not considered in the OS data.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment (Nelfinavir, Immunotherapy, Radiation Therapy) | Overall Survival | OS after 2 years (Renal) | 2 Participants |
| Treatment (Nelfinavir, Immunotherapy, Radiation Therapy) | Overall Survival | OS after 2 years (Melanoma) | 3 Participants |
| Treatment (Nelfinavir, Immunotherapy, Radiation Therapy) | Overall Survival | Patient death occurred prior to 2 years | 12 Participants |
Secondary
Progression-free Survival
No RECIST measurable progression over the course of 2 years post-treatment. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
Time frame: From start of treatment to progression by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, symptomatic deterioration, or death due to any cause, assessed up to 2 years
Population: 2 participants were lost to follow-up before the 2-year mark.~1 Patient passed away during treatment due to a myocardial infraction.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Nelfinavir, Immunotherapy, Radiation Therapy) | Progression-free Survival | 2 Participants |