Metastatic Melanoma
Conditions
Keywords
metastatic melanoma, IL-2, Interleukin 2, Radiation, Stereotactic Body Radiation Treatment, SBRT, Immunotherapy
Brief summary
The purpose of this study is compare the response rates in patients with metastatic melanoma treated with high-dose IL-2 to patients treated with high-dose IL-2 along with radiation therapy.
Detailed description
All patients will receive high-dose IL-2. Half the patients enrolled will be randomly selected to receive radiation therapy to up to three tumors prior to receiving high-dose IL-2. Among the first 20 patients enrolled, those assigned to receive radiation will receive a single dose of radiation and for patients 21-44, those assigned to receive radiation will receive 2 doses of radiation.
Interventions
OTHERRadiation therapy and high-dose IL-2
Patients 1 - 20 will receive a single fraction of radiation. Patients 21 through the completion of the study will receive two fractions. The dose for all patients will be 20 Gy per fraction to the prescription line at the edge of the planning treatment volume (PTV) with the last dose delivered on a Friday before IL-2 administration. For patients receiving two radiation doses, the doses can be administered on the Wednesday and Friday before IL-2 starts. Patients who are assigned to IL-2 monotherapy and have progressive disease after two IL-2 cycles are then eligible to receive SBRT before cycle 3 of IL-2 commences, single fraction for patients 1-20 and two fractions for patients 21- end of study.
DRUGHigh-dose IL-2
IL-2 will be given on a Monday at a dose of 600,000 IU per kilogram IV every 8 hours for up to 14 doses each cycle. The second cycle is planned 16 days after cycle 1 but may be delayed up to one week to allow toxicity to resolve. The maximum number of doses that can be given during two cycles will be 28 doses. Patients who respond after two cycles can receive 4 more cycles of IL-2. Patients with disease progression after 2 cycles may elect to receive radiation before a 3rd cycle of IL-2. If patients crossover, IL-2 will be given on the Monday following the last dose of radiation, at a dose of 600,000 IU per kilogram IV every 8 hours for a maximum of 14 doses each cycle. Another cycle is planned 16 days after cycle 3 but may be delayed up to one week to allow toxicity to resolve.
Sponsors
Providence Health & Services
Prometheus Laboratories
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histological confirmation of melanoma will be required by previous biopsy or cytology. * Patients must be ≥ 18 years of age. * Patients must have tumors amenable to SBRT in lungs, mediastinum, chest wall, bones (other than long bones), or liver (inclusive of immediately adjacent masses), 1 - 3 foci; no minimum size, but none greater than 7 cm. Patients may have other metastases but only a maximum of 3 will be treated. * ECOG performance status of 0-1. * Women of childbearing potential must have a serum or urine pregnancy test performed within 72 hours prior to the start of protocol treatment. The results of this test must be negative in order for the patient to be eligible. In addition, women of childbearing potential as well as male patients must agree to take appropriate precautions to avoid pregnancy. * Patients must sign a study-specific consent form.
Exclusion criteria
* No metastatic site amenable to SBRT. * Patients with brain metastases not candidates for radiosurgery. * Previous radiation to sites proposed for radiation as part of this study. * Patients with active systemic, pulmonary, or pericardial infection. * Pregnant or lactating women. * Evidence of ischemia on exercise tolerance test, stress thallium study, or baseline EKG. * DLCO, FEV1 or FEV1/FVC less than 70% of predicted due to clinically significant underlying pulmonary disease. For any pulmonary function test values less than predicted values, the PI will review, and document the patient's suitability for high dose IL-2 therapy. * WBC \< 3.0 x 109/L * Hgb \< 9.0 g/dL * AST/ALT \> 3 times the upper limit of the normal range * total bilirubin \> 1.9 g/dL * creatinine \> 1.9 g/dL * Patient requires chronic steroids.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Best Overall Tumor Response of High Dose IL-2 vs. SBRT + High Dose IL-2 | At the end of Cycle 2 (Week 14). | Determine the best overall tumor response rate of high dose IL-2 versus SBRT + high-dose IL-2 using RECIST v1.1 assessed by CT/MRI, criteria applied to all target and non-target lesions with the exclusion of sites treated with SBRT. For patients who have SBRT after progression on IL-2 monotherapy, the response rate will be recorded, but not counted as a response for the primary objective. Overall response rate (ORR) includes all measurable and non-measurable target lesions except the lesions treated by SBRT, which were assessed separately. Both CT and positron emission tomography imaging were employed to assess response. Complete Response: disappearance of all target/non-target lesions and no abnormalities on PET; Partial Response: ≥30% decrease in sum of longest diameter (LD) of target lesions; Progressive Disease: ≥20% increase in sum of LD recorded since tx start or appearance of ≥1 new lesions; Stable Disease: Neither qualifying for PR nor PD since tx started. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Response Rate in Crossover Patients | 7 weeks following Cycle 2 (Week 21). | Measure the response rate of patients who have disease progression after the first IL-2 cycles (using RECIST criteria) who received SBRT prior to cycle 3 of IL-2. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORBrendan Curti, M.D.
Providence Health & Services
PRINCIPAL_INVESTIGATORSteven K. Seung, M.D.
Providence Health & Services
PRINCIPAL_INVESTIGATORMarka Crittenden, MD, PhD
Providence Health & Services
Participant flow
Recruitment details
A total of 63 potential patients were screened for eligibility at Providence Cancer Institute Franz Clinic and Compass Oncology East Clinic from 2011 to 2017.
Pre-assignment details
Of the 50 patients who signed consent, six were excluded (3 due to rapid melanoma progression during screening, 2 due to cardiac ischemia on exercise tolerance testing, and 1 due to insurance issues). Of the 44 enrolled patients, 20 were assigned to Arm A, and 7 of those patients chose to participate in the optional crossover portion of the study.
Participants by arm
| Arm | Count |
|---|---|
| Arm A: IL-2 Monotherapy Patients receive standard high-dose IL-2 therapy, with an opportunity to crossover to the experimental arm if there is disease progression noted after two cycles of high-dose IL-2. Crossover patients will be included in Arm A.
High-dose IL-2: IL-2 will be given on a Monday at a dose of 600,000 IU per kilogram IV every 8 hours for up to 14 doses each cycle. The second cycle is planned 16 days after cycle 1 but may be delayed up to one week to allow toxicity to resolve. The maximum number of doses that can be given during two cycles will be 28 doses. Patients who respond after two cycles can receive 4 more cycles of IL-2. Patients with disease progression after 2 cycles may elect to receive radiation before a 3rd cycle of IL-2. If patients crossover, IL-2 will be given on the Monday following the last dose of radiation, at a dose of 600,000 IU per kilogram IV every 8 hours for a maximum of 14 doses each cycle. Another cycle is planned 16 days after cycle 3 but may be delayed up to one week to allow toxicity to resolve. | 20 |
| Arm B: SBRT + IL-2 Patients 1-20 who are assigned to receive radiation therapy will receive a single dose of radiation before IL-2; patients 21-44 assigned to receive radiation will receive two doses of radiation before receiving high-dose IL-2.
Radiation therapy and high-dose IL-2: Patients 1 - 20 will receive a single fraction of radiation. Patients 21 through the completion of the study will receive two fractions. The dose for all patients will be 20 Gy per fraction to the prescription line at the edge of the planning treatment volume (PTV) with the last dose delivered on a Friday before IL-2 administration. For patients receiving two radiation doses, the doses can be administered on the Wednesday and Friday before IL-2 starts. Patients who are assigned to IL-2 monotherapy and have progressive disease after two IL-2 cycles are then eligible to receive SBRT before cycle 3 of IL-2 commences, single fraction for patients 1-20 and two fractions for patients 21- end of study. | 24 |
| Total | 44 |
Baseline characteristics
| Characteristic | Total | Arm B: SBRT + IL-2 | Arm A: IL-2 Monotherapy |
|---|---|---|---|
| Age, Continuous | 57 years | 53 years | 57.5 years |
| BRAF Status Mutated | 18 Participants | 7 Participants | 11 Participants |
| BRAF Status Unknown | 7 Participants | 3 Participants | 4 Participants |
| BRAF Status Wild Type | 19 Participants | 14 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 44 Participants | 24 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 44 Participants | 24 Participants | 20 Participants |
| Region of Enrollment United States | 44 participants | 24 participants | 20 participants |
| Sex: Female, Male Female | 10 Participants | 6 Participants | 4 Participants |
| Sex: Female, Male Male | 34 Participants | 18 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 16 / 20 | 18 / 31 |
| other Total, other adverse events | 2 / 20 | 0 / 31 |
| serious Total, serious adverse events | 17 / 20 | 17 / 31 |
Outcome results
Primary
Best Overall Tumor Response of High Dose IL-2 vs. SBRT + High Dose IL-2
Determine the best overall tumor response rate of high dose IL-2 versus SBRT + high-dose IL-2 using RECIST v1.1 assessed by CT/MRI, criteria applied to all target and non-target lesions with the exclusion of sites treated with SBRT. For patients who have SBRT after progression on IL-2 monotherapy, the response rate will be recorded, but not counted as a response for the primary objective. Overall response rate (ORR) includes all measurable and non-measurable target lesions except the lesions treated by SBRT, which were assessed separately. Both CT and positron emission tomography imaging were employed to assess response. Complete Response: disappearance of all target/non-target lesions and no abnormalities on PET; Partial Response: ≥30% decrease in sum of longest diameter (LD) of target lesions; Progressive Disease: ≥20% increase in sum of LD recorded since tx start or appearance of ≥1 new lesions; Stable Disease: Neither qualifying for PR nor PD since tx started.
Time frame: At the end of Cycle 2 (Week 14).
Population: There will be a comparison of the overall tumor response of patients receiving one versus two SBRT doses. Responses from patients who participated in the crossover portion of the study were excluded.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A: IL-2 Monotherapy | Best Overall Tumor Response of High Dose IL-2 vs. SBRT + High Dose IL-2 | Complete Response (CR) | 15 percentage of participants |
| Arm A: IL-2 Monotherapy | Best Overall Tumor Response of High Dose IL-2 vs. SBRT + High Dose IL-2 | Stable Disease (SD) | 25 percentage of participants |
| Arm A: IL-2 Monotherapy | Best Overall Tumor Response of High Dose IL-2 vs. SBRT + High Dose IL-2 | Partial Response (PR) | 20 percentage of participants |
| Arm A: IL-2 Monotherapy | Best Overall Tumor Response of High Dose IL-2 vs. SBRT + High Dose IL-2 | Progressive Disease (PD) | 40 percentage of participants |
| Arm A: IL-2 Monotherapy | Best Overall Tumor Response of High Dose IL-2 vs. SBRT + High Dose IL-2 | Overall Response Rate (ORR) | 54 percentage of participants |
| Arm B: SBRT + IL-2 | Best Overall Tumor Response of High Dose IL-2 vs. SBRT + High Dose IL-2 | Progressive Disease (PD) | 25 percentage of participants |
| Arm B: SBRT + IL-2 | Best Overall Tumor Response of High Dose IL-2 vs. SBRT + High Dose IL-2 | Overall Response Rate (ORR) | 35 percentage of participants |
| Arm B: SBRT + IL-2 | Best Overall Tumor Response of High Dose IL-2 vs. SBRT + High Dose IL-2 | Complete Response (CR) | 21 percentage of participants |
| Arm B: SBRT + IL-2 | Best Overall Tumor Response of High Dose IL-2 vs. SBRT + High Dose IL-2 | Partial Response (PR) | 33 percentage of participants |
| Arm B: SBRT + IL-2 | Best Overall Tumor Response of High Dose IL-2 vs. SBRT + High Dose IL-2 | Stable Disease (SD) | 21 percentage of participants |
Secondary
Response Rate in Crossover Patients
Measure the response rate of patients who have disease progression after the first IL-2 cycles (using RECIST criteria) who received SBRT prior to cycle 3 of IL-2.
Time frame: 7 weeks following Cycle 2 (Week 21).
Population: This measure is specifically for patients enrolled into IL-2 monotherapy cohort who then opted for radiation therapy in addition to IL-2.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A: IL-2 Monotherapy | Response Rate in Crossover Patients | CR | 1 Count of participants |
| Arm A: IL-2 Monotherapy | Response Rate in Crossover Patients | PR | 2 Count of participants |
| Arm A: IL-2 Monotherapy | Response Rate in Crossover Patients | SD | 0 Count of participants |
| Arm A: IL-2 Monotherapy | Response Rate in Crossover Patients | PD | 4 Count of participants |