Stage IV Uveal Melanoma
Conditions
Keywords
Sir-spheres, Liver Metastases, Selective internal radiation, Yttrium-90, Uveal, Melanoma, Ocular melanoma
Brief summary
The purpose of this study is to determine whether radiation provided locally to the liver tumor vasculature environment will demonstrate a response of tumor decline. This radiation may cause the tumor cells to die. This is a phase II clinical trial to investigate safety and efficacy of radioactive microsphere (SIR-Spheres® microspheres). Uveal melanoma patients with progressing hepatic metastases who received no more than one intra-hepatic arterial treatment will be enrolled. Patients will be first stratified into two groups: Group A, no prior intra-hepatic arterial treatment; Group B, one prior intra-hepatic arterial treatment).
Detailed description
This is an open-label, uncontrolled single institution phase II study for metastatic uveal melanoma. Uveal melanoma patients who received one or less prior trans-arterial embolization treatment of hepatic metastasis are eligible. Patients will be stratified into two groups: Group A, no prior intra-hepatic arterial treatment, n=24; Group B, one prior hepatic trans-arterial embolization treatment, n=24. They will be treated with intra-hepatic arterial infusion of Yttrium-90 radioactive microspheres (SIR-Spheres® microspheres). Within 4 weeks prior to radiosphere treatment, patients undergo the pre-assessment angiogram and technetium-99m-labelled macroaggregated albumin (99m Tc -MAA) nuclear scan to block the collateral flow to non-target organs and to calculate the shunting rate to the lung. Once patients meet the eligibility criteria of the study, the radiosphere treatment will be given. The Yttrium-90 radioactive microsphere treatment generally consists of two sequential uni-lobar treatments, approximately 4 weeks (3 to 5 weeks) apart. In selected patients, if clinically feasible, a biopsy of hepatic metastasis will be obtained prior to radiosphere treatment to investigate the correlation between efficacy of treatments and molecular characteristics of metastatic uveal melanoma. The side effects of Yttrium-90 radioactive microspheres will be monitored every 2 weeks for one month following each treatment and then every month for three months after the last radiosphere treatment. The efficacy of radiosphere treatment will be evaluated every 3 months from the last treatment for 2 years until disease progression or death. If patients experience grade 3 toxicity after the first treatment with Yttrium-90 radioactive microspheres, the second radiosphere treatment will be held until the resolution of toxicity to grade 1 or less or for a maximum of 6 weeks. The dose of the second radiosphere treatment will be decreased by 50% for liver-related grade 3 toxicity. A dose reduction will not be considered for grade 3 GI toxicity unless the next treatment is repeated to the same hepatic lobe. The study treatment will be discontinued for grade 4 toxicity or if patients do not recover from the grade 3 toxicity to at least a grade 1 within 6 weeks. The study will require two years of accrual with an additional two years of follow-up for survival analysis.
Interventions
DEVICESir-Spheres®
Sir-Spheres® Yttrium-90 microspheres given intra-hepatic; once for each lobe involved separated by 4 weeks.
Sponsors
Thomas Jefferson 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
* must have diagnosis of metastatic melanoma liver disease by histological confirmation * one measurable untreated or progressed liver lesion * less than 50% liver involvement * must have ECOG performance status of 0-1 * must have adequate renal and bone marrow function as: serum creatinine ≤ 2.0 mg/dl, granulocyte count ≥1000/mm3 and platelet count ≥100,000/mm3 * must have adequate liver function as: total bilirubin \<1.6 mg/ml and albumin \>3.0 g/dl
Exclusion criteria
* failure to meet any of the inclusion criteria * solitary liver metastasis that is amenable to surgical removal * previous treatment with isolated hepatic perfusion * systemic chemotherapy within 2 weeks of study entry * significant shunting to the lung (\>20%) as identified on Technetium-99m-macro-aggregated albumin nuclear medicine break-through scan * unsuccessful closure of collateral blood flows from the hepatic artery to non-targeted organs such as the GI tract * symptomatic liver failure including ascites and hepatic encephalopathy * metastasis outside of liver requiring systemic treatment within 3 months * untreated brain metastasis * main portal vein occlusion or inadequate collateral flow * uncontrolled hypertension or congestive heart failure * acute myocardial infarction within 6 months * medical complications with implication of less than 6 month survival * uncontrolled severe bleeding tendency or active GI bleed * significant allergic reaction to iodinated contrast * previous radiation that includes the liver in the main radiation field * pregnant or breast-feeding women * biliary obstruction, stent, or prior biliary surgery including sphincterotomy but excluding cholecystectomy * children under the age of 18
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Benefit Rate of Previously Treated and Naive Patients | 3 months post final treatment, an average of 4 months | Evaluation of clinical benefit includes status of complete and partial response as well as stable disease |
| Number of Patients With Adverse Events | 3 months post final treatment, an average of 4 months | Adverse events except for baseline symptoms will be collected from start of first treatment to 3 months post final treatment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | From date of first SIR-Spheres® administration until the date of death from any cause, assessed up to 6 years | Overall survival (OS) is measured from the start of the treatment to patient death. Date and cause of death will be recorded. The cause of death will be categorized as either cancer-related or cancer-unrelated. |
| Progression Free Survival | 2 years post treatment, an average of 10 months | Period of time without progression of liver metastasis |
| Duration of Response | 2 years post treatment, an average of 10 months | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group A: no Prior Intra-hepatic Arterial Treatment Patients with no prior intra-hepatic arterial treatment will be treated with intra-hepatic arterial infusion of Yttrium-90 radioactive microspheres (SIR-Spheres® microspheres). Sir-Spheres® Yttrium-90 microspheres given intra-hepatic; once for each lobe involved separated by 4 weeks. | 24 |
| Group B: One Prior Hepatic Trans-arterial Embolization Treatment Patients with one prior hepatic trans-arterial embolization treatment will be treated with intra-hepatic arterial infusion of Yttrium-90 radioactive microspheres (SIR-Spheres® microspheres). Sir-Spheres® Yttrium-90 microspheres given intra-hepatic; once for each lobe involved separated by 4 weeks. | 24 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Incomplete Lobar Treatment | 1 | 0 |
Baseline characteristics
| Characteristic | Group A: no Prior Intra-hepatic Arterial Treatment | Total | Group B: One Prior Hepatic Trans-arterial Embolization Treatment |
|---|---|---|---|
| Age, Continuous | 63 years | 61 years | 59 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants | 47 Participants | 24 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 | 24 Participants | 48 Participants | 24 Participants |
| Region of Enrollment United States | 24 participants | 48 participants | 24 participants |
| Sex: Female, Male Female | 10 Participants | 25 Participants | 15 Participants |
| Sex: Female, Male Male | 14 Participants | 23 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 24 | 0 / 24 |
| other Total, other adverse events | 16 / 24 | 15 / 24 |
| serious Total, serious adverse events | 0 / 24 | 0 / 24 |
Outcome results
Primary
Clinical Benefit Rate of Previously Treated and Naive Patients
Evaluation of clinical benefit includes status of complete and partial response as well as stable disease
Time frame: 3 months post final treatment, an average of 4 months
Population: Clinical response in the liver metastases will be evaluated 3 months after the last radiosphere treatment using CT scans or MRI of the abdomen. The same modality must be used for serial measurements of target lesions. The sum of the longest diameter (LD) of up to 5 target liver lesions will be used to determine response.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group A - No Prior Embolization | Clinical Benefit Rate of Previously Treated and Naive Patients | Partial Response | 7 Participants |
| Group A - No Prior Embolization | Clinical Benefit Rate of Previously Treated and Naive Patients | Progressive Disease | 3 Participants |
| Group A - No Prior Embolization | Clinical Benefit Rate of Previously Treated and Naive Patients | Stable Disease | 13 Participants |
| Group A - No Prior Embolization | Clinical Benefit Rate of Previously Treated and Naive Patients | Not Evaluated | 1 Participants |
| Group A - No Prior Embolization | Clinical Benefit Rate of Previously Treated and Naive Patients | Complete Response | 0 Participants |
| Group B - Prior Embolization | Clinical Benefit Rate of Previously Treated and Naive Patients | Not Evaluated | 0 Participants |
| Group B - Prior Embolization | Clinical Benefit Rate of Previously Treated and Naive Patients | Complete Response | 0 Participants |
| Group B - Prior Embolization | Clinical Benefit Rate of Previously Treated and Naive Patients | Partial Response | 6 Participants |
| Group B - Prior Embolization | Clinical Benefit Rate of Previously Treated and Naive Patients | Stable Disease | 8 Participants |
| Group B - Prior Embolization | Clinical Benefit Rate of Previously Treated and Naive Patients | Progressive Disease | 10 Participants |
Primary
Number of Patients With Adverse Events
Adverse events except for baseline symptoms will be collected from start of first treatment to 3 months post final treatment
Time frame: 3 months post final treatment, an average of 4 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group A - No Prior Embolization | Number of Patients With Adverse Events | 16 Participants |
| Group B - Prior Embolization | Number of Patients With Adverse Events | 15 Participants |
Secondary
Duration of Response
Time frame: 2 years post treatment, an average of 10 months
Population: One participant from Group A was not evaluated.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A - No Prior Embolization | Duration of Response | 8.1 months |
| Group B - Prior Embolization | Duration of Response | 5.2 months |
Secondary
Overall Survival
Overall survival (OS) is measured from the start of the treatment to patient death. Date and cause of death will be recorded. The cause of death will be categorized as either cancer-related or cancer-unrelated.
Time frame: From date of first SIR-Spheres® administration until the date of death from any cause, assessed up to 6 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A - No Prior Embolization | Overall Survival | 18.9 months |
| Group B - Prior Embolization | Overall Survival | 19.1 months |
Secondary
Progression Free Survival
Period of time without progression of liver metastasis
Time frame: 2 years post treatment, an average of 10 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A - No Prior Embolization | Progression Free Survival | 8.1 months |
| Group B - Prior Embolization | Progression Free Survival | 5.2 months |