A study to detect the effect of radiofrequent ablation in combination with ipilimumab in patients with eye melanoma that spread out to the liver.|
|- candidate number||12907|
|- NTR Number||NTR3488|
|- ISRCTN||ISRCTN wordt niet meer aangevraagd.|
|- Date ISRCTN created|
|- date ISRCTN requested|
|- Date Registered NTR||18-jun-2012|
|- Secondary IDs||N11RFA / NL37985.031.11; NKI-AVL / CCMO|
|- Public Title||A study to detect the effect of radiofrequent ablation in combination with ipilimumab in patients with eye melanoma that spread out to the liver.|
|- Scientific Title||Phase Ib/II study exploring safety and efficacy of the combination of ipilimumab with radiofrequency ablation (RFA) in patients with unresectable uveal melanoma liver metastases.|
|- hypothesis||Uveal melanoma is an uncommon malignancy (0.6-0.7 cases/100.000/year) that, in the case of metastatic stage, has a poor prognosis for response to treatment and survival. It is remarkable for its purely hematogenous pattern of dissemination, most commonly to the liver (60%) and lungs (25%). Only 28 phase I-II studies were performed in uveal melanoma patients between 1980 and 2008, none of them showing convincing improvements of overall survival rates. Current approaches using chemoembolization with cisplatin-based regimens or intrahepatic artery administration of fotemustin resulted in response rates of up to 40% without increasing the overall survival rates beyond 12 months. Ipilimumab has been shown to improve OS in cutaneous melanoma in two phase III studies and seems to have activity in uveal melanoma, based on own experience from another group. Based on preclinical data and the observed activity of ipilimumab monotherapy in uveal melanoma this study will test the safety and efficacy of a combination of RFA and ipilimumab in uveal melanoma patients that have unresectable liver metastases.|
|- Healt Condition(s) or Problem(s) studied||Uveal melanoma, Metastatic liver tumors|
|- Inclusion criteria||1. Adults at least 18 years of age;|
2. World Health Organization (WHO) Performance Status 0 or I;
3. Histologically or cytologically confirmed unresectable metastatic uveal melanoma
(as confirmed by multidisciplinary opinion, including liver surgeon);
4. Subjects must have at least two liver metastases (one irRC measurable) ĘC at least one feasible for RFA;
5. No prior systemic treatment (including chemotherapy, vaccine therapy, monoclonal
Ab-treatment, IL-2, or chemoembolisation);
6. Local pretreatment of uveal melanoma metastases is allowed, as long patients
have progresses with at least two measurable lesions now;
7. No concurrent immunosuppressive medications (including dexamethason, prednisolon, azathioprin);
8. Screening laboratory values must meet the following criteria: WBC ≥ 2.0x109/L,
Neutrophils ≥1.0x109/L, Platelets ≥100 x109/L, Hemoglobin ≥5.5 mmol/L,
Creatinine ≤2x ULN, AST ≤ 5 x ULN, ALT ≤5 x ULN, Total bilirubin ≤3 X ULN, INR
and PTT in normal range;
9. Women of child bearing potential (WOCBP) must agree to use a reliable form of contraceptive during the study treatment period and for at least 180 days following the last dose of study drug;
10. Men must agree to the use of male contraception during the study treatment period and for at least 180 days after the last dose of study drug;
11. Absence of additional severe and/or uncontrolled concurrent disease;
12. No prior, or ongoing other malignancy, except adequately treated basal cell or
squamous cell skin cancer, cervical cancer in situ or adequately treated other
cancer with eradicative intent for which the patient has been continuously diseasefree
for > 2 years.
|- Exclusion criteria||1. Cerebral or meningeal metastasized uveal melanoma;|
2. Subjects with any active autoimmune disease or a documented history of
autoimmune disease, or history of syndrome that required systemic steroids or
immunosuppressive medications, except for subjects with vitiligo or resolved
3. Prior immunotherapy (tumor vaccine, cytokine, or growth factor);
4. Known history of infection with Human Immunodeficiency Virus;
5. Active infection requiring therapy, positive serology for Hepatitis B surface antigen or Hepatitis C ribonucleic acid (RNA);
6. Underlying medical conditions that, in the Investigator's opinion, will make the
administration of study treatment hazardous or obscure the interpretation of toxicity determination or adverse events;
7. Concurrent medical condition requiring the use of immunosuppressive
medications, or immunosuppressive doses of systemic or absorbable topical
8. History of or current immunodeficiency disease, splenectomy or splenic irradiation;
Prior allogeneic stem cell transplantation;
9. Use of other investigational drugs before study drug administration for systemic
10. Pregnancy or nursing.
|- mec approval received||yes|
|- multicenter trial||no|
|- Type||Single arm|
|- planned startdate ||1-apr-2012|
|- planned closingdate||1-apr-2015|
|- Target number of participants||44|
|- Interventions||Radiofrequent ablation combined with intravenous ipilimumab 3 weekly.|
|- Primary outcome||Phase Ib: Toxicity and safety of treatment:|
DLT toxicities will be any unexpected SAE and AE deemed related to the
investigational treatment. DLT observation period ranges from week 1 to week +10
after last Ipilimumab infusion into third patient of cohort.
The phase 1b part of the study will test the safety of the combination of RFA and
ipilimumab in a 3+3 design, and an expansion phase II cohort (consisting of 38
The study will consist of 3 cohorts of each 3 patients, with an interval of 10 weeks
before opening the next dose escalation cohort after the last patient having received
the last ipilimumab treatment. The identified MTDL will be extended to 6 patients.
The uveal melanoma patients will be treated in the phase Ib part with RFA +
ipilimumab in three dose escalation cohorts:
Cohort 1: RFA + ipilimumab 0.3 mg/kg, 4x, q3wk;
Cohort 2: RFA + ipilimumab 3 mg/kg, 4x, q3wk;
Cohort 3: RFA + ipilimumab 10 mg/kg, 4x, q3wk.
Cohort 1 consists of three patients. If 1 DLT is observed then a cohort 2 consisting of additional 3 patients is opened. If 2 DLT of the 6 patients is observed then the
discontinuation of the study will be discussed with the ethics committee and BMS.
In the case of no or only 1 DLT among the 6 patients included in the DLT cohort the
study will continue to accrue to a total of 38 patients at that dosis level.
DLT is also defined as the following treatment-related adverse events or laboratory
abnormalities, graded according to National Cancer Institute Common Terminology
Criteria for Adverse Events (NCI-CTCAE) version 4.0:
1. Non-hematological toxicity ≥ grade 3;
2. irAE ≥ grade 3;
3. Dosing delay ≥ 3 weeks due to toxicity;
4. Hepatic bleeding grade 3 or 4;
5. Treatment related hepatic failure grade 3 or 4.
Grade and type of adverse events in all patients.
Phase II extension: Efficacy and safety.
Response rate as measured by irRC of intra- and extrahepatic lesions, excluding the metastasis that is treated by RFA) at week 12 from the start of RFA and ipilimumab treatment. Response as well as progression will require confirmation through a subsequent scan at least 4 weeks apart.
|- Secondary outcome||Efficacy:|
3. Clinical response benefit (CR, irPR, and irSD as defined by irRC criteria);
4. Immune-related duration of response (for patients achieving an objective response);
5. Response according to MHC expression on the melanoma cells.
Analysis of immunological and genetic changes in the tumor and peripheral blood pre and post- treatment.
Collection of PBMC pre, on day 1, 22, 43, 64, week 12, 16, 28, and every threemonths, and tumor biopsy mandatory day 1 and week 6, and optional in week 12.
|- Trial web site||N/A|
|- status||open: patient inclusion|
|- CONTACT FOR PUBLIC QUERIES||Dr. Christian Blank|
|- CONTACT for SCIENTIFIC QUERIES||Dr. Christian Blank|
|- Sponsor/Initiator ||Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital (NKI AVL) |
(Source(s) of Monetary or Material Support)
|- Brief summary||This is an open label, non-randomized, single centre, mono-arm phase II trial, evaluating the efficacy (as measured by irRC) and safety of the combination of RFA and Ipilimumab in patients with at least two unresectable hepatic metastases of uveal melanoma in first line systemic treatment. This study will include patients >18 years, with histologically or cytologically confirmed unresectable metastatic uveal melanoma, who have a performance status of 0-1.|
|- Main changes (audit trail)|
|- RECORD||18-jun-2012 - 11-jul-2012|
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