Ocular Melanoma Patients Research Articles

Radiation Therapy for Ocular Melanoma – a Narrative Review with Insides from TRIUMF, Canada’s Only Proton Beam Therapy Center

"Ocular melanoma (OM) originates from melanocytes in the eye, predominantly in the uvea, particularly the choroid. The yearly incidence is around six cases per million. OM is not primarily driven by ultraviolet exposure like skin melanoma, but is usually caused by mutations in GNAQ or GNA11. Symptoms like blurry vision and visual field defects appear late. Diagnosis is often made via eye exams, specialized ultrasound, and rarely biopsy. This narrative review describes the radiation treatment modalities of OM and highlights the landscape of proton beam irradiation in Canada. Historically, enucleation was the standard of care for OM. However, current strategies consider tumor size, location, patient age, visual potential, and metastatic presence. Primary treatments include radiation therapy and surgery. Radiation therapy includes plaque brachytherapy (PB), proton beam irradiation (PBI), stereotactic radiosurgery (SRS), and stereotactic radiotherapy (SRT). Surgery includes endoresection, exoresection, and enucleation. Tebentafusp-tebn has been FDA-approved for metastatic cases. PB, the most common radiation therapy for OM, involves radioisotopes delivering radiation into the tumor. Comparable survival rates between PB and enucleation for medium choroidal melanoma have made PB the standard of care. PB has certain limitations, mainly surgical complications. PBI uses a particle accelerator for focused, high-energy proton radiation, yielding high tumor control and survival rates, though the availability of proton facilities is a significant limitation. Vancouver is the only center in Canada for PBI, administered not in a healthcare facility but at TRIUMF (Tri-University Meson Facility). TRIUMF, the world's largest cyclotron particle accelerator, in partnership with BC Cancer and UBC Department of Ophthalmology and Eye Care Center, has treated over 200 ocular melanoma patients between 1995 and 2017, achieving a 91% tumor control rate and 82% five-year survival rate. Emerging combination therapies like Ataxia Telangiectasia Mutated (ATM) protein kinase inhibition before PBI show potential, possibly reducing radiation dose and resistance."

Methylation-driven gene DLL3 is a potential prognostic biomarker in ocular melanoma correlating with metastasis.

Ocular melanoma is an aggressive malignancy with a high rate of metastasis and poor prognosis. Increasing evidence indicated that DNA methylation plays an important role in the occurrence and development of ocular melanoma. Hence, exploring new diagnostic and prognostic biomarkers at the genetic level may be beneficial to the prognosis of patients with ocular melanoma. We collected DNA methylation and gene expression profiles of human UM (uveal melanoma) and CM (conjunctival melanoma) samples from various datasets. We conducted differential methylation and expression analyses to screen the potential biomarkers. Correlation analysis was performed to investigate the relationships between the expression level of DLL3 (delta-like protein 3) and the methylation level of its corresponding CpGs. We explored the prognostic and diagnostic value of DLL3 in UM and CM. Functional annotation and GSEA (gene set enrichment analysis) were applied to get insight into the possible biological roles of DLL3. A cohort of 60 ocular melanoma patients as well as UM and CM cell lines were used to validate our findings in bioinformatic analyses. We found that DLL3 was a methylation-driven gene correlating with UM metastasis. The CpGs of DLL3 are mainly located in the gene body and their methylation level positively correlated to DLL3 expression. Multivariate Cox regression analysis revealed that DLL3 was an independent protective factor for UM patients. High DLL3 expression significantly prolonged the overall survival and disease-free survival of UM patients. DLL3 also showed a promising power to distinguish CM from normal tissues. Functional annotation exhibited that DLL3 may suppress UM progression through modulating immune activities and down-regulating various signaling pathways. External datasets, biospecimens, and cell lines further validated the aberrant expression and prognostic role of DLL3 in ocular melanoma. Methylation-driven gene DLL3 could serve as a new potential diagnostic and prognostic biomarker in ocular melanoma. Our findings may contribute to improving the clinical outcomes of patients with UM or CM.

FOCUS phase 3 trial results: Percutaneous hepatic perfusion (PHP) with melphalan for patients with ocular melanoma liver metastases (PHP-OCM-301/301A).

9510 Background: Ocular melanoma, the most common intraocular malignancy, frequently metastasizes to the liver but to date there is no established standard of care for hepatic-dominant ocular melanoma patients. The FOCUS trial began as a randomized, Ph 3 trial (301) comparing PHP with best alternative care (BAC). The trial was subsequently amended (301A) to halt the BAC arm due to enrollment concerns. Methods: Eligible patients with hepatic-dominant ocular melanoma were randomized 1:1 to receive PHP or BAC (investigator’s choice of TACE, pembrolizumab, ipilimumab, or dacarbazine) on the 301 trial. All eligible patients received PHP on the 301A trial. PHP patients could receive up to 6 PHP treatments, repeated every 6-8 weeks with melphalan dosed at 3.0mg/kg ideal body weight (IBW). Patients with progressive disease (PD) were discontinued from study treatment and all patients are followed until death. Patientswere imaged every 12 (±2) weeks until PD. The primary endpoint, ORR (per RECIST 1.1) as assessed by Independent Review Committee, was characterized by the point estimate and 95% CI for each group (PHP and BAC). Results: 144 patients were enrolled overall; 102 were assigned to PHP (301: n = 43; 301A: n = 59) and 42 were assigned to BAC. 91 PHP patients received treatment (301: n = 40; 301A: n = 51) and 32 BAC patients received treatment. ORR among PHP patients was 35.2% (32/91; 95% CI: 25.44-45.88%). ORR among BAC patients was 12.5% (4/32; 95% CI: 3.51-28.99%; p= 0.0154). The median DOR was 14 months for PHP patients and not calculable for BAC patients. The DCR among PHP patients was 73.6% (67/91; 95% CI: 63.35-82.31%) and among BAC patients was 37.5% (12/32; 95% CI: 21.10-56.31%; p= 0.0002). The median PFS was 9.03 months (95% CI: 6.34-11.56) among PHP patients and was 3.12 months (95% CI: 2.89-5.65) among BAC patients ( p= 0.0007). The median OS was 20.53 months (95% CI: 16.59-24.35) among PHP patients and was 14.06 months (95% CI: 9.99-19.78) among BAC patients. With the last treatment occurring in May 2021, the OS, DOR, and PFS data continues to mature as patients are still being followed for survival. Among the 94 patients assessed for safety after treatment with PHP, 42.6% of patients experienced a serious treatment-emergent adverse event, the majority of which were hematological, transient in nature, and resolved without sequelae. There were no treatment related deaths in the trial. Conclusions: In this analysis of data from the FOCUS trial, PHP demonstrates superior ORR, DOR, DCR, PFS, and OS in comparison with BAC in the treatment of hepatic metastases from ocular melanoma. This therapy offers a potential option for patients with this rare indication that is associated with a poor prognosis and few treatment options. Clinical trial information: NCT02678572.

Clinicopathologic features and survival outcomes of ocular melanoma: a series of 31 cases from a tertiary university hospital

BackgroundWe aimed to determine the effect of clinicopathologic features on overall survival among Caucasian ocular melanoma patients in the Central Anatolia region of Turkey.MethodsThis single-center study included conjunctival (n = 12) and uveal (n = 19) melanoma patients diagnosed between January 2008 and March 2020. Clinicopathologic features and outcomes were reviewed retrospectively. Five cases were tested for BRAF V600 mutations with real-time polymerase chain reaction, and one case was tested with next-generation sequencing. Survival was calculated using the Kaplan-Meier method.ResultsThirty-one patients had a mean initial age of 58.32 years (median, 61 years; range 25 to 78 years). There were 13 male and 18 female patients. The median follow-up time was 43.5 months (range, 6 to 155 months) for conjunctival melanoma and 35 months (range, 8 to 151 months) for uveal melanoma. When this study ended, eight of the 12 conjunctival melanoma patients (66.7%) and nine of the 19 uveal melanoma patients (47.4%) had died. The presence of tumor-infiltrating lymphocytes was related to improved overall survival in conjunctival melanoma (p = .014), whereas the presence of ulceration (p = .030), lymphovascular invasion (p = .051), tumor in the left eye (p = .012), tumor thickness of > 2 mm (p = .012), and mitotic count of >1/mm2 (p = .012) reduced the overall survival in conjunctival melanoma. Uveal melanoma tumors with the largest diameter of 9.1–15 mm led to the lowest overall survival among subgroups (p = .035). Involvement of the conjunctiva (p=.005) and lens (p = .003) diminished overall survival in uveal melanoma. BRAF V600 mutation was present in one case of conjunctival melanoma, GNAQ R183Q mutation was present in one case of uveal melanoma. Patients with uveal melanoma presented with an advanced pathological tumor stage compared to those with conjunctival melanoma (p = .019).ConclusionsThis study confirmed the presence of tumor-infiltrating lymphocytes as a favorable factor in conjunctival melanoma and conjunctival and lens involvement as unfavorable prognostic factors in uveal melanoma for overall survival, respectively.

Percutaneous hepatic perfusion (PHP) with melphalan for patients with ocular melanoma liver metastases: Preliminary results of FOCUS (PHP-OCM-301/301A) phase III trial.

9510 Background: Ocular melanoma, the most common intraocular malignancy, frequently metastasizes to the liver but to date there is no established standard of care for hepatic-dominant ocular melanoma patients. The FOCUS trial began as a randomized, phase III trial (301) comparing PHP with best alternative care (BAC). The trial was subsequently amended (301A) to remove the BAC arm due to enrollment concerns. Methods: Eligible patients with hepatic-dominant ocular melanoma were randomized 1:1 to receive PHP or BAC (investigator’s choice of TACE, pembrolizumab, ipilimumab, or dacarbazine) on the 301 trial. All eligible patients received PHP on the 301A trial. PHP patients could receive up to 6 PHP treatments, repeated every 6-8 weeks with melphalan dosed at 3.0mg/kg ideal body weight (IBW). Patients with progressive disease (PD) were discontinued from study treatment and all patients are followed until death. Patientswere imaged every 12 (±2) weeks until PD. The primary endpoint, ORR (per RECIST 1.1) as assessed by Independent Review Committee, will be characterized by the point estimate and 95% CI for each group (PHP and BAC). Categorical efficacy variables will be presented as frequency counts and percentages and 95% CI. Time-to-event variables will be summarized using Kaplan-Meier methods (median and 95% CI). Results: 144 patients were enrolled overall; 102 were assigned to PHP (301: n=43; 301A: n=59) and 42 were assigned to BAC. 91 PHP patients received treatment (301: n=40; 301A: n=51) and 32 BAC patients received treatment. At the time of this analysis, 4 PHP patients were still ongoing on study treatment with a minimum follow-up of 24 weeks. 79 PHP-treated patients and 29 BAC-treated patients were evaluable for response. ORR among PHP patients was 32.9% (26/79; 95% CI: 22.75-40.40%). ORR among BAC patients was 13.8% (4/29; 95% CI: 3.89-31.66%). The median PFS was 9.03 months (95% CI: 6.24-11.83) among PHP patients and was 3.06 months (95% CI: 2.69-5.65) among BAC patients; this difference was statistically significant ( p=0.0004). Among the 94 patients assessed for safety after treatment with PHP, 40.4% of patients experienced a serious treatment-emergent adverse event, the majority of which were hematological and resolved without sequelae. There were no treatment related deaths in the trial. Conclusions: In this analysis of preliminary data from the FOCUS trial, PHP demonstrates a statistically superior ORR and significantly prolonged PFS in comparison with BAC in the treatment of hepatic metastases from ocular melanoma. The data is encouraging as efficacious treatments for hepatic metastases from ocular melanoma are desperately needed. These early data show an improvement over the previous phase III study in terms of both efficacy (ORR and PFS) as well as toxicity using second generation filters. Clinical trial information: NCT02678572.

Interdisciplinary Surveillance of Ocular Melanomas: Experiences in a German Tertiary Centre.

In contrast to cutaneous melanoma, there are no uniform guidelines regarding surveillance of ocular (uveal, conjunctival) melanomas. A consented standard operating procedure (SOP) by the "Netzwerk onkologische Spitzenzentren" Germany only exists for conjunctival melanoma but not for uveal melanoma. Surveillance is partially based on German S3-guidelines for cutaneous melanoma and is carried out by oncologic centres in a multidisciplinary approach. This study aims to evaluate patients' adherence to surveillance programs and whether surveillance recommendations (examinations, intervals) can be realised. Retrospective analysis of all ocular melanoma patients overseen at the University Hospital of Cologne between 2008 and 2019. The study evaluates rates of successful patient integration into a standardized surveillance program and patients' surveillance adherence, subject to age, gender, primary therapy and tumour entity, respectively. 99 patients were included (56 female, 43 male), 83 of which had uveal melanomas and 16 conjunctival melanomas. Mean follow-up was 59 months. 81% of patients were integrated into a surveillance program. Surveillance was performed according to published recommendations in 78%. 13% of patients dropped out of the surveillance program after a mean period of 38 months. Our data show a growing number of patients in standardized surveillance. However, there are still gaps. There is a need for guidelines specifically designed for ocular melanomas, allowing centres to offer patients an individualized approach.

Personalized treatment planning in eye brachytherapy for ocular melanoma: Dosimetric analysis on ophthalmic structure at risk

PurposeTo evaluate the impact on dose distribution to eye organs-at-risk (eOARs) of a computed tomography (CT)-based treatment planning in eye plaque brachytherapy (EPB) treatment. MethodsWe analyzed 19 ocular melanoma patients treated with ruthenium-106 plaques to a total dose of 100 Gy to tumor apex using conventional central-axis-point dose calculation. Treatments were re-planned using the Plaque Simulator (PS) software implementing two different strategies: a personalized CT-eye-model (CT-PS) and a standard-eye-model (SEM-PS) defined by Collaborative Ocular Melanoma Study. Dice coefficient and Hausdorff distance evaluated the concordance between eye-bulb-models. Mean doses (Dmean) to tumor and eOARs were extracted from Dose-Volume-Histograms and Retinal-Dose-Area-Histogram. Differences between planning approaches were tested by Wilcoxon signed-rank test. ResultsIn the analyzed cohort, 8 patients (42%) had posterior tumor location, 8 (42%) anterior, and 3 (16%) equatorial. The SEM did not accurately described the real CT eye-bulb geometry (median Hausdorff distance 0.8 mm, range: (0.4–1.3) mm). Significant differences in fovea and macula Dmean values were found (p = 0.04) between CT-PS and SEM-PS schemes. No significant dosimetric differences were found for tumor and other eOARs. The planning scheme particularly affects the OARs closest to the tumor with a general tendency of SEM-PS to overestimate the doses to the OARs closest to the tumor. ConclusionThe dosimetric accuracy achievable with CT-PS EPB treatment planning may help to identify ocular melanoma patients who could benefit the most from a personalized eye dosimetry for an optimal outcome in terms of tumor coverage and eOARs sparing. Further research and larger studies are underway.

Phase II single-arm multi-center study of adjuvant ipilimumab in combination with nivolumab in subjects with high-risk ocular melanoma.

TPS10089 Background: Treatment of primary ocular melanoma is often very effective, with local recurrence rates of < 5%. However, distant recurrence is as high as 50% depending on features of the primary tumor. These data emphasize the need for effective adjuvant therapy for patients with locally treated ocular melanoma. Several adjuvant treatments have been developed for patients with high-risk cutaneous melanoma, including ipilimumab and nivolumab monotherapies and an ongoing trial is exploring the nivolumab/ipilimumab combination (CA209-915), but patients with high-risk ocular melanomas have been excluded from these trials. As yet there is no approved adjuvant treatment for high-risk ocular melanoma patients. Methods: We are conducting a Phase II single-arm multi-center study of adjuvant ipilimumab in combination with nivolumab in subjects with high-risk ocular melanoma. This study aims to generate efficacy and safety data for adjuvant this regimen in patients with locally treated high-risk ocular melanoma with 3-year risk of relapse > 50%. The primary endpoint is 3-year relapse-free survival rate. Secondary endpoints are median relapse-free survival, median overall survival, 3-year overall survival rate and safety. All patients will receive nivolumab 240mg IV every 2 weeks plus ipilimumab 1mg/kg IV every 6 weeks. Subjects may receive up to 25 doses of nivolumab and 8 doses of ipilimumab. The accrual goal is 50 patients across all participating institutions. Subjects treated in this study will be matched with controls selected from a contemporaneously collected OM registry, “contemporaneous control” in order to better assess efficacy. Control subjects will be from institutions not participating in this trial, will otherwise meet the trial eligibility criteria and will be further matched with trial participants for various demographic and risk factors to the extent possible. The study is enrolling in 6 comprehensive cancer centers in the US. Clinical trial information: NCT3528408.

Phase II single-arm multicenter study of adjuvant ipilimumab in combination with nivolumab in subjects with high-risk ocular melanoma.

TPS9604 Background: Treatment of primary ocular melanoma is often very effective, with local recurrence rates of < 5%. However, distant recurrence is as high as 50% depending on features of the primary tumor. These data emphasize the need for effective adjuvant therapy for patients with locally treated ocular melanoma. Several adjuvant treatments have been developed for patients with high-risk cutaneous melanoma, including ipilimumab and nivolumab monotherapies and an ongoing trial is exploring the nivolumab/ipilimumab combination (CA209-915), but patients with high-risk ocular melanomas have been excluded from these trials. As yet there is no approved adjuvant treatment for high-risk ocular melanoma patients. Methods: We are conducting a Phase II single-arm multi-center study of adjuvant ipilimumab in combination with nivolumab in subjects with high-risk ocular melanoma. This study aims to generate efficacy and safety data for adjuvant this regimen in patients with locally treated high-risk ocular melanoma with 3-year risk of relapse > 50%. The primary endpoint is 3-year relapse-free survival rate. Secondary endpoints are median relapse-free survival, median overall survival, 3-year overall survival rate and safety. All patients will receive nivolumab 240mg IV every 2 weeks plus ipilimumab 1mg/kg IV every 6 weeks. Subjects may receive up to 25 doses of nivolumab and 8 doses of ipilimumab. The accrual goal is 50 patients across all participating institutions. Subjects treated in this study will be matched with controls selected from a contemporaneously collected OM registry, “contemporaneous control” in order to better assess efficacy. Control subjects will be from institutions not participating in this trial, will otherwise meet the trial eligibility criteria and will be further matched with trial participants for various demographic and risk factors to the extent possible. The study is enrolling in 6 comprehensive cancer centers in the US. Clinical trial information: NCT03528408.

The Patient's Experience of Ocular Melanoma in the US: A Survey of the Ocular Melanoma Foundation

Background: Ocular melanomas threaten patients with early death, visual handicap, and loss of the eye. The aims of this study were to identify aspects of care that patients with ocular melanoma considered most important and to determine whether patients felt their needs had been adequately addressed. Methods: A cross-sectional study including US ocular melanoma patients and their caregivers. An online survey of US ocular melanoma patients was designed and conducted by the Ocular Melanoma Foundation. Results: The cohort included 180 patients with uveal melanoma and 4 with conjunctival melanoma. Median follow-up was 3 years. A third of patients reported that their uveal melanoma had initially been diagnosed as a nevus. Most uveal melanomas were treated with brachytherapy. Almost 50% of patients had no genetic tumor analysis. Screening methods reported most commonly were computed tomography and liver function tests. Metastatic disease developed in 11% of patients. Few patients (13.3%) reported an offer of psychological support. Most dissatisfaction was with lack of advice on financial aspects of care and lack of psychological counseling, with women tending to express more dissatisfaction with care. Many patients complained about the way ophthalmologists delivered bad news to them. Conclusions: This patients' perspective highlights directions for research, education, and other measures to improve the care of patients with ocular melanoma in the US and elsewhere.

Ocular melanoma-when you have seen one, you have not seen them all: a clinical outcome study from the Surveillance, Epidemiology and End Results (SEER) database (1973-2012).

BackgroundOcular melanoma (OM) comprises <5% of all melanomas. Uveal melanoma (UM) is the most common subtype of OM, while conjunctival melanoma (CM) is rare and differs significantly from UM. The purpose of this study is to evaluate a large cohort of OM patients to differentiate demographic, pathologic, and clinical factors between these two neoplasms, which may affect treatment and outcomes.MethodsThe Surveillance, Epidemiology, and End Results database (1973–2012) was used to extract demographic and clinical data on 8,165 OM patients (92.1% UM and 7.9% CM).ResultsBoth CM and UM were most prevalent among Caucasian males in the seventh decade of life. UM patients presented more often with localized disease (90.9% vs 81.2, P<0.01). Surgery (42.8%), radiation (43.0%), or combined surgery and radiation (7.0%) were used in the treatment of UM, while CM was treated almost exclusively with surgery (88.7%). Mean overall survival was longer (15.4 vs 14.6 years; P<0.01) and mortality rates were lower in patients (38.8% vs 46.1%; P<0.01) with CM.ConclusionDespite presenting with more advanced disease than UM, CM is associated with an increased overall survival. Surgery is the primary therapy for CM, whereas radiotherapy is the primary therapy for UM and is associated with prolonged survival.

Point/Counterpoint. Particle therapy is ideal for the treatment of ocular melanomas.

Point/Counterpoint. Particle therapy is ideal for the treatment of ocular melanomas.

Long-term visual acuity outcomes in patients with uveal melanoma treated with 125I episcleral OSU-Nag plaque brachytherapy.

To report our experience in long-term follow-up of ocular melanoma patients treated with custom OSU-Nag eye plaques using (125)I sources. A retrospective chart review was conducted for 113 consecutive ocular melanoma patients with follow-up visual acuity data who were treated with OSU-Nag plaque episcleral brachytherapy at The Ohio State University Medical Center from 1994 to 2009. Visual acuity, complication data, and recurrence rates were recorded up to 120months after brachytherapy. Median age at presentation was 63.0years (range, 22-93). Median follow-up was 65.5months (range, 2-180). Median radiation dose at the prescription point was 85.8Gy (range, 51.8-103.7). Preservation of useful visual acuity, defined as better than 20/200, was noted in 43 of 74 (58%) of patients in the present study at 36months compared with 50.1% of Collaborative Ocular Melanoma Study participants. By 120months, 17 of 30 (57%; 95% confidence interval, 45-69%) progressed to visual acuity worse than 20/200, whereas 9 of 30 (30%) retained visual acuity of 20/40 or better, and 4 of 30 (13%) were 20/50-20/200. The rate of retinopathy after radiation was approximately 40% of all those observed by 60months. Baseline visual acuity, apical tumor height, American Joint Committee on Cancer tumor category, and distance between the tumor and the fovea were all significantly associated with loss of visual acuity. The local tumor control rate by 60months of follow-up was 93% (95% confidence interval, 85-97%). The OSU-Nag custom (125)I plaque is an effective treatment for uveal melanoma, with preservation of useful visual acuity in 58% of eyes 3years after treatment and 43% of eyes 10years after treatment.

Application of alanine dosimetry in dose assessment for ocular melanoma patients undergoing proton radiotherapy – preliminary results

Abstract Basing on alanine solid state/electron paramagnetic resonance (EPR) dosimetry, a supplementary method of cumulatively recording the therapeutic dose received by ocular cancer patients undergoing fractionated proton radiotherapy is proposed. By applying alanine dosimetry during the delivery of consecutive fractions, the dose received within each fraction can be read out by EPR spectrometry and a final permanent cumulative record of the total dose delivered obtained. The dose response of the alanine detector was found to be practically independent on its position within the extended proton Bragg peak region. Dose measurements based on entrance dose recorded in proton beams individually formed for each patient are presented. The described method will be applied as a complementary Quality Assurance procedure for patients undergoing proton radiotherapy at the Institute of Nuclear Physics, Polish Academy of Sciences, Krakow, Poland (IFJ PAN).

Abstract CT106: A phase I/IIa study of IMCgp100: Partial and complete durable responses with a novel first-in-class immunotherapy for advanced melanoma

Abstract Background: IMCgp100 is an affinity-enhanced T cell receptor (TCR) specific for the HLA-A2 restricted melanoma gp100 peptide (YLEPGPVTA) fused to an anti-CD3 antibody fragment. Binding of IMCgp100 to melanoma cells redirects T cell cytotoxicity even in the presence of significant levels of PD-1 and PD-L1. Due to its high affinity, IMCgp100 enables T cells to kill HLA down-regulated melanoma cells otherwise invisible to natural T cell recognition. During phase I dose escalation of a weekly schedule, the Maximum Tolerated Dose (MTD) was 600ng/kg or 50mcg absolute dose. An expanded cohort is accruing at the MTD, and a second dose escalation was initiated to determine the MTD, toxicity and potential activity of a daily x 4 q3w schedule. Methods: Patients enrolled are HLA A2 positive, stage IV or unresectable stage III melanoma, with an ECOG Performance Status (PS) ≤1 and a lymphocyte count of ≥0.5×109/L. The phase II expansion of weekly dosing has a target of 10 patients; accrual will continue until a trio of evaluable biopsies are available from at least six patients. Dose escalation for the daily x 4 q3w regimen began at 10mcg/daily. One cycle is 6 weeks. Results: 16 patients have been treated weekly at MTD (600ng/kg or 50mcg). 63% were male, median age 58 yrs, ECOG PS 0 in 56%. All but one patient had stage IV disease. 63% of patients received ≥2 prior systemic therapies; some patients had prior ipilimumab (56%), RAFi (31%) and anti-PD1 or other immunotherapies (13%). Two patients were subsequently shown to be gp100 negative by IHC. Common toxicities included transient grade 3 pruritic rash and grade 2 pyrexia/edema. Lymphocytes migrated to skin and tumor as evidenced by biopsy analysis, accompanied by chemokine/cytokine release. Three partial responses (PR) and one complete response (CR) were observed and are still ongoing. Two PRs continue after &amp;gt;12 months, one, in an ipilimumab refractory patient continues after &amp;gt;3 months and a CR continues after &amp;gt;4 months; these include responses in the two ocular melanoma patients enrolled (long term PR and CR). Sites of response include lung, liver, lymphatic system and various soft tissues. For the daily x 4 regimen, the 20mcg daily dose is complete, toxicities are tolerable and escalation continues. Conclusions: Toxicities of IMCgp100 were consistent with the mode of action of the drug i.e. IMCgp100 mediated T cell mobilisation, activation and tumor killing. Objective durable responses were observed including in ocular melanoma patients. Additional patients are being accrued at 50mcg weekly. For the daily x 4 regimen, the 20mcg dose was completed, which equates to 80mcg every 3 weeks, or just over half the dose achievable in this period with weekly dosing. Dose escalation in the d x 4 regimen continues. Citation Format: Mark R. Middleton, Pippa Corrie, Mario Sznol, Jeffrey Infante, Clive Mulatero, Jeff Evans, Neil Steven, David Krige, William H. Shingler, Yvonne McGrath, Namir J. Hassan, Bent K. Jakobsen. A phase I/IIa study of IMCgp100: Partial and complete durable responses with a novel first-in-class immunotherapy for advanced melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT106. doi:10.1158/1538-7445.AM2015-CT106

Diffusion-weighted magnetic resonance imaging for predicting and detecting the response of ocular melanoma to proton beam therapy: initial results.

The aim of this study was to investigate the utility of diffusion-weighted magnetic resonance (MR) imaging for prediction and early detection of response to proton beam therapy in ocular melanoma. Ten ocular melanoma patients treated with proton beam therapy were enrolled in the study. All patients underwent conventional MR imaging and diffusion-weighted imaging (DWI) before the start of therapy, and after 1, 3 and 6months of therapy. Tumour volumes and apparent diffusion coefficient (ADC) values of ocular lesions were measured at each examination. Tumour volumes and mean ADC measurements of the four examination series were compared; correlation of ADC values and tumour regression was investigated. Mean ADC value of ocular melanomas significantly increased as early as 3months after therapy; tumour volume significantly decreased as early as 6months after therapy. The ADC values of ocular melanomas before therapy significantly correlated with tumour regression. DWI may provide an early surrogate biomarker for prediction and early detection of tumour response to eye-preserving therapies in ocular melanoma.

Solitary Secondary Malignant Melanoma of Clavicle Two Years after Enuclation for Ocular Melanoma

Solitary metastasis of uveal melanoma to bone is extremely rare and usually associated with other organ involvement. We present a rare case of an ocular melanoma patient presenting with solitary metastasis to the clavicle two years after enucleation, without any other organ involvement. In this report, we tried to present our treatment strategy for the solitary metastasis of bone.

New developments in treatment planning and verification of particle beam therapy.

Charged particle beam therapy has been used for almost 60 years. During the initial 40 years, the medical use of protons and heavy ions was explored at accelerator laboratories in a limited number of patients and for a limited number of cancerous and non-cancerous disease conditions. After the development of computed tomography and 3D treatment planning, it was time to move charged particle therapy into the clinical realm. This happened in October 1991 when an ocular melanoma patient became the first patient to be treated at Loma Linda University Medical Center in California. Due to the increased awareness of the advantages of charged particle therapy and promising results of single-institution experiences, one currently observes a phase of rapid expansion of proton treatment centers throughout the world. A few of these centers are combined proton/carbon ion facilities. It is very important that the technological evolution of charged particle therapy will continue during this phase of clinical expansion to ensure that the increasing number of patients exposed to therapeutic charged particles will benefit most from the advantageous dose distributions that these particles afford. This report will give an overview of translational research activities related to planning and verification of proton therapy in which the authors have been involved for a number of years. While our activities focus on protons, these developments are to a large degree also applicable to carbon ion therapy.

SWOG S0826: A phase II trial of SCH 727965 (NSC 747135) in patients with stage IV melanoma.

8521 Background: Cyclin-dependent kinases (cdks) function to regulate cell cycle control and agents that can target cdks in malignant progression remain viable therapeutic strategies. Selective inhibition of cdk2, in particular, may be of therapeutic value in a subset of patients with melanoma. Methods: 60 patients with metastatic melanoma of cutaneous or mucosal origin were planned to be recruited to a multicenter, single-arm phase II trial of the cdk inhibitor, SCH 727965 (NSC747135). Patients were potentially eligible if they had 0-1 previous treatments, PS of 0-1, and adequate organ function. Ocular melanoma patients and patients with a history of brain metastases were excluded. SCH 727965 50 mg IV every 3 weeks was given until progression with disease assessment occurring every 2 cycles. Co-primary endpoints were 1-year overall survival (OS) and 6-month progression free survival (PFS). Results: 72 patients were enrolled from July 1, 2009 to November 1, 2010 at 24 institutions. 68% of patients had M1c disease and 43% had LDH elevation. 19% had prior therapy for metastatic disease. 28 patients (39%) experienced Grade 4 adverse events, including 20 cases of neutropenia, one case each of cardiac ischemia/infarction, cardiac troponin I elevation, dehydration, abdominal pain, leukopenia, muscle weakness, headache, syncope, and anterior ischemic optic neuropathy. 65 patients are currently evaluable for response. The response rate was 0/65 (95% C.I. (0-6%)). Stable disease was observed in 22%. The estimated median PFS was 1.5 months (95% CI: 1.4 – 1.5); 6-month PFS was 11% (5-20%). Median OS was 8 months (95% CI: 5-11 months); 1-year OS was 36% (95% CI: 24-48%). The null hypothesis of 1-year overall survival=25% was rejected (p=0.04) but 6-month PFS=11% was not (p=0.8). Data Analysis will be updated when missing data are received. Correlative studies of Rb phosphorylation and cyclin expression will be pursued. Conclusions: SCH 727965 appears to be reasonably well tolerated although grade 4 events were relatively common, particularly near the time of infusion. There were no responses but few patients had prolonged disease stabilization that may have resulted in improvement in the 1-year OS rate.

Ex vivo enrichment of circulating anti-tumor T cells from both cutaneous and ocular melanoma patients: clinical implications for adoptive cell transfer therapy

Tumor-infiltrating lymphocytes (TILs) have been successfully used for adoptive cell transfer (ACT) immunotherapy; however, due to their scarce availability, this therapy is possible for a limited fraction of cutaneous melanoma patients. We assessed whether an effective protocol for ex vivo T-cell expansion from peripheral blood mononuclear cells (PBMCs), suitable for ACT of both cutaneous and ocular melanoma patients, could be identified. PBMCs from both cutaneous and ocular melanoma patients were stimulated in vitro with autologous, irradiated melanoma cells (mixed lymphocyte tumor cell culture; MLTCs) in the presence of IL-2 and IL-15 followed by the rapid expansion protocol (REP). The functional activity of these T lymphocytes was characterized and compared with that of TILs. In addition, the immune infiltration in vivo of ocular melanoma lesions was analyzed. An efficient in vitro MLTC expansion of melanoma reactive T cells was achieved from all PBMC’s samples obtained in 7 cutaneous and ocular metastatic melanoma patients. Large numbers of melanoma-specific T cells could be obtained when the REP protocol was applied to these MLTCs. Most MLTCs were enriched in non-terminally differentiated TEM cells homogeneously expressing co-stimulatory molecules (e.g., NKG2D, CD28, CD134, CD137). A similar pattern of anti-tumor activity, in association with a more variable expression of co-stimulatory molecules, was detected on short-term in vitro cultured TILs isolated from the same patients. In these ocular melanoma patients, we observed an immune infiltrate with suppressive characteristics and a low rate of ex vivo growing TILs (28.5% of our cases). Our MLTC protocol overcomes this limitation, allowing the isolation of T lymphocytes with effector functions even in these patients. Thus, anti-tumor circulating PBMC-derived T cells could be efficiently isolated from melanoma patients by our novel ex vivo enrichment protocol. This protocol appears suitable for ACT studies of cutaneous and ocular melanoma patients.Electronic supplementary materialThe online version of this article (doi:10.1007/s00262-011-1179-z) contains supplementary material, which is available to authorized users.