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Phase II trial of the regulatory T cell-depleting agent, denileukin diftitox, in patients with unresectable stage IV melanoma.

ABSTRACT: We previously found that administration of an interleukin 2/diphtheria toxin conjugate (DAB/IL2; Denileukin Diftitox; ONTAK) to stage IV melanoma patients depleted CD4(+)CD25(HI)Foxp3(+) regulatory T cells and expanded melanoma-specific CD8(+) T cells. The goal of this study was to assess the clinical efficacy of DAB/IL2 in an expanded cohort of stage IV melanoma patients.In a single-center, phase II trial, DAB/IL2 (12 ?g/kg; 4 daily doses; 21 day cycles) was administered to 60 unresectable stage IV melanoma patients and response rates were assessed using a combination of 2-[(18)F]-fluoro-2-deoxy-glucose (FDG)-positron emission tomography (PET) and computed tomography (CT) imaging.After DAB/IL2 administration, 16.7% of the 60 patients had partial responses, 5% stable disease and 15% mixed responses. Importantly, 45.5% of the chemo/immuno-naïve sub-population (11/60 patients) experienced partial responses. One year survival was markedly higher in partial responders (80 ± 11.9%) relative to patients with progressive disease (23.7 ± 6.5%; p value < 0.001) and 40 ± 6.2% of the total DAB/IL2-treated population were alive at 1 year.These data support the development of multi-center, randomized trials of DAB/IL2 as a monotherapy and in combination with other immunotherapeutic agents for the treatment of stage IV melanoma.NCT00299689.

SUBMITTER: Telang S

PROVIDER: S-EPMC3293785 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Phase II trial of the regulatory T cell-depleting agent, denileukin diftitox, in patients with unresectable stage IV melanoma.

Telang Sucheta S Rasku Mary Ann MA Clem Amy L AL Carter Karen K Klarer Alden C AC Badger Wesley R WR Milam Rebecca A RA Rai Shesh N SN Pan Jianmin J Gragg Hana H Clem Brian F BF McMasters Kelly M KM Miller Donald M DM Chesney Jason J

BMC cancer 20111213

<h4>Background</h4>We previously found that administration of an interleukin 2/diphtheria toxin conjugate (DAB/IL2; Denileukin Diftitox; ONTAK) to stage IV melanoma patients depleted CD4(+)CD25(HI)Foxp3(+) regulatory T cells and expanded melanoma-specific CD8(+) T cells. The goal of this study was to assess the clinical efficacy of DAB/IL2 in an expanded cohort of stage IV melanoma patients.<h4>Methods</h4>In a single-center, phase II trial, DAB/IL2 (12 μg/kg; 4 daily doses; 21 day cycles) was a ...[more]

PMID: 22165955

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Project description:BACKGROUND:Checkpoint blockade with ipilimumab provides long-term survival to a significant proportion of patients with metastatic melanoma. New approaches to increase survival and to predict which patients will benefit from treatment are needed. This phase II trial combined ipilimumab with carboplatin/paclitaxel (CP) to assess its safety, efficacy, and to search for peripheral and tumor-based predictive biomarkers. METHODS:Thirty patients with untreated unresectable/metastatic melanoma were treated with ipilimumab and CP. Adverse events (AEs) were monitored and response to treatment was evaluated. Tumor tissue and peripheral blood were collected at specified time points to characterize tumor immune markers by immunohistochemistry and systemic immune activity by multiplex assays and flow cytometry. RESULTS:Eighty three percent of patients received all 5 cycles of CP and 93% completed ipilimumab induction. Serious AEs occurred in 13% of patients, and no treatment-related deaths were observed. Best Overall Response Rate (BORR) and Disease Control Rate (DCR) were 27 and 57%, respectively. Median overall survival was 16.2 months. Response to treatment was positively correlated with a higher tumor CD3+ infiltrate (immune score) at baseline. NRAS and BRAF mutations were less frequent in patients who experienced clinical benefit. Assessment of peripheral blood revealed that non-responders had elevated baseline levels of CXCL8 and CCL4, and a higher proportion of circulating late differentiated B cells. Pre-existing high levels of chemokines (CCL3, CCL4 and CXCL8) and advanced B cell differentiation were strongly associated with worse patient overall survival. Elevated proportions of circulating CD8+/PD-1+ T cells during treatment were associated with worse survival. CONCLUSIONS:The combination of ipilimumab and CP was well tolerated and revealed novel characteristics associated with patients likely to benefit from treatment. A pre-existing systemic inflammatory state characterized by elevation of selected chemokines and advanced B cell differentiation, was strongly associated with poor patient outcomes, revealing potential predictive circulating biomarkers. TRIAL REGISTRATION:Clinicaltrials.gov , NCT01676649 , registered on August 29, 2012.

Project description:BackgroundMelanoma in people of Asian descent presents primarily in non-sun-exposed areas, such as acral and mucosal melanoma. Compared with the predominant sun-exposed area melanomas in Caucasians, acral and mucosal melanomas do not respond as well to immunotherapy and are associated with a worse prognosis. Hence, there is an urgent need for improved treatment for melanoma in Asians. This phase Ib trial evaluated the safety and efficacy of the modified herpes simplex virus-1 oncolytic virus OrienX010 in Chinese patients with unresectable stage IIIC-IV melanoma.MethodsPatients were treated in two different cohorts. In cohort 08 (n=12), patients received up to 5 mL of 8×107 pfu/mL OrienX010 intratumoral injections every 2 weeks until disease progression and responses were evaluated every 6 weeks. In cohort 09 (n=14), patients received up to 10 mL of 8×107 pfu/mL OrienX010 intratumoral injections and responses were evaluated every 8 weeks.ResultsBetween June 2014 and May 2017, 26 patients were enrolled, including 18 (69.2%) patients with acral melanoma. Fever and injection site reaction were the most frequent adverse events. Only one patient experienced a grade ≥3 adverse event and no dose-limiting toxicities were observed. The objective response rate was 19.2% and the disease control rate was 53.8%. The median duration of response was 6.0 months. Antitumor effects were observed in 54.6% of injected lesions and 48.8% of non-injected lesions, including one (16.7%) of six evaluable distant lung metastases. The median progression-free survival was 2.9 months and overall survival was 19.2 months. Compared with patients treated in cohort 08, patients treated in cohort 09 had an improved objective response rate (28.6% vs 8.3%) and a median progression-free survival of 3.0 months vs 2.8 months.ConclusionsOrienX010 oncolytic virotherapy has a tolerable safety profile with antitumor effects in both injected and non-injected metastases and warrants further evaluation in patients with melanoma. Based on these results, the higher cohort 09 dose (up to 10 mL of 8×107 pfu/mL every 2 weeks) was selected as the recommended phase II dose for ongoing trials.Trial registration numberCTR20140631 (cohort 08), CTR20150881 (cohort 09).

Dataset Information

Phase II trial of the regulatory T cell-depleting agent, denileukin diftitox, in patients with unresectable stage IV melanoma.

Publications

Phase II trial of the regulatory T cell-depleting agent, denileukin diftitox, in patients with unresectable stage IV melanoma.

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