Dataset Information

A phase I study of intratumoral ipilimumab and interleukin-2 in patients with advanced melanoma.

ABSTRACT:

Purpose

Intratumoral interleukin-2 (IL-2) is effective but does not generate systemic immunity. Intravenous ipilimumab produces durable clinical response in a minority of patients, with potentially severe toxicities. Circulating anti-tumor T cells activated by ipilimumab may differ greatly from tumor-infiltrating lymphocytes activated by intratumoral ipilimumab in phenotypes and functionality. The objective of this study was to primarily assess the safety of intratumoral ipilimumab/IL-2 combination and to obtain data on clinical efficacy.

Results

There was no dose limiting toxicity. While local response of injected lesions was observed in 67% patients (95% CI, 40%-93%), an abscopal response was seen in 89% (95% CI, 68%-100%). The overall response rate and clinical benefit rate by immune-related response criteria (irRC) was 40% (95% CI, 10%-70%) and 50% (95% CI, 19%-81%), respectively. Enhanced systemic immune response was observed in most patients and correlated with clinical responses.

Experimental design

Twelve patients with unresectable stages III/IV melanoma were enrolled. A standard 3+3 design was employed to assess highest tolerable intratumoral dose of ipilimumab and IL-2 based on toxicity during the first three weeks. Escalated doses of ipilimumab was injected into only one lesion weekly for eight weeks in cohorts of three patients. A fixed dose of IL-2 was injected three times a week into the same lesion for two weeks, followed by two times a week for six weeks.

Conclusions

Intratumoral injection with the combination of ipilimumab/IL-2 is well tolerated and generates responses in both injected and non-injected lesions in the majority of patients.

SUBMITTER: Ray A

PROVIDER: S-EPMC5325451 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Publications

A phase I study of intratumoral ipilimumab and interleukin-2 in patients with advanced melanoma.

Ray Abhijit A Williams Matthew A MA Meek Stephanie M SM Bowen Randy C RC Grossmann Kenneth F KF Andtbacka Robert H I RH Bowles Tawnya L TL Hyngstrom John R JR Leachman Sancy A SA Grossman Douglas D Bowen Glen M GM Holmen Sheri L SL VanBrocklin Matthew W MW Suneja Gita G Khong Hung T HT

Oncotarget 20160901 39

<h4>Purpose</h4>Intratumoral interleukin-2 (IL-2) is effective but does not generate systemic immunity. Intravenous ipilimumab produces durable clinical response in a minority of patients, with potentially severe toxicities. Circulating anti-tumor T cells activated by ipilimumab may differ greatly from tumor-infiltrating lymphocytes activated by intratumoral ipilimumab in phenotypes and functionality. The objective of this study was to primarily assess the safety of intratumoral ipilimumab/IL-2 ...[more]

PMID: 27391442

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Project description:BackgroundIntratumoral administration of V937, a bioselected, genetically unmodified coxsackievirus A21, has previously demonstrated antitumor activity in patients with advanced melanoma as monotherapy and in combination with the programmed cell death 1 (PD-1) antibody pembrolizumab. We report results from an open-label, single-arm, phase 1b study (NCT02307149) evaluating V937 plus the cytotoxic T-lymphocyte antigen 4 inhibitor ipilimumab in patients with advanced melanoma.MethodsAdult patients (aged ≥18 years) with histologically confirmed metastatic or unresectable stage IIIB/C or IV melanoma received intratumoral V937 on days 1, 3, 5, 8, and 22 and every 3 weeks (Q3W) thereafter for up to 19 sets of injections plus intravenous ipilimumab 3 mg/kg Q3W administered for four doses starting on day 22. Imaging was performed at screening, on days 43 and 106 and every 6 weeks thereafter; response was assessed by immune-related response criteria per investigator assessment. Primary endpoints were safety in all treated patients and objective response rate (ORR) in all treated patients and in patients with disease that progressed on prior anti-PD-1 therapy.ResultsFifty patients were enrolled and treated. ORR was 30% (95% CI 18% to 45%) among all treated patients, 47% (95% CI 23% to 72%) among patients who had not received prior anti-PD-1 therapy, and 21% (95% CI 9% to 39%) among patients who had experienced disease progression on prior anti-PD-1 therapy. Tumor regression occurred in injected and non-injected lesions. Median immune-related progression-free survival was 6.2 months (95% CI 3.5 to 9.0 months), and median overall survival was 45.1 months (95% CI 28.3 months to not reached). The most common treatment-related adverse events (AEs) were pruritus (n=25, 50%), fatigue (n=22, 44%), and diarrhea (n=16, 32%). There were no V937-related dose-limiting toxicities and no treatment-related grade 5 AEs. Treatment-related grade 3 or 4 AEs, all of which were considered related to ipilimumab, occurred in 14% of patients (most commonly dehydration, diarrhea, and hepatotoxicity in 4% each).ConclusionsResponses associated with intratumoral V937 plus ipilimumab were robust, including in the subgroup of patients who had experienced disease progression on prior anti-PD-1 therapy. Toxicities were manageable and consistent with those of the individual monotherapies.

Project description:High-dose ipilimumab (IPI) and high-dose interleukin-2 (IL-2) are approved agents for metastatic melanoma, but the efficacy and safety of the combination are unknown. The objective of this study was to evaluate the feasibility, safety, and efficacy of combination high-dose IPI and high-dose IL-2 in patients with histologically confirmed advanced unresectable stage III and IV melanoma. This Phase II, multicenter, open-label, single-arm trial was conducted in nine patients enrolled between 12/2014 and 12/2015. Subjects were treated with high-dose IPI 10 mg/kg intravenous (IV) every 3 weeks for four doses starting at week 1 and high-dose IL-2 (600,000 IU/kg IV bolus every 8 h for up to 14 doses) concurrently with IPI at weeks 4 and 7. After the first 12 weeks of combination therapy, maintenance IPI (10 mg/kg IV) monotherapy was administered every 12 weeks for up to 1 year. No patient had received prior PD-1 blockade, and only one received prior vemurafenib. Confirmed partial response was achieved in one (11%), stable disease in four (44%), and progressive disease in four (44%) of nine patients. Two patients achieved durable disease control of 44+ and 50+ months at the most recent follow-up without subsequent therapy. The median overall survival was not reached after a minimum 24 months of follow-up time. One-year and 2-year survival rates were 89 and 67%, respectively. Seven patients (78%) experienced grade 3 or 4 adverse events related to the study therapy, three of which were attributed to both agents. One patient discontinued the treatment due to liver and kidney toxicity. While toxicity was significant, all events were reversible, and there was no treatment-related mortality. In peripheral blood of patients with decreasing tumor burden, the ratio of the non-classical MHC-II proteins HLA-DM to HLA-DO increased 2-fold, raising the possibility of the ratio of HLA-DM:HLA-DO as a novel biomarker of response to treatment. Although the sample size was limited, combination therapy with high-dose IPI and high-dose IL-2 was feasible and associated with clinical benefit. IL-2-based compounds in combination with CTLA-4 blockade should be studied in advanced melanoma patients who fail to benefit from first-line PD-1 blockade. Clinical Trial Registration: ClinicalTrials.gov, NCT02203604. Registered 30 July 2014, https://clinicaltrials.gov/ct2/show/NCT02203604.

Project description:BackgroundIn patients with melanoma, ipilimumab (an antibody against cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4]) prolongs overall survival, and nivolumab (an antibody against the programmed death 1 [PD-1] receptor) produced durable tumor regression in a phase 1 trial. On the basis of their distinct immunologic mechanisms of action and supportive preclinical data, we conducted a phase 1 trial of nivolumab combined with ipilimumab in patients with advanced melanoma.MethodsWe administered intravenous doses of nivolumab and ipilimumab in patients every 3 weeks for 4 doses, followed by nivolumab alone every 3 weeks for 4 doses (concurrent regimen). The combined treatment was subsequently administered every 12 weeks for up to 8 doses. In a sequenced regimen, patients previously treated with ipilimumab received nivolumab every 2 weeks for up to 48 doses.ResultsA total of 53 patients received concurrent therapy with nivolumab and ipilimumab, and 33 received sequenced treatment. The objective-response rate (according to modified World Health Organization criteria) for all patients in the concurrent-regimen group was 40%. Evidence of clinical activity (conventional, unconfirmed, or immune-related response or stable disease for ≥24 weeks) was observed in 65% of patients. At the maximum doses that were associated with an acceptable level of adverse events (nivolumab at a dose of 1 mg per kilogram of body weight and ipilimumab at a dose of 3 mg per kilogram), 53% of patients had an objective response, all with tumor reduction of 80% or more. Grade 3 or 4 adverse events related to therapy occurred in 53% of patients in the concurrent-regimen group but were qualitatively similar to previous experience with monotherapy and were generally reversible. Among patients in the sequenced-regimen group, 18% had grade 3 or 4 adverse events related to therapy and the objective-response rate was 20%.ConclusionsConcurrent therapy with nivolumab and ipilimumab had a manageable safety profile and provided clinical activity that appears to be distinct from that in published data on monotherapy, with rapid and deep tumor regression in a substantial proportion of patients. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; ClinicalTrials.gov number, NCT01024231.).

Project description:Purpose We evaluated the combination of talimogene laherparepvec plus ipilimumab versus ipilimumab alone in patients with advanced melanoma in a phase II study. To our knowledge, this was the first randomized trial to evaluate addition of an oncolytic virus to a checkpoint inhibitor. Methods Patients with unresectable stages IIIB to IV melanoma, with no more than one prior therapy if BRAF wild-type, no more than two prior therapies if BRAF mutant, measurable/injectable disease, and without symptomatic autoimmunity or clinically significant immunosuppression were randomly assigned 1:1 to receive talimogene laherparepvec plus ipilimumab or ipilimumab alone. Talimogene laherparepvec treatment began in week 1 (first dose, ≤ 4 mL × 106 plaque-forming units/mL; after 3 weeks, ≤ 4 mL × 108 plaque-forming units/mL every 2 weeks). Ipilimumab (3 mg/kg every 3 weeks; up to four doses) began week 1 in the ipilimumab alone arm and week 6 in the combination arm. The primary end point was objective response rate evaluated by investigators per immune-related response criteria. Results One hundred ninety-eight patients were randomly assigned to talimogene laherparepvec plus ipilimumab (n = 98), or ipilimumab alone (n = 100). Thirty-eight patients (39%) in the combination arm and 18 patients (18%) in the ipilimumab arm had an objective response (odds ratio, 2.9; 95% CI, 1.5 to 5.5; P = .002). Responses were not limited to injected lesions; visceral lesion decreases were observed in 52% of patients in the combination arm and 23% of patients in the ipilimumab arm. Frequently occurring adverse events (AEs) included fatigue (combination, 59%; ipilimumab alone, 42%), chills (combination, 53%; ipilimumab alone, 3%), and diarrhea (combination, 42%; ipilimumab alone, 35%). Incidence of grade ≥ 3 AEs was 45% and 35%, respectively. Three patients in the combination arm had fatal AEs; none were treatment related. Conclusion The study met its primary end point; the objective response rate was significantly higher with talimogene laherparepvec plus ipilimumab versus ipilimumab alone. These data indicate that the combination has greater antitumor activity without additional safety concerns versus ipilimumab.

Dataset Information

A phase I study of intratumoral ipilimumab and interleukin-2 in patients with advanced melanoma.

Purpose

Results

Experimental design

Conclusions

Publications

A phase I study of intratumoral ipilimumab and interleukin-2 in patients with advanced melanoma.

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