A multi-center phase II study of high dose interleukin-2 sequenced with vemurafenib in patients with BRAF-V600 mutation positive metastatic melanoma
Abstract Background Preclinical studies suggest that BRAF inhibitors enhance anti-tumor immunity and antigen presentation. Combination BRAF inhibition with immunotherapy is an appealing therapeutic approach. We sequenced vemurafenib with HD IL-2 in patients with BRAF-mutated metastatic melanoma to i...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2018-07-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40425-018-0387-x |
| _version_ | 1819169973123153920 |
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| author | Joseph I. Clark Jatinder Singh Marc S. Ernstoff Christopher D. Lao Lawrence E. Flaherty Theodore F. Logan Brendan Curti Sanjiv S. Agarwala Bret Taback Lee Cranmer Jose Lutzky Theresa L. Luna Sandra Aung David H. Lawson |
| author_facet | Joseph I. Clark Jatinder Singh Marc S. Ernstoff Christopher D. Lao Lawrence E. Flaherty Theodore F. Logan Brendan Curti Sanjiv S. Agarwala Bret Taback Lee Cranmer Jose Lutzky Theresa L. Luna Sandra Aung David H. Lawson |
| author_sort | Joseph I. Clark |
| collection | DOAJ |
| description | Abstract Background Preclinical studies suggest that BRAF inhibitors enhance anti-tumor immunity and antigen presentation. Combination BRAF inhibition with immunotherapy is an appealing therapeutic approach. We sequenced vemurafenib with HD IL-2 in patients with BRAF-mutated metastatic melanoma to improve long term outcomes. Methods Eligible patients were HD IL-2 eligible with metastatic BRAF V600 mutated melanoma. Cohort 1 was treatment naïve and received vemurafenib 960 mg BID for 6 weeks before HD IL-2. Cohort 2 received vemurafenib for 7–18 weeks before enrollment. Both cohorts received HD IL-2 at 600,000 IU/kg every 8 h days 1–5 and days 15–19. The primary objective was to assess complete responses (CR) at 10 weeks ±3 (assessment 1) and 26 weeks ±3 (assessment 2) from the start of HD IL-2. Results Fifty-three patients were enrolled, (cohort 1, n = 38; cohort 2, n = 15). Of these, 39 underwent assessment 1 and 15 assessment 2. The CR rate at assessment 1 was 10% (95% CI 3–24) for both cohorts combined, and 27% (95% CI 8–55) at assessment 2. Three-year survival was 30 and 27% for cohort 1 and cohort 2, respectively. No unexpected toxicities occurred. A shift in the melanoma treatment landscape during this trial adversely affected accrual, leading to early trial closure. Conclusions Vemurafenib in sequence with HD IL-2 did not change the known toxicity profile for either agent. Lower than expected response rates to vemurafenib were observed. Overall response rates and durability of responses appear similar to that observed with HD IL-2 alone. Trial registration NCTN, NCT01683188. Registered 11 September 2012, http://www.clinicaltrials.gov/NCT01683188 |
| first_indexed | 2024-12-22T19:28:00Z |
| format | Article |
| id | doaj.art-5cdc7070ed8046e696ecf169baa8612b |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-12-22T19:28:00Z |
| publishDate | 2018-07-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-5cdc7070ed8046e696ecf169baa8612b2022-12-21T18:15:11ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262018-07-01611810.1186/s40425-018-0387-xA multi-center phase II study of high dose interleukin-2 sequenced with vemurafenib in patients with BRAF-V600 mutation positive metastatic melanomaJoseph I. Clark0Jatinder Singh1Marc S. Ernstoff2Christopher D. Lao3Lawrence E. Flaherty4Theodore F. Logan5Brendan Curti6Sanjiv S. Agarwala7Bret Taback8Lee Cranmer9Jose Lutzky10Theresa L. Luna11Sandra Aung12David H. Lawson13Cardinal Bernardin Cancer Center, Loyola University Medical CenterPrimary Biostatistical SolutionsRoswell Park Cancer InstituteUniversity of MichiganThe Karmanos Cancer InstituteIndiana UniversityEarle A. Chiles Research Institute, Providence Cancer CenterSt. Luke’s Hospital and Health NetworkColumbia University/Herbert Irving Comprehensive Cancer CenterFred Hutchinson Cancer Research Center, University of WashingtonMt. Sinai Comprehensive Cancer CenterPrometheus Laboratories IncPrometheus Laboratories IncEmory Winship Cancer Institute at Emory UniversityAbstract Background Preclinical studies suggest that BRAF inhibitors enhance anti-tumor immunity and antigen presentation. Combination BRAF inhibition with immunotherapy is an appealing therapeutic approach. We sequenced vemurafenib with HD IL-2 in patients with BRAF-mutated metastatic melanoma to improve long term outcomes. Methods Eligible patients were HD IL-2 eligible with metastatic BRAF V600 mutated melanoma. Cohort 1 was treatment naïve and received vemurafenib 960 mg BID for 6 weeks before HD IL-2. Cohort 2 received vemurafenib for 7–18 weeks before enrollment. Both cohorts received HD IL-2 at 600,000 IU/kg every 8 h days 1–5 and days 15–19. The primary objective was to assess complete responses (CR) at 10 weeks ±3 (assessment 1) and 26 weeks ±3 (assessment 2) from the start of HD IL-2. Results Fifty-three patients were enrolled, (cohort 1, n = 38; cohort 2, n = 15). Of these, 39 underwent assessment 1 and 15 assessment 2. The CR rate at assessment 1 was 10% (95% CI 3–24) for both cohorts combined, and 27% (95% CI 8–55) at assessment 2. Three-year survival was 30 and 27% for cohort 1 and cohort 2, respectively. No unexpected toxicities occurred. A shift in the melanoma treatment landscape during this trial adversely affected accrual, leading to early trial closure. Conclusions Vemurafenib in sequence with HD IL-2 did not change the known toxicity profile for either agent. Lower than expected response rates to vemurafenib were observed. Overall response rates and durability of responses appear similar to that observed with HD IL-2 alone. Trial registration NCTN, NCT01683188. Registered 11 September 2012, http://www.clinicaltrials.gov/NCT01683188http://link.springer.com/article/10.1186/s40425-018-0387-xHigh-dose interleukin-2VemurafenibBRAF-mutated metastatic melanomaMulticenterPhase II |
| spellingShingle | Joseph I. Clark Jatinder Singh Marc S. Ernstoff Christopher D. Lao Lawrence E. Flaherty Theodore F. Logan Brendan Curti Sanjiv S. Agarwala Bret Taback Lee Cranmer Jose Lutzky Theresa L. Luna Sandra Aung David H. Lawson A multi-center phase II study of high dose interleukin-2 sequenced with vemurafenib in patients with BRAF-V600 mutation positive metastatic melanoma Journal for ImmunoTherapy of Cancer High-dose interleukin-2 Vemurafenib BRAF-mutated metastatic melanoma Multicenter Phase II |
| title | A multi-center phase II study of high dose interleukin-2 sequenced with vemurafenib in patients with BRAF-V600 mutation positive metastatic melanoma |
| title_full | A multi-center phase II study of high dose interleukin-2 sequenced with vemurafenib in patients with BRAF-V600 mutation positive metastatic melanoma |
| title_fullStr | A multi-center phase II study of high dose interleukin-2 sequenced with vemurafenib in patients with BRAF-V600 mutation positive metastatic melanoma |
| title_full_unstemmed | A multi-center phase II study of high dose interleukin-2 sequenced with vemurafenib in patients with BRAF-V600 mutation positive metastatic melanoma |
| title_short | A multi-center phase II study of high dose interleukin-2 sequenced with vemurafenib in patients with BRAF-V600 mutation positive metastatic melanoma |
| title_sort | multi center phase ii study of high dose interleukin 2 sequenced with vemurafenib in patients with braf v600 mutation positive metastatic melanoma |
| topic | High-dose interleukin-2 Vemurafenib BRAF-mutated metastatic melanoma Multicenter Phase II |
| url | http://link.springer.com/article/10.1186/s40425-018-0387-x |
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