IOLite: phase 1b trial of doublet/triplet combinations of dostarlimab with niraparib, carboplatin–paclitaxel, with or without bevacizumab in patients with advanced cancer
Background Doublet combination therapies targeting immune checkpoints have shown promising efficacy in patients with advanced solid tumors, but it is unknown if rational triplet combinations will be well tolerated and associated with improved antitumor activity. The objective of this trial was to de...
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BMJ Publishing Group
2022-03-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/10/3/e003924.full |
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| author | Wei Guo Manish R Patel Nashat Gabrail Jordi Rodon Erika Hamilton Timothy A Yap Meghan Duncan Alberto Bessudo Jasgit Sachdev Lena Evilevitch Sujatha Kumar Sharon Lu Bruce J Dezube |
| author_facet | Wei Guo Manish R Patel Nashat Gabrail Jordi Rodon Erika Hamilton Timothy A Yap Meghan Duncan Alberto Bessudo Jasgit Sachdev Lena Evilevitch Sujatha Kumar Sharon Lu Bruce J Dezube |
| author_sort | Wei Guo |
| collection | DOAJ |
| description | Background Doublet combination therapies targeting immune checkpoints have shown promising efficacy in patients with advanced solid tumors, but it is unknown if rational triplet combinations will be well tolerated and associated with improved antitumor activity. The objective of this trial was to determine the recommended phase 2 doses (RP2Ds) and to assess the safety and efficacy of the programmed cell death protein 1 (PD-1) inhibitor dostarlimab in combination with (1) the poly(ADP-ribose) polymerase inhibitor niraparib with or without vascular endothelial growth factor inhibitor bevacizumab or (2) carboplatin–paclitaxel chemotherapy with or without bevacizumab, in patients with advanced cancer.Methods IOLite is a multicenter, open-label, multi-arm clinical trial. Patients with advanced solid tumors were enrolled. Patients received dostarlimab in combination with niraparib with or without bevacizumab or in combination with carboplatin–paclitaxel with or without bevacizumab until disease progression, unacceptable toxicity, or withdrawal from the study. Prespecified endpoints in all parts were to evaluate the dose-limiting toxicities (DLTs), RP2Ds, pharmacokinetics (PKs), and preliminary efficacy for each combination.Results A total of 55 patients were enrolled; patients received dostarlimab and: (1) niraparib in part A (n=22); (2) carboplatin–paclitaxel in part B (n=14); (3) niraparib plus bevacizumab in part C (n=13); (4) carboplatin–paclitaxel plus bevacizumab in part D (n=6). The RP2Ds of all combinations were determined. All combinations were safe and tolerable, with no new safety signals observed. DLTs were reported in 2, 1, 2, and 0 patients, in parts A–D, respectively. Preliminary antitumor activity was observed, with confirmed Response Evaluation Criteria in Solid Tumors v1.1 complete/partial responses reported in 4 of 22 patients (18.2%), 6 of 14 patients (42.9%), 4 of 13 patients (30.8%), and 3 of 6 (50.0%) patients, in parts A–D, respectively. Disease control rates were 40.9%, 57.1%, 84.6%, and 83.3%, in parts A–D, respectively. Dostarlimab PK was unaffected by any combinations tested. Coadministration of bevacizumab showed no impact on niraparib PKs. The overall mean PD-1 receptor occupancy was 99.0%.Conclusions Dostarlimab was well tolerated in both doublet and triplet regimens tested, with promising antitumor activity observed with all combinations. We observed higher disease control rates in the triplet regimens than in doublet regimens.Trial registration number NCT03307785. |
| format | Article |
| id | doaj-art-e29828d5a2dc440fb2aab02626d02441 |
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| publishDate | 2022-03-01 |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-e29828d5a2dc440fb2aab02626d024412025-08-20T02:16:55ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262022-03-0110310.1136/jitc-2021-003924IOLite: phase 1b trial of doublet/triplet combinations of dostarlimab with niraparib, carboplatin–paclitaxel, with or without bevacizumab in patients with advanced cancerWei Guo0Manish R Patel1Nashat Gabrail2Jordi Rodon3Erika Hamilton4Timothy A Yap5Meghan Duncan6Alberto Bessudo7Jasgit Sachdev8Lena Evilevitch9Sujatha Kumar10Sharon Lu11Bruce J Dezube122 Department of Health Statistics, Naval Medical University, Shanghai, China12Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, FL, USA14Gabrail Cancer Center, Canton, OH, USA3The University of Texas MD Anderson Cancer Center, Houston, TX, USA1Tennessee Oncology, Sarah Cannon Research Institute, Nashville, USADepartment of Investigational Cancer Therapeutics (Phase 1 Program), The University of Texas MD Anderson Cancer Center, Houston, Texas, USA8Xilio Therapeutics, Waltham, MA, USA6Medical Group of North County, Encinitas, CA, USAHonorHealth Research Institute/TGen, Scottsdale, Arizona, USAGlaxoSmithKline, Waltham, Massachusetts, USAGlaxoSmithKline, Waltham, Massachusetts, USAGlaxoSmithKline, Waltham, Massachusetts, USAGlaxoSmithKline, Waltham, Massachusetts, USABackground Doublet combination therapies targeting immune checkpoints have shown promising efficacy in patients with advanced solid tumors, but it is unknown if rational triplet combinations will be well tolerated and associated with improved antitumor activity. The objective of this trial was to determine the recommended phase 2 doses (RP2Ds) and to assess the safety and efficacy of the programmed cell death protein 1 (PD-1) inhibitor dostarlimab in combination with (1) the poly(ADP-ribose) polymerase inhibitor niraparib with or without vascular endothelial growth factor inhibitor bevacizumab or (2) carboplatin–paclitaxel chemotherapy with or without bevacizumab, in patients with advanced cancer.Methods IOLite is a multicenter, open-label, multi-arm clinical trial. Patients with advanced solid tumors were enrolled. Patients received dostarlimab in combination with niraparib with or without bevacizumab or in combination with carboplatin–paclitaxel with or without bevacizumab until disease progression, unacceptable toxicity, or withdrawal from the study. Prespecified endpoints in all parts were to evaluate the dose-limiting toxicities (DLTs), RP2Ds, pharmacokinetics (PKs), and preliminary efficacy for each combination.Results A total of 55 patients were enrolled; patients received dostarlimab and: (1) niraparib in part A (n=22); (2) carboplatin–paclitaxel in part B (n=14); (3) niraparib plus bevacizumab in part C (n=13); (4) carboplatin–paclitaxel plus bevacizumab in part D (n=6). The RP2Ds of all combinations were determined. All combinations were safe and tolerable, with no new safety signals observed. DLTs were reported in 2, 1, 2, and 0 patients, in parts A–D, respectively. Preliminary antitumor activity was observed, with confirmed Response Evaluation Criteria in Solid Tumors v1.1 complete/partial responses reported in 4 of 22 patients (18.2%), 6 of 14 patients (42.9%), 4 of 13 patients (30.8%), and 3 of 6 (50.0%) patients, in parts A–D, respectively. Disease control rates were 40.9%, 57.1%, 84.6%, and 83.3%, in parts A–D, respectively. Dostarlimab PK was unaffected by any combinations tested. Coadministration of bevacizumab showed no impact on niraparib PKs. The overall mean PD-1 receptor occupancy was 99.0%.Conclusions Dostarlimab was well tolerated in both doublet and triplet regimens tested, with promising antitumor activity observed with all combinations. We observed higher disease control rates in the triplet regimens than in doublet regimens.Trial registration number NCT03307785.https://jitc.bmj.com/content/10/3/e003924.full |
| spellingShingle | Wei Guo Manish R Patel Nashat Gabrail Jordi Rodon Erika Hamilton Timothy A Yap Meghan Duncan Alberto Bessudo Jasgit Sachdev Lena Evilevitch Sujatha Kumar Sharon Lu Bruce J Dezube IOLite: phase 1b trial of doublet/triplet combinations of dostarlimab with niraparib, carboplatin–paclitaxel, with or without bevacizumab in patients with advanced cancer Journal for ImmunoTherapy of Cancer |
| title | IOLite: phase 1b trial of doublet/triplet combinations of dostarlimab with niraparib, carboplatin–paclitaxel, with or without bevacizumab in patients with advanced cancer |
| title_full | IOLite: phase 1b trial of doublet/triplet combinations of dostarlimab with niraparib, carboplatin–paclitaxel, with or without bevacizumab in patients with advanced cancer |
| title_fullStr | IOLite: phase 1b trial of doublet/triplet combinations of dostarlimab with niraparib, carboplatin–paclitaxel, with or without bevacizumab in patients with advanced cancer |
| title_full_unstemmed | IOLite: phase 1b trial of doublet/triplet combinations of dostarlimab with niraparib, carboplatin–paclitaxel, with or without bevacizumab in patients with advanced cancer |
| title_short | IOLite: phase 1b trial of doublet/triplet combinations of dostarlimab with niraparib, carboplatin–paclitaxel, with or without bevacizumab in patients with advanced cancer |
| title_sort | iolite phase 1b trial of doublet triplet combinations of dostarlimab with niraparib carboplatin paclitaxel with or without bevacizumab in patients with advanced cancer |
| url | https://jitc.bmj.com/content/10/3/e003924.full |
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