A phase I study of the CDK4/6 inhibitor ribociclib combined with gemcitabine in patients with advanced solid tumors
Abstract Background Based on preclinical data showing addition of CDK4/6 inhibitors to gemcitabine was synergistic, ribociclib was evaluated in combination with gemcitabine to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT). Methods In this single arm multicohort phase...
Saved in:
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-01-01
|
| Series: | BJC Reports |
| Online Access: | https://doi.org/10.1038/s44276-024-00107-0 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832595017298870272 |
|---|---|
| author | Aurora Norman Mahesh Seetharam Jacob Allred Jianping Kong Mateusz Opyrchal Wen Wee Ma Yanyan Lou Grace K. Dy Amit Mahipal S. John Weroha Andrea E. Wahner Hendrickson Joel M. Reid Alex A. Adjei |
| author_facet | Aurora Norman Mahesh Seetharam Jacob Allred Jianping Kong Mateusz Opyrchal Wen Wee Ma Yanyan Lou Grace K. Dy Amit Mahipal S. John Weroha Andrea E. Wahner Hendrickson Joel M. Reid Alex A. Adjei |
| author_sort | Aurora Norman |
| collection | DOAJ |
| description | Abstract Background Based on preclinical data showing addition of CDK4/6 inhibitors to gemcitabine was synergistic, ribociclib was evaluated in combination with gemcitabine to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT). Methods In this single arm multicohort phase I trial, we evaluated the safety and efficacy of ribociclib plus gemcitabine in patients with advanced solid tumors. Patients received gemcitabine intravenously on days 1 and 8 followed by ribociclib days 8–14, with treatment repeated every 3 weeks. Results The study enrolled 43 patients between October 2017 and September 2019. The escalation phase (19 patients) determined the MTD and recommended phase II dose (RP2D) to be ribociclib 800 mg daily and gemcitabine 1000 mg/m2 for the expansion phase (24 patients). One patient experienced Grade 4 thrombocytopenia. Eleven patients experienced Grade 3 adverse events (AE), the most common being neutropenia, thrombocytopenia, and anemia. No partial or complete responses were observed. 15/22 (68%) of efficacy evaluable patients who received the MTD achieved best response of stable disease. Conclusions The addition of ribociclib to gemcitabine was tolerated well and yielded stability of tumors in both cohorts. Biomarkers such as Rb status and activity of CDK2 and CDK4/6 complexes may help to select patients who may respond better to the combination of gemcitabine and ribociclib. Clinical Trial Registration NCT03237390. |
| format | Article |
| id | doaj-art-fda9e4c37b2544cb91d18418d44b5d41 |
| institution | Kabale University |
| issn | 2731-9377 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | BJC Reports |
| spelling | doaj-art-fda9e4c37b2544cb91d18418d44b5d412025-01-19T12:12:48ZengNature PortfolioBJC Reports2731-93772025-01-01311810.1038/s44276-024-00107-0A phase I study of the CDK4/6 inhibitor ribociclib combined with gemcitabine in patients with advanced solid tumorsAurora Norman0Mahesh Seetharam1Jacob Allred2Jianping Kong3Mateusz Opyrchal4Wen Wee Ma5Yanyan Lou6Grace K. Dy7Amit Mahipal8S. John Weroha9Andrea E. Wahner Hendrickson10Joel M. Reid11Alex A. Adjei12Mayo ClinicMayo ClinicMayo ClinicMayo ClinicIndiana UniversityCleveland ClinicMayo ClinicRoswell Park Comprehensive Cancer CenterUniversity Hospitals at Case Western UniversityMayo ClinicMayo ClinicMayo ClinicCleveland ClinicAbstract Background Based on preclinical data showing addition of CDK4/6 inhibitors to gemcitabine was synergistic, ribociclib was evaluated in combination with gemcitabine to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT). Methods In this single arm multicohort phase I trial, we evaluated the safety and efficacy of ribociclib plus gemcitabine in patients with advanced solid tumors. Patients received gemcitabine intravenously on days 1 and 8 followed by ribociclib days 8–14, with treatment repeated every 3 weeks. Results The study enrolled 43 patients between October 2017 and September 2019. The escalation phase (19 patients) determined the MTD and recommended phase II dose (RP2D) to be ribociclib 800 mg daily and gemcitabine 1000 mg/m2 for the expansion phase (24 patients). One patient experienced Grade 4 thrombocytopenia. Eleven patients experienced Grade 3 adverse events (AE), the most common being neutropenia, thrombocytopenia, and anemia. No partial or complete responses were observed. 15/22 (68%) of efficacy evaluable patients who received the MTD achieved best response of stable disease. Conclusions The addition of ribociclib to gemcitabine was tolerated well and yielded stability of tumors in both cohorts. Biomarkers such as Rb status and activity of CDK2 and CDK4/6 complexes may help to select patients who may respond better to the combination of gemcitabine and ribociclib. Clinical Trial Registration NCT03237390.https://doi.org/10.1038/s44276-024-00107-0 |
| spellingShingle | Aurora Norman Mahesh Seetharam Jacob Allred Jianping Kong Mateusz Opyrchal Wen Wee Ma Yanyan Lou Grace K. Dy Amit Mahipal S. John Weroha Andrea E. Wahner Hendrickson Joel M. Reid Alex A. Adjei A phase I study of the CDK4/6 inhibitor ribociclib combined with gemcitabine in patients with advanced solid tumors BJC Reports |
| title | A phase I study of the CDK4/6 inhibitor ribociclib combined with gemcitabine in patients with advanced solid tumors |
| title_full | A phase I study of the CDK4/6 inhibitor ribociclib combined with gemcitabine in patients with advanced solid tumors |
| title_fullStr | A phase I study of the CDK4/6 inhibitor ribociclib combined with gemcitabine in patients with advanced solid tumors |
| title_full_unstemmed | A phase I study of the CDK4/6 inhibitor ribociclib combined with gemcitabine in patients with advanced solid tumors |
| title_short | A phase I study of the CDK4/6 inhibitor ribociclib combined with gemcitabine in patients with advanced solid tumors |
| title_sort | phase i study of the cdk4 6 inhibitor ribociclib combined with gemcitabine in patients with advanced solid tumors |
| url | https://doi.org/10.1038/s44276-024-00107-0 |
| work_keys_str_mv | AT auroranorman aphaseistudyofthecdk46inhibitorribociclibcombinedwithgemcitabineinpatientswithadvancedsolidtumors AT maheshseetharam aphaseistudyofthecdk46inhibitorribociclibcombinedwithgemcitabineinpatientswithadvancedsolidtumors AT jacoballred aphaseistudyofthecdk46inhibitorribociclibcombinedwithgemcitabineinpatientswithadvancedsolidtumors AT jianpingkong aphaseistudyofthecdk46inhibitorribociclibcombinedwithgemcitabineinpatientswithadvancedsolidtumors AT mateuszopyrchal aphaseistudyofthecdk46inhibitorribociclibcombinedwithgemcitabineinpatientswithadvancedsolidtumors AT wenweema aphaseistudyofthecdk46inhibitorribociclibcombinedwithgemcitabineinpatientswithadvancedsolidtumors AT yanyanlou aphaseistudyofthecdk46inhibitorribociclibcombinedwithgemcitabineinpatientswithadvancedsolidtumors AT gracekdy aphaseistudyofthecdk46inhibitorribociclibcombinedwithgemcitabineinpatientswithadvancedsolidtumors AT amitmahipal aphaseistudyofthecdk46inhibitorribociclibcombinedwithgemcitabineinpatientswithadvancedsolidtumors AT sjohnweroha aphaseistudyofthecdk46inhibitorribociclibcombinedwithgemcitabineinpatientswithadvancedsolidtumors AT andreaewahnerhendrickson aphaseistudyofthecdk46inhibitorribociclibcombinedwithgemcitabineinpatientswithadvancedsolidtumors AT joelmreid aphaseistudyofthecdk46inhibitorribociclibcombinedwithgemcitabineinpatientswithadvancedsolidtumors AT alexaadjei aphaseistudyofthecdk46inhibitorribociclibcombinedwithgemcitabineinpatientswithadvancedsolidtumors AT auroranorman phaseistudyofthecdk46inhibitorribociclibcombinedwithgemcitabineinpatientswithadvancedsolidtumors AT maheshseetharam phaseistudyofthecdk46inhibitorribociclibcombinedwithgemcitabineinpatientswithadvancedsolidtumors AT jacoballred phaseistudyofthecdk46inhibitorribociclibcombinedwithgemcitabineinpatientswithadvancedsolidtumors AT jianpingkong phaseistudyofthecdk46inhibitorribociclibcombinedwithgemcitabineinpatientswithadvancedsolidtumors AT mateuszopyrchal phaseistudyofthecdk46inhibitorribociclibcombinedwithgemcitabineinpatientswithadvancedsolidtumors AT wenweema phaseistudyofthecdk46inhibitorribociclibcombinedwithgemcitabineinpatientswithadvancedsolidtumors AT yanyanlou phaseistudyofthecdk46inhibitorribociclibcombinedwithgemcitabineinpatientswithadvancedsolidtumors AT gracekdy phaseistudyofthecdk46inhibitorribociclibcombinedwithgemcitabineinpatientswithadvancedsolidtumors AT amitmahipal phaseistudyofthecdk46inhibitorribociclibcombinedwithgemcitabineinpatientswithadvancedsolidtumors AT sjohnweroha phaseistudyofthecdk46inhibitorribociclibcombinedwithgemcitabineinpatientswithadvancedsolidtumors AT andreaewahnerhendrickson phaseistudyofthecdk46inhibitorribociclibcombinedwithgemcitabineinpatientswithadvancedsolidtumors AT joelmreid phaseistudyofthecdk46inhibitorribociclibcombinedwithgemcitabineinpatientswithadvancedsolidtumors AT alexaadjei phaseistudyofthecdk46inhibitorribociclibcombinedwithgemcitabineinpatientswithadvancedsolidtumors |