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Phase 2 trial of palbociclib and ganitumab in patients with relapsed Ewing sarcoma
BACKGROUND: Ewing sarcoma (EWS) is an aggressive sarcoma with few treatment options for patients with relapsed disease. Cyclin‐dependent kinase 4 (CDK4) is a genomic vulnerability in EWS that is synergistic with IGF‐1R inhibition in preclinical studies. We present the results of a phase 2 study comb...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10417097/ https://www.ncbi.nlm.nih.gov/pubmed/37306107 http://dx.doi.org/10.1002/cam4.6208 |
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author | Shulman, David S. Merriam, Priscilla Choy, Edwin Guenther, Lillian M. Cavanaugh, Kerri L. Kao, Pei‐Chi Posner, Andrew Bhushan, Ketki Fairchild, Grace Barker, Emma Klega, Kelly Stegmaier, Kimberly Crompton, Brian D. London, Wendy B. DuBois, Steven G. |
author_facet | Shulman, David S. Merriam, Priscilla Choy, Edwin Guenther, Lillian M. Cavanaugh, Kerri L. Kao, Pei‐Chi Posner, Andrew Bhushan, Ketki Fairchild, Grace Barker, Emma Klega, Kelly Stegmaier, Kimberly Crompton, Brian D. London, Wendy B. DuBois, Steven G. |
author_sort | Shulman, David S. |
collection | PubMed |
description | BACKGROUND: Ewing sarcoma (EWS) is an aggressive sarcoma with few treatment options for patients with relapsed disease. Cyclin‐dependent kinase 4 (CDK4) is a genomic vulnerability in EWS that is synergistic with IGF‐1R inhibition in preclinical studies. We present the results of a phase 2 study combining palbociclib (CDK4/6 inhibitor) with ganitumab (IGF‐1R monoclonal antibody) for patients with relapsed EWS. PATIENTS AND METHODS: This open‐label, non‐randomized, phase 2 trial enrolled patients ≥12 years with relapsed EWS. All patients had molecular confirmation of EWS and RECIST measurable disease. Patients initially received palbociclib 125 mg orally on Days 1–21 and ganitumab 18 mg/kg intravenously on Days 1 and 15 of a 28‐day cycle. The primary endpoints were objective response (complete or partial) per RECIST and toxicity by CTCAE. An exact one‐stage design required ≥4 responders out of 15 to evaluate an alternative hypothesis of 40% response rate against a null of 10%. The study was closed following enrollment of the 10th patient due to discontinuation of ganitumab supply. RESULTS: Ten evaluable patients enrolled [median age 25.7 years (range 12.3–40.1)]. The median duration of therapy was 2.5 months (range 0.9–10.8). There were no complete or partial responders. Three of 10 patients had stable disease for >4 cycles and 2 had stable disease at completion of planned therapy or study closure. Six‐month progression‐free survival was 30% (95% CI 1.6%–58.4%). Two patients had cycle 1 hematologic dose‐limiting toxicities (DLTs) triggering palbociclib dose reduction to 100 mg daily for 21 days. Two subsequent patients had cycle 1 hematologic DLTs at the reduced dose. Eighty percent of patients had grade 3/4 AEs, including neutropenia (n = 8), white blood cell decreased (n = 7), and thrombocytopenia (n = 5). Serum total IGF‐1 significantly increased (p = 0.013) and ctDNA decreased during the first cycle. CONCLUSIONS: This combination lacks adequate therapeutic activity for further study, though a subset of patients had prolonged stable disease. |
format | Online Article Text |
id | pubmed-10417097 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-104170972023-08-12 Phase 2 trial of palbociclib and ganitumab in patients with relapsed Ewing sarcoma Shulman, David S. Merriam, Priscilla Choy, Edwin Guenther, Lillian M. Cavanaugh, Kerri L. Kao, Pei‐Chi Posner, Andrew Bhushan, Ketki Fairchild, Grace Barker, Emma Klega, Kelly Stegmaier, Kimberly Crompton, Brian D. London, Wendy B. DuBois, Steven G. Cancer Med RESEARCH ARTICLES BACKGROUND: Ewing sarcoma (EWS) is an aggressive sarcoma with few treatment options for patients with relapsed disease. Cyclin‐dependent kinase 4 (CDK4) is a genomic vulnerability in EWS that is synergistic with IGF‐1R inhibition in preclinical studies. We present the results of a phase 2 study combining palbociclib (CDK4/6 inhibitor) with ganitumab (IGF‐1R monoclonal antibody) for patients with relapsed EWS. PATIENTS AND METHODS: This open‐label, non‐randomized, phase 2 trial enrolled patients ≥12 years with relapsed EWS. All patients had molecular confirmation of EWS and RECIST measurable disease. Patients initially received palbociclib 125 mg orally on Days 1–21 and ganitumab 18 mg/kg intravenously on Days 1 and 15 of a 28‐day cycle. The primary endpoints were objective response (complete or partial) per RECIST and toxicity by CTCAE. An exact one‐stage design required ≥4 responders out of 15 to evaluate an alternative hypothesis of 40% response rate against a null of 10%. The study was closed following enrollment of the 10th patient due to discontinuation of ganitumab supply. RESULTS: Ten evaluable patients enrolled [median age 25.7 years (range 12.3–40.1)]. The median duration of therapy was 2.5 months (range 0.9–10.8). There were no complete or partial responders. Three of 10 patients had stable disease for >4 cycles and 2 had stable disease at completion of planned therapy or study closure. Six‐month progression‐free survival was 30% (95% CI 1.6%–58.4%). Two patients had cycle 1 hematologic dose‐limiting toxicities (DLTs) triggering palbociclib dose reduction to 100 mg daily for 21 days. Two subsequent patients had cycle 1 hematologic DLTs at the reduced dose. Eighty percent of patients had grade 3/4 AEs, including neutropenia (n = 8), white blood cell decreased (n = 7), and thrombocytopenia (n = 5). Serum total IGF‐1 significantly increased (p = 0.013) and ctDNA decreased during the first cycle. CONCLUSIONS: This combination lacks adequate therapeutic activity for further study, though a subset of patients had prolonged stable disease. John Wiley and Sons Inc. 2023-06-12 /pmc/articles/PMC10417097/ /pubmed/37306107 http://dx.doi.org/10.1002/cam4.6208 Text en © 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | RESEARCH ARTICLES Shulman, David S. Merriam, Priscilla Choy, Edwin Guenther, Lillian M. Cavanaugh, Kerri L. Kao, Pei‐Chi Posner, Andrew Bhushan, Ketki Fairchild, Grace Barker, Emma Klega, Kelly Stegmaier, Kimberly Crompton, Brian D. London, Wendy B. DuBois, Steven G. Phase 2 trial of palbociclib and ganitumab in patients with relapsed Ewing sarcoma |
title | Phase 2 trial of palbociclib and ganitumab in patients with relapsed Ewing sarcoma |
title_full | Phase 2 trial of palbociclib and ganitumab in patients with relapsed Ewing sarcoma |
title_fullStr | Phase 2 trial of palbociclib and ganitumab in patients with relapsed Ewing sarcoma |
title_full_unstemmed | Phase 2 trial of palbociclib and ganitumab in patients with relapsed Ewing sarcoma |
title_short | Phase 2 trial of palbociclib and ganitumab in patients with relapsed Ewing sarcoma |
title_sort | phase 2 trial of palbociclib and ganitumab in patients with relapsed ewing sarcoma |
topic | RESEARCH ARTICLES |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10417097/ https://www.ncbi.nlm.nih.gov/pubmed/37306107 http://dx.doi.org/10.1002/cam4.6208 |
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