Randomized, double‐blind, phase two study of ruxolitinib plus regorafenib in patients with relapsed/refractory metastatic colorectal cancer
Abstract Background The Janus kinase/signal transducer and activator of transcription (JAK‐STAT) signaling pathway plays a key role in the systemic inflammatory response in many cancers, including colorectal cancer (CRC). This study evaluated the addition of ruxolitinib, a potent JAK1/2 inhibitor, t...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2018-11-01
|
| Series: | Cancer Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/cam4.1703 |
| _version_ | 1797681454231060480 |
|---|---|
| author | David Fogelman Antonio Cubillo Pilar García‐Alfonso María Luisa Limón Mirón John Nemunaitis Daniel Flora Christophe Borg Laurent Mineur Jose M. Vieitez Allen Cohn Gene Saylors Albert Assad Julie Switzky Li Zhou Johanna Bendell |
| author_facet | David Fogelman Antonio Cubillo Pilar García‐Alfonso María Luisa Limón Mirón John Nemunaitis Daniel Flora Christophe Borg Laurent Mineur Jose M. Vieitez Allen Cohn Gene Saylors Albert Assad Julie Switzky Li Zhou Johanna Bendell |
| author_sort | David Fogelman |
| collection | DOAJ |
| description | Abstract Background The Janus kinase/signal transducer and activator of transcription (JAK‐STAT) signaling pathway plays a key role in the systemic inflammatory response in many cancers, including colorectal cancer (CRC). This study evaluated the addition of ruxolitinib, a potent JAK1/2 inhibitor, to regorafenib in patients with relapsed/refractory metastatic CRC. Methods In this two‐part, multicenter, phase 2 study, eligible adult patients had metastatic adenocarcinoma of the colon or rectum; an Eastern Cooperative Oncology Group performance status of 0‐2; received fluoropyrimidine, oxaliplatin, and irinotecan‐based chemotherapy, an anti‐vascular endothelial growth factor therapy (if no contraindication); and if KRAS wild‐type (and no contraindication), an anti‐epidermal growth factor receptor therapy; and progressed following the last administration of approved therapy. Patients who received previous treatment with regorafenib, had an established cardiac or gastrointestinal disease, or had an active infection requiring treatment were excluded. The study was conducted in 95 sites in North America, European Union, Asia Pacific, and Israel. After an open‐label, safety run‐in phase (part 1; ruxolitinib 20 mg twice daily [BID] plus regorafenib 160 mg once daily [QD]), the double‐blind, randomized phase (part 2) was conducted wherein patients were randomized 1:1 to receive ruxolitinib 15 mg BID plus regorafenib 160 mg QD [ruxolitinib group] or placebo plus regorafenib 160 mg QD [placebo group]. Part 2 included substudy 1 (patients with high systemic inflammation, ie, C‐reactive protein [CRP] >10 mg/L) and substudy 2 (patients with low systemic inflammation, ie, CRP ≤10 mg/L); the primary endpoint was overall survival (OS). Results The study was terminated early; substudy 1 was terminated for futility at interim analysis and substudy 2 was terminated per sponsor decision. Ruxolitinib 20 mg BID was well tolerated in the safety run‐in (n = 11). Overall, 396 patients were randomized (substudy 1: n = 175 [ruxolitinib group, n = 87; placebo group, n = 88]; substudy 2: n = 221 [ruxolitinib group, n = 110; placebo group, n = 111]). There was no significant difference in OS or progression‐free survival (PFS) between treatments in substudy 1 (OS: hazard ratio [HR] = 1.040 [95% confidence interval: 0.725‐1.492]; PFS: HR = 1.004 [0.724‐1.391]) and substudy 2 (OS: HR = 0.767 [0.478‐1.231]; PFS: HR = 0.787 [0.576‐1.074]). The most common hematologic adverse event was anemia. No new safety signals with ruxolitinib were identified. Conclusions Although addition of ruxolitinib to regorafenib did not show increased safety concerns in patients with relapsed/refractory metastatic CRC, this combination did not improve OS/PFS vs. regorafenib plus placebo. |
| first_indexed | 2024-03-11T23:45:03Z |
| format | Article |
| id | doaj.art-83944eb504bf49ddba72860007a550e7 |
| institution | Directory Open Access Journal |
| issn | 2045-7634 |
| language | English |
| last_indexed | 2024-03-11T23:45:03Z |
| publishDate | 2018-11-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Medicine |
| spelling | doaj.art-83944eb504bf49ddba72860007a550e72023-09-19T11:30:57ZengWileyCancer Medicine2045-76342018-11-017115382539310.1002/cam4.1703Randomized, double‐blind, phase two study of ruxolitinib plus regorafenib in patients with relapsed/refractory metastatic colorectal cancerDavid Fogelman0Antonio Cubillo1Pilar García‐Alfonso2María Luisa Limón Mirón3John Nemunaitis4Daniel Flora5Christophe Borg6Laurent Mineur7Jose M. Vieitez8Allen Cohn9Gene Saylors10Albert Assad11Julie Switzky12Li Zhou13Johanna Bendell14The University of Texas MD Anderson Cancer Center Houston TexasCentro Integral Oncológico Clara Campal Madrid SpainHospital General Universitario Gregorio Marañón Madrid SpainHospital Universitario Virgen del Rocío Sevilla SpainUniversity of Toledo College of Medicine and Life Sciences Toledo OhioOncology Hematology Care Cincinnati OhioUniversity Hospital of Besançon Besançon FranceInstitut Sainte Catherine Avignon FranceHospital Universitario Central de Asturias Oviedo SpainRocky Mountain Cancer Centers Denver ColoradoCharleston Hematology Oncology Associates Charleston South CarolinaIncyte Corporation Wilmington, DelawareIncyte Corporation Wilmington, DelawareIncyte Corporation Wilmington, DelawareSarah Cannon Research Institute/Tennessee Oncology Nashville TennesseeAbstract Background The Janus kinase/signal transducer and activator of transcription (JAK‐STAT) signaling pathway plays a key role in the systemic inflammatory response in many cancers, including colorectal cancer (CRC). This study evaluated the addition of ruxolitinib, a potent JAK1/2 inhibitor, to regorafenib in patients with relapsed/refractory metastatic CRC. Methods In this two‐part, multicenter, phase 2 study, eligible adult patients had metastatic adenocarcinoma of the colon or rectum; an Eastern Cooperative Oncology Group performance status of 0‐2; received fluoropyrimidine, oxaliplatin, and irinotecan‐based chemotherapy, an anti‐vascular endothelial growth factor therapy (if no contraindication); and if KRAS wild‐type (and no contraindication), an anti‐epidermal growth factor receptor therapy; and progressed following the last administration of approved therapy. Patients who received previous treatment with regorafenib, had an established cardiac or gastrointestinal disease, or had an active infection requiring treatment were excluded. The study was conducted in 95 sites in North America, European Union, Asia Pacific, and Israel. After an open‐label, safety run‐in phase (part 1; ruxolitinib 20 mg twice daily [BID] plus regorafenib 160 mg once daily [QD]), the double‐blind, randomized phase (part 2) was conducted wherein patients were randomized 1:1 to receive ruxolitinib 15 mg BID plus regorafenib 160 mg QD [ruxolitinib group] or placebo plus regorafenib 160 mg QD [placebo group]. Part 2 included substudy 1 (patients with high systemic inflammation, ie, C‐reactive protein [CRP] >10 mg/L) and substudy 2 (patients with low systemic inflammation, ie, CRP ≤10 mg/L); the primary endpoint was overall survival (OS). Results The study was terminated early; substudy 1 was terminated for futility at interim analysis and substudy 2 was terminated per sponsor decision. Ruxolitinib 20 mg BID was well tolerated in the safety run‐in (n = 11). Overall, 396 patients were randomized (substudy 1: n = 175 [ruxolitinib group, n = 87; placebo group, n = 88]; substudy 2: n = 221 [ruxolitinib group, n = 110; placebo group, n = 111]). There was no significant difference in OS or progression‐free survival (PFS) between treatments in substudy 1 (OS: hazard ratio [HR] = 1.040 [95% confidence interval: 0.725‐1.492]; PFS: HR = 1.004 [0.724‐1.391]) and substudy 2 (OS: HR = 0.767 [0.478‐1.231]; PFS: HR = 0.787 [0.576‐1.074]). The most common hematologic adverse event was anemia. No new safety signals with ruxolitinib were identified. Conclusions Although addition of ruxolitinib to regorafenib did not show increased safety concerns in patients with relapsed/refractory metastatic CRC, this combination did not improve OS/PFS vs. regorafenib plus placebo.https://doi.org/10.1002/cam4.1703clinical trialcolorectal cancerinflammationJAK1 protein tyrosine kinaseJAK2 protein tyrosine kinaseruxolitinib |
| spellingShingle | David Fogelman Antonio Cubillo Pilar García‐Alfonso María Luisa Limón Mirón John Nemunaitis Daniel Flora Christophe Borg Laurent Mineur Jose M. Vieitez Allen Cohn Gene Saylors Albert Assad Julie Switzky Li Zhou Johanna Bendell Randomized, double‐blind, phase two study of ruxolitinib plus regorafenib in patients with relapsed/refractory metastatic colorectal cancer Cancer Medicine clinical trial colorectal cancer inflammation JAK1 protein tyrosine kinase JAK2 protein tyrosine kinase ruxolitinib |
| title | Randomized, double‐blind, phase two study of ruxolitinib plus regorafenib in patients with relapsed/refractory metastatic colorectal cancer |
| title_full | Randomized, double‐blind, phase two study of ruxolitinib plus regorafenib in patients with relapsed/refractory metastatic colorectal cancer |
| title_fullStr | Randomized, double‐blind, phase two study of ruxolitinib plus regorafenib in patients with relapsed/refractory metastatic colorectal cancer |
| title_full_unstemmed | Randomized, double‐blind, phase two study of ruxolitinib plus regorafenib in patients with relapsed/refractory metastatic colorectal cancer |
| title_short | Randomized, double‐blind, phase two study of ruxolitinib plus regorafenib in patients with relapsed/refractory metastatic colorectal cancer |
| title_sort | randomized double blind phase two study of ruxolitinib plus regorafenib in patients with relapsed refractory metastatic colorectal cancer |
| topic | clinical trial colorectal cancer inflammation JAK1 protein tyrosine kinase JAK2 protein tyrosine kinase ruxolitinib |
| url | https://doi.org/10.1002/cam4.1703 |
| work_keys_str_mv | AT davidfogelman randomizeddoubleblindphasetwostudyofruxolitinibplusregorafenibinpatientswithrelapsedrefractorymetastaticcolorectalcancer AT antoniocubillo randomizeddoubleblindphasetwostudyofruxolitinibplusregorafenibinpatientswithrelapsedrefractorymetastaticcolorectalcancer AT pilargarciaalfonso randomizeddoubleblindphasetwostudyofruxolitinibplusregorafenibinpatientswithrelapsedrefractorymetastaticcolorectalcancer AT marialuisalimonmiron randomizeddoubleblindphasetwostudyofruxolitinibplusregorafenibinpatientswithrelapsedrefractorymetastaticcolorectalcancer AT johnnemunaitis randomizeddoubleblindphasetwostudyofruxolitinibplusregorafenibinpatientswithrelapsedrefractorymetastaticcolorectalcancer AT danielflora randomizeddoubleblindphasetwostudyofruxolitinibplusregorafenibinpatientswithrelapsedrefractorymetastaticcolorectalcancer AT christopheborg randomizeddoubleblindphasetwostudyofruxolitinibplusregorafenibinpatientswithrelapsedrefractorymetastaticcolorectalcancer AT laurentmineur randomizeddoubleblindphasetwostudyofruxolitinibplusregorafenibinpatientswithrelapsedrefractorymetastaticcolorectalcancer AT josemvieitez randomizeddoubleblindphasetwostudyofruxolitinibplusregorafenibinpatientswithrelapsedrefractorymetastaticcolorectalcancer AT allencohn randomizeddoubleblindphasetwostudyofruxolitinibplusregorafenibinpatientswithrelapsedrefractorymetastaticcolorectalcancer AT genesaylors randomizeddoubleblindphasetwostudyofruxolitinibplusregorafenibinpatientswithrelapsedrefractorymetastaticcolorectalcancer AT albertassad randomizeddoubleblindphasetwostudyofruxolitinibplusregorafenibinpatientswithrelapsedrefractorymetastaticcolorectalcancer AT julieswitzky randomizeddoubleblindphasetwostudyofruxolitinibplusregorafenibinpatientswithrelapsedrefractorymetastaticcolorectalcancer AT lizhou randomizeddoubleblindphasetwostudyofruxolitinibplusregorafenibinpatientswithrelapsedrefractorymetastaticcolorectalcancer AT johannabendell randomizeddoubleblindphasetwostudyofruxolitinibplusregorafenibinpatientswithrelapsedrefractorymetastaticcolorectalcancer |