Randomized, double‐blind, phase two study of ruxolitinib plus regorafenib in patients with relapsed/refractory metastatic colorectal cancer

• Published in: Cancer medicine (Malden, MA) MA), 2018-11, Vol.7 (11), p.5382-5393
• Main Authors: Fogelman, David, Cubillo, Antonio, García‐Alfonso, Pilar, Mirón, María Luisa Limón, Nemunaitis, John, Flora, Daniel, Borg, Christophe, Mineur, Laurent, Vieitez, Jose M., Cohn, Allen, Saylors, Gene, Assad, Albert, Switzky, Julie, Zhou, Li, Bendell, Johanna
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Chemotherapy; Clinical Cancer Research; clinical trial; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - pathology; Coronary artery disease; Double-Blind Method; Double-blind studies; Drug Resistance, Neoplasm; Epidermal growth factor; Female; Gastrointestinal diseases; Growth factors; Heart diseases; Humans; Inflammation; Irinotecan; JAK1 protein tyrosine kinase; JAK2 protein tyrosine kinase; Janus kinase; Janus Kinase 1 - antagonists & inhibitors; Janus Kinase 2 - antagonists & inhibitors; Kinases; Male; Metastases; Metastasis; Middle Aged; Neoplasm Recurrence, Local - drug therapy; Neoplasm Recurrence, Local - pathology; Original Research; Oxaliplatin; Phenylurea Compounds - therapeutic use; Protein Kinase Inhibitors - therapeutic use; Pyrazoles - therapeutic use; Pyridines - therapeutic use; Rectum; Recurrence; ruxolitinib; Safety; Signal transduction; Survival; Targeted cancer therapy; Transcription; Treatment Outcome; Vascular endothelial growth factor
• ISSN: 2045-7634; 2045-7634
• DOI: 10.1002/cam4.1703

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