Substudy 1 was terminated for futility at interim analysis and Substudy 2 was terminated per sponsor decision.

The purpose of this study was to determine if ruxolitinib, in combination with regorafenib, is safe and effective in the treatment of metastatic colorectal cancer.

The study consisted of an open-label, Part 1 safety run-in (consisting of 1 to 3 cohorts of 9 subjects each), to confirm the safety of the regorafenib/ruxolitinib combination in subjects with relapsed or refractory metastatic colorectal cancer (CRC). If determined to be tolerable, Part 2 was to proceed as a randomized, double-blind study evaluating ruxolitinib or placebo in combination with regorafenib in subjects with relapsed or refractory metastatic CRC previously treated with fluoropyrimidine, oxaliplatin, and/or irinotecan based chemotherapy, an anti-vascular endothelial growth factor (VEGF) therapy and if Kirsten rat sarcoma (KRAS) wild type an anti-epidermal growth factor receptor (EGFR) therapy.

Subjects in the safety run-in received open-label ruxolitinib and regorafenib; for the randomized, double-blind portion of the study all subjects received regorafenib and either ruxolitinib or placebo in a 1:1 blinded manner. Treatment for all subjects consisted of repeating 28-day cycles. Regorafenib was self-administered for the first 21 days of each cycle, and ruxolitinib/placebo was self-administered during the entire 28-day cycle. Treatment cycles continued as long as the regimen is tolerated, and the subject does not meet the discontinuation criteria. When subjects discontinued regorafenib, ruxolitinib or placebo they remained in the study and were followed for subsequent treatment regimens which were initiated and survival.

Inclusion Criteria:

• Histologically or cytologically confirmed adenocarcinoma of the colon or rectum that is metastatic.
• Previous treatment with fluoropyrimidine-, oxaliplatin- and irinotecan- based chemotherapy, an anti-VEGF therapy (if no contraindication) and if KRAS wild type and no contraindication, an anti-EGFR therapy.
• Radiographically measurable or evaluable disease (per RECIST v1.1)
• Life expectancy of ≥ 12 weeks.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
• Three or more weeks have elapsed from the completion of previous treatment regimen and subjects must have recovered or be at a new stable baseline from any related toxicities.
• Prior radiotherapy to disease sites is allowed with certain protocol-defined restrictions.

Exclusion Criteria:

• Prior treatment with regorafenib.
• Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption of drugs.
• Active peptic ulcer disease, inflammatory bowel disease (eg, ulcerative colitis, Crohn's disease), diverticulitis, or other gastrointestinal conditions with increased risk of perforation or gastrointestinal bleeding.
• Recent history (≤ 3 months) or ongoing partial or complete bowel obstruction unless due to disease under study and corrected with surgery.
• Blood pressure ≥ 140/90 mmHg.
• Active bleeding diathesis or history of any major bleeding (eg, requiring transfusion of red blood cells (RBCs), central nervous system (CNS) bleeding, or significant hemoptysis within 6 months of enrollment. Subjects with bleeding secondary to underlying disease (including gastrointestinal (GI) perforation or fistula) that has been corrected by surgery or alternative procedure may be included.
• Clinically significant cardiac disease including unstable angina, acute myocardial infarction within 6 months from Day 1 of study drug administration, New York Heart Association Class II, III, or IV congestive heart failure, and arrhythmia requiring therapy.