Study of Ruxolitinib in Colorectal Cancer Patients

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.