SARC024: A Blanket Protocol to Study Oral Regorafenib in Patients With Selected Sarcoma Subtypes

Although regorafenib was approved for use in patients who had progressive GIST despite
imatinib and/or sunitinib on the basis of phase II and phase III data, it has not been
examined in a systematic fashion in patients with other forms of sarcoma.

Given the activity of sorafenib, sunitinib and pazopanib in soft tissue sarcomas, and
evidence of activity of sorafenib in osteogenic sarcoma and possibly Ewing/Ewing-like
sarcoma, there is precedent to examine SMOKIs (small molecule oral kinase inhibitors) such as
regorafenib in sarcomas other than GIST. It is also recognized that SMOKIs (small molecule
oral kinase inhibitors)such as regorafenib, sorafenib, pazopanib, and sunitinib have
overlapping panels of kinases that are inhibited simultaneously. While not equivalent, most
of these SMOKIs (small molecule oral kinase inhibitors) block vascular endothelial growth
factor and platelet derived growth factors receptors (VEGFRs and PDGFRs), speaking to a
common mechanism of action of several of these agents

Inclusion Criteria:

- Age ≥ 10 year for Liposarcoma, Osteosarcoma, and Ewing sarcoma; Age ≥ 5 years for
Rhabdomyosarcoma cohorts

- Weight ≥ 15 kg (33 lb)

- Patients must have histologically or cytologically confirmed advanced/metastatic
liposarcoma, osteogenic sarcoma, Ewing/Ewing-like sarcoma of soft tissue or bone,
fusion-positive alveolar rhabdomyosarcoma or embryonal
rhabdomyosarcoma/fusion-negative alveolar rhabdomyosarcoma

- WHO Performance Status 0, 1 or 2. A maximum of 1/3 of patients in cohorts A & B may be
WHO performance status 2

- At least one prior line of systemic therapy for the sarcoma diagnosis (neoadjuvant,
adjuvant or metastatic disease)

- All acute toxic effects of any prior treatment have resolved to NCI-CTCAE v 4.0 Grade
1 or less (except alopecia) at the time of signing the Informed Consent Form (ICF)

- Subject must be able to swallow and retain oral medication

- At least one site of measurable disease on x-ray/CT/MRI scan as defined by RECIST 1.1

- Adequate organ function within 14 days of registration

- Evidence of progression of disease as defined by RECIST 1.1 (i.e. new disease sites or
20% growth of index lesions) within 6 months of registration

- Patients with central nervous system disease are eligible for enrollment if they have
received prior radiotherapy or surgery to sites of CNS (central nervous system)
metastatic disease and are without evidence of clinical progression for at least 12
weeks after therapy

Exclusion Criteria:

- Patients with documentation of well differentiated liposarcoma only (of the well
differentiated/dedifferentiated liposarcoma family) are specifically excluded, owing
to its characteristically slow growth. If high grade areas are suspected
(dedifferentiation), but not proved by pathology analysis (e.g. after primary
resection of a well-differentiated liposarcoma), a biopsy must be performed to
demonstrate the high-grade dedifferentiated disease

- Prior systemic therapy with a small molecule oral kinase inhibitor, including but not
limited to: pazopanib, sunitinib, sorafenib, everolimus, sirolimus, vemurafenib,
dasatinib and trametinib

- Previous assignment to treatment during this study. Subjects permanently withdrawn
from study participation will not be allowed to re-enter study. Patients who progress
on placebo are specifically allowed to enroll on the treatment arm of the study if
they meet all other entry criteria

- Concurrent, clinically significant, active malignancies within 12 months of study
enrollment

- Patients with severe and/or uncontrolled concurrent medical disease that in the
opinion of the investigator could cause unacceptable safety risks or compromise
compliance with the protocol

- Major surgery within 28 days prior to study registration or those patients who have
not recovered adequately from prior surgery

- Patients who have received wide field radiotherapy ≤ 28 days (defined as > 50% of
volume of pelvis bones or equivalent) or limited field radiation for palliation < 14
days prior to study registration or those patients who have not recovered adequately
from side effects of such therapy

- Patients who have received prior systemic therapy < 14 days prior to study
registration or have not recovered adequately from toxicities to CTCAE v. 4.03 grade 1
or less; prior investigational therapy may not have been given < 5 half-lives of last
dose of treatment, or < 14 days, whichever is greater

- Uncontrolled hypertension (systolic pressure >140 mm Hg or diastolic pressure > 90 mm
Hg [NCI-CTCAE v 4.0] on repeated measurement) despite optimal medical management

- Active or clinically significant cardiac disease including: Congestive heart
failure-New York Heart Association (NYHA) > class II, Active coronary artery disease,
Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or
digoxin, Unstable angina (anginal symptoms at rest), new onset angina within 3 months
before randomization, or myocardial infarction within 6 months before randomization

- Evidence or history of bleeding diathesis

- Any hemorrhage or bleeding event ≥ NCI CTCAE Grade 3 within 4 weeks prior to study
registration

- Subjects with thrombotic, embolic, venous, or arterial events, such as cerebrovascular
accident (including transient ischemic attacks) deep vein thrombosis or pulmonary
embolism within 6 months of start of study treatment

- Known history of human immunodeficiency virus (HIV) infection or current chronic or
active hepatitis B or C infection requiring treatment with antiviral therapy.

- Ongoing infection > Grade 2 NCI-CTCAE v 4.03

- Presence of a non-healing wound, non-healing ulcer, or benign bone fracture (patients
with stress insufficiency fractures e.g. from osteoporosis or pathological fracture
from tumor are eligible for study)

- Patients with seizure disorder requiring medication

- Proteinuria > 100 mg/dl on urine analysis

- Interstitial lung disease with ongoing signs and symptoms at the time of informed
consent

- Pleural effusion or ascites that causes respiratory compromise (≥ NCI-CTCAE version
4.03 Grade 2 dyspnea)

- History of organ allograft (including corneal transplant).

- Known or suspected allergy or hypersensitivity to regorafenib, or excipients of the
formulations given during the course of this trial

- Any malabsorption condition.

- Women who are pregnant or breast-feeding.

- Any condition which, in the investigator's opinion, makes the subject unsuitable for
trial participation

- Substance abuse, medical, psychological or social conditions that may interfere with
the subject's participation in the study or evaluation of the study results

- Inability to comply with protocol required procedures

- Use of any herbal remedy (e.g. St. John wort [Hypericum perforatum])