Study of Regorafenib and Sildenafil for Advanced Solid Tumors

This study is a single-arm, open-label, phase 1 trial to determine the RP2D of the
combination of regorafenib and sildenafil. Both study medications will be taken orally on
days 1-21 of each 28-day cycle.

Using a modified 3+3 dose escalation design, 3-6 patients with an advanced solid tumor will
be enrolled at each dose level. Additional patients will be enrolled at the MTD until a total
of 12 patients have been treated at the MTD.

Eligible patients will have received available standard treatments. Patients with solid
tumors for which regorafenib would be considered a standard treatment are eligible as long as
regorafenib has not been previously administered.

Blood samples will be collected for correlative studies including PK, PD, and CTCs. Tumor
samples archived from a previous biopsy or surgery will also be collected for correlative
studies.

Inclusion Criteria:

• Advanced solid tumor that has progressed during or after treatment with approved
therapies or for which there is no standard effective therapy available

- Note: patients with solid tumors for which regorafenib would be considered a standard
treatment are eligible as long as regorafenib has not been previously administered

- Measurable or evaluable disease by RECIST v1.1

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

- Absolute neutrophil count (ANC) >= 1500/mm^3

- Platelets >= 100,000/mm^3

- Hemoglobin > 9 g/dL (untransfused)

- Creatinine =< 1.5 x upper limit of normal (ULN) for the laboratory or calculated
or actual creatinine clearance >= 60 mL/min

- Proteinuria =< grade 1 (ie, =< 1+ [30 mg/dL] using a random urine sample or < 1.0
gm using a 24-hour sample)

- Note: if urine sample indicates >= grade 2 proteinuria (ie, 2+ [100 mg/dL]), a 24-hour
urine sample must be collected and tested; urine protein in the 24-hour sample must be
< 1.0 gm/24 hours • Total bilirubin =< 1.5 x ULN for the laboratory

- Exception: if a patient has documented Gilbert's syndrome and a total bilirubin is >
1.5 x ULN, the total bilirubin requirement may be waived provided the direct bilirubin
is within normal limits (WNL) for the laboratory

- Aspartate aminotransferase (AST) =< 2.5 x ULN for the laboratory

- Alanine aminotransferase (ALT) =< 2.5 x ULN for the laboratory

- Alkaline phosphatase =< 2.5 x ULN for the laboratory (=< 5 x ULN for patients
with cancer involving the liver and/or bone)

- Non-hematologic toxicities from previous cancer therapies resolved to =< grade 1

- International normalized ratio (INR) is =< 1.5

- Activated partial thromboplastin time (aPTT) =< 1.5 x ULN for the laboratory

- Left ventricular ejection fraction (LVEF) assessed by echocardiogram within 3
months prior to initiation of study treatment indicates an LVEF of >= 50%

- A woman of childbearing potential (WCBP), defined as a woman who is < 60 years of
age and has not had a hysterectomy, must have a documented negative serum
pregnancy test within 7 days prior to initiating study treatment

- A WCBP and a male patient with a partner who is a WCBP must agree to use a
medically accepted method for preventing pregnancy for the duration of study
treatment and for 2 months following completion of study treatment

- Ability to understand and willingness to sign the consent form written in English

- Note: the consent form must be signed prior to the conduct of any trial-specific
procedure

Exclusion Criteria:

- Meningeal metastases or brain metastases that are symptomatic or untreated * Note:
patients who are asymptomatic and have had post-treatment imaging that indicates
stable brain disease are eligible; (patients with meningeal metastasis are not
eligible even if stable following treatment); also, note that brain imaging is
required within 8 weeks prior to initiation of study therapy

- Any investigational agent within 4 weeks prior to initiating study treatment

- Previous therapy with regorafenib

- If sorafenib was previously administered, intolerance to sorafenib

- Inability to swallow medication

- Known or suspected malabsorption condition or obstruction

- Contraindications to sildenafil including:

- Known retinitis pigmentosa

- History of priapism related to PDE5 inhibitors (eg, sildenafil, vardenafil,
tadalafil)

- Presence of nonmalignant hematologic disorders, such as sickle cell disease, that
may increase the risk of priapism

- Contraindication to antiangiogenic agents, including:

- Serious non-healing wound, non-healing ulcer, or bone fracture

- Major surgical procedure or significant traumatic injury within 4 weeks prior to
initiating study treatment

- Pulmonary hemorrhage/bleeding event >= grade 2 within 12 weeks prior to
initiating study treatment

- Any other hemorrhage/bleeding event >= grade 3 within 12 weeks prior to
initiating study treatment

- History of organ allograft including corneal transplant

- Any documented history of thrombotic, embolic, venous, or arterial events, such as
cerebrovascular accident, transient ischemic attack, deep vein thrombosis, or
pulmonary embolism within 6 months prior to initiating study treatment

* Note: patients with a tumor-associated thrombus of locally-involved vessels should
not be excluded from participating in the study

- Evidence of bleeding diathesis or coagulopathy

- Resting systolic blood pressure (BP) < 100 mmHg

- Hypertension defined as systolic BP >= 140 mmHg or diastolic BP >= 90 mmHg despite
optimal medical management

- Active or clinically significant cardiac disease including any of the following:

- Unstable angina (eg, anginal symptoms at rest) or onset of angina within 3 months
prior to initiating study treatment

- Myocardial infarction within 6 months prior to initiating study treatment

- Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers

- New York Heart Association (NYHA) class III or IV congestive heart failure

- Seizure disorder requiring medication

- Serious (ie, >= grade 3) uncontrolled infection

- Known human immunodeficiency virus (HIV) seropositivity

* Note: HIV testing is not required

- Chronic or active hepatitis B or C infection requiring treatment with antiviral
therapy

- Pleural effusion or ascites that causes respiratory compromise (ie, >= grade 2
dyspnea)

- Untreated or metastatic pheochromocytoma

- Planned ongoing treatment with other drugs thought to potentially have adverse
interactions with either of the medications included in the study treatment, for
example:

- Alpha 1-blockers

- Vasodilators, such as nitrates

- Other PDE5 inhibitors, eg, vardenafil, tadalafil

- Therapeutic anticoagulation with vitamin K antagonists (eg, warfarin), heparins
and heparinoids, or direct thrombin inhibitors (DTIs) ** Note: prophylactic
low-dose anticoagulation to maintain vascular access devices or low-dose daily
aspirin for cardiac health is permitted

- Immunosuppressants such as tacrolimus, leflunomide or tofacitinib, roflumilast,
pimecrolimus

** Note: administration of steroids as part of symptom management or for other
supportive care purposes is permitted

- STRONG cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inhibitors
and/or STRONG CYP3A4 inducers ** Note: if such medications have been used,
patients must have discontinued these agents >= 2 weeks prior to initiating study
treatment

- Pregnancy or breastfeeding

- Medical, psychological, or social condition that, in the opinion of the investigator,
may increase the patient's risk or limit the patient's adherence with study
requirements