Phase II Combination of Temsirolimus and Sorafenib in Advanced Hepatocellular Carcinoma

The hypothesis of this single-arm phase II study is that the combination of temsirolimus and
sorafenib will achieve a clinically-meaningful median time to progression (TTP) of at least 6
months, with null hypothesis of less than or equal to 3 months, in first-line systemic
therapy for patients with advanced HCC. A randomized trial would be required to formally
compare the efficacy of this combination to sorafenib alone and will be indicated if this
phase II study achieves a median TTP of at least 6 months. An interim safety analysis will
employ stopping rules after 30% of planned patients have been treated with at least one dose
of protocol therapy to ensure the combination does not confer excessive toxicity.

A key aspect of this study will be the requirement of histologic confirmation along with
adequate archival tissue for correlative tissue analyses to explore new biomarkers of
response to mTOR inhibition. Circulating biomarker data including enumeration of circulating
tumor cells (CTC) and measurement of the tumor marker AFP will be performed at specific
timepoints to evaluate for predictive value. Specimen banking of tissue, serum, and
peripheral blood mononuclear cells will be undertaken to enable future novel biomarker
studies. Modified RECIST will be performed in addition to standard RECIST 1.1 to explore for
improved imaging predictors of response.

INCLUSION CRITERIA

1. Patients must have histologically diagnosed AJCC stage II, III, or IV HCC not eligible
for curative resection, transplantation, or ablative therapies

2. Radiographically measurable disease by RECIST version 1.1 in at least one site not
previously treated with chemoembolization, radioembolization, or other local ablative
procedures (i.e. must have at least one measurable target lesion, either within the
liver or in a measurable metastatic site); a new area of tumor progression within or
adjacent to a previously-treated lesion, if clearly measurable by a Radiologist, is
acceptable

3. No prior systemic cytotoxic chemotherapy or targeted therapy (including sorafenib) for
HCC

4. Prior chemoembolization, local ablative therapies, or hepatic resection permitted if
completed ≥ 4 weeks prior to study enrollment if patient has recovered with ≤ grade 1
toxicity and if measurable disease (criterion 2) is present

5. Prior radiation for bone or brain metastases is permitted if patient is now
asymptomatic and has completed all radiation and steroid therapy (if applicable) for
brain or bone metastases ≥ 2 weeks prior to study enrollment.

6. Age ≥ 18 years.

7. Child-Pugh score of A or B with ≤ 7 points and meeting laboratory eligibility for all
parameters

8. ECOG performance status of 0 or 1

9. Life expectancy greater than 3 months

10. Treatment with appropriate antiviral therapy for patients with active HBV infection is
required

11. Treatment for clinically-significant hyperglycemia, hyperlipidemia, or hypertension
that develops on study is required

12. Baseline blood pressure must be adequately controlled with or without antihypertensive
medications prior to enrollment (systolic ≤ 150 mm Hg, diastolic ≤ 90 mm Hg)

13. Baseline cholesterol must be < 350 mg/dL and triglycerides < 300 mg/dL (with or
without the use of antihyperlipidemic medications)

14. Baseline fasting blood glucose must be ≤ 140 mg/dL and hemoglobin A1c less than 7.5%
(with or without the use of anti-diabetic medications)

15. Adequate baseline organ and marrow function as defined below

Adequate bone marrow function:

absolute neutrophil count ≥ 1,000/mcL platelets ≥ 75,000/mcL hemoglobin ≥ 8.5 g/dL

Adequate hepatic function:

total bilirubin ≤ 2 mg/dL or ≤ 1.5 times ULN AST(SGOT) & ALT (SGPT) ≤ 5 X ULN INR ≤1.
5 X ULN

Adequate renal function:

albumin ≥ 2.8 g/dL creatinine ≤1. 5 X ULN

16. Able to tolerate oral therapy.

17. Ability to understand and willingness to provide informed consent, and the willingness
to comply with the requirements of the protocol. Informed consent may be obtained with
the assistance of a medical translator according to institutional policies.

18. The effects of temsirolimus on the developing human fetus are unknown. For this reason
and because sorafenib - also being used in this trial - is known to be teratogenic,
women of child-bearing potential must have a negative pregnancy test within 14 days of
study enrollment.

Also, women of child-bearing potential and men must agree to use two methods adequate
contraception (hormonal plus barrier or two forms of barrier) or abstinence prior to
study entry and for the duration of study participation. Should a woman become
pregnant or suspect she is pregnant while she or her partner is participating in this
study, she needs to inform her treating physician immediately. Men treated or enrolled
on this protocol must also agree to use adequate contraception prior to the study, or
be surgically sterile, for the duration of study participation, and for 3 months after
completion of study drug administration.

19. Eligibility of patients receiving any medications or substances known to affect or
with potential to affect the activity or pharmacokinetics of temsirolimus and/or
sorafenib will be determined following review of the case by the Study Chair. Efforts
should be made to switch patients who are taking enzyme-inducing anti-convulsant
agents to other medications.

20. mixed histology (mixed HCC-cholangiocarcinoma) tumors if deemed appropriate for HCC
therapy by treating MD

EXCLUSION CRITERIA:

1. Mixed tumor histology or fibrolamellar variant tumors are excluded.

2. Prior systemic or antiangiogenic therapy for HCC (including thalidomide, sorafenib,
sunitinib, or bevacizumab). Prior systemic therapy for other diagnoses is permitted if
greater than 6 months have elapsed since last dose, any prior toxicity has recovered
to ≤ grade 1 by CTCAE v4.0, and treatment was not discontinued for toxicity.

3. Prior treatment with mTOR inhibitor or other molecularly targeted therapy.

4. Prior systemic cytotoxic therapies for HCC (chemoembolization is permitted if
inclusion criteria are met).

5. Treatment with other investigational agents.

6. Immunosuppressive medications including systemic corticosteroids unless used for
adrenal replacement, appetite stimulation, acute therapy for asthma or bronchitis
exacerbation (≤ 2 weeks), or antiemesis

7. Patients with known HIV infection are ineligible due to risk of pharmacokinetic
interactions between anti-retroviral therapy and the study drugs, as well as potential
for significant immunosuppression and serious infections with mTOR inhibition.

8. Patients who have undergone liver transplantation are excluded.

9. Uncontrolled hypertension (> 150/90 mmHg).

10. Uncontrolled hyperlipidemia (total cholesterol > 350 or triglycerides > 300).

11. Symptomatic brain or bone metastases; prior radiation and/or steroid therapy for brain
or bone metastases (if applicable) must be completed ≥ 2 weeks prior to study
enrollment.

12. History of seizure disorder requiring antiepileptic medication or brain metastases
with seizures.

13. Serious non-healing wound, ulcer, bone fracture, or abscess.

14. Major surgical procedure less than 4 weeks from start of protocol treatment.

15. Patients requiring chronic anticoagulation with warfarin are excluded. Patients
treated with low molecular weight heparin or unfractionated heparin are eligible if on
a stable dose without evidence of clinically significant bleeding for at least 2 weeks
prior to enrollment.

16. Active second malignancy other than non-melanoma skin cancer or cervical carcinoma in
situ. (Patients with history of malignancy are not considered to have a "currently
active" malignancy if they have completed therapy and are now considered by their
physician to be at less than 30% risk for relapse.)

17. Uncontrolled intercurrent illness including, but not limited to: Ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris,
uncontrolled cardiac arrhythmia, uncontrolled peripheral vascular disease, myocardial
infarction within preceding 12 months, cerebrovascular accident within preceding 12
months, pulmonary disease impairing functional status or requiring oxygen, impairment
in gastrointestinal function that may affect or alter absorption of oral medications
(such as malabsorption or history of gastrectomy or bowel resection).

18. Patients will be excluded if there is any history of allergic reaction(s) attributed
to compounds of similar composition to temsirolimus, sorafenib, their metabolites, or
any component of their formulation (including excipients and polysorbate 80). This
includes hypersensitivity to macrolide antibiotics due to potential for
cross-reactivity with temsirolimus.

19. Pregnant or lactating women are excluded from this study because temsirolimus and
sorafenib are drugs with the potential for teratogenic or abortifacient effects.
Because there is an unknown but potential risk for adverse events in nursing infants
secondary to treatment of the mother with temsirolimus or sorafenib, breastfeeding
should be discontinued if the mother is receiving temsirolimus/sorafenib treatment.

20. Patients who require prohibited medications with potential for serious interactions
with protocol therapy, and who cannot have therapeutic substitution are excluded.
Patients receiving any medications or substances that are inhibitors or inducers of
CYP450 enzyme(s) are ineligible. Lists of prohibited medications and substances known,
or with the potential to interact with the specified CYP450 enzyme(s) isoenzymes are
provided in Appendices 6-9 Prohibited Medications

21. Psychiatric illness, other significant medical illness, or social situation which, in
the investigator's opinion, would limit compliance or ability to comply with study
requirements.