Temsirolimus and Sorafenib in Advanced Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide with an
incidence of over 600,000 new cases and almost as many deaths annually.1 Advanced stages of
disease at diagnosis often preclude curative treatments, and the overall prognosis of
patients diagnosed with advanced HCC remains dismal with median survival of approximately 8
months.2-4 Until recently, systemic therapies for advanced HCC have demonstrated minimal
benefit in these patients, largely due to compromised hepatic function from underlying liver
disease as well as intrinsic tumor chemoresistance.5-9 In the past year, however,
publication of the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP)
phase III trial demonstrated a significant improvement in overall survival (OS) in patients
with advanced HCC treated with the biologic agent, sorafenib.4 Despite improvements in
outcome with sorafenib, however, the median OS for patients with advanced HCC remains less
than a year, and new therapies and combinations are in great need to combat this grim
disease.

Sorafenib is a small molecule bi-aryl urea with multikinase inhibitor activity. A primary
target is the serine-threonine kinase, Raf-1. Sorafenib also has antiangiogenic activity,
inhibiting receptor tyrosine kinases including vascular endothelial growth factor (VEGF)
receptors 2 and 3 and the platelet derived growth factor receptor (PDGFR).10-12 Preclinical
studies in HCC show that Raf-1 kinase signaling along with prolific tumor angiogenesis are
common features, providing a molecular rationale for the efficacy of this agent.11,13-16
Radiographically, HCC is a hypervascular tumor, providing additional clinical relevance to
the exuberant angiogenesis observed in this tumor type in the preclinical setting.15 The
efficacy of sorafenib in the SHARP trial validates the importance of these signaling
pathways in HCC.

Another signaling pathway which may play a role in hepatocarcinogenesis is the phosphatase
and tensin homolog (PTEN)/phosphatidylinositol-3'kinase (PI-3'K)/AKT pathway which activates
the mammalian target of rapamycin (mTOR) kinase, in turn triggering multiple downstream cell
growth, survival, and angiogenesis signals.26-28 Dysregulated phosphorylation and activation
of mTOR signaling may occur due to loss of function of the PTEN tumor suppressor gene,
constitutive activation of PI-3'K, or activation of AKT by aberrant upstream growth factor
receptor signaling.27 Activated mTOR forms complexes with other proteins, including
regulatory associated protein of mTOR (Raptor) and Rictor.26 The mTOR-Raptor complex in turn
phosphorylates protein 70 S6 kinase (p70S6K) as well as eukaryotic initiation factor 4E
(eIF-4E) binding protein-1 (4E-BP1). P70S6K and 4E-BP1 regulate translation of a host of
proteins, including several proteins involved in cell proliferation. Signaling through mTOR
also stimulates angiogenesis.26,28-30 Activation of mTOR may induce endothelial cell
proliferation as well as increase levels of hypoxia inducible factor (HIF)-1α and HIF-2α,
potentially via p70S6K-mediated translation versus decreased oxygen-dependent
degradation.31-33 HIFs induce angiogenesis in response to cellular hypoxia by
transcriptional activation of target genes including VEGF.32,34,35

The mTOR inhibitor, sirolimus, is a macrocyclic lactone rapamycin produced by the soil
bacterium, Streptomyces hygroscopicus. Sirolimus demonstrates fungicidal, immunosuppressive,
and antiproliferative properties and is widely used as an immunosuppressant in transplant
patients to prevent allograft rejection.26,36 Inhibitors of mTOR are also under
investigation as potential anti-cancer agents in multiple human malignancies due to the
known proliferative effects of mTOR activation. Temsirolimus, everolimus, and deforolimus
are derivatives of sirolimus with similar antiproliferative properties in vitro.26

Temsirolimus is a soluble ester analogue of sirolimus.37 Temsirolimus has been approved by
the FDA for treatment of advanced renal cell carcinoma (RCC) and demonstrated a survival
benefit as monotherapy by comparison with interferon alpha in a multicenter phase III
trial.38,39 In that trial, 626 patients with previously untreated, poor prognosis,
metastatic RCC were randomized to receive temsirolimus 25 mg intravenously weekly, 3 million
units of interferon alpha subcutaneously three times weekly, or combination therapy with 15
mg of temsirolimus weekly plus 6 million units of interferon alpha three times weekly.39 The
primary endpoint, overall survival, was 10.9 months in the temsirolimus group, by comparison
with 7.3 months with interferon alpha and 8.4 months with combination therapy; both overall
survival and progression free survival (PFS) were significantly prolonged in the
temsirolimus group by comparison with interferon alpha alone (P = 0.008 and P < 0.001,
respectively).

Combination of molecularly targeted therapies offers the theoretical potential for additive
or synergistic inhibition of shared targets as well as targets in parallel pathways which
may provide escape mechanisms from single-pathway inhibition. In the case of mTOR
inhibitors, combination therapy with Ras pathway inhibition may augment efficacy by blocking
a pathway upstream of mTOR kinase, while combination with antiangiogenic agents may enhance
antiangiogenic effect.26,27

Inclusion Criteria

- Histologically or clinically* diagnosed AJCC stage III or IV HCC not amenable to
curative resection and with no prior systemic cytotoxic or molecularly-targeted
therapies. *Clinical diagnosis is acceptable if tumor meets radiographic criteria.

- Age ≥ 18 years.

- Child-Pugh score A or score of B with 7 points only and bilirubin ≤ 2 mg/dL.

- ECOG performance status ≤ 2.

- Radiographically measurable disease in at least one site not previously treated with
chemoembolization, radioembolization, or other local ablative procedures.

- Prior chemoembolization, local ablative therapies, or hepatic resection permitted if
completed ≥ 6 weeks prior to study enrollment and if criterion 6 is present.

- 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.

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

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

- Baseline blood pressure must be adequately controlled with or without
antihypertensive medications prior to enrollment (systolic < 140 mm Hg, diastolic <
90 mm Hg).

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

- Baseline fasting blood glucose must be ≤ 140 mg/dL and hemoglobin A1c less than 7%
(with or without the use of anti-diabetic medications).

- Adequate baseline organ and marrow function as defined below:

- Absolute neutrophil count ≥ 1,500/mcL

- Platelets ≥ 75,000/mcL

- Hemoglobin ≥ 8.5 g/dL

- Total bilirubin ≤ 2 mg/dL or ≤ 1.5 times ULN

- AST(SGOT)/ALT(SGPT) ≤ 5 times ULN

- INR ≤ 1.5 times ULN

- Albumin ≥ 2.8 g/dL

- Creatinine ≤ 1.5 times ULN

- Able to tolerate oral therapy.

- Ability to give written informed consent and willingness to comply with the
requirements of the protocol.

- Effective means of contraception are required in fertile, sexually-active patients.

Exclusion Criteria

- Mixed tumor histology or fibrolamellar variant tumors are excluded.

- Prior antiangiogenic therapy (including thalidomide, sorafenib, sunitinib, or
bevacizumab).

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

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

- Treatment with other investigational agents.

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

- Patients with known HIV infection are excluded.

- Patients who have undergone liver transplantation are excluded.

- 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.

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

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

- 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.

- Active second malignancy other than non-melanoma skin cancer or cervical carcinoma in
situ.

- Uncontrolled intercurrent illness.

- No required concomitant medications with potential for significant interaction with
study drugs.

- Any other condition that compromises compliance with the objectives and procedures of
this protocol, as judged by the Study Chair, is also grounds for exclusion.