Trial Information

A Pilot Study of Chemoradiotherapy Plus Temsirolimus (Torisel) for Advanced Head and Neck Cancer

Approximately 30,000 new cases of local-regionally advanced head and neck carcinoma (HNC)
and head and neck squamous cell carcinoma (HNSCC) are diagnosed each year for which surgery
is either insufficient, non-curative or not feasible. For these patients, radiation therapy
is the mainstay of treatment often with the use of concurrent chemotherapy and/or concurrent
cetuximab therapy. Radiation therapy is also commonly employed in the post-operative
setting for patients with high risk features predisposing to recurrent disease. Although
progress has been made, the prominent pattern of failure among these aggressively treated
patients remains loco-regional failure.

The epidermal growth factor receptor (EGFR), a member of the ErbB family of receptor
tyrosine kinases, is abnormally activated in nearly all epithelial cancers, including HNC.
Nearly all HNC expressing high levels of EGFR have been associated with poor outcomes.
Radiation therapy can lead to increased expression of EGFR in cancer cells, and blockade of
EGFR signaling has been shown to sensitize cells to ionizing radiation. The use of
monoclonal antibodies directed against EGFR has a rich pre-clinical record. However, it was
not until the publication of the Bonner trial that combined radiotherapy plus anti-EGFR
therapy was shown to be successful in the clinic to treat HNSCC. This study showed that the
addition of single agent cetuximab 250 mg/m2 given weekly with concurrent radiation therapy
improved median overall survival from 29 to 49 months. Furthermore, progression-free
survival was improved from 12 to 17.1 months. In addition, patients were able to tolerate
the regimen with no difference in rates of mucositis. Other toxicities were also similar to
radiotherapy alone, with the exceptions of a small risk of infusion reactions, and the
common - but non-dose limiting - occurrence of an acneiform rash.

Temsirolimus is a specific inhibitor of the mammalian target of rapamycin (mTOR), an enzyme
that regulates cell growth and proliferation. Temsirolimus prevents progression from the G1
phase to the S phase of the cell cycle through inhibition of mTOR, which is a novel
mechanism of action for an anticancer drug. This is also important for concurrent treatment
with radiation, since S-phase represents the most radiation resistant phase of the cell
cycle.

Temsirolimus is a structural analog of sirolimus (rapamycin) that has been formulated for IV
or oral administration for the treatment of various malignancies. Sirolimus was shown to
have potent immunosuppressive as well as antifungal and antitumor properties. Its mechanism
of action results in part from binding to an intracellular cytoplasmic protein, FK506
(tacrolimus) binding protein (FKBP)-12. The complex of sirolimus bound to FKBP-12 blocks the
activity of mTOR.

Cetuximab is an important agent in the treatment of HNSCC; however its success may be
limited by downstream signaling molecules which may up-regulate and cause the malignant
phenotype to persist. MET proto-oncogene amplification has been hypothesized to lead to
EGFR-independent activation of the PI3K-Akt-mTOR pathway through activation of
HER3-dependent signaling. We hypothesize that attacking HNC at two key points in the
cellular proliferation and survival system will maximize HNC cell killing and irradicate
subpopulations of cells which may be able to bypass the EGFR inhibition with independent
activation of the PI3K-Akt-mTOR pathway. The concomitant use of cetuximab and temsirolimus
permits active inhibition of both EGF, and the VEGF pathway related with angiogenesis, with
synergistic responses as seen in experimental models.

Although patients who have pre-existing renal or functional conditions - preventing the
administration of cisplatin - receive cetuximab concurrently with radiation as standard of
care, there is a clear phenomenon of the development of EGFR inhibitor resistance.
Therefore, the ability to target one of the escape pathways of EGFR inhibitor resistance via
blockade of the PI3K pathway, possibly in the synergistic manner, provides an important and
novel method for achieving high rates of complete and durable response to treatment in
patients who are unable to tolerate traditional chemotherapeutic agents.

In most patients who do not have pre-existing renal or functional conditions, cisplatin is
considered the standard of care. However, given the relatively poor rates of disease free
survival with platinum and radiation combinations, the Radiation Therapy Oncology Group
(RTOG) 0522 phase III trial of a combination of accelerated radiation therapy with cisplatin
and cetuximab was completed to accrual in March 2009. The results of that trial are still
pending, although the fact that it closed to accrual indicates that it was a tolerable
regimen.

In patients who can receive cisplatin, they will receive temsirolimus together with
cisplatin, cetuximab and radiation in a phase I study. In patients judged by the medical
oncologist as being unable to receive cisplatin, they will receive temsirolimus together
with cetuximab and radiation in a separate arm in this phase I study. We will show the
maximum tolerated doses of temsirolimus as a primary objective, with a secondary objective
of examining progression-free survival at 12 months in each of these two arms.