Combination of Cisplatin, Cetuximab and Temsirolimus in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck

The epidermal growth factor receptor (EGFR) pathway is a key molecular pathway in the
pathogenesis of SCCHN. Cetuximab, a therapy targeting the EGFR pathway, has shown great
promise in SCCHN. The EXTREME study found that by combining cetuximab to a regimen of
cisplatin and 5-fluorouracil, PFS could be extended to 5.6 months from 3.3 months, and that
overall survival increased to 10.1 months versus 7.4 months. While this study proved a
survival benefit with the addition of cetuximab, there were high rates of Grade 3 or 4
toxicities to the chemotherapy backbone of high dose cisplatin with 5-fluorouracil.

The mammalian target of rapamycin (mTOR) pathway is activated when conditions favor cellular
growth and proliferation. The PI3K-Akt pathway is one of the key modulators in the
activation of mTOR. Phosphorylated Akt is detected in the majority of SCCHN tumors by
immunohistochemistry.

Temsirolimus is an mTOR inhibitor that has been shown to have a synergistic effect with
cisplatin and carboplatin in other tumor models. Due to the minimal toxicities associated
with temsirolimus in clinical studies to date, this is an ideal agent to use in combination
with other chemotherapies.

There is limited experience for the combination of EGFR inhibitors and mTOR inhibitors in
human subjects. These agents have been combined with a suggested synergistic effect in
preclinical models of colon cancer xenografts and cell lines from non-small cell lung,
pancreas, colon, and breast cancers. Cetuximab has been safely combined with everolimus (on
oral mTOR inhibitor) in human subjects.

There is sufficient evidence to suggest that the addition of the mTOR inhibitor,
temsirolimus, may increase both the cytotoxicity seen from platinum-based chemotherapy as
well as augment the effect of EGFR pathway inhibition from cetuximab, and possibly provide
clinical benefit of its own. It is hypothesized that the combination of cisplatin,
cetuximab, and temsirolimus will be an effective, well tolerated regimen for patients with
R/M SCCHN.

Inclusion Criteria:

1. Patients must be ≥ 18 years of age and have a histologically confirmed diagnosis of
R/M SCCHN which is no longer amenable to curative surgical or radiation therapy.

2. Patients must sign a written informed consent form and HIPAA statement.

3. Patients must undergo biopsy for confirmation of R/M disease within 6 weeks (42 days)
of study entry and be willing and able to comply with peripheral blood collections
for the purpose of correlative studies. Biopsy of primary or metastatic site(s) is
allowed, provided the site has not been previously irradiated.

4. Patients must have measurable disease as defined by RECIST.

5. Patients must have ECOG PS 0 or 1.

6. Patients must have adequate hematologic function as defined by an ANC ≥ 1,500,
hemoglobin ≥ 10 g/dL, and a platelet count ≥ 75,000 obtained within 14 days prior to
treatment.

7. Patients must have adequate hepatic function as defined by a total bilirubin ≤ 1.5
mg/dL and AST (SGOT) and ALT (SGPT) ≤ 2 times the ULN obtained within 14 days prior
to treatment.

8. Patients must have adequate renal function defined as a serum creatinine ≤ 1.5 mg/dL
or calculated CrCl ≥ 55 mL/minute (calculations should be conducted using the
Cockroft-Gault equation).

9. Patients must have adequate lipid control defined as a serum cholesterol ≤ 350 mg/dL
and serum triglycerides ≤ 300 mg/dL obtained within 14 days prior to treatment.

10. Patients must not have received previous chemotherapy for the treatment of R/M SCCHN.
Previous curative-intent treatment with chemotherapy, radiation therapy,
chemoradiotherapy, or surgery for locoregional disease is allowed provided at least 3
months have elapsed since the completion of previous therapies and the patient has
recovered from all treatment related toxicities.

11. Patients may have received prior radiation therapy for symptomatic sites of disease
progression provided that ≥ 21 days have elapsed since treatment and the patient has
recovered from any treatment related toxicities.

12. Males and females of reproductive potential must agree to use effective contraception
for the duration of study participation.

Exclusion Criteria:

1. Patients with active or prior CNS metastases.

2. Patients with a history of previous hypersensitivity reaction to study drugs.

3. Patients with other active malignancies are excluded. Patients with a history of
non-melanoma skin cancers, in-situ cervical cancer, definitively treated stage I or
II cancers from which the patient is in remission, or a history of other malignancies
from which the patient has been disease free for ≥ 5 years are permitted.

4. Concurrent therapy with any other anti-cancer treatments.

5. Ongoing or active clinically serious infection requiring IV antibiotics or active HIV
infection.

6. Patients with a history of symptomatic congestive heart failure, unstable angina
pectoris, cardiac arrhythmia, or any medical condition that could compromise the
safety of the patient.

7. Patients with, in the best judgment of the investigator, psychosocial, family,
sociological, or geographical limitations which could impact the patient's ability to
comply with study procedures.

8. Pregnant or lactating females.

9. Employees of the investigator or study center with direct involvement in this or
other studies under the direction of the investigative team.

10. Patients currently taking any of the following medications are ineligible: phenytoin,
carbamazepine, phenobarbitor, and/or rifampin as these are all strong Cyp3A4/5
inducers.