Temsirolimus With or Without Cetuximab in Patients With Recurrent and/or Metastatic Head and Neck Cancer Who Did Not Respond to Previous Therapy

PRIMARY OBJECTIVES:

I. Primary endpoint is progression free survival (PFS) of cetuximab/temsirolimus combination
cohort (Arm A) compared to temsirolimus alone (Arm B).

SECONDARY OBJECTIVES:

I. Progression-free survival (PFS) of cetuximab/temsirolimus combination group (Arm A) and
temsirolimus control group (Arm B) compared to a historic control cohort.

II. Subgroup analysis of myofibroblast (+) cohort (PFS). III. Overall survival (OS). IV.
Toxicities. V. Response (Response Evaluation Criteria in Solid Tumors [RECIST])/absolute
tumor shrinkage (waterfall plot analysis).

VI. Activity of combination therapy (temsirolimus/cetuximab) after failure (progressive
disease [PD]) of temsirolimus monotherapy.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive temsirolimus intravenously (IV) over 30-60 minutes and cetuximab IV
over 1-2 hours once weekly. Courses repeat every 4 weeks in the absence of disease
progression or unacceptable toxicity.

ARM B: Patients receive temsirolimus as in Arm A. Courses repeat every 4 weeks in the
absence of disease progression or unacceptable toxicity. Patients with progressive disease
may cross over to Arm A.

After completion of study therapy, patients are followed up for a minimum of 8 weeks and
then once a year for 5 years.

Inclusion Criteria:

- Histologically/cytologically confirmed diagnosis of squamous cell carcinoma of head
and neck origin not amenable to curative intent therapy; information on prior
exposure to cetuximab (duration, single agent/combined with chemotherapy/combined
with radiation, best response, interval prior to study entry) will be collected

- Progressive disease by RECIST criteria (or unequivocal clinical progression) on a
cetuximab based therapy in any line of therapy for recurrent/metastatic disease;
prior use of cetuximab for recurrent/metastatic disease is defined as palliative
intent use either alone or in combination with chemotherapy with a minimum of 2 weeks
of uninterrupted treatment with cetuximab; treatment with cetuximab during
radiotherapy or chemoradiotherapy is not sufficient

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

- Presence of measurable lesions by RECIST: patients must have measurable disease,
defined as at least one lesion that can be accurately measured in at least one
dimension (longest diameter to be recorded) as >= 20 mm with conventional techniques
or as >= 10 mm with spiral computed tomography (CT) scan

- Knowledge of the anatomic site of the original tumor (oropharynx versus
non-oropharynx) or alternatively human papilloma virus (HPV) status; the trial will
stratify patients by oropharynx versus non-oropharynx origin; HPV(+) tumors will be
counted in the oropharynx cohort, HPV(-) tumors in the non-oropharynx cohort; at a
later point all patients will undergo HPV testing as part of this trial; any widely
used form of HPV testing is acceptable (including but not limited to HPV in situ
hybridization [ISH], p16 testing [immunohistochemistry (IHC)], HPV16 testing,
polymerase chain reaction [PCR], hybrid capture, etc)

- Availability of formalin-fixed, paraffin-embedded (FFPE) tissue and blood

- FFPE: >=14 slides containing tumor, 18 recommended

- 7-10 slides 5 um thick, AND 7-10 slides 10 um thick, and cut with a clean
blade (use new blade if possible or clean vigorously to avoid RNA/DNA,
RNase contamination)

- Blood: two 10 cc ethylenediaminetetraacetic acid (EDTA) purple top tubes
(blood); two 2 ml cryovials (serum)

- Patients with human immunodeficiency virus (HIV), not requiring highly active
antiretroviral treatment (HAART) therapy are eligible

- Life expectancy of greater than 8 weeks

- Leukocytes >= 2,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Total bilirubin within normal institutional limits (unless proven Gilbert's disease,
which after principal investigator [PI] approval patient may be included)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 X institutional upper limit of normal

- Creatinine within 1.5 X normal institutional limits

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and
for the duration of study participation

- Ability to understand and the willingness to sign a written informed consent document

- Fasting glucose of =< 120 mg/dl and glycosylated hemoglobin (HbA1c) =< 7.5%

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 2 weeks earlier

- Patients may not be receiving any other investigational agents

- Patients with known, active brain metastases should be excluded from this clinical
trial; patients with treated brain metastases stable for >= 12 weeks are eligible

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to temsirolimus or cetuximab

- Concurrent life-threatening diseases: patients with diseases which with reasonable
certainty do not limit life expectancy to 12 months or less are eligible; assessment
of such concurrent illnesses should be by the principal investigator

- Use of strong inhibitors/inducers of CYP3A4 is not permitted

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnant women are excluded from this study

- Breastfeeding should be discontinued if the mother is treated with temsirolimus

- HIV-positive patients with normal immune function (CD4 count > 200) are eligible if
there are no drug interactions with temsirolimus or cetuximab; patients with impaired
immune function are ineligible due to the risk of additional immunosuppression from
temsirolimus therapy

- Concurrent administration of temsirolimus with vaccinations is to be avoided and a
14-day window from administration of the vaccine is advised; in emergent situations
this policy may be revisited by the PI if deemed important for the patient's health

- Poorly controlled hyperglycemia (HbA1C > 7.5%) or hyperlipidemia are exclusion
criteria; hyperglycemia or hyperlipidemia need to be appropriately managed and
controlled

- Concurrent use of warfarin is allowed, but requires close monitoring of prothrombin
time (PT)/international normalized ratio (INR)

- Patients with clinically significant pneumonitis/pulmonary infiltrates unless there
is a known and treatable cause for the condition