Study of Albumin Bound-Paclitaxel for Treatment of Recurrent or Metastatic Head and Neck Cancer With Cetuximab

OBJECTIVES

Primary Objective: To assess the overall response rate (complete and partial response) to
Abraxane in patients with recurrent or metastatic head and neck cancer with the addition of
Cetuximab on disease progression.

Secondary Objectives: 1. To assess the frequency and severity of toxicities associated with
this treatment. 2. To evaluate overall survival and progression-free survival in patients
with recurrent or metastatic head and neck cancer treated with single agent Abraxane. 3.To
assess whether the addition of Cetuximab will re-sensitize head and neck cancer to Abraxane
after progression on single agent Abraxane.

BACKGROUND AND RATIONALE

Approximately 40,000 new cases of head and neck cancer are diagnosed annually in the United
States (Jemal et al, 2003), and over 30% of these patients are expected to die of their
malignancy. Squamous cell carcinoma accounts for more than 90% of head and neck cancer cases.
Although metastatic disease at the time of diagnosis is rather uncommon, and despite
aggressive use of up-front concurrent radiation and cisplatin-based chemotherapy,
approximately 20% of the patients will develop metastases. Patients with recurrent or
metastatic squamous cell carcinoma of the head and neck (SCCHN) have a poor prognosis. Their
median survival is about 6-8 months. Selected patients with locally recurrent disease can be
treated with a curative intent with locoregional therapies, such as salvage surgery or
radiation (De Crevoisier et al, 1998); however the majority of these patients die of their
disease. Despite high response rates, combination chemotherapy has not been shown to produce
a survival benefit compared to single agents in randomized trials in patients with
recurrent/metastatic head and neck cancer (Forastiere et al, 1992; Jacobs et al, 1992; Clavel
et al, 1994). A phase III randomized study conducted by Southwest Oncology Group (SWOG)
compared cisplatin-based combination chemotherapy to single agent methotrexate (Forastiere et
al, 1992). The objective response rates were 32%, 21%, and 10%, for cisplatin/5-Fluorouracil
(5-FU), carboplatin/5-FU, and single methotrexate, respectively, but the median overall
survival was not statistically different between the three arms (ranged between 5 to 6.6
months). Moreover, toxicity was increased with combination therapy, especially with the
cisplatin-based regimen. Another randomized study conducted in the US demonstrated a
significantly higher response rate of 32% for the combination of cisplatin and 5-FU versus
17% and 13% for single agent cisplatin and 5-FU, respectively (Jacobs et al, 1992). However,
the median survival of all patients was 5.7 months, with no difference between the three
arms. Hematologic toxicity was increased in the combination arm.

A subsequent randomized study conducted by ECOG (E1393) compared high-dose paclitaxel (200
mg/m2) as a 24-hour infusion plus cisplatin 75 mg/m2 with granulocyte-colony stimulating
factor (G-CSF) support, to low dose paclitaxel (135 mg/m2) as a 24-hour infusion, plus
cisplatin 75 mg/m2 (Forastiere et al, 2001). Patients with newly diagnosed metastatic or
recurrent squamous cell carcinoma of the head and neck, excluding nasopharyngeal primaries
were eligible. No prior treatment for recurrent/metastatic disease was allowed, but patients
could have received chemotherapy as a part of the initial curative therapy that should have
been completed 6 months prior to study. Tow hundred and ten patients were randomized between
the 2 arms. No significant difference in outcome was observed. The response rate was 35% vs
36% and the median survival was 7.6 vs 6.8 months, in the high-dose vs low-dose paclitaxel
arms respectively. Patients with metastatic disease performed worse in terms of survival.
Previously untreated patients achieved a higher response rate of 58% compared to a response
rate of 32% observed in patients who have failed prior curative therapies. Substantial
toxicities were observed in this trial. Grade 4 neutropenia was seen in 61-71% of patients
and febrile neutropenia with hospitalization occurred in 27-39% of patients. The toxic death
rate was 10% (12% vs 9%) (Forastiere et al, 2001). It was concluded that the 24-hour
paclitaxel infusion was associated with unacceptable toxicity when combined with cisplatin.
Instead, a 3-hour paclitaxel infusion combined with cisplatin was advanced to further
testing. A more recent randomized trial conducted by ECOG (E1395) compared the combination of
paclitaxel 175 mg/m2 as a 3-hour infusion and cisplatin 75 mg/m2 to a standard cisplatin and
5-FU regimen. No statistically significant difference could be demonstrated either in
response rates or survival between the two arms (Murphy et al, 2001). This study, however,
indicated that paclitaxel, a member of the taxane class of anti-tumor agent, is active in
head and neck cancer.

Recently, another member anti-tumor class of taxane, Docetaxel (Taxotere) has been shown to
be active in advanced head and neck cancer. In a randomized phase III trial of
intensification of induction chemotherapy followed by radiation, the addition of docetaxel to
the induction regimen of cisplatin and 5-fluoruracil when compared to cisplatin and
5-fluoruracil alone resulted in a 3-month improvement in overall survival (Vermorken et al,
2004). Thus both members of the taxane family, paclitaxel and docetaxel, have proven
anti-tumor activity in head and neck cancer.

New agents to treat head and neck cancer need to be investigated. Abraxane, an albumin-bound
formulation of paclitaxel has shown significant single-agent activity in breast cancer and in
head and neck cancer. Recently, Abraxane has approved for use in metastatic breast cancer.
Given previous randomized phase III trials indicated single agent chemotherapy fared as well
as combination chemotherapy regimen in terms of overall survival, this novel formulation
should be actively investigated in head and neck cancer.

Abraxane in solid tumor The clinical database included two single arm studies enrolling a
total of 106 patients and one multi-center randomized trial. The multi-center trial was
conducted in 460 patients with metastatic breast cancer who were randomized to receive either
Abraxane 260 mg/m² administered as a 30-minute infusion or paclitaxel 175 mg/m² given over 3
hours. Sixty-four percent of patients had impaired performance status (ECOG 1 or 2) at study
entry. Seventy-nine percent had visceral metastases and 76% had > 3 sites of metastases.
Fifty-nine percent of patients had received one or more prior chemotherapy regimens, and 77%
had received an anthracycline-containing regimen. The objective response rate verified by
central review was 21.5% (95% Confidence interval (CI): 16.2% to 26.7%) for Abraxane compared
to 11.1% (95% CI: 6.9% to 15.1%) for paclitaxel (p=0.003). The conclusion of this phase III
trial is that Abraxane had statistically significant higher target lesion response rate (the
trial primary endpoint) (O'Shaughnessy et al, 2003).

On January 7, 2005 the U. S. Food and Drug Administration approved Abraxane (albumin-bound
paclitaxel) for treatment of breast cancer after failure of combination chemotherapy for
metastatic disease or relapse within 6 months of adjuvant chemotherapy based on the
statistically significant superior response rate from the randomized phase III trial
mentioned above. The recommended dose of Abraxane is 260 mg/m² administered intravenously
over 30 minutes every 3 weeks. No premedication to prevent hypersensitivity reactions is
required prior to Abraxane administration.

Abraxane in Head and Neck Cancer The role of Abraxane in Head and Neck cancer has been
explored in a phase I study (Damascelli et al, 2001). Abraxane was injected intra-arterially
(carotid artery) in 31 patients with advanced Head and Neck cancer. The maximum tolerated
dose in a single administration was determined to be 270 mg/m2 which is very close to the
approved dose of 260 mg/m2. Three patients achieved complete response and 19 patients
achieved partial response for a combined response rate of 76%. Side effects are very
tolerable including three patients with grade 4 neutropenia, and grade 2 non-hematologic
toxicities included: keratitis [1 patient], skin toxicity [5 patients], neurologic toxicities
[4 patients], and flu-like syndrome [7 patients]. However, intra-arterial administration is
technically challenging with potential serious side effects, cumbersome and not the
conventional way of delivering chemotherapy. In another phase 1 study of Abraxane in advanced
solid tumors, 3 out of 5 patients with nasopharyngeal carcinoma had responses lasting 25, 18
and 13+ weeks (Teng et al, 2005).

Given the hint of anti-tumor activity of Abraxane in advanced Head and Neck cancer from the
above mentioned studies, this current study will seek to determine the efficacy of Abraxane
in recurrent or metastatic head and neck cancer at the dose of 260 mg/m2 given intravenously
every 3 weeks in a systemic manner. Abraxane is not FDA approved in the treatment of this
study disease; however, it is approved for patient use in the treatment of advanced breast
cancer that have failed traditional therapy.

Abraxane is a natural substance and is far more superior to conventional chemistry. Abraxane
is an effective treatment for aggressive cancers because it adversely affects the process of
cell division by preventing this restructuring. Other cells are also affected adversely, but
since cancer cells divide much faster than non-cancerous cells, they are far more susceptible
to Abraxane treatment, thus, the safety of the drug is no more or less then other
chemotherapy regimens.

Human albumin will be used along with the Abraxane.

Description of Cetuximab (IMC-225) (Erbitux) (NSC-714692) Cetuximab, a chimerized antibody of
the immunoglobulin gamma-1 (IgG1) subclass was originally derived from a mouse myeloma cell
line. The chimerization resulted in an antibody with binding affinity to epidermal growth
factor receptors (EGFR) greater than the natural ligand epidermal growth factor (EGF).
Cetuximab blocks binding EGF and transforming growth factor (TGFa) to EGFR and inhibits
ligand-induced activation of this tyrosine kinase receptor. Cetuximab also stimulates EGFR
internalization, effectively removing the receptor from the cell surface for interaction with
ligand.

Safety Precaution Cetuximab therapy should be used with caution in patients with known
hypersensitivity to Cetuximab, murine proteins, or any component of this product.

Administration of Cetuximab: In an effort to prevent a hypersensitivity reaction, all
patients should be premedicated with dexamethasone 20 mg by IV and diphenhydramine
hydrochloride 50 mg by IV given 30-60 minutes prior to the infusion of cetuximab.

The initial/loading dose of cetuximab is 400 mg/m2 IV administered over 120 minutes. Patients
must be continuously observed during the infusion for signs of anaphylaxis and standard
resuscitative meds should be in close proximity. Vital signs should be taken prior to,
during, post and 1-hour post infusion for the initial dose. For subsequent infusions, vital
signs are recommended to be taken to and 1-hour post infusion.

Following the loading dose, patients will receive weekly treatment with cetuximab IV over 60
minutes. The infusion rate of cetuximab should never exceed 5 mL/min. Patients should be
closely monitored for treatment-related adverse events, especially hypersensitivity
reactions, during the infusion and post-infusion.

Cetuximab is used for the treatment of patients with advanced head and neck cancer that has
spread to other parts of the body.

Inclusion Criteria:

- All patients must have histologically or cytologically confirmed carcinoma of the head
and neck region. Primary tumor sites include: lip and oral cavity, major salivary
glands, pharynx (oropharynx, nasopharynx, hypopharynx), or larynx (supraglottis,
glottis, subglottis), nasal cavity and paranasal sinuses, and thyroid

- Patients must have metastatic or locally recurrent squamous cell carcinoma of the head
and neck. Patients with locoregional disease must be considered incurable by means of
locoregional therapy.

- All sites of disease must be assessed and designated as measurable or non-measurable
disease as documented by CT, MRI, X-ray physical exam or nuclear exam. All measurable
and non-measurable disease must be assessed within 28 days prior to registration.

- Patients may have prior chemotherapy for recurrent/metastatic disease. However, all
chemotherapy must be completed at least 21 days prior to scheduled start of Abraxane.

- Patients must have adequate bone marrow reserve as documented by absolute neutrophil
count (ANC) > 1,500 μl and platelets > 100,000/ μl obtained within 14 days prior to
registration.

- Patients must have adequate hepatic as documented by serum bilirubin < 1.5 x the
institutional upper limit of normal. These tests must be obtained within 14 days prior
to registration.

- All patients must be 18 years of age or older

- Patients must have a Zubrod performance of 0-3

Exclusion Criteria:

- Patients must not have prior therapy with Abraxane

- Patients with any evidence of active or uncontrolled infection, recent myocardial
infection, unstable angina, or life-threatening arrhythmia are not eligible.

- Patients with baseline grade 3 peripheral neuropathy are not eligible.

- Patients with known brain metastasis are not eligible. However, brain-imaging studies
are not required for eligibility if the patient has no neurological signs or symptoms.
If brain-imaging studies are performed, they must be negative for disease.