Chemotherapy AND Bcl-xL Inhibitor (AT-101) For Organ Preservation In Adults With Advanced Laryngeal Cancer

Published data demonstrate equal efficacy and improved quality of life when platinum and a
taxane were compared with platinum and 5-Fluorouracil [31]. Additionally, weekly cisplatin
regimens (30-40 mg/m2) with radiotherapy appear to be equally efficacious and better
tolerated than standard high-dose cisplatin (100 mg/ m2) regimens with radiation therapy for
locally advanced SCCHN [32] The investigators will thus attempt to reduce toxicity from
induction chemotherapy with the use of docetaxel/cisplatin (or carboplatin) (TP) in place of
our previously used standard regimen of cisplatin and 5-fluorouracil (PF) and administer
weekly cisplatin (or carboplatin) with radiation for those patients who are responders to
induction therapy. Finally, Phase I/II testing of the small molecule inhibitor, AT-101, has
recently been completed, and suggests activity in solid tumors when combined with cytotoxic
agents. Since the investigators have achieved such high survival rates with our treatment
selection approach in laryngeal cancer, our ultimate goal is to reduce the rate of salvage
laryngectomy which should improve quality of life. The investigators hypothesize that
specific inhibition of Bcl-2/Bcl-xL function can increase response rates to neoadjuvant
chemotherapy and decrease the need for salvage laryngectomy. Hence, the investigators propose
this study: the treatment of patients with advanced SCC of the larynx with one cycle of
platinum plus docetaxel with AT-101, followed by chemoradiotherapy for those responding to
this induction regimen and reserving total laryngectomy for those who are non-responders.

Inclusion Criteria:

- Patients must have pathologically confirmed, previously untreated, resectable,
squamous cell carcinoma of the larynx or hypopharynx.

- Disease must be Stage III or IV

- Tumor must be potentially surgically resectable and curable with conventional surgery
and radiation therapy

- Patients must undergo pre-treatment endoscopic tumor staging and CT scanning

- ECOG Performance status 0-1

- Adequate WBC (white blood cell), granulocyte and platelet counts

- Creatinine clearance of ≥ 60cc/min for cisplatin candidates and ≥ 30 cc/min for
carboplatin candidates

- Adequate bilirubin, AST (aspartate aminotransferase), and ALT (alanine transaminase)
function

Exclusion Criteria:

- Prior head and neck malignancy or history of other prior non-head and neck malignancy
within the past 3 years

- Prior head and neck radiation or prior chemotherapy.

- Documented evidence of distant metastases

- Active infection

- Pregnancy or lactation

- Any medical or psychiatric illness which in the opinion of the principal investigator
would compromise the patient's ability to tolerate this treatment

- Patients residing in prison

- Patients with psychiatric/ social situations that would limit compliance with study
requirements

- Patients with Grade > 2 peripheral neuropathy

- History of severe hypersensitivity reaction to docetaxel

- Class 3 or 4 cardiac disease

- Unstable angina or history of myocardial ischemia within prior 6 months

- Malabsorption syndrome, disease significantly affecting gastrointestinal function, or
resection of the stomach or small bowel, ulcerative colitis, inflammatory bowel
disease, partial or complete small bowel obstruction

- Prior use of gossypol or AT-101, or known hypersensitivity to gossypol or AT-101

- Patients taking any other concurrent approved or investigational anti-cancer therapy