Chemotherapy and R-(-)-Gossypol Acetic Acid in Preserving the Larynx in Patients with Stage III or IV Laryngeal or Hypopharyngeal Cancer

Status: complete

This randomized phase II trial studies how well chemotherapy and R-(-)-gossypol acetic acid work in preserving the larynx in patients with stage III or IV laryngeal or hypopharyngeal cancer. Drugs used in chemotherapy, such as docetaxel, cisplatin, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. R-(-)-gossypol acetic acid may kill tumor cells by blocking their growth. Giving R-(-)-gossypol acetic acid together with docetaxel, cisplatin, and carboplatin may be an effective treatment in preserving the larynx in patients with laryngeal or hypopharyngeal cancer.

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 direct laryngoscopy (DL) endoscopic tumor staging and CT scanning
Eastern Cooperative Oncology Group (ECOG) performance status 0-1
White blood cell >= 3500/ul
Granulocyte >= 1500/ul
Platelet count >= 100,000/ul
Calculated or measured creatinine clearance >= 60 cc/min for cisplatin candidates, >= 30 cc/min for carboplatin candidates
Total bilirubin =< 1.5 x upper limit of normal (ULN)
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN
Patients must give documented informed consent to participate in this study

Exclusion Criteria

History of secondary malignancy or history of other malignancy within the last three years (patients who have been disease-free for three years, or have a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible)
Prior head and neck radiation or prior chemotherapy
Documented evidence of distant metastases
Active infection
Pregnancy or lactation; patients must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry, for the duration of study participation and for 3 months after discontinuing therapy
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 are not eligible
Patients with prior radiation to the head and neck
Patients with grade >= 2 peripheral neuropathy
Any history of severe hypersensitivity reaction to docetaxel or other drugs formulated with polysorbate 80
Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification
Unstable angina or a 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 (e.g. chemotherapy, immunotherapy, targeted or biologic therapy)

PRIMARY OBJECTIVES:

I. To determine the salvage surgery rates of this treatment paradigm compared to the salvage surgery rates of patients treated on University of Michigan Cancer Center (UMCC) 9520.

II. To estimate the overall response rate to induction chemotherapy with platinum and docetaxel plus AT-101 (R-(-)-gossypol acetic acid) following one and/or two cycles in patients with advanced laryngeal cancer.

III. To determine the progression-free survival rates of this treatment paradigm compared to the progression-free survival rates of patients treated on UMCC 9520.

IV. To determine toxicities of induction chemotherapy plus AT-101 and chemoradiation in patients on this treatment.

SECONDARY OBJECTIVES:

I. To determine expression of B-cell lymphoma 2 (Bcl2)/BCL-extra large (BclxL), epidermal growth factor receptor (EGFR) and tumor protein 53 (p53) in pre and posttreatment biopsy specimens.

II. To compare the overall response rates of the first (1st) cycle of induction chemotherapy with platinum and docetaxel to platinum and docetaxel plus AT-101.

III. To compare the overall response rates of induction chemotherapy with platinum and docetaxel plus AT-101 to the rates of induction chemotherapy with cisplatin and 5-fluorouracil (fluorouracil) from the historical group treated on UMCC 9520.

IV. To estimate overall and cause-specific survival rates in patients on this treatment.

V. To evaluate the quality of life (QOL) of this treatment paradigm.

VI. To evaluate tumor vascular perfusion in response to induction chemotherapy utilizing computed tomography (CT) with perfusion.

OUTLINE:

INDUCTION CHEMOTHERAPY: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive docetaxel intravenously (IV) over 1 hour on day 1 and cisplatin IV over 1 hour or carboplatin IV on day 1. Patients with partial response (PR) or no response (NR) at day 23 receive an additional course of induction therapy.

ARM II: Patients receive docetaxel and cisplatin or carboplatin as in Arm I. Patients also receive R-(-)-gossypol acetic acid orally (PO) twice daily (BID) on days 1-3. Patients with PR or NR at day 23 receive an additional course of induction therapy.

Patients with NR after induction chemotherapy undergo early salvage laryngectomy followed by radiation therapy or chemoradiotherapy. Patients with PR or complete response (CR) after induction chemotherapy receive chemoradiotherapy. Patients with positive laryngeal biopsies after chemoradiotherapy undergo late salvage laryngectomy.

After completion of study treatment, patients are followed up every 6-8 weeks for 1 year, every 2 months for 1 year and then every 3 months for 1 year.

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Chemotherapy and R-(-)-Gossypol Acetic Acid in Preserving the Larynx in Patients with Stage III or IV Laryngeal or Hypopharyngeal Cancer

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