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

Study Overview
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Brief Summary
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To evaluate a new treatment approach for adults with advanced laryngeal cancer: induction chemotherapy with platinum and docetaxel plus AT-101. AT-101 is an investigational drug for the treatment of advanced cancer. It is hoped that the combination of this chemotherapy regimen will allow cancer patients to keep their voice box and to improve/maintain voice-related quality of life. The ultimate goal of this study is to prevent the surgery to remove subjects voice box.

Detailed Description
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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.

Official Title
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Concomitant Chemotherapy AND Bcl-xL Inhibitor (AT-101) For Bio-selection For Organ Preservation In Patients With Advanced Laryngeal Cancer

Conditions
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Laryngeal Cancer

Intervention / Treatment
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* Drug: AT-101
* Drug: Docetaxel
* Drug: Cisplatin
* Drug: Carboplatin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: platinum/docetaxel + AT-101<br>platinum/docetaxel + AT-101 The platinum will either be cisplatin or carboplatin as deemed best by the medical oncologist. (Both Arms) Day #1: Patients will undergo induction chemotherapy with (TP) docetaxel (Taxotere) 75 mg/m2 and cisplatin 100 mg/m2 (or Carboplatin AUC 6). (AT-101 Arm) Days #1-3: Patients will receive AT-101 40 mg orally twice daily On Day 23 (+/- 3 days), there will be a direct laryngoscopy (DL) with tumor biopsy and blood draw, repeat CT scan of the neck with perfusion within a week biopsy. | Drug: AT-101<br>* Patients will receive AT-101 40 mg orally two times a day.<br>* Other names: Bcl-xL INHIBITOR;Drug: Cisplatin<br>* Cisplatin 100 mg/m2<br>Drug: Carboplatin<br>* Carboplatin AUC (area under the curve) 6. Maximum dose of 700 mg<br>|
| Active Comparator: Active Comparator arm<br>(Both Arms) Day #1: Patients will undergo induction chemotherapy with (TP) docetaxel (Taxotere) 75 mg/m2 and cisplatin 100 mg/m2 (or Carboplatin AUC 6). Day #23 (+/- 3 days): Patients will undergo a direct laryngoscopy (DL) with biopsy. Patients will also undergo a repeat CT scan of the neck with perfusion within a week (+/-) of their perspective biopsies. | Drug: Docetaxel<br>* Docetaxel (Taxotere) 75 mg/m2<br>* Other names: Taxotere;Drug: Cisplatin<br>* Cisplatin 100 mg/m2<br>Drug: Carboplatin<br>* Carboplatin AUC (area under the curve) 6. Maximum dose of 700 mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Alive and Free From Indication for Laryngectomy Three Months Post Treatment | The primary clinical objective of this trial is to compare the larynx preservation rates in a treatment paradigm that uses induction chemotherapy plus AT-101 to select patients for either concurrent chemoradiation or surgery. Organ preservation rate, defined as alive and free from indication for laryngectomy three months post treatment, was chosen as the primary endpoint because it provides evidence to fully characterize clinically the effect of the treatment strategy | Up to 3 months after end of treatment | 
| Progression-free Survival | Time from randomization to the time of first indication of local failure or metastases. Estimated non-parametrically using the Kaplan-Meier method. | Up to 3 years after randomization | 
| Overall Response Rate (ORR) | ORR (Complete Response [CR] plus Partial Response [PR]) to induction chemotherapy with platinum and docetaxel plus AT-101 following one and/or two cycles in patients with advanced laryngeal cancer. | Up to approximately 60 days | 
| Percentage of Patients Experiencing Grade 3 or Higher Adverse Events. | Toxicities will be evaluated using the Common Terminology Criteria for Adverse Events (CTCAE), version 3. | Up to 3 years after end of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Head and Neck Related Quality of Life (QOL) | University of Michigan Head and Neck Quality of Life Instrument (HN-QOL) will be administered prior to treatment (i.e. pre-induction chemotherapy) and at 6 months, 12 months, and 24 months (+/- 4 months) after completion of chemo-RT or surgery-RT (or surgery-chemoRT, as indicated). Scale is 0-100 with high scores indicating a better outcome. | Up to 28 months post treatment | 
| Voice Related QOL | The University of Michigan Voice Related Quality of Life Measure (V-RQOL) will be administered prior to treatment (i.e. pre-induction chemotherapy) and at 6 months, 12 months, and 24 months (+/- 4 months) after completion of chemo-RT or surgery-RT (or surgery-chemoRT, as indicated). Scale is 0-50 (10 items scale 1-5) with high scores indicating a worse outcome. | Up to 28 months post treatment | 
| Functional Assessment QOL | University of Michigan Head and Neck Quality of Life Instrument (HN-QOL) will be administered prior to treatment (i.e. pre-induction chemotherapy) and at 6 months, 12 months, and 24 months (+/- 4 months) after completion of chemo-RT or surgery-RT (or surgery-chemoRT, as indicated). Scale is 0-100 with high scores indicating a better outcome. EATING Domain is reported here as a functional assessment. | Up to 28 months post treatment |