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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01633541
Recruitment Status : Active, not recruiting
First Posted : July 4, 2012
Last Update Posted : May 10, 2019
Information provided by (Responsible Party):
University of Michigan Rogel Cancer Center

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Laryngeal Cancer Drug: AT-101 Drug: Docetaxel Drug: Cisplatin Drug: Carboplatin Phase 2

Detailed Description:
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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 59 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Concomitant Chemotherapy AND Bcl-xL Inhibitor (AT-101) For Bio-selection For Organ Preservation In Patients With Advanced Laryngeal Cancer
Study Start Date : March 2012
Estimated Primary Completion Date : November 2021
Estimated Study Completion Date : November 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Docetaxel

Arm Intervention/treatment
Experimental: platinum/docetaxal + AT-101

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
Patients will receive AT-101 40 mg orally two times a day.
Other Name: Bcl-xL INHIBITOR

Drug: Cisplatin
Cisplatin 100 mg/m2

Drug: Carboplatin
Carboplatin AUC (area under the curve) 6. Maximum dose of 700 mg

Active Comparator: Active Comparator arm

(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
Docetaxel (Taxotere) 75 mg/m2
Other Name: Taxotere

Drug: Cisplatin
Cisplatin 100 mg/m2

Drug: Carboplatin
Carboplatin AUC (area under the curve) 6. Maximum dose of 700 mg

Primary Outcome Measures :
  1. Number of patients alive and free from indication for laryngectomy three months post treatment [ Time Frame: 3 months ]
    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

  2. Progression-free survival [ Time Frame: Up to 3 years after randomization ]
    Time from randomization to the time of first indication of local failure or metastases. Estimated non-parametrically using the Kaplan-Meier method.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01633541

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United States, Michigan
University of Michigan Comprehensive Cancer Center
Ann Arbor, Michigan, United States, 48109
Sponsors and Collaborators
University of Michigan Rogel Cancer Center
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Principal Investigator: Frank Worden, MD University of Michigan Rogel Cancer Center

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Responsible Party: University of Michigan Rogel Cancer Center Identifier: NCT01633541     History of Changes
Other Study ID Numbers: UMCC 2010.101
HUM00043975 ( Other Identifier: University of Michigan IRBMED )
First Posted: July 4, 2012    Key Record Dates
Last Update Posted: May 10, 2019
Last Verified: May 2019

Additional relevant MeSH terms:
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Laryngeal Neoplasms
Otorhinolaryngologic Neoplasms
Head and Neck Neoplasms
Neoplasms by Site
Laryngeal Diseases
Respiratory Tract Diseases
Respiratory Tract Neoplasms
Otorhinolaryngologic Diseases
Gossypol acetic acid
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Phytogenic
Contraceptive Agents, Female
Contraceptive Agents
Reproductive Control Agents
Physiological Effects of Drugs
Spermatocidal Agents
Antispermatogenic Agents
Contraceptive Agents, Male