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

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

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.

Study Overview

• Status: Completed
• Conditions: Laryngeal Cancer
• Intervention / Treatment: Drug: AT-101; Drug: Cisplatin; Drug: Carboplatin; Drug: Docetaxel

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.

• Study Type: Interventional
• Enrollment (Actual): 55
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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: Cisplatin; Cisplatin 100 mg/m2; Drug: Carboplatin; Carboplatin AUC (area under the curve) 6. Maximum dose of 700 mg; Drug: Docetaxel; Docetaxel (Taxotere) 75 mg/m2; Other Names: Taxotere
Experimental: platinum/docetaxel + 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 Names: Bcl-xL INHIBITOR; Drug: Cisplatin; Cisplatin 100 mg/m2; Drug: Carboplatin; Carboplatin AUC (area under the curve) 6. Maximum dose of 700 mg

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Michigan Rogel Cancer Center
• Investigators: Principal Investigator: Paul Swiecicki, MD, University of Michigan Rogel Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2012
• Primary Completion (Actual): November 6, 2021
• Study Completion (Actual): November 6, 2021

Study Registration Dates

• First Submitted: June 29, 2012
• First Submitted That Met QC Criteria: July 3, 2012
• First Posted (Estimated): July 4, 2012

Study Record Updates

• Last Update Posted (Actual): July 20, 2023
• Last Update Submitted That Met QC Criteria: July 18, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Neoplasms by Site; Respiratory Tract Neoplasms; Otorhinolaryngologic Neoplasms; Head and Neck Neoplasms; Otorhinolaryngologic Diseases; Laryngeal Diseases; Laryngeal Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Docetaxel; Carboplatin
• Other Study ID Numbers: UMCC 2010.101; HUM00043975 (Other Identifier: University of Michigan IRBMED)