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

Primary Purpose

Laryngeal Cancer

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
AT-101
Docetaxel
Cisplatin
Carboplatin
Sponsored by
University of Michigan Rogel Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Laryngeal Cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of Michigan Comprehensive Cancer Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

platinum/docetaxel + AT-101

Active Comparator arm

Arm Description

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.

(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.

Outcomes

Primary Outcome Measures

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
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.
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.
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.

Secondary Outcome Measures

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.
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.
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.

Full Information

First Posted
June 29, 2012
Last Updated
July 18, 2023
Sponsor
University of Michigan Rogel Cancer Center
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1. Study Identification

Unique Protocol Identification Number
NCT01633541
Brief Title
Chemotherapy AND Bcl-xL Inhibitor (AT-101) For Organ Preservation In Adults With Advanced Laryngeal Cancer
Official Title
Concomitant Chemotherapy AND Bcl-xL Inhibitor (AT-101) For Bio-selection For Organ Preservation In Patients With Advanced Laryngeal Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Completed
Study Start Date
March 2012 (Actual)
Primary Completion Date
November 6, 2021 (Actual)
Study Completion Date
November 6, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Michigan Rogel Cancer Center

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Laryngeal Cancer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
55 (Actual)

8. Arms, Groups, and Interventions

Arm Title
platinum/docetaxel + AT-101
Arm Type
Experimental
Arm Description
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.
Arm Title
Active Comparator arm
Arm Type
Active Comparator
Arm Description
(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.
Intervention Type
Drug
Intervention Name(s)
AT-101
Other Intervention Name(s)
Bcl-xL INHIBITOR
Intervention Description
Patients will receive AT-101 40 mg orally two times a day.
Intervention Type
Drug
Intervention Name(s)
Docetaxel
Other Intervention Name(s)
Taxotere
Intervention Description
Docetaxel (Taxotere) 75 mg/m2
Intervention Type
Drug
Intervention Name(s)
Cisplatin
Intervention Description
Cisplatin 100 mg/m2
Intervention Type
Drug
Intervention Name(s)
Carboplatin
Intervention Description
Carboplatin AUC (area under the curve) 6. Maximum dose of 700 mg
Primary Outcome Measure Information:
Title
Number of Patients Alive and Free From Indication for Laryngectomy Three Months Post Treatment
Description
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
Time Frame
Up to 3 months after end of treatment
Title
Progression-free Survival
Description
Time from randomization to the time of first indication of local failure or metastases. Estimated non-parametrically using the Kaplan-Meier method.
Time Frame
Up to 3 years after randomization
Title
Overall Response Rate (ORR)
Description
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.
Time Frame
Up to approximately 60 days
Title
Percentage of Patients Experiencing Grade 3 or Higher Adverse Events.
Description
Toxicities will be evaluated using the Common Terminology Criteria for Adverse Events (CTCAE), version 3.
Time Frame
Up to 3 years after end of treatment
Secondary Outcome Measure Information:
Title
Head and Neck Related Quality of Life (QOL)
Description
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.
Time Frame
Up to 28 months post treatment
Title
Voice Related QOL
Description
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.
Time Frame
Up to 28 months post treatment
Title
Functional Assessment QOL
Description
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.
Time Frame
Up to 28 months post treatment

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Paul Swiecicki, MD
Organizational Affiliation
University of Michigan Rogel Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Michigan Comprehensive Cancer Center
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States

12. IPD Sharing Statement

Learn more about this trial

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

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