Safety and Efficacy of A-007 Topical Gel in the Treatment of High-Grade Squamous Intraepithelial Lesions (HSIL) of the Cervix

A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Trial of the Use of 4,4'-Dihydroxybenzophenone-2,4-Dinitrophenyl-hydrazone (A-007) Topical Gel in the Treatment of High-Grade Squamous Intraepithelial Lesions (HSIL) of the Cervix

A-007 is an investigational therapy which may be effective in the treatment of pre-cancerous cervical dysplasia (abnormal cell growth). The purpose of this study is to evaluate the safety and efficacy of A-007, when used to treat high-grade cervical dysplasia.

Study Overview

• Status: Completed
• Conditions: Cervical Intraepithelial Neoplasia; Uterine Cervical Dysplasia
• Intervention / Treatment: Drug: placebo; Drug: A007

Detailed Description

This is a randomized, double-blind, placebo-controlled study. It will randomize patients in a 1:1 ratio to topical cervical treatment with A-007, or placebo gel. Following biopsy confirmation of High Grade Squamous Intraepithelial Lesions (HSIL), women will treat themselves with gel applied to the cervix via an intravaginal applicator. Patients will apply gel once daily for 5 consecutive days of a 28-day cycle for 2 cycles. Women will return to clinic for safety assessments, colposcopy, cytology, and virologic and immunologic testing.

• Study Type: Interventional
• Enrollment (Actual): 147
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35205
      • University of Alabama Highlands, Dept. of OB/GYN
  • Arizona
    • Phoenix, Arizona, United States, 85032
      • HOPE Research Institute, LLC
    • Tucson, Arizona, United States, 85712
      • Visions Clinical Research-Tucson
  • California
    • Carmichael, California, United States, 95608
      • Northern California Research Corp
    • Colton, California, United States, 92324
      • Arrowhead Regional Medical Center
    • Costa Mesa, California, United States, 92629
      • Robin Black OGNP
    • San Diego, California, United States, 92121
      • IGO Medical Group of San Diego
  • Connecticut
    • New London, Connecticut, United States, 06320
      • Coastal Connecticut Research, LLC
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Washington Hospital Center
  • Florida
    • Boynton Beach, Florida, United States, 33437
      • Visions Clinical Research
    • Pembroke Pines, Florida, United States, 33024
      • Global OB/GYN Centers of Florida
    • Sarasota, Florida, United States, 34239
      • Physician Care Clinical Research, LLC.
    • West Palm Beach, Florida, United States, 33401
      • OB/GYN Specialists of the Palm Beaches
  • Georgia
    • Atlanta, Georgia, United States, 30328
      • Mount Vernon Clinical Research, LLC
    • Augusta, Georgia, United States, 30912
      • Medical College of Georgia
  • Louisiana
    • Metairie, Louisiana, United States, 70006
      • East Jefferson OB/GYN
  • Nevada
    • Las Vegas, Nevada, United States, 89128
      • Office of R. Garn Mabey, MD
  • New Jersey
    • Neptune, New Jersey, United States, 07754
      • Jersey Shore University Medical Center
  • New York
    • Bronx, New York, United States, 10461
      • Jacobi Medical Center
    • Bronx, New York, United States, 10461
      • Montefiore Medical Center-Weiler Division Dept of OB/GYN & Women's Health
    • New York, New York, United States, 10038
      • New York Downtown Hospital
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • Greater Cincinnati OB/GYN, Inc.
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center Dept of OB/GYN
  • Pennsylvania
    • Allentown, Pennsylvania, United States, 18102
      • Lehigh Valley Hospital
    • Pittsburgh, Pennsylvania, United States, 15213
      • Magee-Womens Hospital, Dept of OB/GYN & Reproductive Services
  • South Carolina
    • Columbia, South Carolina, United States, 29210
      • South Carolina Oncology Associates
  • Texas
    • Austin, Texas, United States, 78737
      • Hill Country OB/GYN
    • Houston, Texas, United States, 77004
      • Planned Parenthood of Houston & Southeast Texas, Inc.
    • Plano, Texas, United States, 75093
      • 4601 Old Shepard Place; Bldg 2, Suite 201

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

Patients may be enrolled in the study only if they meet all of the following criteria:

• 18 years of age or older
• The patient or her authorized representative must sign and date an Ethical Review Board-approved informed consent document. All aspects of the protocol must be explained and written informed consent obtained.
• Patients must have histological proof of HSIL (CIN 2/3) disease documented.
• Cervical swabs must test positive for HPV (by Hybrid Capture 2).
• Patients must have a Hb ≥ 9 g/dl, a peripheral WBC ≥ 3000 mm3 and platelet counts ≥ 100,000 mm3.
• Normal hepatic and renal functions - AST and ALT < 2.5 x ULN and creatinine < 1.5 x ULN, respectively.
• Females of childbearing potential must use one of the following birth control methods during the treatment period and 2 weeks thereafter: oral, implantable, injectable contraceptives; abstinence (celibacy). Contraceptive sponges, IUD, spermicides, sponges, condoms, or partner's vasectomy are not acceptable methods of birth control.

Exclusion Criteria:

Patients will be excluded from the study for any of the following preexisting reasons:

• Patients with LSIL (CIN 1) or invasive squamous cell carcinoma (SCC).
• SIL (CIN) involving the endocervix as determined by endocervical curettage, or otherwise not amenable to adequate colposcopic follow-up evaluations, i.e. unsatisfactory colposcopy.
• CIN 3 involving more than two cervical quadrants on colposcopy.
• Patients treated for cervical SIL within the past year.
• Patients with other malignancy (except for non-melanoma skin) within the past 5 years.
• Patients with any active infections (including HIV) other than HPV.
• Patients with known clinically relevant immunological deficiency.
• Concurrent treatment with cytotoxic, radiation, or immuno-stimulative therapy, or with systemic corticosteroids at a dose of > 5 mg/d of prednisone (or its equivalent).
• Participation in another investigational medication trial concurrently or within 30 days, or prior participation in an HPV vaccine trial. Treatment within the last 30 days with a medication that has not received regulatory approval at the time of study entry.
• Concomitant use of topical vaginal medications.
• Significant acute or chronic medical or psychiatric illness that, in the judgment of the Investigator, could compromise subject safety, limit the subject's ability to complete the study, and/or compromise the objectives of the study.
• History of allergy or hypersensitivity to cosmetics, toiletries, or other topical or dermatologic products.
• Pregnant or lactating females who are nursing and will not consent to cease nursing.
• Investigators, site personnel directly affiliated with this study, and their immediate families. Immediate family is defined as a spouse, parent, child or sibling, whether biological or legally adopted.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Placebo administered topically to the cervix via intravaginal applicator for 5 consecutive days of a 28-day cycle for 2 cycles.	Drug: placebo; 5 days of 28 day cycle for 2 cycles
Experimental: A007; 0.25% A007 administered topically to the cervix via intravaginal applicator for 5 consecutive days of a 28-day cycle for 2 cycles.	Drug: A007; 5 days of 28 day cycle

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathological Response	Pathological resonse is defined as a patient who regressed from Cervical intraepithelial neoplasia (CIN) 2/3 to normal at the end of 4 months.	baseline and 4 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Local Tolerability and Systemic Safety of A-007 Will be Assessed by Way of CTCAE 3.0.	over the course of the trial
Eradication of Human Papilloma Virus (HPV) Will be Assessed by Way of Cervical Cytology and Swab Collection.	over the course of the trial
Immunologic Parameters B/T Cells Will be Assessed by B/T Cell Profile Collection.	over the course of the trial

Collaborators and Investigators

• Sponsor: Tigris Pharmaceuticals
• Investigators: Principal Investigator: John A Burigo, MD, OB/GYN Specialists of the Palm Beaches; Principal Investigator: Ramon Cestero, MD, Arrowhead Regional Medical Center; Principal Investigator: Paul M Fine, MD, Planned Parenthood of Houston & Southeast Texas, Inc.; Principal Investigator: Keith A Aqua, MD, Visions Clinical Research; Principal Investigator: Steven C Blank, MD, Mount Vernon Clinical Research, LLC; Principal Investigator: Douglas G Young, MD, Northern California Research Corp; Principal Investigator: Allan T Sawyer, MD, HOPE Research Institute, LLC; Principal Investigator: Mark H Einstein, MD, Montefiore Medical Center-Weiler Division; Principal Investigator: Robert M Spitz, MD, Coastal Connecticut Research, LLC; Principal Investigator: Thomas A deHoop, MD, Greater Cincinnati OB/GYN, Inc.; Principal Investigator: Lance R Bruck, MD, Jacobi Medical Center; Principal Investigator: Warner K Huh, MD, University of Alabama Highlands, Dept. of OB/GYN; Principal Investigator: Giuseppe Del Priore, MD, New York Presbyterian Hospital; Principal Investigator: Michael A Gold, MD, University of Oklahoma Health Sciences Center Dept of OB/GYN; Principal Investigator: Richard S Guido, MD, Magee-Womens Hospital, Dept of OB/GYN & Reproductive Services; Principal Investigator: Philip E Young, MD, IGO Medical Group of San Diego; Principal Investigator: Daron G. Ferris, MD, Augusta University; Principal Investigator: Cynthia J Goldberg, MD, Visions Clinical Research-Tucson; Principal Investigator: Ana Eduardo, MD, Hill Country OB/GYN; Principal Investigator: Phyllis Gee, MD, OB/GYN; Principal Investigator: Robert Pfeffer, MD, Robin Black OGNP, Costa Mesa California; Principal Investigator: Jonathan A Cosin, MD, MedStar Health Research Institute; Principal Investigator: James A Williams, MD, South Carolina Oncology Associates; Principal Investigator: Vincent A Culotta, Jr, MD, East Jefferson OB/GYN; Principal Investigator: G. Michael Swor, MD, Physician Care Clinical Research, LLC.; Principal Investigator: Garn R Mabey, MD, Office of R. Garn Mabey, MD; Principal Investigator: Martin Martino, MD, Lehigh Valley Hospital; Principal Investigator: Robert Klein, MD, Global OB/GYN Centers of Florida; Principal Investigator: William J Mann, MD, Jersey Shore University Medical Center

Publications and helpful links

General Publications

• Morgan LR, Thangaraj K, LeBlanc B, Rodgers A, Wolford LT, Hooper CL, Fan D, Jursic BS. Design, synthesis, and anticancer properties of 4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone and analogues. J Med Chem. 2003 Oct 9;46(21):4552-63. doi: 10.1021/jm0301080.
• Morgan, LR, Hooper, CL, Rodgers, AH, LoRusso, P, Eilender, DE and Culotta, VA. 4,4'-Dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone (A-007): A CD4+ T-Lymphocyte Modulator Useful in the Treatment of Advanced Cancer. Chemotherapy - accepted 2005.
• Morgan, LR, Hooper, CL, Rodgers, AH Culotta, V et al. 4,4'-Dihydroxy benzophenone -2,4-dinitrophenylhydrazone (A-007) A Modulator of CD45+ T Lymphocytes in HPV Infected Anogenital Epithelium. In: HPV Vaccines and Immune Therapy, Cambridge, United Kingdom, 2003

Study record dates

Study Major Dates

• Study Start: January 1, 2006
• Primary Completion (Actual): April 1, 2008
• Study Completion (Actual): June 1, 2008

Study Registration Dates

• First Submitted: January 30, 2006
• First Submitted That Met QC Criteria: January 30, 2006
• First Posted (Estimate): February 1, 2006

Study Record Updates

• Last Update Posted (Estimate): October 11, 2010
• Last Update Submitted That Met QC Criteria: September 23, 2010
• Last Verified: September 1, 2010

More Information

Terms related to this study

• Keywords: Human Papilloma Virus (HPV); Cervical Intraepithelial Neoplasia (CIN); High-grade Cervical Intraepithelial Neoplasia; High-grade Squamous Intraepithelial Lesions (HSIL); High-Grade Cervical Intraepithelial Lesions (CIN 2/3)
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Carcinoma; Neoplasms, Glandular and Epithelial; Uterine Cervical Diseases; Uterine Diseases; Precancerous Conditions; Neoplasms, Squamous Cell; Neoplasms; Carcinoma in Situ; Cervical Intraepithelial Neoplasia; Carcinoma, Squamous Cell; Uterine Cervical Dysplasia; Squamous Intraepithelial Lesions of the Cervix
• Other Study ID Numbers: TG-001