Trial of Fenretinide/LXS Plus Ketoconazole in Recurrent Ovarian Cancer and Primary Peritoneal Carcinoma

The recruitment status of this study is unknown because the information has not been verified recently.
Verified February 2012 by University of Texas Southwestern Medical Center.
Recruitment status was  Not yet recruiting
Sponsor:
Collaborator:
South Plains Oncology Consortium
Information provided by (Responsible Party):
University of Texas Southwestern Medical Center
ClinicalTrials.gov Identifier:
NCT01550692
First received: February 24, 2012
Last updated: March 7, 2012
Last verified: February 2012
  Purpose

The purpose of this study is to find out whether an investigational (non-FDA approved) drug called fenretinide (4-HPR) plus ketoconazole can treat recurrent ovarian better or more safely than standard medication.


Condition Intervention Phase
Recurrent Ovarian Cancer
Drug: Ketoconazole and HPR/LXS
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I/II Trial of Fenretinide/LXS Oral Powder (NSC 374551) Plus Ketoconazole in Recurrent Ovarian Cancer and Primary Peritoneal Carcinoma

Resource links provided by NLM:


Further study details as provided by University of Texas Southwestern Medical Center:

Primary Outcome Measures:
  • Change of Target and Non-Target Lesion Measurements from baseline. [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Percent of evaluable patients whose best response is Complete Remission or Partial Response. [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    Complete Remission is defined as complete disappearance of all target lesions. Partial Response is identified when there is at least a 30% decrease in the sum of longest diameter(LD) of target lesions taking as reference the baseline sum LD.


Estimated Enrollment: 40
Study Start Date: March 2012
Estimated Study Completion Date: March 2014
Estimated Primary Completion Date: March 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Ketoconazole and HPR/LXS
400 mg of Ketoconazole once a day with 800 mg of HPR/LXS two times a day
Drug: Ketoconazole and HPR/LXS
400 mg of Ketoconazole once a day with 800 mg of HPR/LXS two times a day

Detailed Description:

Fenretinide (N-(4-hydroxyphenyl)retinamide, 4-HPR), is a cytotoxic retinoid that has activity against ovarian cancer cell lines invitro in a dose-related manner. A phase II study of 4-HPR oral capsules in recurrent, platinum-refractory ovarian cancer (NCT00026091) demonstrated a significantly better overall survival in patients obtaining 4-HPR plasma levels of > 9 mM, suggesting that obtaining high 4-HPR exposures in all such patients could yield clinical benefits. Fenretinide has proven clinical tolerability at plasma concentrations of 1 - 13 mM when given orally using a 100 mg, corn-oil containing capsule (NCI, IND #40294). However, the 4-HPR oral capsule has low bioavailability, requiring numerous capsules to be consumed daily, and produces a wide interpatient variability in steady-state plasma levels obtained.

A novel oral 4-HPR powder formulation (4-HPR/LXS oral powder, ~2.2% by weight 4-HPR) has been prepared using an organized lipid matrix technology, called Lym-X-Sorb (LXS). 4-HPR/LXS oral powder is suitable for delivery in low milk fat-containing foods and liquids. A pediatric phase I study in recurrent neuroblastoma (NCT00295919) demonstrated that 4-HPR/LXS oral powder consistently produced higher 4-HPR plasma levels on a mg-per-mg 4-HPR basis than the corn-oil capsule formulation. Increased 4-HPR exposures were associated with greater clinical activity, including complete responses (CR), than similar studies conducted using the fenretinide capsule. A recent adult phase I study of 4-HPR/LXS oral powder (NCT00589381) also suggested that 4-HPR exposures could be increased above those obtained using the capsule formulation. Additionally, murine studies have demonstrated that ketoconazole (at standard human-equivalent doses), acting as an inhibitor of 4-HPR metabolism, can further increase 4-HPR plasma, tissue and tumor xenograft levels when given concurrently with 4-HPR/LXS oral powder. Given these data, we hypothesize that concurrently administering 4-HPR/LXS oral powder + ketoconazole will reliably achieve 4-HPR plasma levels > 10 mM in recurrent ovarian cancer patients with tolerable systemic toxicity and result in beneficial anti-tumor activity.

Given the minimal systemic toxicity observed with 4-HPR and the association of improved survival with higher 4-HPR exposures in the capsule 4-HPR phase II study, we further hypothesize that 4-HPR/LXS oral powder + ketoconazole: 1) may achieve objective responses against recurrent ovarian cancer; 2) will improve progression-free and overall survival of patients by achieving 4-HPR levels > 10 mM in the majority of patients.

This trial is a single arm Phase II study of 4-HPR/LXS oral powder (given TID) + ketoconazole given daily, concurrently, x 7 days, every three weeks, to women with recurrent ovarian cancer. PRIMARY STUDY AIMS are: (1) To define the systemic toxicity profile of 4-HPR/LXS oral powder + ketoconazole given concurrently for 6 months or until disease progression; (2) Determine if 4-HPR exposures > 10 mM (steady state peak plasma) are associated with objective tumor responses. (3) Define the EFS, PFS, and/or OS for women with recurrent ovarian cancer and primary peritoneal carcinoma treated with 4-HPR/LXS oral powder + ketoconazole given concurrently. SECONDARY STUDY AIMS are: (1) To determine the pharmacokinetics of 4-HPR in women when given as 4-HPR/LXS oral powder + ketoconazole over a 6 month period or until disease progression. For the latter, levels of 4-HPR, and its metabolites, will be determined in plasma and peripheral blood mononuclear cells (PBMC) six hours after the AM dose of 4-HPR/LXS oral powder on Day 6 of the First, Third, and Sixth Courses of therapy. The study calls for 40 post-progression patients (~20/year) with primary analysis planned at two years after initiating the study.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients with histologically confirmed recurrent or metastatic epithelial ovarian cancer or primary peritoneal carcinoma defined as:
  • Biochemical recurrence: defined as a CA-125 greater than or equal to two times the upper normal limit. Patients whose CA125 is less than 100 U/mL must undergo a second confirmatory value within a period of not more than 4 weeks. Patients with a level greater than or equal to 100 U/mL may be entered without confirmatory measurement.
  • Measurable disease (RECIST): defined as at least one lesion that can be accurately measured in at least one dimension (longest dimension to be recorded). Each lesion must be more than or equal to 20 mm when measured by conventional techniques, MRI or CT, or more than or equal to 10 mm when measured by spiral CT.
  • Non-measurable disease: includes patients with symptomatic ascites or pleural effusions, lesions that do not meet RECIST criteria as defined in (2) or biopsy proven recurrence. Patients with clinically evident nonmeasurable disease must have either an elevated CA125 as defined in (1) or histological confirmation of recurrence.
  • Unidimensionally measurable disease, as defined in section 10.1.1. Indicator lesions must not have been irradiated unless they have grown following radiation therapy.
  • SWOG Performance Status 0 - 2.
  • Patients must have previously received a platinum and paclitaxel containing regimen.
  • Patients are allowed to receive ≤ 2 prior chemotherapy regimens for recurrent disease. Patients who are rechallenged with the same chemotherapy regimen are considered to have had that regimen only once.
  • Projected life expectancy must be at least 3 months.
  • Signed informed consent.
  • Absolute neutrophil count ≥ 1500/micro liter and platelet count ≥ 100,000 micro liter.
  • Bilirubin ≤ 2 times the institutional limit of normal and ALT or AST ≤3 times the upper limit of normal.
  • Measured or calculated creatinine clearance ≥60 ml/min.
  • Fasting triglycerides ≤ 5x time the upper limit of normal. Patients above this level may be eligible with permission of the Study Chair. Triglycerides may be "normalized" prior to study entry with use of an antilipemic agent (atorvastatin, fenofibrate)
  • Patients must have recovered from acute toxicities from surgery, radiation or chemotherapy. At least 3 weeks will have elapsed since any prior therapy directed at the malignant tumor.
  • Patients of childbearing potential must agree to use an approved method of birth control.

Exclusion Criteria:

  • Prior fenretinide is not allowed. Prior 13-cis, 9-cis or all-trans retinoic acid are allowed.
  • Patients with a second malignancy within the last 5 years are not allowed, except for those with non-melanomatous skin cancer and carcinoma-in-situ of the cervix. All prior invasive malignancies must be in complete remission.
  • The use of concomitant antioxidants, such as vitamin C or E, is not allowed.
  • Patients with concurrent medical, psychological or social conditions of such severity that the investigator deems it unwise to enter the patient on protocol.
  • Untreated or symptomatic brain metastases.
  • Pregnant or nursing women.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01550692

Contacts
Contact: Jayanthi Lea, MD 214-648-3026 Jayanthi.Lea@utsouthwestern.edu

Locations
United States, Texas
UTSouthwestern Medical Center Not yet recruiting
Dallas, Texas, United States, 75390
Principal Investigator: Jayanthi Lea, MD         
Sponsors and Collaborators
University of Texas Southwestern Medical Center
South Plains Oncology Consortium
Investigators
Study Chair: Jayanthi Lea, MD University of Texas Southwestern Medical Center
  More Information

No publications provided

Responsible Party: University of Texas Southwestern Medical Center
ClinicalTrials.gov Identifier: NCT01550692     History of Changes
Other Study ID Numbers: SPOC-2011-001
Study First Received: February 24, 2012
Last Updated: March 7, 2012
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Carcinoma
Ovarian Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Endocrine Gland Neoplasms
Neoplasms by Site
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Ketoconazole
Fenretinide
14-alpha Demethylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antifungal Agents
Anti-Infective Agents
Therapeutic Uses
Antineoplastic Agents
Anticarcinogenic Agents
Protective Agents
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on April 17, 2014