Clinical trial NCT00387504: Fenretinide in Treating Patients With Metastatic or Unresectable Malignant Solid Tumors
Official title: Phase I Trial of Intravenous Fenretinide (4-HPR) for Patients With Malignant Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Unspecified Adult Solid Tumor, Protocol Specific
Keywords: unspecified adult solid tumor, protocol specific
Lead sponsor: California Cancer Consortium
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
First posted: 2006-10-13
Enrollment: 21
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: RATIONALE: Drugs used in chemotherapy, such as fenretinide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing.

PURPOSE: This phase I trial is studying the side effects and best dose of fenretinide in treating patients with metastatic or unresectable malignant solid tumors.

Detailed description: OBJECTIVES:

* Determine the maximum tolerated dose of fenretinide in patients with metastatic or unresectable malignant solid tumors.
* Determine the toxic effects of this drug in these patients.
* Determine the pharmacokinetics and in vivo activity of this drug in these patients.
* Determine, preliminarily, disease or tumor response in patients treated with this drug.

OUTLINE: This is a dose-escalation, multicenter study.

Patients receive fenretinide IV continuously on days 1-5. Treatment repeats every 3 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients who achieve a complete or partial response may continue to receive fenretinide at the discretion of the study chair.

Cohorts of 3-6 patients receive escalating doses of fenretinide until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD.

Patients undergo blood sample collection to determine plasma concentrations (pharmacokinetics) of fenretinide periodically during course 1 and at the end of courses 2-6.

After completion of study treatment, patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 21 patients will be accrued for this study.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Histologically or cytologically confirmed solid tumor malignancy

  * Metastatic and/or unresectable disease
* No standard curative or palliative measures exist or remain effective
* Measurable or evaluable disease
* No known brain metastases unless previously resected or irradiated with no treatment with steroids for more than 1 month

PATIENT CHARACTERISTICS:

* ECOG performance status (PS) 0-2 or Karnofsky PS 60-100%
* Life expectancy \> 3 months
* WBC ≥ 3,000/mm³
* Absolute neutrophil count ≥ 1,500/mm³
* Platelet count ≥ 75,000/mm³
* Bilirubin \< 1.5 times upper limit of normal (ULN)
* AST and ALT ≤ 2.5 times ULN (5 times ULN for patients with known liver metastases)
* Creatinine normal OR creatinine clearance ≥ 60 mL/min
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception prior to, during, and for ≥ 6 months after completion of study treatment
* No uncontrolled diabetes mellitus at high risk for hypertriglyceridemia (i.e., fasting serum glucose concentration \> 200 mg/dL OR hemoglobin A1C \> 7.5%)
* No egg allergy
* No history of allergic reactions to compounds of similar chemical or biologic composition to fenretinide (e.g., isotretinoin, vitamin A, or tretinoin)
* No uncontrolled intercurrent illness including, but not limited to, any of the following:

  * Ongoing or active infection
  * Symptomatic congestive heart failure
  * Unstable angina pectoris
  * Cardiac arrhythmia
  * Psychiatric illness or social situation that would preclude compliance with study requirements
* No known hypertriglyceridemia requiring medication
* No identified familial hyperlipidemia disorder

PRIOR CONCURRENT THERAPY:

* Recovered from all prior therapy
* Prior treatment with oral fenretinide is allowed provided no severe toxicity occurred
* At least 2 weeks since prior major surgery
* More than 4 weeks since prior chemotherapy or radiotherapy

  * At least 6 weeks since prior nitrosoureas or mitomycin C
* No other concurrent investigational agents
* No other concurrent anticancer chemotherapy
* No other concurrent antioxidants\*
* No concurrent hormone-ablative agents, including steroids, except for adrenal replacement or anti-inflammatory indications
* No other concurrent anticancer agents or therapies
* No concurrent herbal or other alternative therapies\*
* No concurrent vitamin supplements (e.g., vitamin A, ascorbic acid, or vitamin E)\*

  * Standard-dose multivitamin allowed
* No other concurrent medications that may act as modulators of intracellular ceramide levels or ceramide cytotoxicity, sphingolipid transport, p-glycoprotein, multidrug resistance protein 1 (MRP1), or MRP1 drug/lipid transporters, including any of the following\*:

  * Cyclosporine or any of its analogues
  * Verapamil
  * Tamoxifen or its analogue
  * Ketoconazole
  * Chlorpromazine
  * Mifepristone
  * Indomethacin
  * Sulfinpyrazone NOTE: \*Patients who have discontinued these drugs for ≥ 1 week are eligible
* No concurrent medications that may cause pseudotumor cerebri, including any of the following:

  * Tetracycline
  * Nalidixic acid
  * Nitrofurantoin
  * Phenytoin
  * Sulfonamides
  * Lithium
  * Amiodarone
* No concurrent total parenteral nutrition (TPN) with intralipids
* No concurrent combination antiretroviral therapy for HIV-positive patients

Primary outcomes:
measure: Maximum tolerated dose (MTD) of fenretinide
timeFrame: at end of study
measure: Toxicity as measured by type (organ affected or laboratory determination such as absolute neutrophil count), severity (NCI CTCAE v3.0), time of onset (course number), duration, and reversibility or outcome
timeFrame: ongoing
measure: Survival and time to failure as measured by Kaplan-Meier
timeFrame: at end of study
Secondary outcomes:
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope Comprehensive Cancer Center
state: California
city: Los Angeles
country: United States
facility: Childrens Hospital Los Angeles
state: California
city: Los Angeles
country: United States
facility: USC/Norris Comprehensive Cancer Center and Hospital
state: California
city: Martinez
country: United States
facility: Contra Costa Regional Medical Center
state: California
city: Pasadena
country: United States
facility: City of Hope Medical Group
state: California
city: Sacramento
country: United States
facility: University of California Davis Cancer Center
state: California
city: Lubbock
country: United States
facility: Texas Tech University Health Sciences Center
state: Texas
Study officials:
affiliation: University of Southern California
name: Jacek Pinski, MD
role: STUDY_CHAIR
References: