Clinical trial NCT01023477: Study of the Efficacy of Chloroquine in the Treatment of Ductal Carcinoma in Situ (The PINC Trial)
Official title: Preventing Invasive Breast Neoplasia With Chloroquine (PINC) Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Carcinoma, Intraductal, Noninfiltrating
DCIS
Ductal Carcinoma In Situ
Keywords: Carcinoma, Intraductal, Noninfiltrating
Ductal Carcinoma In Situ
DCIS
Carcinoma, Intraductal
Breast Cancer
Breast Tumors
chloroquine
autophagy
Autophagic Cell Death
Autophagocytosis
Programmed Cell Death, Type II
Autophagy, Cellular
Autophagic Programmed Cell Death
Lead sponsor: Inova Health Care Services
Sponsor class: OTHER
Collaborators: name: George Mason University
name: University of Pittsburgh Medical Center
name: United States Department of Defense
name: U.S. Army Medical Research and Development Command
First posted: 2009-12-02
Enrollment: 12
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to test the hypothesis that chloroquine will reduce the ability of ductal carcinoma in situ (DCIS) to survive and spread. Participants will receive either chloroquine standard dose (500mg/week) or chloroquine low dose (250mg/week) for 1 month prior to surgical removal of the tumor.

Detailed description: The purpose of this study is to test the hypothesis that inhibiting the autophagy pathway in DCIS will reduce the capacity of DCIS to survive and invade. The study will examine the safety and effectiveness of neoadjuvant chloroquine administration for a one month period to patients with low, intermediate grade, or high grade DCIS. We will evaluate whether this treatment will reduce the capacity of DCIS neoplastic cells, existing within the duct, to survive, induce lesion regression, and kill the invasive DCIS progenitor cells.

Eligibility criteria: Inclusion Criteria:

* Patients must have a tissue diagnosis of low, intermediate or high grade ductal carcinoma in situ or ductal carcinoma in situ with microinvasion.
* Patients with ductal carcinoma in situ undergoing either lumpectomy/radiation or mastectomy.
* Patients must be female at least 18 years of age.
* Patients must have a signed tissue acquisition consent and have at minimum, adequate samples of primary fresh tissue or blood available for use in this study.
* No history of a previous invasive cancer in the last five years with the exception of minimally invasive non-melanoma skin cancer.
* Normal liver function based on Liver Function Tests (Total Bilirubin and Asparate transaminase (AST) \<1.5 X Upper Limit of Normal).
* Normal White Blood Count (WBC) (3.5-10.8 x 103µL), Platelet count (PLT) (140-400 x 103µL), and Hematocrit (HCT)(37-52%)
* Potassium within the normal range of 3.5-5.3 mEq/L
* Adequate renal sufficiency (serum creatinine \<1.5 mg/dL).
* Eastern Cooperative Oncology Group performance status 0-2.
* Are able to swallow and retain oral medication.
* No underlying ocular/retinal pathology.
* No medically documented preexisting auditory damage.
* Subjects should be willing to abstain from use of hormonal therapies (e.g. hormone replacement therapy, oral contraceptive pills, hormone-containing Intra Uterine Device (IUD)s, and E-string) and chronic non-steroidal anti-inflammatory (NSAID) s for the duration of the study (chronic use of NSAID's is defined as a frequency \>3 times/week for more than two weeks per year and includes low dose aspirin).
* Subjects with child-bearing potential must agree to use adequate contraception (total abstinence (no sexual intercourse), use of condom with spermicide or sterilization surgery, including tubal ligation (tubes tied) or hysterectomy (removal of the uterus or womb)) prior to study entry and for the duration of study treatment phase. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately.

If a subject is of child-bearing potential (women are considered not of child-bearing potential if they are at least one year postmenopausal and/or surgically sterile), she must have a documented negative serum or urine pregnancy test before starting treatment.

Exclusion Criteria:

* Patients with a prior history of chemotherapy, hormonal ablation therapy and/or radiation therapy.
* History of other invasive cancer in the previous 5 years other than minimally invasive non-melanoma skin cancer.
* Patient desires not to participate in the study.
* Inability to consent.
* Current or recent pregnancy (within 12 months),
* Current use of hormone-containing forms of birth control such as implants (i.e. Norplants, or injectables ( i.e. depo-provera)
* Currently lactating.
* Patients with history of renal or hepatic insufficiency.
* Current diagnosis for depression, including treatment with an Selective Serotonin Reuptake Inhibitor (SSRI).
* History of prior treatment with chloroquine for malaria within past 24 months.
* History of allergic reactions to quinolones or chloroquine.
* Active diagnosis of psoriasis or currently receiving treatment for psoriasis.
* History of porphyria.
* History of known Glucose-6-Phosphate Dehydrogenase (G-6-PD) deficiency.
* Alcoholism or hepatic disease.
* History of epilepsy or seizures in the past 20 years.
* History of deep vein thrombosis or pulmonary embolism.
* History of human immunodeficiency virus (HIV) disease and/or treatment with anti-HIV agents.
* Receiving concurrent treatment with prohibited medications (refer to Table 1 for details on prohibited medications); Examples include: ampicillin, antacids, cimetidine, cyclosporine, kaolin, magnesium trisilicate, coumarin-type anticoagulants, macrolide antibiotics (e.g., clarithromycin, isoniazid, and erythromycin), anti-HIV agents (e.g., ritonavir and delavirdine), antidepressants (e.g. fluoxetine and fluvoxamine), calcium channel blockers (e.g. verapamil and diltiazem), steroids and their modulators (e.g., gestodene, raloxifene, and mifepristone), and several herbal and dietary components (e.g. bergamottin and glabridin).
* Used an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of study medication.

Primary outcomes:
measure: Average Change in the Longest Diameter of the Breast MRI Target Lesion
timeFrame: Immediately preceding study drug treatment and again after treatment prior to surgery. The total time interval was up to 8 weeks
Secondary outcomes:
measure: Total Number of Treatment-Related Adverse Events
timeFrame: The patients were monitored from the time of diagnosis through 6 months of surgical follow up.
measure: Effect of Chloroquine on Proliferating Cell Nuclear Antigen (PCNA) Proliferation Index
timeFrame: At the time of breast biopsy and again at time of surgery.
measure: Impact of Chloroquine Treatment on the Cell Signaling Kinase Levels in DCIS Lesions.
timeFrame: At the time of surgery
Other outcomes:
Locations:
city: Fairfax
country: United States
facility: Medical Oncology and Hematology Associates of Northern Virginia
state: Virginia
city: Fairfax
country: United States
facility: Virginia Cancer Specialists, PC
state: Virginia
city: Fairfax
country: United States
facility: Virginia Surgery Associates
state: Virginia
city: Falls Church
country: United States
facility: Inova Fairfax Hospital
state: Virginia
Study officials:
affiliation: Inova Fairfax Hospital Cancer Center
name: Kirsten H Edmiston, MD, FACS
role: PRINCIPAL_INVESTIGATOR
affiliation: Magee-Women's Hospital of UPMC
name: Priscilla McAuliffe, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Martinez-Outschoorn UE, Pavlides S, Whitaker-Menezes D, Daumer KM, Milliman JN, Chiavarina B, Migneco G, Witkiewicz AK, Martinez-Cantarin MP, Flomenberg N, Howell A, Pestell RG, Lisanti MP, Sotgia F. Tumor cells induce the cancer associated fibroblast phenotype via caveolin-1 degradation: implications for breast cancer and DCIS therapy with autophagy inhibitors. Cell Cycle. 2010 Jun 15;9(12):2423-33. doi: 10.4161/cc.9.12.12048. Epub 2010 Jun 15.