Oral CDB-4124 vs. Placebo in Stage I-II Primary Breast Cancer

Presurgical Phase IIB Trial of Oral CDB-4124 vs. Placebo in Women With Stage I-II Primary Breast Cancer

The purpose of this study is to determine whether or not the medication that blocks the effects of the hormone progesterone (CDB-4124 or Proellex) will decrease the growth rate of breast cancer cells as compared to a placebo. CDB-4124 (also called Proellex) is a medication that works against the hormone, progesterone. The researchers in this study would like to compare changes in breast cancer cells of women who have taken CDB-4124 prior to surgery to those from women who have taken a placebo pill prior to surgery.

PRIMARY OBJECTIVES:

I. To test the hypothesis that treatment with the selective progesterone receptor modulator (SPRM) CDB-4124 (telapristone acetate) will have an anti-tumor effect in women with early-stage breast cancer, defined as a significant decrease in tumor proliferation (Ki67 labeling index).

SECONDARY OBJECTIVES:

I. Measure changes in apoptosis using IHC (cleaved caspase 3 or TUNEL). II. Measure changes in blood estradiol and progesterone levels. III. Compare the breast tissue concentrations of CDB-4124 and its metabolite (CDB4453) to plasma concentrations at the end of therapy.

IV. Assess adverse events.

TERTIARY OBJECTIVES:

I. Measure protein expression of related targets (including estrogen receptor alpha (ERA), estrogen receptor beta (ERB), progesterone receptor isoforms progesterone receptor alpha [PRA], progesterone receptor beta [PRB], tumor necrosis factor receptor superfamily, member 11a, NFKB activator [RANK], tumor necrosis factor (ligand) superfamily, member 11 [RANKL], and either cyclin-dependent kinase 2 [cdk2] or cyclin-dependent kinase 4 [cdk4],) using IHC at baseline and after treatment.

II. Perform ribonucleic acid (RNA) microarray analysis comparing tumors and normal tissue from the intervention and control groups.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive telapristone acetate orally (PO) once daily (QD) for 2-10 weeks and then undergo surgical resection.

ARM II: Patients receive placebo orally once daily for 2-10 weeks and then undergo surgical resection.

After completion of study treatment, patients are followed up for 1 month.

Inclusion Criteria:

• Subjects must be females with a histological diagnosis of invasive breast cancer clinical stage T1-2, N01 and be candidates for primary resection of this cancer; note: subjects with bilateral cancer are eligible

  • Primary tumor stage T1-2 at the time of initial diagnosis and ipsilateral nodes must be N0-1 by clinical evaluation. Staging is routinely based on the NCCN Clinical Practice Guidelines and TNM Nomenclature for Breast Cancer from AJCC Cancer Staging Manual. All breast cancer patients routinely undergo axillary ultrasound to evaluate nodal involvement.

• Subjects must have greater than 0.5 cm of IBC on core (5 cores).

• Subjects must be age > or = 18 years.

• Subjects must exhibit an ECOG performance status of 0 or 1.

• Subjects must be able and willing to schedule surgical resection of their tumor 2 or more weeks following the start of the study agent.

• Subjects must have adequate hepatic and renal function, within 6 weeks prior to registration. The liver function tests include total bilirubin (<1.5xULN; Gilbert"s allowed 3x ULN), ALT/ AST (<2.5xULN) and alkaline phosphatase(<2.5xULN); the standard renal function tests include blood urea nitrogen (BUN), and creatinine and must be < 2XULN.

• Subjects of child-bearing potential must agree to use adequate contraception (barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 90 days following completion of therapy.

  • A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:

    • Has not undergone a hysterectomy or bilateral oophorectomy; OR
    • Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months).

  • Subjects of child bearing potential must have a negative urine pregnancy test within 5 days prior to first dose of the study drug.

• Subjects must have the ability to understand and the willingness to sign a written informed consent. Informed consent must be obtained prior to registration on the study

Exclusion Criteria

• Subjects must not have a breast cancer diagnosis of ductal carcinoma in situ only (DCIS)
• Subjects must not have received any other breast cancer-specific therapy prior to registration
• Subjects must not have received any oral contraceptive or postmenopausal hormones within one month prior to their diagnostic biopsy AND must agree not to use exogenous sex hormones while on the study
• Subjects must not have a history of any significant renal or hepatic disease requiring ongoing medical therapy or clinical intervention
• Subjects must not have a history of thromboembolic disorder or cerebral vascular disease
• Subjects must not have a body mass index (BMI) > 39
• Subjects must not be pregnant or nursing
• Subjects must not be receiving any other investigational agents
• Subjects must not have allergies to any compounds similar to CDB-4124
• While participating, subjects must agree not to use soy supplements, over the counter estrogen supplements like Estroven, Chinese herbs, or other over-the-counter (OTC) herbal products