Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

Fulvestrant With or Without Lapatinib and/or Aromatase Inhibitor therapy in Treating Postmenopausal Women With Metastatic Breast Cancer That Progressed After Previous Aromatase Inhibitor Therapy

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase III Treatment Active 18 and over Other, Pharmaceutical / Industry GIM-GIM8-OVER GIM8-OVER, EUDRACT-2007-006031-30, EU-20853, GSK-GIM-GIM8-OVER, ZENECA-GIM-GIM8-OVER, OVER, NCT00688194

Objectives

Primary

1. To compare the progression-free survival of postmenopausal women with progressive metastatic breast cancer treated with fulvestrant with or without lapatinib tosylate and/or aromatase inhibitor therapy.

Secondary

1. To compare time to progression in these patients.
2. To compare overall survival of these patients.
3. To compare response rates in these patients.
4. To compare clinical benefit rates in these patients.

Entry Criteria

Disease Characteristics:

• Histologically or cytologically confirmed breast cancer
  • Metastatic disease



• Confirmed disease progression after treatment with an aromatase inhibitor (AI) administered in the adjuvant or metastatic setting
  • Must have demonstrated a prior response to AI therapy (i.e., responded after > 2 years of treatment in the adjuvant setting OR complete or partial response or stable disease after ≥ 24 weeks of treatment in the metastatic setting) AND have subsequent disease progression after completion of AI therapy



• Meets 1 of the following criteria:
  • Measurable disease, defined as ≥ 1 lesion that can be accurately measured in ≥ 1 dimension (longest diameter to be recorded) as ≥ 20 mm with conventional techniques or ≥ 10 mm with spiral CT scan
  • Evaluable disease, defined as bone lesions, lytic or mixed (lytic and sclerotic), evaluable by plain x-ray, CT scan, or MRI
    • Lesions identified only by radionucleotide bone scan are not allowed



• No HER2/neu-overexpressing tumor (IHC 3+ or FISH+)



• Hormone receptor status:
  • Estrogen receptor- and/or progesterone receptor-positive primary or metastatic tumor

Prior/Concurrent Therapy:

• See Disease Characteristics
• Prior radiotherapy for the primary or metastatic tumor allowed
• More than 4 months since prior LHRH analogues
• More than 30 days (or 5 half-lives, whichever is longer) since prior investigational agents
• More than 14 days since prior and no concurrent CYP3A4 inducers*, including any of the following:
  • Rifampin, rifapentine, rifabutin, or other rifamycin class agents
  • Phenytoin, carbamazepine, or barbiturates (e.g., phenobarbital)
  • Efavirenz or nevirapine
  • Oral glucocorticoids (e.g., cortisone [> 50 mg], hydrocortisone [> 40 mg], prednisone [> 10 mg], methylprednisolone [> 8 mg], or dexamethasone [> 1.5 mg])
  • Modafinil
• More than 14 days since prior and no concurrent herbal or dietary supplements*, including any of the following:
  • St. John's wort
  • Ginkgo biloba
  • Kava
  • Grape seed
  • Valerian
  • Ginseng
  • Echinacea
  • Evening primrose oil
• More than 7 days since prior and no concurrent CYP3A4 inhibitors*, including any of the following:
  • Clarithromycin, erythromycin, or troleandomycin
  • Itraconazole, ketoconazole, fluconazole (> 150 mg daily), or voriconazole
  • Delaviridine, nelfinavir, amprenavir, ritonavir, indinavir, saquinavir, or lopinavir
  • Verapamil or diltiazem
  • Nefazodone or fluvoxamine
  • Cimetidine or aprepitant
  • Grapefruit or grapefruit juice
• More than 6 months since prior and no concurrent amiodarone*
• No prior fulvestrant and/or lapatinib tosylate
• No prior resection of the stomach or small bowel
• No other concurrent anticancer therapy, including chemotherapy, immunotherapy, and biologic therapy
  • Concurrent bisphosphonates allowed
• No other concurrent investigational therapy
• No concurrent participation in another clinical trial

 [Note: *For patients randomized to receive lapatinib]

Patient Characteristics:

• Female
• Postmenopausal, as defined by any of the following criteria:
  • At least 60 years of age
  • 45 to 59 years of age and meets ≥ 1 of the following criteria:
    • Amenorrhea for ≥ 12 months and intact uterus
    • Amenorrhea for < 12 months and follicle-stimulating hormone within the postmenopausal range (including patients with hysterectomy, prior hormone replacement therapy, or chemotherapy-induced amenorrhea)
      • Patients who received prior luteinizing hormone-releasing hormone (LHRH) analogues must not have restarted their menses after cessation of therapy
  • Over 18 years of age and bilateral oophorectomy
• WHO performance status 0-2
• Life expectancy ≥ 8 months
• Leukocytes ≥ 3,000/μL
• Absolute neutrophil count ≥ 1,500/μL
• Platelet count ≥ 100,000/μL
• Total bilirubin normal
• AST/ALT ≤ 2.5 times upper limit of normal
• Creatinine normal OR creatinine clearance ≥ 60 mL/min
• LVEF normal as measured by ECHO or MUGA
• Able to swallow and retain oral medication
• No ulcerative colitis
• No malabsorption syndrome or disease significantly affecting gastrointestinal function
• No known history of uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure
• No known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to fulvestrant, aromatase inhibitors, lapatinib tosylate, or excipients
• No unresolved or unstable serious toxicity from prior therapy
• No active or uncontrolled infection
• No dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent
• No other malignancy within the past 5 years except for adequately treated cervical carcinoma in situ, melanoma in situ, or basal cell or squamous cell carcinoma of the skin
• No other concurrent disease or condition that would make the patient inappropriate for study participation
• No serious medical disorder that would interfere with patient safety

Expected Enrollment

Outcomes

Progression-free survival

Time to progression
Overall survival
Response rate
Clinical benefit rate

Outline

This is a multicenter study. Patients are stratified according to timing of progressive disease (during adjuvant therapy vs > 12 months after completion of adjuvant therapy vs during treatment for metastatic disease). Patients are randomized to 1 of 4 treatment arms.

• Arm I: Patients receive fulvestrant intramuscularly (IM) on days 0, 14, and 28 of course 1 and on day 1 of all subsequent courses. Patients also receive oral placebo once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.



• Arm II: Patients receive fulvestrant and placebo as in arm I. Patients also receive aromatase inhibitor (AI) therapy (e.g., exemestane, anastrozole, or letrozole) according to standard treatment regulations.



• Arm III: Patients receive fulvestrant as in arm I and oral lapatinib tosylate once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.



• Arm IV: Patients receive fulvestrant as in arm I and lapatinib as in arm III. Patients also receive AI therapy according to standard treatment regulations.

Trial Contact Information

Trial Lead Organizations

Gruppo Italiano Mammella

Sabino De Placido, MD, Principal investigator		Ph: 39-081-746-2062-746 Email: deplacid@unina.it

Italy
	Naples
	Federico II University Medical School
		Contact Person	Ph:  39-081-746-3660

Registry Information
Official Title		Overcoming Endocrine Resistance in Metastatic Breast Cancer: A Randomized Trial with factorial Design comparing Fulvestrant ± Lapatinib ± Aromatase Inhibitor in metastatic breast cancer progressing after Aromatase Inhibitor therapy
Trial Start Date		2008-05-05
Trial Completion Date		2013-05-05 (estimated)
Registered in ClinicalTrials.gov		NCT00688194
Date Submitted to PDQ		2008-05-16
Information Last Verified		2008-05-29