Cisplatin, Paclitaxel, and Everolimus in Treating Patients With Metastatic Breast Cancer

A Phase I Study of Cisplatin, Paclitaxel, and RAD001 Patients With Metastatic Breast Cancer

RATIONALE: Drugs used in chemotherapy, such as cisplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving more than one drug (combination chemotherapy) together with everolimus may kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of cisplatin, paclitaxel, and everolimus when given together for the treatment of patients with metastatic breast cancer.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: cisplatin; Drug: everolimus; Drug: paclitaxel

Detailed Description

OBJECTIVES:

Primary

• To establish the safety profile and the maximum tolerated dose of the combination of cisplatin, paclitaxel, and everolimus in patients with metastatic breast cancer.

Secondary

• To explore the antitumor activity of this regimen, in terms of response rate and time to progression in these patients.

OUTLINE: This is a multicenter study.

Patients receive cisplatin intravenously (IV) over 1 hour and paclitaxel IV over 1 hour on days 1, 8, and 15. Patients receive oral everolimus on days 1, 8, 15, and 21. Courses repeat every 4 weeks in the absence of disease progression and unaccepted toxicity.

After completion of study therapy, patients are followed at 4 weeks.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37232-6838
      • Vanderbilt-Ingram Cancer Center
    • Nashville, Tennessee, United States, 37064
      • Vanderbilt-Ingram Cancer Center - Cool Springs
    • Nashville, Tennessee, United States, 37064
      • Vanderbilt-Ingram Cancer Center at Franklin
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Cancer Center at Centennial Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

DISEASE CHARACTERISTICS:

• Histologically confirmed invasive mammary carcinoma

  • Stage IV disease
• No locally recurrent breast cancer
• Patients with HER2/neu overexpressing tumors must have received prior trastuzumab (Herceptin®) in first-line treatment of metastatic breast cancer
• Patients with estrogen receptor- or progesterone receptor-expressing tumors must have received prior endocrine therapy (i.e., aromatase inhibitors, fulvestrant, tamoxifen, or ovarian ablation) in first-line treatment of metastatic breast cancer

• No symptomatic brain metastases

  • Patients with a history of brain metastases must be clinically stable and not taking steroids or therapeutic anticonvulsants that are CYP3A4 modifiers
  • Patients with asymptomatic brain metastases on prophylactic convulsants that are CYP3A4 modifiers are not eligible
• Hormone receptor status not specified

PATIENT CHARACTERISTICS:

• Menopausal status not specified
• ECOG performance status 0-1
• Life expectancy ≥ 6 months
• ANC ≥ 1000/mm^3
• Platelet count ≥ 100,000/mm^3
• Creatinine ≤ 1.5 times upper limit of normal (ULN)
• Bilirubin ≤ 1.5 times ULN (3 times ULN if liver metastasis present)
• SGOT and SGPT ≤ 1.5 times ULN (3 times ULN if liver metastasis present)
• Alkaline phosphatase ≤ 3 times ULN if liver metastasis present
• Able to swallow and retain oral medication
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 3 months after completion of study treatment
• Must be disease-free from prior invasive cancers for > 5 years with the exception of completely resected basal cell or squamous cell carcinoma of the skin or successfully treated cervical carcinoma in situ
• No malabsorption syndrome, disease significantly affecting gastrointestinal function, or ulcerative colitis

• No uncontrolled intercurrent illness including, but not limited to:

  • Ongoing or active infection requiring parenteral antibiotics
  • Impairment of lung function (i.e., chronic obstructive pulmonary disease or lung conditions requiring oxygen therapy)
  • Symptomatic New York Heart Association class III-IV congestive heart failure
  • Unstable angina pectoris, angioplasty, stenting, or myocardial infarction within the past 6 months
  • Uncontrolled hypertension (systolic blood pressure [BP] > 180 mm Hg or diastolic BP > 100 mm Hg)
  • Clinically significant cardiac arrhythmia (i.e., multifocal premature ventricular contractions, bigeminy, trigeminy, or ventricular tachycardia that is symptomatic or requires treatment)
  • Uncontrolled diabetes
  • Psychiatric illness/social situations that would preclude compliance with study requirements
• No known history of uncontrolled or symptomatic neuropathy ≥ grade 2
• No hypersensitivity to paclitaxel, or drugs using the vehicle Cremophor, Chinese hamster ovary cell products, or other recombinant human antibodies

Exclusion Criteria:

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• Recovered from all prior treatment
• Must not have exceeded a total cumulative dose of life-time exposure of doxorubicin hydrochloride ≤ 360 mg/m² or epirubicin hydrochloride ≤ 640 mg/m²
• At least 2 weeks since other prior investigational drugs
• No prior resection of the stomach or small bowel

• No more than 4 prior chemotherapy regimens in the metastatic setting

  • This restriction does not include endocrine therapies or single agent biologic therapies (i.e., trastuzumab)
• Concurrent radiotherapy to painful bone metastases or areas of impending bone fracture allowed as long as radiotherapy is initiated prior to study entry
• No concurrent trastuzumab
• No concurrent endocrine therapy
• No concurrent CYP3A4 modifiers
• No concurrent herbal supplement
• No other concurrent anticancer therapy (chemotherapy, radiotherapy, surgery, immunotherapy, hormonal therapy, or biological therapy)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Therapeutic Intervention

Drug: cisplatin; Dose Level: -3 20mg/m2/week 3-6 patients; Dose Level: -2 20mg/m2/week 3-6 patients; Dose Level: -1 25mg/m2/week 3-6 patients; Dose Level: 1 25mg/m2/week 3-6 patients; Dose Level: 2 25mg/m2/week 3-6 patients; Dose Level: 3 25mg/m2/week 3-6 patients; Other Names: Platinol; Drug: everolimus; Dose Level: -3 20mg/m2/week 3-6 patients; Dose Level: -2 20mg/m2/week 3-6 patients; Dose Level: -1 20mg/m2/week 3-6 patients; Dose Level: 1 20mg/m2/week 3-6 patients; Dose Level: 2 25mg/m2/week 3-6 patients; Dose Level: 3 30mg/m2/week 3-6 patients; Other Names: RAD001; Drug: paclitaxel; Dose Level: -3 65mg/m2/week 3-6 patients; Dose Level: -2 70mg/m2/week 3-6 patients; Dose Level: -1 70mg/m2/week 3-6 patients; Dose Level: 1 80mg/m2/week 3-6 patients; Dose Level: 2 80mg/m2/week 3-6 patients; Dose Level: 3 80mg/m2/week 3-6 patients; Other Names: Taxol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety profile and maximum tolerated dose	The Maximum Tolerated Dose (MTD) will be the dose level at which fewer than 2 of 6 (or 33% of) patients experience dose limiting toxicity (DLT).	At 4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Antitumor activity	Cisplatin + Paclitaxel + RAD001 combination by determining response rates (RR) and time to progression (TTP) achieved with treatment	Date of study entry to date of progression of disease
Response rate		at baseline and every 8 weeks to disease progression
Time to progression		date of study entry to date of disease progression

Collaborators and Investigators

• Sponsor: Vanderbilt-Ingram Cancer Center
• Collaborators: National Cancer Institute (NCI)

Study record dates

Study Major Dates

• Study Start: May 1, 2008
• Primary Completion (Actual): August 1, 2009
• Study Completion (Actual): December 1, 2010

Study Registration Dates

• First Submitted: May 18, 2008
• First Submitted That Met QC Criteria: May 18, 2008
• First Posted (Estimate): May 20, 2008

Study Record Updates

• Last Update Posted (Estimate): March 8, 2013
• Last Update Submitted That Met QC Criteria: March 7, 2013
• Last Verified: March 1, 2013

More Information

Terms related to this study

• Keywords: stage IV breast cancer; male breast cancer
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Paclitaxel; Everolimus
• Other Study ID Numbers: VICC BRE 0770; VU-VICC-BRE-0770