Phase 2b Study of Taxol Plus Sorafenib or Placebo in Patients With Advanced Breast Cancer

A Double-Blind, Randomized Phase 2b Study Evaluating the Efficacy and Safety of Sorafenib Compared to Placebo When Administered in Combination With Paclitaxel in Patients With Locally Recurrent or Metastatic Breast Cancer

RATIONALE: Drugs used in chemotherapy, such as paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Giving paclitaxel together with sorafenib may kill more tumor cells.

PURPOSE: This randomized phase II trial is studying how well paclitaxel works when given together with or without sorafenib in treating patients with locally recurrent or metastatic breast cancer.

Study Overview

• Status: Unknown
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: paclitaxel; Drug: sorafenib tosylate; Other: placebo

Detailed Description

OBJECTIVES:

Primary

• Compare progression-free survival of patients with locally recurrent or metastatic breast cancer treated with sorafenib tosylate and paclitaxel versus placebo and paclitaxel as first-line therapy.

Secondary

• Compare the objective response rate and duration of response in patients treated with these regimens.
• Compare the time to progression in patients treated with these regimens.
• Compare the survival of patients treated with these regimens.
• Compare the safety of patients treated with these regimens.
• Compare the change from baseline in the Functional Assessment of Cancer Therapy for Breast Cancer quality of life assessment score in patients treated with these regimens.

OUTLINE: This is a double-blind, randomized, multicenter study. Patients are stratified according to site of metastatic disease (visceral [i.e., soft internal organs of the body, including lungs, heart, and the organs of the digestive, excretory, and reproductive systems] vs nonvisceral [i.e., osseous or soft tissue] sites). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive paclitaxel IV over 1 hour once weekly for 3 weeks. Patients also receive oral sorafenib tosylate twice daily on days 1-28.
• Arm II: Patients receive paclitaxel as in arm I and oral placebo twice daily on days 1-28.

In both arms, treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed at baseline, and every 8 weeks for 24 weeks, and then every 12 weeks for the duration of study participation.

After completion of study therapy, patients are followed every 4 months.

• Study Type: Interventional
• Enrollment (Anticipated): 180
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Muscle Shoals, Alabama, United States, 35661
      • Northwest Alabama Cancer Center, PC - Muscle Shoals
  • Arkansas
    • Fayetteville, Arkansas, United States, 72703
      • Highlands Oncology Group - Fayetteville
  • California
    • Anaheim, California, United States, 92801
      • Pacific Cancer Medical Center, Incorporated
    • Fountain Valley, California, United States, 92708
      • Pacific Coast Hematology/Oncology Medical Group, Incorporated
    • Rancho Mirage, California, United States, 92270
      • Desert Hematology-Oncology Medical Group, Incorporated
    • Sacramento, California, United States, 95816
      • Sutter Cancer center
    • Saint Helena, California, United States, 94574
    • Soquel, California, United States, 95073
      • Cancer Prevention and Treatment Center at Dominican and Watsonville Community Hospital
  • Connecticut
    • Hartford, Connecticut, United States, 06102-5037
      • Helen and Harry Gray Cancer Center at Hartford Hospital
    • Norwich, Connecticut, United States, 06360
      • Eastern Connecticut Hematology and Oncology Associates
    • Waterbury, Connecticut, United States, 06708
      • Medical Oncology and Hematology, PC at Harold Leever Cancer Center
  • District of Columbia
    • Washington, District of Columbia, United States, 20037
      • George Washington University Cancer Institute
  • Florida
    • Brooksville, Florida, United States, 34613
      • Pasco Hernando Oncology Associates, PA - Brooksville
    • New Port Richey, Florida, United States, 34652
      • Pasco Hernando Oncology Associates, PA - New Port Richey
  • Georgia
    • Athens, Georgia, United States, 30607
      • Northeast Georgia Cancer Care, LLC - Medical Oncology
  • Idaho
    • Boise, Idaho, United States, 83712
      • Mountain States Tumor Institute at St. Luke's Regional Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60611-3013
      • Robert H. Lurie Comprehensive Cancer Center at Northwestern University
    • Chicago, Illinois, United States, 60611-2998
      • Hematology-Oncology Associates of Illinois
    • Decatur, Illinois, United States, 62526
      • Decatur Memorial Hospital Cancer Care Institute
    • Elk Grove Village, Illinois, United States, 60007-3397
      • Cancer Institute at Alexian Brothers
    • Galesburg, Illinois, United States, 61401
      • Medical And Surgical Specialists, Llc
    • Hinsdale, Illinois, United States, 60521
      • Hinsdale Hematology Oncology Associates
    • Joliet, Illinois, United States, 60432
      • Midwest Center for Hematology/Oncology
    • Oak Park, Illinois, United States, 60302
      • Kellogg Cancer Care Center
    • Skokie, Illinois, United States, 60076
      • Hematology/Oncology of the North Shore at Gross Point Medical Center
  • Indiana
    • Fort Wayne, Indiana, United States, 46885-5099
      • Fort Wayne Medical Oncology and Hematology
    • Vincennes, Indiana, United States, 47591
      • Family Medicine of Vincennes Clinical Trial Center
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Kentuckiana Cancer Institute, PLLC
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70809-3482
      • Mary Bird Perkins Cancer Center - Baton Rouge
  • Missouri
    • Columbia, Missouri, United States, 65201
      • Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center
  • Nebraska
    • Lincoln, Nebraska, United States, 68510-2482
      • Nebraska Hematology-Oncology, PC
  • New Jersey
    • Belleville, New Jersey, United States, 07109
      • Essex Oncology of North Jersey
    • Sparta, New Jersey, United States, 07871
      • Sussex County Medical Associates - Sparta
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27103
      • Piedmont Hematology-Oncology Associates
  • Ohio
    • Canton, Ohio, United States, 44718
      • Tri-County Hematology/Oncology Associates, Incorporated
    • Columbus, Ohio, United States, 43235
      • Hematology Oncology Consultants, Incorporated
    • Sandusky, Ohio, United States, 44870
      • North Coast Cancer Care, Incorporated
  • Rhode Island
    • Cranston, Rhode Island, United States, 02920
      • Hematology and Oncology Associates of Rhode Island
  • Tennessee
    • Memphis, Tennessee, United States, 38120
      • West Clinic - East Memphis
  • Texas
    • Carrollton, Texas, United States, 75010-4602
      • Patients' Comprehensive Cancer Center - Carrollton
    • Houston, Texas, United States, 77024
      • Oncology Consultants - Memorial City
  • Washington
    • Kirkland, Washington, United States, 98034-3013
      • Cascade Cancer Center at Evergreen Hospital Medical Center
  • Wisconsin
    • La Crosse, Wisconsin, United States, 54601
      • Gundersen Lutheran Center for Cancer and Blood

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed adenocarcinoma of the breast

  • Locally recurrent or metastatic disease

    • Locally recurrent disease not amenable to resection with curative intent
• Measurable or evaluable disease

• No HER-2 overexpression (defined as positive for gene amplification by FISH or 3+ overexpression by IHC)

  • No unknown HER-2 status

• No active brain metastases

  • Patients with neurological symptoms and known brain metastases treated with definitive therapy must undergo contrast CT scan or brain MRI to exclude active brain metastasis

    • Previously treated brain metastases allowed provided at least 3 months since prior definitive therapy (including steroids) AND no evidence of disease
• Hormone receptor status not specified

PATIENT CHARACTERISTICS:

• Male or female
• Menopausal status not specified
• ECOG performance status 0-1
• Not pregnant or nursing for ≥ 2 weeks after completion of study therapy
• Negative pregnancy test
• Fertile patients must use effective contraception during and for ≥ 2 weeks after completion of study therapy
• Hemoglobin ≥ 9.0 g/dL
• ANC ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Total bilirubin ≤ 1.5 times the upper limit of normal (ULN)
• ALT and AST ≤ 2.5 times ULN (≤ 5 times ULN for patients with liver involvement)

• INR ≤ 1.5 and aPTT within normal limits

  • Anticoagulation therapy (e.g., warfarin or heparin) allowed

    • Stable INR required for patients on warfarin
• Creatinine ≤ 1.5 times the ULN
• Able to swallow and retain oral medication
• More than 4 weeks since prior significant traumatic injury
• No evidence or history of bleeding diathesis or coagulopathy
• No serious nonhealing wound, ulcer, or bone fracture
• No substance abuse or medical, psychological, or social condition that would interfere with study participation or evaluation of study results
• No pre-existing peripheral neuropathy ≥ grade 2

• No clinically significant cardiac disease, including any of the following:

  • New York Heart Association class II-IV congestive heart failure
  • Unstable angina (i.e., angina symptoms at rest) or new-onset angina within the past 3 months
  • Myocardial infarction within the past 6 months
• No cardiac ventricular arrhythmias requiring anti-arrhythmic therapy
• No uncontrolled hypertension (i.e., systolic blood pressure [BP] > 150 mm Hg or diastolic BP > 90 mm Hg despite optimal medical management)
• No thrombolic, embolic, venous, or arterial events such as a cerebrovascular accident, including transient ischemic attacks within the past 6 months
• No pulmonary hemorrhage or bleeding event > grade 2 within the past 4 weeks
• No other hemorrhage or bleeding event ≥ grade 3 within the past 4 weeks
• No active clinically serious infection > grade 2
• No known HIV infection or chronic hepatitis B or C
• No other prior or concurrent cancer except carcinoma in situ of the cervix, treated basal cell skin cancer, superficial bladder tumors (e.g., Ta and Tis), or any cancer curatively treated for > 5 years
• No known or suspected allergy to sorafenib tosylate or hypersensitivity to paclitaxel or drugs using the vehicle Cremophor

PRIOR CONCURRENT THERAPY:

• More than 12 months since prior adjuvant or neoadjuvant taxane therapy
• At least 3 weeks since other prior adjuvant chemotherapy
• At least 3 weeks since prior hormonal therapy for locally recurrent or metastatic disease
• No prior chemotherapy for locally recurrent or metastatic breast cancer
• More than 4 weeks since prior major surgery or open biopsy

• At least 3 weeks since prior radiotherapy

  • Previously irradiated area must not be the only site of disease

• More than 30 days or 5 half-lives, whichever is longer, since prior investigational drug

  • No prior or concurrent bevacizumab or any other licensed or investigational drugs that target VEGF or VEGF-receptor
• More than 3 weeks since prior and no concurrent Hypericum perforatum (St. John's wort ) or rifampin (rifampicin)
• No concurrent cytochrome P450 enzyme-inducing antiepileptic drugs (e.g., phenytoin, carbamazepine, or phenobarbital)
• No concurrent irinotecan hydrochloride or doxorubicin hydrochloride
• No other concurrent anticancer therapy (i.e., chemotherapy, radiotherapy, surgery, immunotherapy, biologic therapy, or tumor embolization)
• No concurrent nonconventional therapies (e.g., herbal)
• No concurrent palliative radiotherapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I; Patients receive paclitaxel IV over 1 hour once weekly for 3 weeks. Patients also receive oral sorafenib tosylate twice daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.	Drug: paclitaxel; given IV; Drug: sorafenib tosylate; given orallly
Active Comparator: Arm II; Patients receive paclitaxel as in arm I and oral placebo twice daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.	Drug: paclitaxel; given IV; Other: placebo; given orally

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Progression-free survival	At disease progression or death

Secondary Outcome Measures

Outcome Measure	Time Frame
Overall survival	At time of death
Time to progression	At time of disease progression
Overall response rate	At the time of progression of disease
Duration of overall response	At time of disease progression
Treatment-emergent adverse events as assessed by NCI CTCAE v3.0	During treatment and up to 30 days post-treatment

Collaborators and Investigators

• Sponsor: Northwestern University
• Collaborators: Amgen

Study record dates

Study Major Dates

• Study Start: June 1, 2007
• Primary Completion (Anticipated): December 1, 2020
• Study Completion (Anticipated): December 1, 2022

Study Registration Dates

• First Submitted: July 10, 2007
• First Submitted That Met QC Criteria: July 10, 2007
• First Posted (Estimate): July 11, 2007

Study Record Updates

• Last Update Posted (Actual): May 3, 2019
• Last Update Submitted That Met QC Criteria: May 1, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: stage IV breast cancer; stage IIIA breast cancer; recurrent breast cancer; stage IIIB breast cancer; male breast cancer; stage IIIC breast cancer
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Protein Kinase Inhibitors; Paclitaxel; Sorafenib
• Other Study ID Numbers: NU 07B1 (Other Identifier: Northwestern University); STU00000776 (Other Identifier: Northwestern University IRB)