ZD6474 (Zactima) and Metronomic Chemotherapy in Advanced Breast Cancer

A Phase I Study of ZD6474 (Zactima) and Metronomic Chemotherapy in Advanced Breast Cancer

The purpose of this research study is to determine the safety and tolerability of the combination of Zactima with metronomic chemotherapy. Zactima is an oral anti-angiogenesis drug, which means it fights cancer by cutting off a tumor's blood supply. Thus, the drug starves the tumor by preventing the delivery of nutrients and oxygen. Metronomic chemotherapy is low dose oral chemotherapy pills which are taken daily. Unlike traditional chemotherapy, metronomic chemotherapy is thought to fight cancer like Zactima, by cutting off the blood supply to tumors. Because the dose is very low, the side effects are generally mild and very different from those with higher dose chemotherapy given by vein.

Study Overview

• Status: Completed
• Conditions: Metastatic Breast Cancer
• Intervention / Treatment: Drug: Vandetanib; Drug: Cyclophosphamide; Drug: Methotrexate

Detailed Description

• Each study cycle is 28 days long. Participants will take the study drug, Zactima, by mouth once a day. The dose of Zactima the participant will receive will be determined by the time when they enroll on the study. They will also take the metronomic chemotherapy by mouth. This consists of two drugs: cyclophosphamide and methotrexate. Cyclophosphamide is taken every day and methotrexate is taken on days 1 and 2 of each week.
• A physical exam will be performed on Day 1 of each cycle. Vital signs, including height, weight, blood pressure, and temperature will be done on Day 1 of each cycle, as well as at week 3 of Cycles 1 and 2.
• Electrocardiograms will be performed at various points to assess heart function. This will be done at week 1, 3, 5, 7, and 9, and then every 3 months for the rest of the study.
• Routine blood tests will be done on Day 1 of each cycle, as well as at week 3 for the first two cycles. Urine tests will be done on Day 1 of each cycle.
• An ultrasound will be done at Brigham and Women's Hospital in the Department of Vascular Medicine at week 3 and week 7.
• Participants will have scans done to assess their tumor every 2 cycles (8 weeks). These may include a CT scan, MRI, PET scan, x-rays, and/or bone scans.

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber Cancer Institute
    • Boston, Massachusetts, United States, 02215
      • Massachusetts General Hospital

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:

• Patients must have histologically or cytologically confirmed Stage IV breast cancer
• Patients may have prior treatment with 0-4 prior chemotherapeutic regimens for metastatic disease.
• 18 years of age and older
• Life expectancy of greater than 3 months as assessed by patient's primary oncologist
• ECOG Performance Status of 0-2.
• LVEF > 45%, as assessed by echocardiogram or nuclear medicine gate study within 30 days prior to initiating protocol-based treatment
• Negative Serum pregnancy test
• No receipt of any investigational agents within 30 days prior to commencing study treatment

Exclusion Criteria:

• Abnormal laboratory results as outlined in the protocol
• Therapeutic anti-coagulation. The use of low dose warfarin, intermittent doses of TPA, or heparin flushes to prophylax against central venous catheter associated clots is acceptable.
• Brain metastases or spinal cord compression, unless treated at least 4 weeks before entry and stable without steroid treatment for one week. Leptomeningeal disease is not eligible.
• Evidence of severe or uncontrolled systemic disease or any concurrent condition which in the Investigator's opinion makes it undesirable for the patient to participate
• Clinically significant cardiac event such as myocardial infarction; NYHA classification of heart disease greater than or equal to 2; or presence of cardiac disease that increases the risk of ventricular arrhythmia
• History of arrhythmia which is symptomatic or requires treatment or asymptomatic sustained ventricular tachycardia
• Previous history of QTc prolongation as a result from other medication that required discontinuation of that medication
• Congenital long QT syndrome, or 1st degree relative with unexplained sudden death under 40 years of age
• Presence of left bundle branch block
• QTc with Bazett's correction that is unmeasurable or greater than 480msec on screening ECG.
• Any concomitant medication that may cause QTc prolongation, induce Torsades de Pointes or induce CYP3A4 function
• Hypertension not controlled by medical therapy
• Currently active diarrhea that may affect the ability of the patient to absorb the Zactima or tolerate diarrhea
• Previous or current non-breast malignancies within the last 5 years, with the exception of cervical carcinoma in situ and adequately treated basal cell or squamous cell carcinoma of the skin
• Major surgery within 4 weeks, or incompletely healed surgical incision before starting study therapy
• Patients with large or rapidly accumulating pleural or abdominal effusions
• Women who are currently pregnant or breastfeeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Vandetenib; Cyclophosphamide 50 mg daily, methotrexate 2.5 mg days 1-2 weekly, and daily vandetanib (zactima) in 3 dose-escalation cohorts (100mg=Cohort 1) (200mg=Cohort 2) (300mg=Cohort3)	Drug: Vandetanib; Taken orally once a day in 28-day cycles (the dose will vary); Other Names: ZD6474; Zactima; Drug: Cyclophosphamide; Metronic Chemotherapy: Low dose pills taken every day of each 28-day cycle; Drug: Methotrexate; Metronic Chemotherapy: low dose pills taken on days 1 and 2 of each week

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
To determine the safety and tolerability of combination therapy with ZD6474 (Zactima) and metronomic chemotherapy	2 years

Secondary Outcome Measures

Outcome Measure	Time Frame
To determine the response rate of combination therapy with ZD6474 (Zactima) and metronomic chemotherapy in patients with measurable disease.	2 years

Collaborators and Investigators

• Sponsor: Dana-Farber Cancer Institute
• Collaborators: Massachusetts General Hospital; AstraZeneca; Brigham and Women's Hospital

Study record dates

Study Major Dates

• Study Start: July 1, 2007
• Primary Completion (ACTUAL): August 1, 2008
• Study Completion (ACTUAL): March 1, 2009

Study Registration Dates

• First Submitted: July 3, 2007
• First Submitted That Met QC Criteria: July 3, 2007
• First Posted (ESTIMATE): July 4, 2007

Study Record Updates

• Last Update Posted (ESTIMATE): November 18, 2013
• Last Update Submitted That Met QC Criteria: November 14, 2013
• Last Verified: November 1, 2013

More Information

Terms related to this study

• Keywords: Stage IV breast cancer; metronomic chemotherapy
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Dermatologic Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Cyclophosphamide; Methotrexate
• Other Study ID Numbers: 06-402