Gefitinib, Trastuzumab, and Docetaxel in Treating Patients With Metastatic Breast Cancer

• ClinicalTrials.gov Identifier: NCT00086957
• Recruitment Status: Completed
• First Posted: July 12, 2004
• Results First Posted: February 27, 2017
• Last Update Posted: February 27, 2017
• Sponsor: City of Hope Medical Center
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): City of Hope Medical Center

Tracking Information

• First Submitted Date: July 8, 2004
• First Posted Date: July 12, 2004
• Results First Submitted Date: November 4, 2016
• Results First Posted Date: February 27, 2017
• Last Update Posted Date: February 27, 2017
• Study Start Date: January 2004
• Actual Primary Completion Date: August 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 6, 2017)

• Number of Participants With at Least One Dose Limiting Toxicity in Phase I [ Time Frame: 4 weeks from start of treatment, up to 2 years ]
  Dose Limiting Toxicity (DLT) defined as any treatment-related grade 3 or greater except for hematological toxicities which must be grade 4. Interstitial Lung Disease (ILD) related to treatment should be considered as a DLT regardless of the grade.
• Recommended Phase II Dose [ Time Frame: 4 weeks from start of treatment, up to 2 years ]
  The maximum tolerated dose (MTD): subjects received gefitinib 250 mg orally daily, trastuzumab 6 mg/kg intravenously every 3 weeks (after an initial dose of 8 mg/kg with cycle 1), and docetaxel 75 mg/m^2 intravenously every 3 weeks. This was to serve as the phase II dose if no dose-limiting toxicities (DLTs) occurred in the first three subjects. If one DLT occurred in the first three subjects, another three subjects where to be enrolled at this dose, whereas if two DLTs occurred in the first three subjects, the docetaxel dose was to be decreased to 60 mg/m^2. The study would then be continued only if no more than one patient had a DLT at this dose. Once the dose of docetaxel was established, all further subjects were to be treated at the phase II MTD dose.

• Original Primary Outcome Measures: Not Provided

Current Secondary Outcome Measures (submitted: January 6, 2017)

• Progression-free Survival [ Time Frame: Until disease progression, up to 5 years. ]
  Estimated using the product-limit method of Kaplan and Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST), as a 20% increase in the sum of the longest diameter of target lesions, or the appearance of new lesions.
• Objective Response Rate [ Time Frame: After 3 cycles of treatment, up to 2 years. ]
  Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Objective Response Rate defined as percentage of patients achieving a Best Response of either CR or PR.
• Overall Survival [ Time Frame: Until death from any cause, up to 5 years. ]
  Estimated using the product-limit method of Kaplan and Meier.

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Gefitinib, Trastuzumab, and Docetaxel in Treating Patients With Metastatic Breast Cancer
• Official Title: Phase I/II Trial of ZD1839 (Iressa®), Trastuzumab (Herceptin®), and Docetaxel (Taxotere®) in Patients With erbB-2 (HER-2) Overexpressing, Stage IV Breast Carcinoma

Brief Summary

RATIONALE: Gefitinib may stop the growth of tumor cells by blocking the enzymes necessary for their growth. Monoclonal antibodies such as trastuzumab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Drugs used in chemotherapy, such as docetaxel, work in different ways to stop tumor cells from dividing so they stop growing or die. Combining gefitinib and trastuzumab with docetaxel may kill more tumor cells.

PURPOSE: This phase I/II trial is studying the best dose of docetaxel when given together with gefitinib and trastuzumab in treating patients with metastatic breast cancer.

Detailed Description

OBJECTIVES:

Primary

• Determine the safety and efficacy of gefitinib, trastuzumab (Herceptin®), and docetaxel, in terms of time to disease progression, in patients with HER2/neu-overexpressing metastatic adenocarcinoma of the breast.

Secondary

• Determine the objective tumor response rate in patients treated with this regimen.
• Correlate expression and/or degree of phosphorylation of epidermal growth factor receptor, HER2/neu, c-fos, Akt, ERK½, P13K, p53, p21, and p27 with outcome in patients treated with this regimen.

OUTLINE: This is a phase I, multicenter, dose-escalation study of docetaxel followed by a phase II study. Patients are stratified according to trastuzumab (Herceptin®)-naive vs trastuzumab-failure.

• Phase I: Patients receive oral gefitinib once daily on days 2-14. Patients also receive trastuzumab* IV over 30-90 minutes and docetaxel IV over 1 hour on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

NOTE: *Trastuzumab is given at a higher dose (loading dose) in course 1 and then at a lower dose in subsequent courses.

Cohorts of 3-6 patients receive docetaxel at dose level 1. If no dose-limiting toxicity (DLT) is observed in the first cohort of 3 patients, the dose of docetaxel remains the same. If 1 DLT is observed in the first cohort of 3 patients, 3 additional patients are added (for a total of 6 patients) to dose level 1. If no further DLTs are observed at dose level 1, the dose of docetaxel remains the same. If 2 of 3 or 2 of 6 patients experience DLT at dose level 1, the dose of docetaxel is considered above the maximum tolerated dose (MTD) and is subsequently reduced. If 2 of 3 or 2 of 6 patients experience DLT at the reduced dose of docetaxel, the study is stopped.

• Phase II: Patients receive docetaxel at the MTD and gefitinib and trastuzumab as in phase I.

Patients are followed for survival.

PROJECTED ACCRUAL: A total of 3-76 patients will be accrued for this study within 26 months.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Breast Cancer

Intervention

• Biological: trastuzumab
  Cycle 1 loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks for subsequent cycles.
• Drug: docetaxel
  75 mg/m2 every three weeks, or 60 mg/m2 every three weeks depending on study findings
• Drug: gefitinib
  250 mg daily or 250 mg daily on days 2 through 14 depending on study findings

Study Arms

Experimental: ZD1839, Trastuzumab and Docetaxel

Interventions:

• Biological: trastuzumab
• Drug: docetaxel
• Drug: gefitinib

• Publications *: Somlo G, Koczywas M, Luu T, et al.: A phase I-II study of trastuzumab, gefitinib, and docetaxel as first line chemotherapy in patients with HER-2 overexpressing stage IV breast carcinoma. [Abstract] Breast Cancer Research and Treatment 94 (Suppl 1): A-2035, 2005.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 20, 2015): 31
• Original Enrollment: Not Provided
• Actual Study Completion Date: August 2015
• Actual Primary Completion Date: August 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the breast

  • Metastatic disease
• HER-2/neu overexpression (3+ by immunohistochemistry OR 2+ by fluorescence in situ hybridization)
• Measurable or evaluable disease

• Hormone receptor status:

  • Not specified

PATIENT CHARACTERISTICS:

Age

• 18 and over

Sex

• Male or female

Menopausal status

• Not specified

Performance status

• ECOG 0-2

Life expectancy

• Not specified

Hematopoietic

• Absolute granulocyte count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3

Hepatic

• AST and ALT < 2.5 times upper limit of normal (ULN) (5.0 times ULN in the presence of liver metastases)
• Bilirubin < 1.5 times ULN
• No unstable or uncompensated hepatic disease

Renal

• Creatinine < 1.6 mg/dL
• No unstable or uncompensated renal disease

Cardiovascular

• LVEF > 45% by echocardiogram or MUGA
• No prior New York Heart Association class I-IV heart disease
• No prolonged PR interval or atrioventricular block on ECG
• No unstable or uncompensated cardiac disease

Pulmonary

• No unstable or uncompensated respiratory disease

• No clinically active interstitial lung disease

  • Patients who are asymptomatic and have chronic stable radiographic changes are allowed

Immunologic

• No autoimmune disorders
• No conditions of immunosuppression
• No severe hypersensitivity to taxane or gefitinib or any of its excipients

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No other prior or concurrent malignancy within the past 5 years except basal cell carcinoma or carcinoma in situ of the cervix
• No other severe or uncontrolled systemic disease
• No other acute or chronic medical condition that would preclude study participation
• No other significant clinical disorder or laboratory finding that would preclude study participation
• No psychiatric illness that would preclude study compliance

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Prior adjuvant trastuzumab (Herceptin®) allowed if > 6 months elapsed before disease recurrence
• No prior trastuzumab for metastatic breast cancer
• No prior monoclonal antibodies directed at the epidermal growth factor receptor (EGFR)

Chemotherapy

• Prior adjuvant chemotherapy (or as first-line therapy for metastatic breast cancer) allowed
• Prior adjuvant taxane allowed if completed > 6 months before diagnosis of metastatic breast cancer
• No prior docetaxel for metastatic breast cancer

Endocrine therapy

• Prior adjuvant hormonal therapy (or as first-line therapy for metastatic breast cancer) allowed

• No concurrent hormonal therapy

  • Concurrent steroids allowed provided dose is stable

Radiotherapy

• Not specified

Surgery

• Fully recovered from prior oncologic or other major surgery
• No concurrent surgery within 7 days of gefitinib administration

Other

• Recovered from prior anticancer therapy (alopecia allowed)
• More than 30 days since prior non-approved drug or investigational agent
• No other prior EGFR-directed therapy (i.e., tyrosine kinase inhibitors)

• No concurrent use of any of the following medications:

  • Phenytoin
  • Carbamazepine
  • Barbiturates
  • Rifampin
  • Hypericum perforatum (St. John's wort)
• No other concurrent anticancer therapy
• No concurrent cardioprotective drugs
• No concurrent oral retinoids
• Concurrent participation in the City of Hope indium-labeled trastuzumab imaging study allowed

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00086957
• Other Study ID Numbers: 03049; P30CA033572 ( U.S. NIH Grant/Contract ); CHNMC-03049; ZENECA-1839US/0274; ZENECA-IRUSIRES0012; CDR0000371908 ( Registry Identifier: NCI PDQ )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: City of Hope Medical Center
• Study Sponsor: City of Hope Medical Center
• Collaborators: National Cancer Institute (NCI)

Investigators

• Principal Investigator: George Somlo, MD; City of Hope Medical Center

• PRS Account: City of Hope Medical Center
• Verification Date: January 2017