Docetaxel and Trastuzumab With or Without Carboplatin in Treating Women With HER2-Positive Breast Cancer

Sponsor

Jonsson Comprehensive Cancer Center (Other)

Overall Status

Completed

CT.gov ID

NCT00047255

Collaborator

(none)

263

Enrollment

Location

Arms

Duration (Months)

2.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Monoclonal antibodies such as trastuzumab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. It is not yet known if docetaxel and trastuzumab are more effective with or without carboplatin in treating women who have HER2-positive breast cancer.

PURPOSE: Randomized phase III trial to study the effectiveness of combining docetaxel and trastuzumab with or without carboplatin in treating women who have HER2-positive stage IIIB or stage IV breast cancer.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Biological: trastuzumab Drug: carboplatin Drug: docetaxel Biological: trastuxumab Drug: Docetaxel	Phase 3

Detailed Description

OBJECTIVES:

Compare the time to disease progression in women with HER2-positive stage IIIB, IIIC, or IV breast cancer treated with docetaxel and trastuzumab (Herceptin) with or without carboplatin.
Compare the response rate and duration of overall response in patients treated with these regimens.
Compare the overall survival of patients treated with these regimens.
Compare rate of clinical benefit, defined as complete response, partial response, or stable disease for more than 24 weeks, in patients treated with these regimens.
Compare the toxicity of these regimens in these patients.
Determine pathologic and molecular markers for predicting efficacy of these regimens in these patients.
Determine genetic and biochemical markers for predicting risk of cardiac dysfunction and later cardiac events in patients receiving these regimens.
Determine whether peripheral levels of shed HER2 extracellular domain constitute a prognostic and/or predictive factor of time to progression and survival of patients receiving these regimens.

OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified according to prior adjuvant and/or neoadjuvant chemotherapy (none vs with taxanes vs without taxanes) and participating center. Patients are randomized to 1 of 2 treatment arms.

Arm I:
Course 1: Patients receive trastuzumab (Herceptin) IV over 30-90 minutes on days 1, 8, and 15. Patients receive docetaxel IV over 1 hour and carboplatin IV over 30-60 minutes on day 2.
Courses 2 and all subsequent courses: Patients receive docetaxel IV over 1 hour and carboplatin IV over 30-60 minutes on day 1 and trastuzumab IV over 30 minutes on days 1, 8, and 15.
Arm II: Patients receive docetaxel and trastuzumab as in arm I. In both arms, treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity. After completion of 8 courses, patients continue to receive trastuzumab IV over 30 minutes every 21 days in the absence of disease progression.

Patients are followed every 2 months for 3 years.

PROJECTED ACCRUAL: A total of 250 patients (125 per treatment arm) will be accrued for this study within 18 months.

Study Design

Study Type:

Interventional

Actual Enrollment :

263 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Multicenter Phase III Randomized Trial Comparing Docetaxel (Taxotere) and Trastuzumab (Herceptin) With Docetaxel (Taxotere), Carboplatin and Trastuzumab (Herceptin) as First Line Chemotherapy for Patients With Advanced Breast Cancer Containing the HER2 Gene Amplification

Study Start Date :

May 1, 2002

Actual Primary Completion Date :

Jan 1, 2006

Actual Study Completion Date :

Apr 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Herceptin plus docetaxel Cycle 1: Day 1: Herceptin (H) 4 mg/kg loading dose administered by IV infusion over 90 minutes, Day 2: Docetaxel (T) 100 mg/m2 by IV infusion over 30 minutes, Day 8: (H) 2mg/kg administered by IV infusion over 30 minutes, Day 15: 2mg/kg administered by IV infusion over 30 minutes. Subsequent cycles: Day 1: (T) 100mg/m2 as 1 hour IV infusion given every 3 weeks, followed by (H) 2 mg/kg IV infusion over 30 minutes, Day 8: (H) 2 mg/kg administered by IV infusion over 30 minutes, Day 15: (H) 2 mg/kg administered by IV infusion over 30 minutes. Last cycle: Day 1: (T) 100mg/m2 as 1 hour IV infusion followed by (H) 2 mg/kg IV infusion over 30 minutes, Day 8: (H) 2 mg/kg administered by IV infusion over 30 minutes, Day 15: (H) 2 mg/kg administered by IV infusion over 30 minutes, Day 22: (H) 6 mg/kg administered by IV infusion over 30 minutes.	Drug: docetaxel Cycle 1: Day 1: Herceptin (H) 4 mg/kg loading dose administered by IV infusion over 90 minutes, Day 2: Docetaxel (T) 100 mg/m2 by IV infusion over 30 minutes, Day 8: (H) 2mg/kg administered by IV infusion over 30 minutes, Day 15: 2mg/kg administered by IV infusion over 30 minutes. Subsequent cycles: Day 1: (T) 100mg/m2 as 1 hour IV infusion given every 3 weeks, followed by (H) 2 mg/kg IV infusion over 30 minutes, Day 8: (H) 2 mg/kg administered by IV infusion over 30 minutes, Day 15: (H) 2 mg/kg administered by IV infusion over 30 minutes. Last cycle: Day 1: (T) 100mg/m2 as 1 hour IV infusion followed by (H) 2 mg/kg IV infusion over 30 minutes, Day 8: (H) 2 mg/kg administered by IV infusion over 30 minutes, Day 15: (H) 2 mg/kg administered by IV infusion over 30 minutes, Day 22: (H) 6 mg/kg administered by IV infusion over 30 minutes. Other Names: taxotere Biological: trastuxumab Cycle 1: Day 1: Herceptin (H) 4 mg/kg loading dose administered by IV infusion over 90 minutes, Day 2: Docetaxel (T) 100 mg/m2 by IV infusion over 30 minutes, Day 8: (H) 2mg/kg administered by IV infusion over 30 minutes, Day 15: 2mg/kg administered by IV infusion over 30 minutes. Subsequent cycles: Day 1: (T) 100mg/m2 as 1 hour IV infusion given every 3 weeks, followed by (H) 2 mg/kg IV infusion over 30 minutes, Day 8: (H) 2 mg/kg administered by IV infusion over 30 minutes, Day 15: (H) 2 mg/kg administered by IV infusion over 30 minutes. Last cycle: Day 1: (T) 100mg/m2 as 1 hour IV infusion followed by (H) 2 mg/kg IV infusion over 30 minutes, Day 8: (H) 2 mg/kg administered by IV infusion over 30 minutes, Day 15: (H) 2 mg/kg administered by IV infusion over 30 minutes, Day 22: (H) 6 mg/kg administered by IV infusion over 30 minutes. Other Names: herceptin
Experimental: Docetaxel, Carboplatin, and Herceptin Cycle 1: Day 1: Herceptin (H) 4 mg/kg loading dose admin by IV over 90 mins, Day 2: Docetaxel (T) 75 mg/m2 by IV over 1 hour followed by carboplatin (C) at target AUC=6 mg/mL/min admin by IV over 30-60 mins, Day 8: (H) 2mg/kg admin by IV over 30 mins, Day 15: 2mg/kg admin by IV over 30 mins. Subsequent cycles: Day 1: (T) 75mg/m2 as 1 hour IV followed by (C) at target AUC=6 mg/mL/min admin by IV 30-60 mins every 3 weeks followed by (H) 2 mg/kg IV over 30 mins, Day 8: (H) 2 mg/kg admin by IV over 30 mins, Day 15: (H) 2 mg/kg admin by IV over 30 mins. Last cycle: Day 1: (T) 75mg/m2 as 1 hour IV followed by (C) at target AUC=6 mg/mL/min admin by IV 30-60 mins every 3 weeks followed by (H) 2 mg/kg IV over 30 mins, Day 8: (H) 2 mg/kg admin by IV over 30 mins, Day 15: (H) 2 mg/kg admin by IV over 30 mins, Day 22: (H) 6 mg/kg admin by IV over 30 mins.	Biological: trastuzumab Cycle 1: Day 1: Herceptin (H) 4 mg/kg loading dose admin by IV over 90 mins, Day 2: Docetaxel (T) 75 mg/m2 by IV over 1 hour followed by carboplatin (C) at target AUC=6 mg/mL/min admin by IV over 30-60 mins, Day 8: (H) 2mg/kg admin by IV over 30 mins, Day 15: 2mg/kg admin by IV over 30 mins. Subsequent cycles: Day 1: (T) 75mg/m2 as 1 hour IV followed by (C) at target AUC=6 mg/mL/min admin by IV 30-60 mins every 3 weeks followed by (H) 2 mg/kg IV over 30 mins, Day 8: (H) 2 mg/kg admin by IV over 30 mins, Day 15: (H) 2 mg/kg admin by IV over 30 mins. Last cycle: Day 1: (T) 75mg/m2 as 1 hour IV followed by (C) at target AUC=6 mg/mL/min admin by IV 30-60 mins every 3 weeks followed by (H) 2 mg/kg IV over 30 mins, Day 8: (H) 2 mg/kg admin by IV over 30 mins, Day 15: (H) 2 mg/kg admin by IV over 30 mins, Day 22: (H) 6 mg/kg admin by IV over 30 mins. Other Names: herceptin Drug: carboplatin Cycle 1: Day 1: Herceptin (H) 4 mg/kg loading dose admin by IV over 90 mins, Day 2: Docetaxel (T) 75 mg/m2 by IV over 1 hour followed by carboplatin (C) at target AUC=6 mg/mL/min admin by IV over 30-60 mins, Day 8: (H) 2mg/kg admin by IV over 30 mins, Day 15: 2mg/kg admin by IV over 30 mins. Subsequent cycles: Day 1: (T) 75mg/m2 as 1 hour IV followed by (C) at target AUC=6 mg/mL/min admin by IV 30-60 mins every 3 weeks followed by (H) 2 mg/kg IV over 30 mins, Day 8: (H) 2 mg/kg admin by IV over 30 mins, Day 15: (H) 2 mg/kg admin by IV over 30 mins. Last cycle: Day 1: (T) 75mg/m2 as 1 hour IV followed by (C) at target AUC=6 mg/mL/min admin by IV 30-60 mins every 3 weeks followed by (H) 2 mg/kg IV over 30 mins, Day 8: (H) 2 mg/kg admin by IV over 30 mins, Day 15: (H) 2 mg/kg admin by IV over 30 mins, Day 22: (H) 6 mg/kg admin by IV over 30 mins. Drug: Docetaxel Cycle 1: Day 1: Herceptin (H) 4 mg/kg loading dose admin by IV over 90 mins, Day 2: Docetaxel (T) 75 mg/m2 by IV over 1 hour followed by carboplatin (C) at target AUC=6 mg/mL/min admin by IV over 30-60 mins, Day 8: (H) 2mg/kg admin by IV over 30 mins, Day 15: 2mg/kg admin by IV over 30 mins. Subsequent cycles: Day 1: (T) 75mg/m2 as 1 hour IV followed by (C) at target AUC=6 mg/mL/min admin by IV 30-60 mins every 3 weeks followed by (H) 2 mg/kg IV over 30 mins, Day 8: (H) 2 mg/kg admin by IV over 30 mins, Day 15: (H) 2 mg/kg admin by IV over 30 mins. Last cycle: Day 1: (T) 75mg/m2 as 1 hour IV followed by (C) at target AUC=6 mg/mL/min admin by IV 30-60 mins every 3 weeks followed by (H) 2 mg/kg IV over 30 mins, Day 8: (H) 2 mg/kg admin by IV over 30 mins, Day 15: (H) 2 mg/kg admin by IV over 30 mins, Day 22: (H) 6 mg/kg admin by IV over 30 mins. Other Names: taxotere

Arm

Intervention/Treatment

Experimental: Herceptin plus docetaxel

Cycle 1: Day 1: Herceptin (H) 4 mg/kg loading dose administered by IV infusion over 90 minutes, Day 2: Docetaxel (T) 100 mg/m2 by IV infusion over 30 minutes, Day 8: (H) 2mg/kg administered by IV infusion over 30 minutes, Day 15: 2mg/kg administered by IV infusion over 30 minutes. Subsequent cycles: Day 1: (T) 100mg/m2 as 1 hour IV infusion given every 3 weeks, followed by (H) 2 mg/kg IV infusion over 30 minutes, Day 8: (H) 2 mg/kg administered by IV infusion over 30 minutes, Day 15: (H) 2 mg/kg administered by IV infusion over 30 minutes. Last cycle: Day 1: (T) 100mg/m2 as 1 hour IV infusion followed by (H) 2 mg/kg IV infusion over 30 minutes, Day 8: (H) 2 mg/kg administered by IV infusion over 30 minutes, Day 15: (H) 2 mg/kg administered by IV infusion over 30 minutes, Day 22: (H) 6 mg/kg administered by IV infusion over 30 minutes.

Drug: docetaxel

Other Names:

taxotere

Biological: trastuxumab

Other Names:

herceptin

Experimental: Docetaxel, Carboplatin, and Herceptin

Cycle 1: Day 1: Herceptin (H) 4 mg/kg loading dose admin by IV over 90 mins, Day 2: Docetaxel (T) 75 mg/m2 by IV over 1 hour followed by carboplatin (C) at target AUC=6 mg/mL/min admin by IV over 30-60 mins, Day 8: (H) 2mg/kg admin by IV over 30 mins, Day 15: 2mg/kg admin by IV over 30 mins. Subsequent cycles: Day 1: (T) 75mg/m2 as 1 hour IV followed by (C) at target AUC=6 mg/mL/min admin by IV 30-60 mins every 3 weeks followed by (H) 2 mg/kg IV over 30 mins, Day 8: (H) 2 mg/kg admin by IV over 30 mins, Day 15: (H) 2 mg/kg admin by IV over 30 mins. Last cycle: Day 1: (T) 75mg/m2 as 1 hour IV followed by (C) at target AUC=6 mg/mL/min admin by IV 30-60 mins every 3 weeks followed by (H) 2 mg/kg IV over 30 mins, Day 8: (H) 2 mg/kg admin by IV over 30 mins, Day 15: (H) 2 mg/kg admin by IV over 30 mins, Day 22: (H) 6 mg/kg admin by IV over 30 mins.

Biological: trastuzumab

Other Names:

herceptin

Drug: carboplatin

Drug: Docetaxel

Other Names:

taxotere

Outcome Measures

Primary Outcome Measures

Evaluate time to disease progression after treatment with either Herceptin in with single-agent docetaxel (TH) or Herceptin with Carboplatin and TH in metastatic breast cancer pts previously untreated with chemo whose cancer contains the HER2 gene amp. [till disease progression]

Secondary Outcome Measures

To compare response rate, duration of overall response, overall survival. [undefined]
To evaluate and compare the rate of clinical benefit, defined as CR, PR, or stable disease > 24 weeks. [undefined]
To compare toxicity between the 2 arms. [2 years]
To evaluate pathologic and molecular markers for predicting efficacy. [2 years]
Correlate peripheral levels of shed HER2 extracellular domain (ECD) with FISH results and to determine whether peripheral levels of shed HER2 ECD consitute a prognostic and/or predicitive factor vis-a-vis time to progression and survival. [undefined]
To evaluate genetic and biochemical markers for predicting risk of developing cardiac dysfunction and later cardiac events in this patient population. [2 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Histologically or cytologically confirmed adenocarcinoma of the breast
Stage IIIB, IIIC, or IV
HER2-positive
Measurable or evaluable disease
Patients with osteolytic bone lesions as only site of disease must have at least 2 lytic sites confirmed by bone x-ray, MRI, or CT scan
None of the following are eligible as only manifestation of metastatic disease:
Blastic bone metastases
Mixed bone metastases
Lymphangitic carcinomatosis
Ascites
Pleural/pericardial effusion
Lymphangitis cutis/pulmonis
Inflammatory breast disease
Abdominal masses not confirmed and followed by imaging techniques
Cystic lesions
No prior or known concurrent clinical manifestation of brain or leptomeningeal involvement
Hormone receptor status:
Not specified

PATIENT CHARACTERISTICS:

Age

18 to 75

Sex

Female

Menopausal status

Pre- or post-menopausal

Performance status

Karnofsky 60-100%

Life expectancy

Not specified

Hematopoietic

Neutrophil count at least 2,000/mm3
Platelet count at least 100,000/mm3
Hemoglobin at least 10 g/dL

Hepatic

Bilirubin no greater than upper limit of normal (ULN)
AST and ALT no greater than 5 times ULN
Alkaline phosphatase no greater than 5 times ULN (unless due to bone metastases or any nonmalignant bone disease and in absence of liver disorders)
AST and/or ALT greater than 1.5 times ULN AND alkaline phosphatase greater than 2.5 times ULN ineligible

Renal

Creatinine no greater than 2 mg/dL
Creatinine clearance at least 60 mL/min

Cardiovascular

LVEF normal by MUGA or echocardiogram
No myocardial infarction within the past year
No unstable angina pectoris
No documentation of congestive heart failure
No concurrent grade 3 or 4 cardiovascular arrhythmia
No poorly controlled hypertension (i.e., diastolic pressure greater than 100 mmHg)

Pulmonary

No severe dyspnea due to complications of advanced malignancy
No respiratory insufficiency requiring supplemental oxygen

Other

No significant neurologic or psychiatric disorders (e.g., psychotic disorders, dementia, or seizures) that would preclude study
No pre-existing sensory or motor neuropathy grade 2 or greater
No other serious illness or medical condition
No active uncontrolled infection
No active peptic ulcer disease
No unstable diabetes mellitus
No other prior or concurrent malignancy except for:
Curatively treated nonmelanoma skin cancer
Carcinoma in situ of the cervix
Other curatively treated cancer and disease free for at least 10 years
No known allergic reactions to study drugs
No contraindications for the use of corticosteroids
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy

See Chemotherapy
No prior trastuzumab (Herceptin) for locally advanced or metastatic disease
Prior trastuzumab-containing regimen (except with taxane) as adjuvant or neoadjuvant therapy allowed provided relapse occurred at least 6 months after therapy

Chemotherapy

No prior chemotherapy for locally advanced or metastatic disease or local recurrence
No prior chemotherapy with anthracycline or anthracenedione regimens with cumulative doses of more than 360 mg/m2 of doxorubicin, 720 mg/m2 of epirubicin, or 72 mg/m2 of mitoxantrone
No prior platinum-containing regimen as adjuvant or neoadjuvant chemotherapy
At least 4 weeks since prior anthracyclines or anthracenediones
Prior taxanes as adjuvant or neoadjuvant chemotherapy allowed provided relapse occurred at least 6 months after therapy
Prior taxane with trastuzumab as adjuvant or neoadjuvant chemotherapy allowed provided relapse occurred at least 12 months after therapy
No concurrent amifostine

Endocrine therapy

Prior hormonal therapy in the adjuvant or metastatic setting allowed provided patient has progressive disease and therapy has stopped before study entry
Concurrent chronic corticosteroids allowed if initiated more than 6 months before study entry and at a low dose (no greater than 20 mg methylprednisolone or equivalent)
No concurrent raloxifene, tamoxifen, or other selective estrogen receptor modulators
No concurrent hormonal therapy

Radiotherapy

No prior radiotherapy to study lesion unless clear progression
At least 4 weeks since prior radiotherapy (unless radiotherapy involved only a single field to treat a single metastatic bone lesion)
Concurrent radiotherapy for palliative treatment allowed

Surgery

Not specified

Other

Recovered from prior antitumor therapy
At least 30 days since prior experimental drugs
No other concurrent experimental drugs
No other concurrent anticancer therapy
No concurrent bisphosphonates if osteolytic bone metastases are only site of disease
If receiving concurrent bisphosphonates other than for bone metastases only, must have been started at least 3 months before study entry
No concurrent primary prophylactic antibiotics
No concurrent cardioprotectors (e.g., dexrazoxane)