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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT00625898




Registration number
NCT00625898
Ethics application status
Date submitted
21/02/2008
Date registered
29/02/2008
Date last updated
10/09/2020

Titles & IDs
Public title
BETH Study: Treatment of HER2 Positive Breast Cancer With Chemotherapy Plus Trastuzumab vs Chemotherapy Plus Trastuzumab Plus Bevacizumab
Scientific title
A Multicenter Phase III Randomized Trial of Adjuvant Therapy for Patients With HER2-Positive Node-Positive or High Risk Node-Negative Breast Cancer Comparing Chemotherapy Plus Trastuzumab With Chemotherapy Plus Trastuzumab Plus Bevacizumab
Secondary ID [1] 0 0
CIRG (TRIO) 011
Secondary ID [2] 0 0
NSABP B-44-I
Universal Trial Number (UTN)
Trial acronym
BETH
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Breast Cancer 0 0
Condition category
Condition code
Cancer 0 0 0 0
Breast

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Docetaxel
Treatment: Drugs - Trastuzumab
Treatment: Drugs - Carboplatin
Treatment: Drugs - Bevacizumab
Treatment: Drugs - 5-Fluorouracil
Treatment: Drugs - Epirubicin
Treatment: Drugs - Cyclophosphamide

Active Comparator: 1A: TCH-H - Docetaxel (T), Carboplatin (C), and Trastuzumab (H) followed by Trastuzumab (H)

Experimental: 1B: TCHB-HB - Docetaxel (T), Carboplatin (C), Trastuzumab (H), Bevacizumab (B) followed by Trastuzumab (T) and Bevacizumab (B)

Active Comparator: 2A: TH-FEC-H - Docetaxel (T) and Trastuzumab (H) followed by 5-fluorouracil (F), Epirubicin (E), and Cyclophosphamide (C) followed by Trastuzumab (H)

Experimental: 2B: THB-FEC-HB - Docetaxel (T), Trastuzumab (H), and Bevacizumab (B) followed by 5-Fluorouracil (F), Epirubicin (E), and Cyclophosphamide (C) followed by Trastuzumab (H) and Bevacizumab (B)


Treatment: Drugs: Docetaxel
75 mg/m2 IV on day 1 every 3 weeks for cycles 1-6, Arms 1A and 1B
100 mg/m2 on day 1 every 3 weeks for cycles 1-3, Arms 2A and 2B

Treatment: Drugs: Trastuzumab
First dose: 8 mg/kg IV on day 1 of cycle 1 only. Subsequent doses: 6 mg/kg IV on day 1 every 3 weeks for cycles 2-6. Following completion of chemotherapy cycles: 6 mg/kg IV every 3 weeks until 1 year following first trastuzumab dose. Arms 1A and 1B
First dose: 8 mg/kg IV on day 1 of cycle 1 only. Subsequent doses: 6 mg/kg IV on day 1 every 3 weeks for cycles 2-3. 21 days after last dose of FEC: 8 mg/kg IV first post-FEC dose only; subsequent doses 6 mg/kg IV every 3 weeks for a total of 1 year. Arms 2A and 2B

Treatment: Drugs: Carboplatin
6 mg/ml/min IV on day 1 every 3 weeks for cycles 1-6

Treatment: Drugs: Bevacizumab
15 mg/kg IV on day 1 every 3 weeks for cycles 1-6. Following completion of chemotherapy cycles: 15 mg/kg IV on day 1 every 3 weeks until 1 year following first bevacizumab dose. Arm 1B
15 mg/kg IV on day 1 every 3 weeks for cycles 1-3. 21 days after the last dose of FEC: 15 mg/kg IV on day 1 every 3 weeks until 1 year following first bevacizumab dose. Arm 2B

Treatment: Drugs: 5-Fluorouracil
600 mg/m2 IV on day 1 every 3 weeks for cycles 4-6

Treatment: Drugs: Epirubicin
90 mg/m2 IV on day 1 every 3 weeks for cycles 4-6

Treatment: Drugs: Cyclophosphamide
600 mg/m2 IV on day 1 every 3 weeks for cycles 4-6
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Invasive Disease-free Survival (IDFS)
Timepoint [1] 0 0
up to 10 years
Secondary outcome [1] 0 0
Invasive disease-free survival (IDFS) within chemotherapy cohorts
Timepoint [1] 0 0
up to 10 years
Secondary outcome [2] 0 0
Disease-free survival (DFS)
Timepoint [2] 0 0
up to 10 years
Secondary outcome [3] 0 0
Overall survival (OS)
Timepoint [3] 0 0
Time from randomization until death from any cause or up to a maximum of 10 years from study entry
Secondary outcome [4] 0 0
Recurrence-free interval (RFI)
Timepoint [4] 0 0
Time from randomization until local, regional or distant recurrence or up to a maximum of 10 years from study entry
Secondary outcome [5] 0 0
Distant recurrence-free interval (DRFI)
Timepoint [5] 0 0
Time from randomization until distant disease recurrence only or up to a maximum of 10 years from study entry
Secondary outcome [6] 0 0
Cardiac toxicity. Cumulative incidence of severe cardiac events defined as definite or probable cardiac death, or NYHA Class III or IV CHF
Timepoint [6] 0 0
2-3 weeks after cycle 3; 2-3 weeks after last chemotherapy dose; 7, 10, 18, 36, and 60 months from randomization
Secondary outcome [7] 0 0
Non-cardiac toxicity. Frequencies of adverse events categorized using the NCI CTCAE v3.0.
Timepoint [7] 0 0
within 3 days of each chemotherapy cycle; 2-3 weeks following last chemotherapy dose; every 6 weeks during targeted therapy; every 6 months through year 5; every 12 months years 6 - 10
Secondary outcome [8] 0 0
Identification of biomarkers (from tumor and serum/plasma) predictive for the level of benefit from the addition of bevacizumab to standard adjuvant systemic treatment for HER2-positive breast cancer as well as for cardiac toxicity
Timepoint [8] 0 0
baseline, during therapy and follow-up, within 2 weeks of LVEF assessments, any protocol-specified cardiac event, and after diagnosis of recurrence

Eligibility
Key inclusion criteria
- Life expectancy of at least 10 years, excluding their diagnosis of breast cancer.

- Women who have had breast reconstruction utilizing tissue expanders must be in
agreement with delaying surgery to replace the tissue expanders with permanent
implants until 3 months following the last dose of bevacizumab

- Women of reproductive potential must agree to use an effective non-hormonal method of
contraception (for example condoms, some intrauterine devices, diaphragms,
vasectomized partner, or abstinence) during therapy and for at least 6 months after
the last dose of bevacizumab and/or trastuzumab.

- Submission of tumor samples from the breast surgery for central HER2 testing is
required for all patients prior to enrollment in the BETH Trial

- Signed and dated IRB/EC-approved consent

- ECOG performance status of 0 or 1

- The tumor must be unilateral invasive adenocarcinoma of the breast on histologic
examination.

- The breast cancer must be HER2-positive based on test results as follows: Local
testing (if available) should demonstrate that the tumor is IHC 2+ or 3+ or is
considered to be HER2-positive for gene amplification by FISH, CISH, or other in situ
hybridization (ISH) method. If local ISH test results are considered equivocal, the
tumor can be submitted for central HER2 testing. (If local testing is not possible,
the tumor can be submitted for central HER2 testing.) Central testing (a requirement
for ALL patients) must demonstrate that the tumor is HER2-positive which is defined as
FISH-positive and/or IHC 3+.

- All of the following staging criteria (according to the 6th edition of the AJCC Cancer
Staging Manual) must be met: By pathologic evaluation, primary tumor must be pT1-3; By
pathologic evaluation, ipsilateral nodes must be pN0, pN1 (pN1mi, pN1a, pN1b, pN1c),
pN2a, pN3a, or pN3b. If pN0, at least one of the following criteria must be met:
Pathologic tumor size > 2.0 cm; ER negative and PgR negative; Histologic and/or
nuclear grade 2 (intermediate) or 3 (high); or Age < 35 years

- Patients must have undergone either a total mastectomy or breast conserving surgery
(lumpectomy).

- For patients who undergo lumpectomy, the margins of the resected specimen must be
histologically free of invasive tumor and ductal carcinoma in situ (DCIS) as
determined by the local pathologist. If pathologic examination demonstrates tumor at
the line of resection, additional operative procedures may be performed to obtain
clear margins. If tumor is still present at the resected margin after re-excision(s),
the patient must undergo total mastectomy to be eligible. (Patients with margins
positive for lobular carcinoma in situ [LCIS] are eligible without additional
resection.)

- For patients who undergo mastectomy, margins must be free of gross residual tumor.
Patients with microscopic positive margins are eligible.

- Patients must have completed one of the following procedures for evaluation of
pathologic nodal status: Sentinel lymphadenectomy followed by removal of additional
non-sentinel lymph nodes if the sentinel node (SN) is positive; Sentinel
lymphadenectomy alone if pathologic nodal staging based on sentinel lymphadenectomy is
pN0, pN1mi or pN1b; or Axillary lymphadenectomy without SN isolation procedure.

- The interval between the last surgery for breast cancer (treatment or staging) and
randomization must be at least 28 days but no more than 84 days.

- Patients must have ER analysis performed on the primary tumor prior to randomization.
If ER analysis is negative, then PgR analysis must also be performed.

- The most recent postoperative blood counts, performed within 6 weeks prior to
randomization, must meet the following criteria: ANC must be greater than or equal to
1200/mm3; Platelet count must be greater than or equal to 100,000/mm3; and Hemoglobin
must be greater than or equal to 10 g/dL.

- The following criteria for evidence of adequate hepatic function must be met based on
the results of the most recent postoperative tests performed within 6 weeks prior to
randomization: total bilirubin must be less than or equal to upper limit of normal
(ULN) for the lab unless the patient has a bilirubin elevation > ULN to 1.5 x ULN due
to Gilbert's disease or similar syndrome involving slow conjugation of bilirubin; and
alkaline phosphatase must be less than or equal to 2.5 x ULN for the lab; and AST must
be less than or equal to 1.5 x ULN for the lab. Alkaline phosphatase and AST may not
both be > the ULN.

- Patients with AST or alkaline phosphatase > ULN are eligible for inclusion in the
study if liver imaging (CT, MRI, PET scan, or PET-CT scan performed within 3 months
prior to randomization) does not demonstrate metastatic disease and the requirements
for evidence of adequate hepatic function are met.

- Patients with alkaline phosphatase that is > ULN but less than or equal to 2.5 x ULN
are eligible for inclusion in the study if a bone scan,PET scan, or PET-CT scan
(performed within 3 months prior to randomization) does not demonstrate metastatic
disease.

- The following criteria for renal function must be met based on the results of the most
recent postoperative tests performed within 6 weeks prior to randomization: Serum
creatinine must be less than or equal to ULN for the lab. Measured or calculated
creatinine clearance must be > 60 mL/min.

- A urine sample must be tested for protein by determination of the urine
protein/creatinine (UPC) ratio or by urine dipstick. UPC ratio must be less than 1.0.
Urine dipstick must indicate 0-1+ protein. If dipstick reading is greater than or
equal to 2+, determine the UPC ratio, which must be less than 1.0, or collect a
24-hour urine specimen, which must demonstrate < 1.0 g of protein per 24 hours.

- LVEF assessment must be performed within 3 months prior to randomization. The LVEF
must be greater than or equal to 55% regardless of the cardiac imaging facility's
lower limit of normal (LLN).

- The ECG (performed within 3 months prior to randomization) must not have demonstrated
any of the following conditions: ventricular arrhythmias except for benign premature
ventricular contractions; supraventricular and nodal arrhythmias requiring a pacemaker
or not controlled with medication; and conduction abnormality requiring a pacemaker.
Minimum age
18 Years
Maximum age
No limit
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
- Inflammatory breast cancer.

- Definitive clinical or radiologic evidence of metastatic disease. (Chest imaging
[mandatory for all patients] and other imaging [if required] must have been performed
within 3 months prior to randomization.)

- Synchronous or previous contralateral invasive breast cancer (Patients with
synchronous or previous contralateral DCIS or LCIS are eligible).

- History of ipsilateral invasive breast cancer regardless of treatment or ipsilateral
DCIS treated with excision and RT. (Patients with history of ipsilateral LCIS are
eligible.)

- History of non-breast malignancies within the 5 years prior to study entry, except for
the following: carcinoma in situ of the cervix, carcinoma in situ of the colon,
melanoma in situ, and basal cell and squamous cell carcinomas of the skin.

- Previous therapy with anthracyclines, taxanes, carboplatin, trastuzumab, or
bevacizumab for any malignancy.

- RT, chemotherapy, and/or targeted therapy, administered for the currently diagnosed
breast cancer prior to randomization.

- Continued therapy with any hormonal agent such as raloxifene or tamoxifen (or other
SERM) or an aromatase inhibitor. (Patients are eligible if these medications are
discontinued prior to randomization.)

- Any sex hormonal therapy, e.g., birth control pills, ovarian hormone replacement
therapy, etc. Patients are eligible if these medications are discontinued prior to
randomization.

- Cardiac disease (history of and/or active disease) that would preclude the use of the
drugs included in the treatment regimens. This includes but is not confined to: Active
cardiac disease - angina pectoris that requires the use of anti-anginal medication;
ventricular arrhythmias except for benign premature ventricular contractions;
supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with
medication; conduction abnormality requiring a pacemaker; valvular disease with
documented compromise in cardiac function; and symptomatic pericarditis. History of
cardiac disease - myocardial infarction documented by elevated cardiac enzymes or
persistent regional wall abnormalities on assessment of LV function; history of
documented CHF; and documented cardiomyopathy.

- Uncontrolled hypertension defined as systolic blood pressure (BP) > 150 mmHg or
diastolic BP > 90 mmHg, with or without anti-hypertensive medication. (BP must be
assessed within 28 days prior to randomization.) Patients with initial BP elevations
are eligible if initiation or adjustment of BP medication lowers pressure to meet
entry criteria.

- History of hypertensive crisis or hypertensive encephalopathy.

- History of TIA or CVA.

- History of any arterial thrombotic event within 12 months before randomization.

- Symptomatic peripheral vascular disease.

- Intrinsic lung disease resulting in dyspnea.

- Unstable diabetes mellitus.

- Active infection or chronic infection requiring chronic suppressive antibiotics.

- Any significant bleeding within 6 months before randomization, exclusive of
menorrhagia in premenopausal women.

- Non-healing wound, skin ulcers, or incompletely healed bone fracture.

- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to planned start of study therapy.

- Anticipation of need for major surgical procedures during study therapy and for at
least 3 months following completion of bevacizumab.

- Gastroduodenal ulcer(s) documented by endoscopy to be active within 6 months before
randomization.

- History of GI perforation, abdominal fistulae, or intra-abdominal abscess.

- Known bleeding diathesis or coagulopathy.

- Requirement for therapeutic doses of coumadin or equivalent.

- Sensory/motor neuropathy greater than or equal to grade 2, as defined by the NCI CTCAE
v3.0.

- Conditions that would prohibit administration of corticosteroids.

- Chronic daily treatment with corticosteroids (dose of > 10 mg/day methylprednisolone
equivalent) (excluding inhaled steroids).

- History of hypersensitivity reaction to drugs formulated with polysorbate 80.

- Pregnancy or lactation at the time of study entry. (Note: Pregnancy testing must be
performed within 14 days prior to randomization according to institutional standards
for women of child-bearing potential.)

- Other non-malignant systemic disease that would preclude the patient from receiving
study treatment or would prevent required follow-up.

- Psychiatric or addictive disorders or other conditions that, in the opinion of the
investigator, would preclude the patient from meeting the study requirements.

- Use of any investigational product within 4 weeks prior to enrollment in the study.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Terminated
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
1/04/2008
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
1/07/2014
Sample size
Target
Accrual to date
Final
3509
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,VIC,WA
Recruitment hospital [1] 0 0
Macarthur Cancer Center - Campbelltown
Recruitment hospital [2] 0 0
St. George Hospital - Kogarah
Recruitment hospital [3] 0 0
Cancer Therapy Center - Liverpool
Recruitment hospital [4] 0 0
North Shore Private Hospital - St. Leonards
Recruitment hospital [5] 0 0
Royal North Shore Hospital - St. Leonards
Recruitment hospital [6] 0 0
Southern Medical Day Care - Wollongong
Recruitment hospital [7] 0 0
Royal Brisbane & Women's Hospital - Herston
Recruitment hospital [8] 0 0
Mater Adult Hospital - South Brisbane
Recruitment hospital [9] 0 0
Ashford Cancer Center - Ashford
Recruitment hospital [10] 0 0
Flinders Medical Centre - Bedford
Recruitment hospital [11] 0 0
Frankston Hospital - Frankston
Recruitment hospital [12] 0 0
The Alfred Hospital - Melbourne
Recruitment hospital [13] 0 0
Mount Medical Center - Perth
Recruitment hospital [14] 0 0
Berdat Family Comprehensive Cancer Centre - Subiaco
Recruitment postcode(s) [1] 0 0
2560 - Campbelltown
Recruitment postcode(s) [2] 0 0
2217 - Kogarah
Recruitment postcode(s) [3] 0 0
1871 - Liverpool
Recruitment postcode(s) [4] 0 0
2065 - St. Leonards
Recruitment postcode(s) [5] 0 0
2500 - Wollongong
Recruitment postcode(s) [6] 0 0
4029 - Herston
Recruitment postcode(s) [7] 0 0
4101 - South Brisbane
Recruitment postcode(s) [8] 0 0
5035 - Ashford
Recruitment postcode(s) [9] 0 0
5042 - Bedford
Recruitment postcode(s) [10] 0 0
3199 - Frankston
Recruitment postcode(s) [11] 0 0
3004 - Melbourne
Recruitment postcode(s) [12] 0 0
6000 - Perth
Recruitment postcode(s) [13] 0 0
6008 - Subiaco
Recruitment outside Australia
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Country [107] 0 0
Germany
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Truro

Funding & Sponsors
Primary sponsor type
Other
Name
NSABP Foundation Inc
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
Cancer International Research Group (CIRG)
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Commercial sector/Industry
Name [2] 0 0
Hoffmann-La Roche
Address [2] 0 0
Country [2] 0 0
Other collaborator category [3] 0 0
Commercial sector/Industry
Name [3] 0 0
Genentech, Inc.
Address [3] 0 0
Country [3] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
The trial will determine the value of adding bevacizumab to chemotherapy plus trastuzumab in
patients with resected node-positive or high risk node-negative, HER2-positive breast cancer.
Trial website
https://clinicaltrials.gov/ct2/show/NCT00625898
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Norman Wolmark, MD
Address 0 0
NSABP Foundation Inc
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT00625898