Trial document





This study has been imported from ClinicalTrials.gov without additional data checks.
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  DRKS00004497

Trial Description

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Title

A Randomized Phase II Trial Investigating the Addition of Carboplatin to Neoadjuvant Therapy for Triple-negative and HER2-positive Early Breast Cancer

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Trial Acronym

GeparSixto

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URL of the Trial

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Brief Summary in Lay Language

Study participants with primary breast cancer will receive a standard chemotherapy with an
anthracycline and a taxane as well as trastuzumab in case of HER2-positive tumors at doses
and duration in concordance to current treatment guidelines. Patients will be receive and
benefit in addition currently not in the neoadjuvant setting registered medication as
lapatinib or bevacizumab of which significant increases of cure (pCR) rates have been
reported in previous phase III studies. Patients randomized to carboplatin will receive in
addition to the described backbone therapies a potentially active agent which suggested
synergy of efficacy with chemotherapies as well as targeted agents. Patients might have the
risk of an increase in toxicities due to the added agents and will have additional burden
due to investigations required for study participation. However, due to the severity of the
underlying disease and the high risk of relapse and death due to the stage of disease, this
increase in toxicity and burden appears less relevant compared to the potential higher
efficacy and finally cure rate by the incorporated treatments.

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Brief Summary in Scientific Language

Anthracycline/taxane based combination chemotherapy of at least 18 weeks represents the
standard of care in the neoadjuvant setting. In HER2-positive disease trastuzumab is given
simultaneously to chemotherapy. Recent data from the Neo-Altto and Neosphere trials suggest
that a dual blockage of the HER2 receptor with e.g. trastuzumab and lapatinib reach
significantly higher pCR rates than trastuzumab alone and should therefore represent the
treatment back-bone of new neoadjuvant trials. A preplanned subgroup analysis of the
GeparQuinto study demonstrated that in TNBC the addition of bevacizumab resulted in a
significant increase of pCR rates (HR 1.4).

Having a better cardiac tolerability profile compared to conventional anthracyclines, the
non-pegylated liposomal encapsulated doxorubicin (NPLD) Myocet® might provide the
possibility to combine taxane, anthracycline, platinum salt as well with targeted agents as
double HER2 blockage or bevacizumab.

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Organizational Data

  •   DRKS00004497
  •   2012/11/30
  •   2011/08/17
  •   yes
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Secondary IDs

  •   2011-000553-23 
  •   NCT01426880  (ClinicalTrials.gov)
  •   GBG 66  (German Breast Group)
  •   2011-000553-23 
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Health Condition or Problem studied

  •   Tubular Breast Cancer Stage II
  •   Mucinous Breast Cancer Stage II
  •   Breast Cancer Female NOS
  •   Invasive Ductal Breast Cancer
  •   Tubular Breast Cancer Stage III
  •   HER-2 Positive Breast Cancer
  •   Inflammatory Breast Cancer Stage IV
  •   Inflammatory Breast Cancer
  •   C50 -  Malignant neoplasm of breast
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Interventions/Observational Groups

  •   Drug: Carboplatin
  •   Drug: background treatment according to standards fpr triple negative and Her2pos breast cancer patients
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Characteristics

  •   Interventional
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  •   Randomized controlled trial
  •   Open (masking not used)
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  •   Active control
  •   Treatment
  •   Parallel
  •   II-III
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Primary Outcome

- Pathological complete response of breast and lymph nodes (ypT0 ypN0; primary endpoint); time frame: 24 weeks (time window -3 weeks); Pathological response will be assessed considering all removed breast and lymphatic tissues from all surgeries. Surgery takes place shortly after the 18 weeks (six 3-week cycles) chemotherapy treatment. No microscopic evidence of residual viable tumor cells in all resected specimens of the breast and axilla meets the primary endpoint.

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Secondary Outcome

- 1.ypT0/is ypN0; ypT0; ypT0/is; ypN0, and regression grades; time frame: 24 weeks (time window -3 weeks)
- Clinical and imaging response; time frame: 24 weeks (time window -3 weeks); To determine the response rates of the breast tumor and axillary nodes based on physical examination and imaging tests. (sonography, mammography, or MRI) after treatment in both arms.
- loco-regional invasive recurrence free survival (LRRFS), regional recurrence free survival (RRFS), local recurrence free survival (LRFS), distant-disease- free survival (DDFS), invasive disease-free survival (IDFS), and overall survival (OS); time frame: 5 years; LRRFS, RRFS, LRFS, DDFS, IDFS and OS are defined as the time period between registration and first event and will be analyzed after the end of the study by referring to data from GBG patient's registry.
- Tolerability and Safety; time frame: during treatment 18 weeks; Tolerability and Safety: Descriptive statistics for the 4 treatments will be given on the number of patients whose treatment had to be reduced, delayed or permanently stopped
- pCR rates per arm; time frame: 24 weeks (time window -3 weeks); • To assess the pCR rates per arm separately in patients with triple-negative tumors and HER2-positive tumors.
- Breast and axilla conservation rate; time frame: 24 weeks (time window -3 weeks); To determine the breast and axilla conservation rate after each treatment.
- pCR rate and local recurrence free survival in correlation to clinical complete response and negative core biopsy before surgery; time frame: 5 years; To determine the pCR rate and local recurrence free survival (LRFS) in patients with a clinical complete response (cCR) and a negative core biopsy before surgery.
- Clinical and imaging response; time frame: 6 weeks; To determine the response rates of the breast tumor and axillary nodes based on physical examination and imaging tests. (sonography, mammography, or MRI) after treatment in both arms.
- PCR rate in patients with a clinical complete response and a negative core biopsy; time frame: 24 weeks (time window -3 weeks); To assess the pCR rate in patients with a clinical complete response and a negative core biopsy before surgery.
- Regional recurrence free survival (RRFS)in patients with initial node-positive axilla; time frame: until event occurs - no events for cured patients; To assess regional recurrence free survival (RRFS) in patients with initial node-positive axilla converted to negative at surgery and treated with sentinel node biopsy alone.
- Examination and comparison of molecular markers; time frame: Baseline, 6 weeks and 24 weeks; To examine and compare pre-specified molecular markers such as BRCA1-mRNA, P53, ALDH1, p4E-BP1, IL-8 metagene, B-Cell metagene as well as exploratory analyses and lymphocyte infiltration on core biopsies before and surgical tissue after end of chemotherapy. The aim is to identify potential predictive short and long term parameters.
- CTC Substudy; time frame: Baseline, 6 weeks and 24 weeks; To assess, characterize, and correlate circulating tumor cells and proteins with the effect of treatment.
- Pharmacogenetic substudy; time frame: Baseline; To correlate Single Nucleotide Polymorphisms (SNPs) of genes with the associated toxicity and histologically assessed treatment effect.
- Ovarian Substudy; time frame: Baseline, 6 months, 12 months, 18 months, 24 months, 30 months; To assess ovarian function measured by amenorrhea rate in correlation with changes in E2, FSH, Anti-Müller Hormone, ultrasound-follicle count in patients aged <45 years.

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

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Recruitment

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  •   2011/08/31
  •   600
  •   Multicenter trial
  •   National
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Inclusion Criteria

  •   Female
  •   18   Years
  •   no maximum age
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Additional Inclusion Criteria

- 1.Written informed consent for all study procedures according to local regulatory
requirements prior to beginning specific protocol procedures.

- 2.Complete baseline documentation must be submitted via Medcodes® and approved by GBG
Forschungs GmbH.

- 3.Unilateral or bilateral primary carcinoma of the breast, confirmed histologically
by core biopsy. Fine-needle aspiration is not sufficient. Incisional biopsy is not
allowed. In case of bilateral cancer, the investigator has to decide prospectively
which side will be evaluated for the primary endpoint.

- 4.Tumor lesion in the breast with a palpable size of ≥ 2 cm or a sonographical size
of ≥ 1 cm in maximum diameter. The lesion has to be measurable in two dimensions,
preferably by sonography. In case of inflammatory disease, the extent of inflammation
can be used as measurable lesion.

- 5.Patients should be in the following stages of disease: cT2 - cT4a-d or cT1c and cN+
or pNSLN+

- 6.In patients with multifocal or multicentric breast cancer, the largest lesion
should be measured.

- 7.Centrally confirmed ER/PR/HER-2 and Ki-67 status detected on core biopsy. ER/PR
positive is defined as >1% stained cells and HER2-positive is defined as HercepTest
IHC 3+ or FISH ratio ≥ 2.2. Formalin-fixed, paraffin-embedded (FFPE) breast tissue
from core biopsy has therefore to be sent to the Dept. of Pathology at the Charité,
Berlin prior to randomization.

- 8.Age ≥ 18 years.

- 9.Karnofsky Performance status index ≥ 80%.

- 10.Normal cardiac function must be confirmed by ECG and cardiac ultrasound (LVEF or
shortening fraction) within 3 months prior to randomization. LVEF must be above 55%.

- 11.Laboratory requirements: Hematology

- Absolute neutrophil count (ANC) ≥ 2.0 x 109 / L and

- Platelets ≥ 100 x 109 / L and

- Hemoglobin ≥ 10 g/dL (≥ 6.2 mmol/L) Hepatic function

- Total bilirubin < 1.5x UNL and

- ASAT (SGOT) and ALAT (SGPT) ≤ 1.5x UNL and

- Alkaline phosphatase ≤ 2.5x UNL. Renal function

- Creatinine ≤ 175 µmol/L (2 mg/dL) < 1.5x UNL

- Proteinuria: Urine dipstick for proteinuria < 2+. Patients discovered to have ≥ 2+
proteinuria on dipstick urinalysis should undergo a 24-hour urine collection and must
demonstrate ≤ 1 g of protein in 24 hours. If creatinine is between 140 - 175 umol/L
(1.6-2.0 mg/dL), the creatinine clearance (calculated or measured) should be ≥ 45
mL/min.

- 12.Negative pregnancy test (urine or serum) within 14 days prior to randomization for
all women of childbearing potential.

- 13.Complete staging work-up within 3 months prior to randomization. All patients must
have bilateral mammography, breast ultrasound (≤ 21 days), breast MRI (optional),
chest X-ray (PA and lateral), abdominal ultrasound or CT scan or MRI, and bone scan
done. In case of positive bone scan, bone X-ray (or CT or MRI) is mandatory. Other
tests may be performed as clinically indicated.

- 14.Patients must be available and compliant for central diagnostics, treatment and
follow-up.

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Exclusion Criteria

1. Prior chemotherapy for any malignancy.

2. Prior radiation therapy for breast cancer.

3. Pregnant or lactating patients. Patients of childbearing potential must implement
adequate non-hormonal contraceptive measures (barrier methods, intrauterine
contraceptive devices, sterilization) during study treatment.

4. Inadequate general condition (not fit for anthracycline-taxane-targeted agents-based
chemotherapy).

5. Previous malignant disease being disease-free for less than 5 years (except CIS of
the cervix and non-melanomatous skin cancer).

6. Known or suspected congestive heart failure (>NYHA I) and / or coronary heart
disease, angina pectoris requiring antianginal medication, previous history of
myocardial infarction, evidence of transmural infarction on ECG, uncontrolled or
poorly controlled arterial hypertension (i.e. BP >160 / 90 mm Hg under treatment with
two antihypertensive drugs), rhythm abnormalities requiring permanent treatment,
clinically significant valvular heart disease.

7. Previous thromboembolic event (except when thrombophily screening is negative).

8. Known hemorrhagic diathesis or coagulopathy with increased bleeding risk.

9. History of significant neurological or psychiatric disorders including psychotic
disorders, dementia or seizures that would prohibit the understanding and giving of
informed consent

10. Pre-existing motor or sensory neuropathy of a severity ≥ grade 2 by NCI-CTC criteria
v 4.0.

11. Currently active infection.

12. Active peptic ulcer.

13. Incomplete wound healing or unhealed bone fracture.

14. Disease significantly affecting gastrointestinal function, e.g. malabsorption
syndrome, resection of the stomach or small bowel, ulcerative colitis.

15. History of abdominal fistula or any grade 4 non-gastrointestinal fistula,
gastrointestinal perforation or intra-abdominal abscess within 6 months of enrolment.

16. Severe pulmonary condition / illness.

17. Major surgery within the last 28 days or anticipation of the need for major surgery
during study treatment with bevacizumab. Minor surgeries including insertion of an
indwelling catheter or sentinel lymph node biopsy within 24 h prior to chemotherapy.

18. Definite contraindications for the use of corticosteroids except inhalative
corticoids.

19. Known hypersensitivity reaction to one of the compounds or incorporated substances
used in this protocol;

20. Concurrent treatment with:

- chronic corticosteroids unless initiated > 6 months prior to study entry and at
low dose (≤ 10 mg methylprednisolone or equivalent).

- sex hormones. Prior treatment must be stopped before study entry.

- virostatic agents like sorivudine or analogs like brivudine, concurrent
treatment with aminoglycosides.

- anticoagulants: heparin, warfarin as well as acetylic acid (e.g. Aspirin®) at a
dose of > 325 mg/day or clopidogrel at a dose of > 75 mg/day.

- other experimental drugs or any other anti-cancer therapy.

- drugs recognized as being strong inhibitors or inducers of the isoenzyme CYP3A,
e.g. Rifabutin, Rifampicin, Clarithromycin, Ketoconazole, Itraconazole,
Ritonavir, Telithromycin, Erythromycin, Verapamil, Diltiazem within the last 5
days or the expected need for these treatments during study participation.

21. Participation in another clinical trial with any investigational, not marketed drug
within 30 days prior to study entry.

22. Male patients.

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Addresses

  • start of 1:1-Block address primary-sponsor
    • German Breast Group
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    • TEVA
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    • Roche Pharma AG
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    • GlaxoSmithKline
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  • start of 1:1-Block address scientific-contact
    • ASCO, AACR, ESMO, DKG, DGGG, AGO, DGS, BIG, BCIRG, St. Gallen Consensus Panel
    • Gunter von Minckwitz, MD, Prof 
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    • ASCO, AACR, ESMO, DKG, DGGG, AGO, DGS, BIG, BCIRG, St. Gallen Consensus Panel
    • Gunter von Minckwitz, MD, Prof 
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Sources of Monetary or Material Support

  • start of 1:1-Block address materialSupport
    • Bitte wenden Sie sich an den Sponsor / Please refer to primary sponsor
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Status

  •   Recruiting complete, follow-up continuing
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Trial Publications, Results and other Documents

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The parameters in ClinicalTrials.gov and DRKS are not identical. Therefore the data import from ClinicalTrials.gov required adjustments. For full details please see the DRKS FAQs .
  •   6
  •   2013/10/30
* This entry means the parameter is not applicable or has not been set.