Trial document





This study has been imported from ClinicalTrials.gov without additional data checks.
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  DRKS00005396

Trial Description

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Title

Adjuvant Phase III Trial to Compare Intense Dose-dense Adjuvant Treatment With EnPC to Dose Dense, Tailored Therapy With dtEC-dtD for Patients With High-risk Early Breast Cancer (GAIN-2)

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Trial Acronym

GAIN-2

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URL of the Trial

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Brief Summary in Lay Language

two-armed trial to compare E-nP-C against tailored dtEC-dtD in patients with high risk early
breast cancer

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Brief Summary in Scientific Language

The Norton-Simon-Hypothesis on log cell kill suggests that chemotherapy should be given at
maximum dosages at minimum intervals. Combination chemotherapy, which always has to make
compromises regarding the doses of each drug and treatment intervals due to acute as well as
cumulative toxicities, does therefore not comply with this theory. Sequential application of
monotherapies, however, allows very high single agent doses and dose-dense treatment
intervals. Regimens designed according to the Norton-Simon-Hypothesis have shown to be
highly active as adjuvant treatment for early breast cancer. As the number of cycles of each
agent can be restricted to 3, as previously done in the AGO ETC trial by Möbus et al.,
cumulative toxicities do not really occur.

Two large scale trials of dose-dense chemotherapy have proven very high protective activity
against tumor recurrence (AGO ETC (Ref.1) and CALGB 9741 (Ref.2)). Especially the ETC trial
(epirubicin, solvent-based paclitaxel, and cyclophosphamide) showed an impressive superior
DFS and OS in 1284 high-risk breast cancer patients with > 4positive lymph nodes. The doses
used are exceptional at maximum dosage and minimum intervals with epirubicin 150 mg/m²,
Paclitaxel 225 mg/m² and cyclophosphamide 2.5 g/m² given every 2 weeks based on the above
described Norton-Simon-Hypothesis. However, as each drug was given only 3 times at intervals
of 2 weeks, this regimen is feasible and safe with primary support of G-CSF and ESF. The ETC
schedule is today considered standard of care for high-risk breast cancer patients in
Germany.

However, both trials, ETC and CALGB 9741, compared the dose-dense concept against EC-P q3w
which is nowadays considered to be an inferior regimen compared to EC-P weekly or EC-Doc.
The GAIN trial had a 2x2 factorial design and explored ETC versus EC-TX and ibandronate vs.
observation. The trial closed recruitment after 3023 pts in July 2008. In the Panther trial,
a joint effort of SBG, ABCSG, AGO-B and GBG, the tailored, dose-dense EC-Doc (dtEC-dtD)
regimen was tested against conventional dosed FEC-Doc. Efficacy results are to be awaited,
safety results will be published in 2012.

Nab-paclitaxel (nP) provides a better toxicity profile and a higher efficacy compared to
solvent based taxanes (paclitaxel and docetaxel). It might therefore be the preferred
component in an intense dose-dense regimen. Assuming that the corresponding dose of
nab-paclitaxel to 175 mg/m² paclitaxel is 260 mg/m², an appropriate dose would be 330 mg/m²
nab-paclitaxel to substitute paclitaxel at 225 mg/m². So far, no experience with such a dose
of nab-paclitaxel is available. However, initial experience with 300mg/m² q3w and 150mg/m²
weekly (in 3 out of 4 weeks) showed a good safety profile even when given for a median of 8
cycles (Ref.3). Another pilot study showed a good tolerability of 260 mg/m² nab-paclitaxel
given q2w for 4 cycles (Ref.4+5).

The GAIN-2 trial will allow for comparing the toxicity and effectiveness of a predefined
intense dose-dense regimen (EnPC) vs. a dose-dense regimen with modification of single doses
depending on individual haematological and non-haematological toxicities. The primary aim of
the GAIN-2 trial will be to compare the invasive disease-free survival after adjuvant
chemotherapy with EnPC or dtEC-dtD in patients with primary node-positive or high risk node
negative breast cancer. To explore the maximum dose of nab-paclitaxel in this setting, a
run-in phase with varying doses of nab-paclitaxel is included in the study design.

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Organizational Data

  •   DRKS00005396
  •   2013/10/28
  •   2012/08/29
  •   yes
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Secondary IDs

  •   NCT01690702  (ClinicalTrials.gov)
  •   GBG 68  (German Breast Group)
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Health Condition or Problem studied

  •   Breast Cancer
  •   C50 -  Malignant neoplasm of breast
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Interventions/Observational Groups

  •   Drug: Epirubicin
  •   Drug: nab-Paclitaxel
  •   Drug: Cyclophosphamide
  •   Drug: Docetaxel
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Characteristics

  •   Interventional
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  •   Randomized controlled trial
  •   Open (masking not used)
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  •   Active control (effective treament of control group)
  •   Treatment
  •   Parallel
  •   III
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Primary Outcome

- invasive disease-free survival (IDFS); time frame: 5 years; The IDFS is defined as the time period between the registration and the first invasive event. It will be analyzed after the end of the study by referring to data from GBG patient's registry.

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Secondary Outcome

- locoregional relapse-free survival (LRRFS); time frame: 5 years; The LRRFS is defined as the time period between the registration and the first locoregional event. It will be analyzed after the end of the study by referring to data from GBG patient's registry.
- overall survival (OS); time frame: 5 years; The OS is defined as the time period between the registration and the death of a patient. It will be analyzed after the end of the study by referring to data from GBG patient's registry (relatives can give the information regarding death as well).
- distant disease-free survival (DDFS); time frame: 5 years; The DDFS is defined as the time period between the registration and the first distant event. It will be analyzed after the end of the study by referring to data from GBG patient's registry.
- local relapse-free survival (LRFS); time frame: 5 years; LRFS is defined as the time period between registration and first local event and will be analyzed after the end of the study by referring to data from GBG patient's registry.
- regional relapse-free survival (RRFS); time frame: 5 years; RRFS is defined as the time period between registration and first regional event and will be analyzed after the end of the study by referring to data from GBG patient's registry.
- brain metastasis free survival (in the subgroup of TNBC and HER2+); time frame: 5 years; brain metastasis free survival is defined as the time period between registration and first brain metastasis event and will be analyzed after the end of the study by referring to data from GBG patient's registry.
- compliance; time frame: 5 years; compliance is defined as the adherence to protocol and will be analyzed after the end of the therapy by referring to data from CRF.
- safety; time frame: 5 years; safety is defined by the AE that occur and will be analyzed after the end of the therapy by referring to data from CRF (including time to resolve neuropathy to grade 1)
- side effects of taxane; time frame: 5 years; Side effects of taxane are measured before, during and after chemotherapy by FACT-taxane questionnaires. the questionnaires will be analyzed after the end of the therapy.
- treatment effects by intrinsic subtypes; time frame: 5 years; the treatment effect will be analyzed after the end of the therapy by referring to data from CRF and later by using the data from patient registry to compare the outcome in the different subtypes. The intrinsic subtypes are: 0-3, 4-9 or 10+ involved nodes as well as Ki-67.
- 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, LH , Anti-Müller Hormone, ultrasound-follicle count in patients aged <45 years.
- Pharmacogenetic substudy; time frame: Baseline; To correlate Single Nucleotide Polymorphisms (SNPs) of genes with the associated toxicity and histologically assessed treatment effect.
- biology of lymph node metastases; time frame: baseline; The correlation of lymph node metastases with biological markers is investigated

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  •  
  •  
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Recruitment

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  •   2012/09/30
  •   2886
  •   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. Histologically confirmed unilateral or bilateral primary carcinoma of the breast

3. Age at diagnosis at least 18 years, female, and biologically not older than 65 years

4. Adequate surgical treatment with histological complete resection (R0) of the invasive
breast tumor. Choice of axilla surgery (clearance or sentinel node biopsy) is up to
the participating site.

5. Centrally confirmed ER/PR/HER2 and Ki-67 status detected on surgical biopsy. ER/PR
positive is defined as ≥1% stained cells and HER2-positive is defined as IHC 3+ in
>10% immunoreactive cells or FISH (or equivalent test) ratio ≥2.0. Formalin-fixed,
paraffin-embedded (FFPE) breast tissue has therefore to be sent to the Dept. of
Pathology at the Charité, Berlin prior to randomization

6. High risk breast cancer as defined as:

- HER2-positive or triple-negative tumors irrespective of nodal status

- luminal B-like tumors (ER and/or PgR positive, HER2 negative, Ki-67 >20%) with
involved lymph nodes

- 4 or more involved lymph nodes

7. Complete staging work-up within 3 months prior to randomization. All patients must
have bilateral mammography, breast ultrasound, 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

8. Karnofsky Performance status index at least 80%

9. Estimated life expectancy of at least 10 years irrespective of the diagnosis of
breast cancer

10. Confirmed normal cardiac function by ECG and cardiac ultrasound (LVEF or shortening
fraction) within 2 weeks prior to randomization for patients with HER2-positive
disease. LVEF must be above 55%

11. Laboratory requirements:

Haematology

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

- Platelets at least 100 x 109/L and

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

- Total bilirubin ≤ 1.5x times above upper normal limits (UNL) and

- ASAT (SGOT) and ALAT (SGPT) more tham 1.5x UNL and

- Alkaline phosphatase more than 2.5x UNL. Renal function

- Creatinine ≤ 1.25 UNL,

- Creatinine Clearance > 30ml/min (if Creatinine is above UNL, according to
Cockcroft-Gault)

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

13. Complete baseline documentation must be submitted via MedCODES® and approved by GBG
Forschungs GmbH

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

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Exclusion Criteria

1. Patients with luminal A-like tumors (ER and or PgR positive, HER2 negative and Ki-67
≤ 20%)and less than 4 involved lymph nodes

2. Non-operable breast cancer

3. Time since axillary dissection or SLNB >3 months (optimal < 1 month)

4. Previous and already (neoadjuvant or adjuvant) treated invasive breast carcinoma

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. Evidence for infection including wound infections, HIV, hepatitis

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

9. Pre-existing motor or sensory neuropathy of a severity at least grade 1 by NCI-CTC
criteria v 4.0

10. Other severe and relevant co-morbidity that would interact with the application of
cytotoxic agents or the participation in the study

11. Previous or concurrent treatment with:

- concurrent chronic corticosteroids unless initiated > 6 months prior to study
entry and at low dose (less than 10 mg methylprednisolone or equivalent) (except
inhalative corticoids)

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

- concurrent treatment with any investigational, not marketed drug within 30 days
prior to study entry

- previous or concurrent anti-cancer therapy for any reason

12. Absolute contraindications for the use of corticosteroids

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

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

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Addresses

  • start of 1:1-Block address primary-sponsor
    • German Breast Group
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    • Celgene Corporation
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    • Amgen
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    • German Breast Group
    • Gunter von Minckwitz, Prof. 
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    • Kai Büchsenschütz, Dr. 
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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 ongoing
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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 .
  •   7
  •   2013/10/23
* This entry means the parameter is not applicable or has not been set.