Study of Nab-Paclitaxel in High Risk Early Breast Cancer (GAIN-2)

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2012 by German Breast Group
Sponsor:
Collaborators:
Celgene Corporation
Amgen
Information provided by (Responsible Party):
German Breast Group
ClinicalTrials.gov Identifier:
NCT01690702
First received: August 29, 2012
Last updated: November 26, 2012
Last verified: October 2012
  Purpose

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


Condition Intervention Phase
Breast Cancer
Drug: Epirubicin
Drug: nab-Paclitaxel
Drug: Cyclophosphamide
Drug: Docetaxel
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official 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)

Resource links provided by NLM:


Further study details as provided by German Breast Group:

Primary Outcome Measures:
  • invasive disease-free survival (IDFS) [ Time Frame: 5 years ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • locoregional relapse-free survival (LRRFS) [ Time Frame: 5 years ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    The correlation of lymph node metastases with biological markers is investigated


Other Outcome Measures:
  • prognostic/predictive factors [ Time Frame: 5 years ] [ Designated as safety issue: No ]
    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 correlate the outcome with biological markers.


Estimated Enrollment: 2886
Study Start Date: September 2012
Estimated Study Completion Date: December 2020
Estimated Primary Completion Date: January 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: dtEC-dtD
Epirubicin and Cyclophosphamide with a tailored dose 4 cycles q2w followed by one additional week followed by Docetaxel with a tailored dose 4 cycles q2w.
Drug: Epirubicin Drug: Cyclophosphamide Drug: Docetaxel
Experimental: EnPC
Epirubicin 150mg/qm 3 cycles q2w followed by nabPaclitaxel 260-330mg/qm (to be determined in run-in-phase) 3 cycles q2w followed by Cyclophosphamide 2000mg/qm 3 cycles q2w
Drug: Epirubicin Drug: nab-Paclitaxel Drug: Cyclophosphamide

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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.

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01690702

Contacts
Contact: Kai Büchsenschütz, Dr. 0049-(0)6102-7480-434 kai.buechsenschuetz@germanbreastgroup.de

Locations
Germany
Klinikum Frankfurt Höchst Recruiting
Frankfurt, Hessen, Germany, 65929
Contact: Volker Möbus, Professor    0049-(0)69-3106 ext 3552    volker-moebus@klinikumfrankfurt.de   
Principal Investigator: Volker Möbus, Professor         
German Breast Group Not yet recruiting
Neu-Isenburg, Hessen, Germany, 63263
Contact: Kai Büchsenschütz, Dr.    0049-(0)6102-7480 ext 434    kai.buechsenschuetz@germanbreastgroup.de   
Sponsors and Collaborators
German Breast Group
Celgene Corporation
Amgen
Investigators
Study Chair: Gunter von Minckwitz, Prof. German Breast Group
  More Information

No publications provided

Responsible Party: German Breast Group
ClinicalTrials.gov Identifier: NCT01690702     History of Changes
Other Study ID Numbers: GBG 68
Study First Received: August 29, 2012
Last Updated: November 26, 2012
Health Authority: Germany: Federal Institute for Drugs and Medical Devices

Keywords provided by German Breast Group:
breast cancer
tailored
high-risk

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Cyclophosphamide
Docetaxel
Epirubicin
Paclitaxel
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Antineoplastic Agents, Phytogenic
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators

ClinicalTrials.gov processed this record on August 20, 2014