Study of Nab-Paclitaxel in High Risk Early Breast Cancer (GAIN-2)
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|ClinicalTrials.gov Identifier: NCT01690702|
Recruitment Status : Active, not recruiting
First Posted : September 24, 2012
Last Update Posted : July 13, 2017
|Condition or disease||Intervention/treatment||Phase|
|Breast Cancer||Drug: Epirubicin Drug: nab-Paclitaxel Drug: Cyclophosphamide Drug: Docetaxel||Phase 3|
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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||2886 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Official Title:||Neo-/Adjuvant Phase III Trial to Compare Intense Dose-dense Chemotherapy to Tailored Dose-dense Chemotherapy in Patients With High-risk Early Breast Cancer (GAIN-2)|
|Study Start Date :||September 2012|
|Estimated Primary Completion Date :||January 2020|
|Estimated Study Completion Date :||December 2020|
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|
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|
- 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.
- 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
- prognostic/predictive factors [ 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 correlate the outcome with biological markers.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01690702
|Klinikum Frankfurt Höchst|
|Frankfurt, Hessen, Germany, 65929|
|Study Chair:||Gunter von Minckwitz, Prof.||German Breast Group|