Study of Nab-Paclitaxel in High Risk Early Breast Cancer
Condition: Breast Cancer
MeSH terms: Breast Neoplasms
Study type: Interventional
Phase: Phase 3

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

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.
    

Intervention name(s): Epirubicin; nab-Paclitaxel; Cyclophosphamide; Docetaxel
Intervention type(s): Drug; Drug; Drug; Drug
Intervention MeSH terms: Paclitaxel; Docetaxel; Cyclophosphamide; Epirubicin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: breast cancer; tailored; high-risk