WSG ADAPT - adjuvant dynamic marker-adjusted personalized therapy trial optimizing risk assessment and therapy response prediction in early breast cancer: study protocol for a prospective, multi-center, controlled, non-blinded, randomized, investigator initiated phase II/III trial

Daniel Hofmann, Ulrike Nitz, Oleg Gluz, Ronald E Kates, Timo Schinkoethe, Peter Staib, Nadia Harbeck, Daniel Hofmann, Ulrike Nitz, Oleg Gluz, Ronald E Kates, Timo Schinkoethe, Peter Staib, Nadia Harbeck

Abstract

Background: Adjuvant treatment decision-making based on conventional clinical/pathological and prognostic single molecular markers or genomic signatures is a therapeutic area in which over-/under-treatment are still key clinical problems even though substantial and continuous improvement of outcome has been achieved over the past decades. Response to therapy is currently not considered in the decision-making procedure.ADAPT is one of the first new generation (neo)adjuvant trials dealing with individualization of (neo)adjuvant decision-making in early breast cancer and aims to establish early predictive surrogate markers, e.g., Ki-67, for therapy response under a short induction treatment in order to maximally individualize therapy and avoid unnecessary toxicity by ineffective treatment.

Methods/design: The prospective, multi-center, controlled, non-blinded, randomized, investigator initiated phase II/III ADAPT trial has an innovative "umbrella" protocol design. The "umbrella" is common for all patients, consisting of dynamic testing of early therapy response. ADAPT will recruit 4,936 patients according to their respective breast cancer subtype in four distinct sub-trials at 80 trial sites in Germany; 4,000 patients with hormone receptor positive (HR+) and HER2 negative disease will be included in the ADAPT HR+/HER2- sub-trial, where treatment decision is based on risk assessment and therapy response to induction therapy, and 380 patients will be included in ADAPT HER2+/HR+. A further 220 patients will be included in ADAPT HER2+/HR- and 336 patients will be recruited for ADAPT Triple Negative. These three sub-trials focus on identification of early surrogate markers for therapy success in the neoadjuvant setting. Patients will be allocated to the respective sub-trial according to the result of their diagnostic core biopsy, as reported by local/central pathology for HR and HER2 status.

Discussion: Recent trials, such as the GeparTrio, have shown that response-guided therapy using clinical response may improve outcome. For chemotherapy or HER2-targeted treatment, pathologic complete response in a neoadjuvant setting is an excellent predictor of outcome. For endocrine therapy, response to short induction treatment - as defined by decrease in tumor cell proliferation - strongly correlates with outcome. ADAPT now aims to combine static prognostic and dynamic predictive markers, focusing not just on single therapeutic targets, but also on general markers of proliferation and cell death. Biomarker analysis will help to optimize selection of subtype-specific treatment.

Trial registration: ClinicalTrials.gov: ADAPT Umbrella: NCT01781338; ADAPT HR+/HER2-: NCT01779206; ADAPT HER2+/HR+: NCT01745965; ADAPT HER2+/HR-: NCT01817452; ADAPT TN:NCT01815242.

Figures

Figure 1
Figure 1
ADAPT CONSORT flow diagram. Patients are allocated to one of four distinct ADAPT sub-trials, depending on the hormone receptor (HR) and HER2 status of the tumor. Randomization is always subject to the respective sub-trial after allocation. Patients will be treated subtype-specific according to their individual disease. Follow-up is scheduled for five years following registration.
Figure 2
Figure 2
ADAPT Umbrella trial design. Patients are included in the trial based on the results of the diagnostic core biopsy and local pathology for histologically confirmed tumors. Based on the subtype classification, patients are allocated to the respective sub-trial and start subtype-specific induction therapy for three weeks. Central pathology assessment includes hormone receptors, HER2 and Ki-67. For HR+ tumors, an initial RS is determined by Oncotype DX®. Following three weeks of induction therapy, efficacy estimation is done using repeat core biopsy or surgical specimen (in case of adjuvant treatment; HR+/HER2- only). The ADAPT Umbrella comprises two sequential tumor samples and the three week subtype-specific induction therapy. Further subtype-specific therapy is subject to the ADAPT sub-trials.
Figure 3
Figure 3
ADAPT HR+/HER2- trial design. Patients with HR+/HER2- disease receive three weeks of endocrine induction therapy according to current AGO guidelines. After pathologic assessment patients are classified according to RS risk groups (low/intermediate/high risk of recurrence). Low-risk is defined as N0-1 RS ≤11 and will be allocated to adjuvant endocrine therapy alone. Definition of intermediate-risk is based on N0-1 and RS 12–25. Patients with early therapy response as measured by Ki-67post ≤10% also receive endocrine therapy only. Intermediate-risk patients with low therapy response and Ki-67post >10% are randomized to one of the two chemotherapy arms just like all high-risk patients, i.e., N2-3 or N0-1 and RS ≥26. Patients at high risk (pN ≥2 or RS ≥26) with clear need for chemotherapy may omit induction therapy and undergo immediate randomization.
Figure 4
Figure 4
ADAPT HER2+/HR+ trial design. HER2+/HR+ patients receive either T-DM1 monotherapy or T-DM1 in combination with endocrine therapy or Trastuzumab in combination with endocrine therapy as induction therapy according to their randomization. Randomization is only allowed after HR and HER2 status are confirmed by central pathology. The randomized regimen is applied in the neoadjuvant setting for twelve weeks followed by surgery.
Figure 5
Figure 5
ADAPT HER2+/HR- trial design. HER2+/HR- patients receive either dual anti-HER2 blockade with Trastuzumab and Pertuzumab or dual anti-HER2 blockade with Trastuzumab and Pertuzumab and chemotherapy backbone with Paclitaxel for induction therapy, which is subject to randomization. Randomization is only applicable after HR and HER2 status are confirmed by central pathology. The randomized regimen is applied in the neoadjuvant setting for twelve weeks followed by surgery.
Figure 6
Figure 6
ADAPT Triple Negative trial design. Triple negative (HER2-/HR-) patients are treated with either nab-Paclitaxel and Gemcitabine or nab-Paclitaxel and Carboplatin for induction therapy, which is subject to randomization. Randomization is only applicable after HR and HER2 status are confirmed by central pathology. The randomized regimen is applied in the neoadjuvant setting for twelve weeks followed by surgery.

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