Ospedale Misericordia, Grosseto Triple Negative Albumin-bound paclitaxel Combination International Treatment Study: TnAcity Trial ABI-007-MBC-001 Carmelo Bengala UOC Oncologia Medica , Dipartimento di Oncologia, Istituto Toscano Tumori Ospedale Misericordia, Grosseto

TnAcity Trial Multicenter, International Phase 2/3 randomized trial Open-label First line treatment, TN metastatic breast cancer

Study schema

Endpoints - Phase 2 Primary Endpoint: Secondary Endpoints: PFS (investigator assessment of response -RECIST 1.1) Secondary Endpoints: Efficacy ORR, investigator-determined, Percentage of subjects who initiated Cycle 6 OS Safety Incidence/Grade of treatment-emergent adverse events (TEAEs), SAEs, laboratory abnormalities Incidence of subjects experiencing dose modifications (dose interruptions and reductions) Percentage of subjects who discontinued for adverse event Biomarkers: Tumor sample (paraffin block and/or slides) will be collected to evaluate molecular profiles (protein, tumor cell mutations and gene expression) and identify potential predictive markers of clinical response and to determine possible correlation with efficacy outcomes. The most recently obtained tumor sample will be submitted for receptor/biomarker assessment . Blood samples will be collected at the beginning of cycle 1 and of cycle 3 to assess treatment efficacy vs. subject pharmacogenomic characteristics, tumor DNA and miRNA characteristics, and tumor-derived exosome characteristics. Exploratory analysis of CTCs will be performed to assess any significant correlation of CTC levels with relevant clinical benefits. Sample collection for this exploratory analysis may be limited to selected clinical centers.

Phase II part: Objective The objective of the Phase 2 portion of the study is to select the nab-paclitaxel experimental arm to be investigated in the Phase 3 portion of the study. The evaluations of the efficacy and safety of the two nab-paclitaxel experimental arms will be primarily based on the point estimates of the 5 efficacy and safety endpoints

Selection criteria for Phase III experimental arm

Endpoints – Phase 3 Primary Endpoint: PFS (independent blinded radiologist(s) - RECIST 1.1) Key Secondary Endpoints ORR with a confirmed complete or partial response OS Other Secondary Endpoints Efficacy Investigator Assessment of PFS Disease Control Rate (CR, PR and SD ≥ 16 weeks) Duration of response in subjects with a confirmed objective complete or partial response Safety: Incidence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), laboratory abnormalities Exploratory Endpoints: same as phase 2, added HRU: Healthcare Resource Utilization Endpoints (in all countries where legal and feasible): relative incidence of items related to primary chemotherapy (e.g., number of doses, all premedication and resources for drug delivery), the most relevant supportive care (e.g., intravenous antibiotics, analgesics), hematopoietic growth-factor use, blood product use, management of AEs that are probably or possibly related to therapy, related hospitalizations, clinic visits and medical procedures. QoL: Relative quality of life scores between the two treatment arms, as assessed by the EORTC QLQ-C30 and the EORTC QLQ-BR23 questionnaires.

Key Inclusion Criteria Age > 18 years ECOG PS 0-1 Pathologically confirmed metastatic breast carcinoma Pathologically confirmed “triple negative” per ASCO/CAP guidelines 2007 ER, PgR negative (< 1 % IHC positive cells) HER-2 negative (IHC score 0, 1+ or 2+ FISH negative or FISH negative (HER2/CEP17 ratio < 1.8, Average HER2 gene copy number of < 4 signals/nucleus) Prior adjuvant or neoadjuvant anthracycline or controindication No prior cytotoxic therapy for metastatic disease Measurable disease (RECIST 1.1)

Major Exclusion Criteria Male breast cancer CNS metastases Bone disease only Peripheral neuropathy > grade 2 (NCI CTCAE 4.0) Class II-IV CHF or myocardial infarction within 6 months History of lung abnormalities

Sample size A sample size of 80 patients per group was selected for the phase II segment to permit qualitative comparisons of toxicity between the 2 nab-P arms and to provide preliminary data on antitumor activity Exploratory pair-wise comparisons will test the effect of nab-P when 96 PFS events have been observed from 160 patients This should provide approximately 80% marginal power with a 2-sided significance level of 0.2 to differentiate the regimens, assuming a median PFS of 4.6 months for gem + carbo and 7.1 months for the selected nab-P combination arm The phase III design provides ≈ 90% power to detect a hazard ratio of 0.70 for PFS with a 2-sided 5% significance level, which represents a 43% improvement in median PFS (+ 1.97 mo) and OS (+ 5.4 mo) for the nab-P experimental arm Sample size 550 patients; 24 months accrual

Exploratory end-points Phase II Time to second line therapy or death Tumor tissue sample for predictive markers of response CTCs to assess correlation with relevant clinical benefits Phase III Health care Resources Utilization Endpoints Quality of life scores

Global Enrollment As of February 2015

Study enrolment by country (142 pts)