347PMulticenter phase I trial of trastuzumab emtansine (T-DM1) in combination with non-pegylated liposomal doxorubicin (NPLD) in HER2[+] metastatic breast cancer (MBC). THELMA study

Abstract Background EMILIA, TH3RESA, and KAMILLA phase III trials showed that T-DM1 is highly active and safe as single agent in HER2[+] MBC. T-DM1 and NPLD may be safely combined to increase antitumor effect compared to each agent alone. The aim of this trial is to determine the dose-limiting toxicity (DLT) and maximum tolerate dose (MTD) of T-DM1 plus NPLD in HER2[+] MBC. Methods A 3 + 3 dose escalation design was used. Main selection criteria were: (1) Women with HER2[+] MBC ≥ 18 years (yrs); (2) Patients (pts) relapsed or progressed on or after taxanes and trastuzumab-based therapy; (3) No prior treatment with T-DM1 or anthracyclines; (4) Measurable or non-measurable disease with bone lesions. The initial dose was T-DM1 (3.6 mg/kg IV) plus NPLD (45 mg/m2 IV) on Day 1, q3w for up to 6 cycles of NPLD (cohort 1). In the next dose levels, only the NPLD dose was increased to 50 mg/m2 (cohort 2) and 60 mg/m2 (cohort 3). The MTD was the highest dose level at which 0/3 pts or ≤ 1/6 pts experienced DLT during the first 2 cycles. Six additional pts were enrolled at the MTD. T-DM1 treatment was continued as a single agent until disease progression or intolerable toxicity. Secondary objectives included safety, efficacy, and pharmacokinetic (PK) profile. Results Fifteen pts were enrolled (cohort 1, n = 3; cohort 2, n = 3; and cohort 3 [NPLD 60 mg/m2 as MTD], n = 9). Median age was 49.5 yrs (range, 31-62), 26.7% received ≥2 prior metastatic treatments, and 80% included trastuzumab plus pertuzumab combination. The only DLT was in the cohort 3 (neutrophil count Conclusions T-DM1 plus NDLP is a safe and active combination for pts with previously treated HER2[+] MBC. Clinical trial identification NCT02562378. First Posted: September 29, 2015. Legal entity responsible for the study Medica Scientia Innovation Research (MedSIR); Experior. Funding Roche Pharma AG. Disclosure E. Lopez-Miranda: Full / Part-time employment: Medica Scientia Innovation Research (MedSIR). S. Di Cosimo: Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy: Pfizer, TEVA, EpiOnpharma, Bayer; Travel / Accommodation / Expenses: Roche, GSK, Celgene; Advisory / Consultancy, Grant reviewer compensation: Swiss Cancer League; Research grant / Funding (institution): EISAI. E. Brain: Research grant / Funding (institution): TEVA (Cephalon), HalioDX (Qiagen/Ipsogen), Amgen; Honoraria (institution), Advisory / Consultancy: AstraZeneca, BMS, Celgene, Clinigen, Hospira, Janssen, Mylan, OBI Pharma, Pfizer, Puma, Roche, Samsung. M. Ravnik: Advisory / Consultancy, Board member: Roche; Advisory / Consultancy, Board member: Pfizer; Advisory / Consultancy, Board member: Eli Lilly; Advisory / Consultancy, Board member: Merck. S. Escriva-de-Romani: Advisory / Consultancy: Roche, Pierre Fabre; Speaker Bureau / Expert testimony: Roche, Pierre-Fabre, Kyowa-Kirin, Eisai, Celgene; Travel / Accommodation / Expenses: Roche, Daiichi Sankyo, Pierre Fabre. L. Calabuig: Full / Part-time employment: Medica Scientia Innovation Research (MedSIR). M. Sampayo: Full / Part-time employment: Medica Scientia Innovation Research (MedSIR). J.M. Perez-Garcia: Advisory / Consultancy: Roche, Lilly; Full / Part-time employment: Medica Scientia Innovation Research (MedSIR). F. Riva: Full / Part-time employment: Medica Scientia Innovation Research (MedSIR). A. Malfettone: Full / Part-time employment: Medica Scientia Innovation Research (MedSIR). A. Llombart Cussac: Honoraria (self), Advisory / Consultancy: Roche, GlaxoSmithKline, Novartis, Celgene, Eisai, AstraZeneca; Research grant / Funding (self): GlaxoSmithKline, Sanofi, Puma Biotechnology; Leadership role, Shareholder / Stockholder / Stock options, Officer / Board of Directors: Medica Scientia Innovation Research (MedSIR). J. Cortes: Advisory / Consultancy: Roche, Celgene, Cellestia, AstraZeneca, Biothera Pharmaceutical, Merus, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex; Honoraria (institution): Roche, Novartis, Celgene, Eisai, Pfizer, Samsung.; Research grant / Funding (institution): Roche, Ariad pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, F.Hoffman-La Roche, Guardanth health, Merck SharpD Advisory / Consultancy, Shareholder / Stockholder / Stock options, Officer / Board of Directors: Medica Scientia Innovation Research (MedSIR). All other authors have declared no conflicts of interest.