2674 - Multicenter Phase I Trial of Trastuzumab Emtansine (T-DM1) in Combination with Non-Pegylated Liposomal Doxorubicin (NPLD) in HER2[+] Metastatic Breast Cancer (MBC). THELMA Study

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 <0.5x10⁹/L lasted 13 days). The most common ≥G3 adverse events (AEs) were neutropenia (53.3%), AST increase (13.3%), and thrombocytopenia (13.3%). No ≥G3 cardiac AEs occurred. The median duration of treatment and relative dose intensity were 3.7 months and 85%, respectively. The median progression-free survival (mPFS), overall response rate (ORR), and clinical benefit rate (CBR) was 7.2 months, 40%, and 46.7%, respectively. The mPFS, ORR, and CBR in cohort 3 was 7.2 months, 33.3%, and 44.4%, respectively. The analysis of PK profile is ongoing.

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.

Editorial acknowledgement

Legal entity responsible for the study

Medica Scientia Innovation Research (MedSIR); Experior.

Funding

Roche Pharma AG.

Disclosure

E. López-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. Escrivá-de-Romaní: 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. Pérez-García: 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. Cortés: 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 Sharp&Dohme, Pfizer, Piqur Therapeutics, Puma C, Queen Mary University of London; Advisory / Consultancy, Shareholder / Stockholder / Stock options, Officer / Board of Directors: Medica Scientia Innovation Research (MedSIR). All other authors have declared no conflicts of interest.