Background: Patients treated with Ado-Trastuzumab-Emtansine (T-DM1) are at risk of thrombocytopenia with the reported rate of 13% in metastatic patients of >3 toxicity. A recent report supports that off-target uptake of T-DM1 into megakaryocyte precursors may result in thrombocytopenia. It is unclear if this is the only mechanism to explain the thrombocytopenia since many patients have lower grade effects on platelets and often report mild mucosal bleeding. In this study, we will test whether platelet half-life in circulation or platelet function are also affected by treatment with T-DM1.

Trial design: We initiated a single institution Phase 1 study of T-DM1 in metastatic or unresectable breast cancer in any line of therapy. The general method is to collect autologous platelets, radiolabel the platelets ex vivo, and reinfuse them into patients to measure recovery (twice, at day 4 and again on day 7-9 days). The first 21-day cycle on protocol is to measure baseline platelet recovery (no T-DM1) followed by two cycles where platelet recovery is measured after T-DM1 infusion. Only, three radiolabeled platelet infusions occur on trial (2 with drug) after which disease response is assessed and patients can remain on drug at the discretion of the primary treating oncologist. In addition, patients will have platelet aggregation studies and bleeding times measured. Adult patients with Her2+ breast cancer are eligible for treatment provided they have adequate bone marrow (ANC > 1500 cells/mm3, Platelet >100,000/mm3, hemoglobin >9 g/dL), cardiac (Ejection fraction > 50%), kidney and liver function at baseline and have an ECOG performance score better than 2. Patients' prior treatment with chemotherapy or trastuzumab, if any, must have a >21 day washout period. Prior T-DM1 treatment is not permitted nor is a personal history of known platelet disorder (ITP, von Willebrand's disease). Patients with brain metastases are permitted to participate provided the disease is treated and is stable for >30 days.

Statistical methods: The primary goal is to measure platelet T1/2 following T-DM1 exposure and to compare this to baseline recovery. The proposed sample size of 20 participants is selected to insure that at least 15 patients will have complete data for all time points and study procedures. The first test performed will compare pre-therapy platelet lifespan to platelet lifespan on T-DM1 (cycles 1 and 2). Using platelet lifespan from normal controls to approximate pre-therapy values (mean 10.7 days, standard deviation 2.0), for 15 patients a two-sided paired t-test with alpha=0.05 would have 82% power to detect a 15% (1.605 days) decrease in platelet lifespan, assuming a correlation of 0.5 between paired values. The actual analysis will fit a linear mixed effects model, using a two-sided Wald test to compare pre-therapy to the two post-therapy values.

Accrual: The study activated in January 2015. One patient has undergone all study procedures. 3 Additional patients have been screened and 2 of these patients chose not to participate citing that the study had too many procedures and one was discovered to have had prior T-DM1 treatment. The investigators are in the process of opening the study to Her2 positive non-breast cancer patients to accelerate accrual.

Citation Format: Gadi VK, Butler BS, Corson J, Slichter SJ. Thrombokinetic studies of ado-trastuzumab emtansine (T-DM1). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT3-01-11.