Abstract PD1-01: Trilaciclib (T), a CDK4/6 inhibitor, dosed with gemcitabine (G), carboplatin (C) in metastatic triple negative breast cancer (mTNBC) patients: Preliminary phase 2 results
Authors: O'Shaughnessy J , Wright GS , Thummala AR , Danso MA , Popovic L , Pluard TJ , Cheung E , Han HS , Daniel BR , Vojnovic Z , Vasev N , Ling M , Richards DA , Wilks ST , Milenkovic D , Sorrentino JA , Roberts PJ , Bomar M , Yang Z , Antal JM , Malik RK , Morris SR , Tan A 
Published: May 2019

Abstract
Background: Cytotoxic chemotherapy-induced damage of hematopoietic stem and progenitor cells (HSPCs) results in acute toxicities consisting of multi-lineage myelosuppression, and late onset toxicities consisting of progressive bone marrow suppression with increased incidence of therapy-related myeloid neoplasms. T is an IV CDK4/6 inhibitor in development to preserve HSPC and immune system function during cytotoxic chemotherapy (myelopreservation). Proof of concept for myelopreservation with T was observed in a randomized, placebo-controlled Phase 2 trial in small-cell lung cancer patients receiving 1st-line chemotherapy. This trial in mTNBC patients (NCT02978716) was designed to explore the utility of T in combination with GC.
Methods: This Phase 2, randomized, open-label study enrolled patients in the US and EU with mTNBC who had received 0-2 prior systemic cytotoxic therapies in the locally recurrent or metastatic setting and had no symptomatic brain metastases. Patients were randomized (1:1:1) to GC alone (Group 1) or T plus GC (Group 2) using a standard schedule (D1, 8 every 21 days) or to an alternative schedule (T on D1, 2, 8 and 9 with GC on D2 and 9 every 21 days; Group 3). On those days when both T and GC were scheduled, T was administered iv prior to GC infusion. Prophylactic growth factors were not administered in cycle 1; otherwise supportive care was allowed as needed. Primary objectives were safety and tolerability; tumor response was evaluated using RECIST v1.1 and PFS and OS were assessed. Myelopreservation endpoints reflecting the potential effects of T on multiple cellular lineages include occurrence of Grade 4 neutropenia (primary), RBC and platelet transfusions (primary), and lymphocyte counts with immune profiling (secondary and exploratory). A signature of CDK4/6 independence developed from preclinical data will be used to evaluate archival tumor tissue samples and data analysis is ongoing.
Results: 95 patients were dosed; median age 57 years (range 32,86), ECOG PS 0 (53%) or 1 (47%), 25% had liver metastases at baseline, and approximately 50% had received no systemic therapy in the recurrent/metastatic setting. Fifty-five patients remain on treatment. Disease progression was the most common reason for drug discontinuation (22/40; 55%). Overall the most common (≥ 25%) TEAEs were anemia (47%), nausea (35%), fatigue (34%), neutropenia (32%), platelet count decreased (25%), and vomiting (25%). The most frequent (≥ 15%) Grade 3 or 4 TEAEs were hematologic toxicities, i.e. neutropenia (28%), anemia (21%), neutrophil count decreased (21%) and thrombocytopenia (16%). These were also the most frequent drug-related TEAEs observed. Tumor efficacy data are being evaluated.
Conclusions: This trial, assessing the myelopreservation effects of T when combined with GC in patients with mTNBC, has completed enrollment. Myelopreservation data, immune profiling, as well as ORR and preliminary PFS results will be presented by study arm at the meeting.
Citation Format: O'Shaughnessy J, Wright GS, Thummala AR, Danso MA, Popovic L, Pluard TJ, Cheung E, Han HS, Daniel BR, Vojnovic Z, Vasev N, Ling M, Richards DA, Wilks ST, Milenkovic D, Sorrentino JA, Roberts PJ, Bomar M, Yang Z, Antal JM, Malik RK, Morris SR, Tan A. Trilaciclib (T), a CDK4/6 inhibitor, dosed with gemcitabine (G), carboplatin (C) in metastatic triple negative breast cancer (mTNBC) patients: Preliminary phase 2 results [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD1-01.