Abstract A49: Clinically efficacy of the BET bromodomain inhibitor TEN-010 in an open-label substudy with patients with documented NUT-midline carcinoma (NMC)

Introduction: The chemical probe JQ-1 is a thienodiazepine BET-bromodomain inhibitor targeting BRD4 with previously reported efficacy in a patient-derived xenograft mouse model of NMC. TEN-010 is structurally related to JQ1 with superior chemical and biological properties currently under clinical study study solid tumors, including NMC, and hematologic malignancies. NMC is a squamous cell carcinoma commonly observed in midline structures in the lung and mediastinum, and commonly involves a t(15:19) chromosomal translocation encoding a chimeric BRD4-NUT fusion protein. This rare, with estimates of less than 100 people in the United States, disease is typically unresectable, poorly responsive to chemotherapies and clinically aggressive with median survival of ∼ 6 months establishing an unmet need for targeted therapy. Design: A Phase 1 dose escalation “3+3” multi-center study is being conducted in adults with advanced solid tumors. A separate sub-study enrolls patients with NMC at the highest tolerated dose level at the time of patient screening. The NMC patients received subcutaneous daily dosing of TEN-010 for three weeks in a four-week cycle. Patients must have documented NMC by FISH or IHC and cannot not be on chemotherapy at time of treatment. Patients are monitored for safety, pharmacokinetics and pharmacodynamics measured at initial dose and at steady-state, and assessment of anti-tumor activity assessed by RECIST 1.1. (CT) or PET/CT. Pharmacodynamics use a peripheral blood bioassay serially examining systemic integrin expression with TEN-010 dosing. Results: Data are available for the three NMC patients; 1 patient received TEN-010 at 0.1 mg/kg and 2 received 0.45 mg/kg. The 0.1 mg/kg patient had disease progression after 2 weeks. Both patients at the 0.45 mg/kg dose had clinical responses. One patient exhibited a 30% and 50% NMC tumor regression after cycles 1 and 2, respectively. This patient demonstrated rapid symptomatic improvement within two weeks, and remains on therapy into Cycle 3. The other patient exhibited a reduction of ∼50% summed SUV(max) by PET/CT with symptomatic improvement evident after three weeks of therapy during Cycle 1. This patient received two cycles of therapy before having disease progression. Plasma LDH in the 0.45 mg/kg patients, but not the 0.1 mg/kg patient, decreased after one week on treatment; the first 0.45 mg/kg pt had normal LDH through Cycle 2 with continued values in the normal range. On-target pharmacodynamic activity corroborated LDH response. This regimen has been tolerated with grade 1 irritation of the injection site and mild/moderate increases in indirect bilirubin and anorexia. All adverse events have been reversible. Discussion: This is the first documented partial response in NMC using a BET inhibitor. Reduced metabolic activity and clinical responses also are observed Overall the results serve as proof of concept and validate pre-clinical xenograft studies. Further testing and exploration of the optimal dosing regimen are on-going. The results support the promise for TEN-010 as an important new needed treatment for NMC. Citation Format: Geoffrey I. Shapiro, Afshin Dowlati, Patricia M. LoRusso, Joseph P. Eder, Adrienne Anderson, Khanh T. Do, Michael H. Kagey, Cynthia Sirard, James E. Bradner, Steven B. Landau. Clinically efficacy of the BET bromodomain inhibitor TEN-010 in an open-label substudy with patients with documented NUT-midline carcinoma (NMC). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A49.