Abstract P5-11-05: The cardo-oncology concerns of combining tamoxifen and ribociclib based on the TEEL trial
Authors: Ismail-Khan Roohi , Soliman Hatem , Hogue Deanna , Han Hyo Sook , Extermann Martine , Fradley Michael 
Published: March 2020

Background: The TEEL Study was an open labeled, non-randomized; phase I dose escalation followed by a planned phase Ib dose expansion trial of Tamoxifen (Tam) with Ribociclib (Ribo) in adult patients with advanced ER+ (HER2 negative) breast cancer. Ribo is an inhibitor of cyclin D1/CDK4 and CDK6 and has been successfully combined with Letrozole to improve PFS. This trial was done to examine the safety of the combination of Tam and Ribo in pre- and post-menopausal pts. The goal of the phase 1 expansion was to help confirm safety and develop a daily dosing schedule. Both Tam and Ribo were known to cause QTC prolongation and this was a major safety concern of the study. Method: This was an open labeled, non-randomized, phase I escalation study with a phase Ib dose expansion. The phase I portion of the study was a dose escalation to determine the safety of the combination and to determine the MTD and the RP2D for Ribo with Tam. Breast cancer patients with HR+/HER2- locally advanced or metastatic breast cancer with any prior endocrine therapy and up to two lines of prior cytotoxic chemotherapy regimens administered in the metastatic or locally advanced setting. The planned Phase Ib dose expansion was not done but was planned to better characterize the toxicity profile and assess the anti-tumor activity Ribo + Tam and to further evaluate the safety of the combination. Triplicate EKG were done at baseline, at C1D1, C1D15, C1D22, and then every subsequent cycle at day 1. Results: A total of 12 patients were screened and 7 patients were enrolled (with 5 screen failures). Ribociclib was given at 400 mg po daily for 21 days on and 7 days off. Tamoxifen was given per standard at 20 mg daily. The best response was partial response. Each cycle was 4 weeks and 1 patient remained on this combination for at least 12 cycles with PR, after cycle 3 and SD thereafter. Two patients developed significant QTC prolongation. Pt. # 3 was taken off study for QTC prolongation after cycle 8 with QTC &gt;501. Prior to that, her treatment had been interrupted twice due to QTC prolongation. Her First EKG was manually calculated at: QT 370ms, QTcb 427ms, QTcf 407ms. Her Longest EKG: QT 402ms, QTcb 514ms, QTcf 473ms. Pt #12 was also taken off study during cycle 6 due to QTC&gt;501. Her first EKG: QTc382ms, QTcb 480ms, QTcf 445ms. “Longest ekg” QTc 432ms, QTcb 496ms, QTcf 473ms. Both of these patients had prolonged QTC based on manual EKG. Dose limiting toxicity was noted in patient #10 who was noted to develop progression of disease (new leptomeningeal disease) after cycle 1 and subsequently had a CVA off study, thought to be associated with progressive disease. Table 1 describes highest QTC vs. cycle of therapy and there does not appear to be evidence of worsening prolongation with the number of cycles on study drugs. Other AEs were noted - please see table 2 for AEs. Conclusions: The combination of Tam and Ribo was not considered to be safe and there were two DLTs in the phase 1 part of the study, leading to the early stopping. The phase I expansion was not completed. There were 5 events of prolonged QTC, one event was determined to be a DLT. The other DLT was a CVA described above (associated with CNS disease). Unfortunately, the combination was limited by the synergistic effects of QTC prolongation of both Tam and Ribo. The importance of manually calculating the EKGs and utilizing the Fridericia formula was noted in this study. The Fidercicia is more accurate in oncology patients as it demonstrates less overcorrection than the Bazzett formula at faster heart rates which a were re quite common in cancer patients. Rational limits must be implemented to ensure patient safety without unnecessary withholding of potentially lifesaving cancer therapies. The relative risk of arrhythmia is 1.2 for QT intervals &gt;500ms and is exceedingly low at QT intervals less than 500ms.

QTC duirng each cycleCyclesC1C3C5C7C9C10C11C12Pt. 1475475468465477457481477Pt. 2412421412Pt. 3463462494689479Pt. 8450443Pt. 10420Pt. 11431435437Pt. 12480475513525

Citation Format: Roohi Ismail-Khan, Hatem Soliman, Deanna Hogue, Hyo Sook Han, Martine Extermann, Michael Fradley. The cardo-oncology concerns of combining tamoxifen and ribociclib based on the TEEL trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-11-05.