Abstract P1-19-13: A phase II trial assessing the safety of an alternative dosing schedule of palbociclib (palbo) in hormone receptor positive (HR+), HER2 negative (HER2-) metastatic breast cancer (MBC): Alt Dose Palbo
Authors: Krishnamurthy Jairam , Luo Jingqin , Ademuyiwa Foluso , Suresh Rama , Rigden Caron , Reardon Timothy , Weilbaecher Katherine , Frith Ashley , Roshal Anna , Tandra Pavan , Cherian Mathew , Summa Tracy , Thomas Shana , Hernandez-Aya Leonel , Peterson Lindsay , Ma Cynthia 
Published: March 2020

Introduction: Palbo is approved in combination with an aromatase inhibitor or fulvestrant (FUL) for the treatment of HR+ HER2- MBC. The incidence of grade (G) 3/4 neutropenia (ANC) approaching 66% has been observed in phase 3 trials of palbo. We hypothesize that an alternative schedule of palbo, 5 days on/2 days off every 7 days, reduces the severity of neutropenia, therefore allowing continued weekly dosing and less dose reduction and discontinuation. Methods: A single arm phase II study (Alt Dose Palbo) was conducted in patients (pts) with HR+ HER2- MBC who had ≤1 prior systemic therapy in the metastatic setting (NCT03007979). Pts were treated with palbo 125 mg daily on a 5 days on/2 days off every 7-day schedule, along with letrozole (LET) or FUL per treating physician. Goserelin was administered if premenopausal. The primary objective was to determine the rate of G3/4 ANC within the first 29 days of treatment. Secondary objectives included determining the rate of G3/4 ANC during all cycles, rate of palbo dose reduction/interruption/discontinuation, adverse event (AE) profile per CTCAE v5, progression free survival (PFS), objective response rate (ORR) and clinical benefit rate (CBR) by RECIST 1.1. The sample size of 47 was calculated to provide 90% power based on one-sample binomial exact test at a 5% alpha level to test the one-sided null hypothesis of G3/4 ANC rate &gt;62% versus the alternative of &lt;40%. If G3/4 ANC was not observed in 24 or more pts, this alternative dosing will be deemed to have a better toxicity profile than standard schedule. Results: Between July 2017 to June 2019, 48 pts were enrolled at 2 institutions. 3 pts withdrew/went off during cycle 1 unrelated to the study, leaving 45 pts (33 LET, 12 FUL) with a median age of 63 (range: 34-87) years and visceral metastases in 23 (51%). Prior (neo) adjuvant chemotherapy and endocrine therapy (ET) were received in 20 (44%) and 25 (56%) pts, respectively. Six (13%) had 1 prior ET in the metastatic setting. 19 (42%) had primary or secondary endocrine resistance defined according to the ESMO advanced breast cancer guideline prior to enrollment to the study. As of July 1, 2019, with a median follow up of 9.5 months, 28 (62%) pts are still receiving study drug. 42 pts were evaluable for toxicities. There were no G4 AEs. Nine (21%) and 15 (36%) pts experienced G3 ANC in cycle 1 (up to day 29), and all cycles, respectively. 33 pts in cycle 1 and 27 pts in all cycles, did not experience G3/4 ANC during all cycles, exceeding the predefined boundary for better tolerability of this schedule. Palbo was dose reduced in 10 (23.8%) pts. Two (4.8%) discontinued palbo due to AE (one with G3 ANC not recovering to G1 in 2 wks and the other died (G5 event) with acute subdural hematoma with concurrent G3 thrombocytopenia). The common treatment related AEs are shown in the Table 1. The ORR was 48% (2 CR, 10 PR, 95% Wilson CI: 30-66.5%) among 25 evaluable pts. The CBR (defined by CR or PR or stable disease for at least 24 wks) was 76.74% (33 of 43 evaluable pts, 95% Wilson CI: 62.3-86.9%). PFS has not been evaluated. Conclusion: The Alt Dose Palbo trial with palbo scheduled at 5 days on/2 days off every 7 days, with no weeks off therapy, met its primary endpoint with reduced G3/4 ANC. Survival data is not yet mature and will be updated at the presentation. However, preliminary efficacy data appears comparable to prior report. Encouraging data from this study should be confirmed in a randomized study.

Table 1C1 D1-29 AEG1G2G3TotalWBC decreased26%50%17%93%ANC decreased10%43%21%74%Anemia38%12%0%50%Fatigue29%0%0%29%Platelets decreased14%0%2%17%Nausea12%2%0%14%All cycle AEG1G2G3TotalWBC decreased19%50%26%95%ANC decreased5%40%36%81%Anemia50%21%2%74%Fatigue36%5%0%40%Nausea26%2%0%29%Platelets decreased24%0%2%26%Alopecia21%0%0%21%Mucositis19%0%0%19%Hot flashes17%2%0%19%Constipation14%0%0%14%Arthralgia12%2%0%14%AST elevated10%0%2%12%Anorexia12%0%0%12%ALT elevated7%0%5%12%

Citation Format: Jairam Krishnamurthy, Jingqin Luo, Foluso Ademuyiwa, Rama Suresh, Caron Rigden, Timothy Reardon, Katherine Weilbaecher, Ashley Frith, Anna Roshal, Pavan Tandra, Mathew Cherian, Tracy Summa, Shana Thomas, Leonel Hernandez-Aya, Lindsay Peterson, Cynthia Ma. A phase II trial assessing the safety of an alternative dosing schedule of palbociclib (palbo) in hormone receptor positive (HR+), HER2 negative (HER2-) metastatic breast cancer (MBC): Alt Dose Palbo [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 P1-19-13.