Abstract PS11-33: A first-in-human Phase 1/1b multicenter, open-label dose escalation study to assess safety and tolerability of PMD-026, a first-in-class oral RSK inhibitor, in metastatic breast cancer patients
Authors: Beeram Murali , Wang Judy S. , Chalasani Pavani , Mina Lida , Patnaik Amita , Pambid Mary Rose , Jayanthan Aarthi , Huynh My-my , Los Gerrit , Dunn Sandra E. , Dorr F. Andrew 
Published: February 2021

Abstract
Background: Metastatic breast cancer (mBC) remains an aggressive disease with limited durable treatment options; the worst prognosis among the breast cancer subtypes is typically seen in metastatic triple-negative breast cancer (mTNBC). Given that unmet need, we sought to identify an actionable molecular target to combat mTNBC. Promising preclinical activity identified p90 ribosomal s6 kinase 2 (RSK2) as a key kinase in mTNBC. PMD-026 is a potent, oral, small molecular RSK inhibitor with high selectivity for the RSK2 isoform. RSK is a major convergence point in the important MAPK and PDK-1 signaling pathways, which drive TNBC cell survival, proliferation, and drug resistance.
Methods: The primary aim of this single-arm, open-label, first-in-human, phase 1/1b study (NCT04115306) is to evaluate the safety of single agent PMD-026 in patients with mBC. Secondary endpoints are clinical activity, pharmacokinetics (PK) and correlative biomarker expression on tumor specimens. Patients are dosed orally once or twice daily in 21-day cycles with measures to adapt the dosing schedule based on the PK data, as needed. In dose escalation, patients must have mBC with evaluable or measurable disease by RECIST v1.1. In dose expansion, patients must have mTNBC with measurable disease by RECIST v1.1. Patients must have progressed on or after standard of care therapy. Tumor tissue is required to retrospectively correlate RSK2 activity with clinical outcomes via immunohistochemistry using a CAP/CLIA certified companion diagnostic (CDx).
Results: Twelve mBC patients (ER+ mBC n=5, mTNBC n=7) who have failed standard chemotherapy as well as targeted therapies such as CDK4/6 inhibitors and immunotherapies have been enrolled to date. Patients have been treated in escalating cohorts of 25, 50, 100, 200, 400 (200 q12) or 600 mg (300 q12) of PMD-026 administered orally daily. At 400 mg the dose schedule was changed from daily to q12 hrs based on PK results to optimize drug exposure over a 24-hr timeframe in patients. The PK of PMD-026 showed linear exposure and a high volume of distribution. The AUC was ~9100 hr*ng/ml on Day 1 when PMD-026 was dosed at 200 mg qd demonstrating high exposure. In addition, when dosed at 200 mg q12 hrs, PMD-026 serum levels approached the preclinically established desired level of 1 µM over 24 hrs. In the 200 mg q12 hrs cohort, adverse events consisted of G2 GERD (n=1) and G2 neutropenia (n=1). Initial signs of activity were observed as CT-identified necrosis in a neck node metastasis (n=1) and transient decrease in CA 27-29 (n=1). While the 200 mg q12 hrs dose was generally well-tolerated, there were 2 dose limiting toxicities at 300 mg q12 hrs including syncope (n = 1) and vomiting with dehydration leading to reversible acute kidney injury (n = 1). To further understand the patient population, RSK2 activation was assessed in tumor samples from all patients. RSK2 was activated in all of the tumors and the H-Score ranged from 110 to 198 using the CDx platform.
Conclusions: Preliminary evidence indicates that PMD-026 is well-tolerated at dose levels up to 200 mg q12 with initial signs of activity; pharmacokinetics showed good linear exposure. Updated safety, clinical activity, pharmacokinetic and biomarker analyses will be presented; target accrual for Phase 1b Expansion is approximately 20 mTNBC patients. (clinicaltrials.gov NCT04115306).
Citation Format: Murali Beeram, Judy S. Wang, Pavani Chalasani, Lida Mina, Amita Patnaik, Mary Rose Pambid, Aarthi Jayanthan, My-my Huynh, Gerrit Los, Sandra E. Dunn, F. Andrew Dorr. A first-in-human Phase 1/1b multicenter, open-label dose escalation study to assess safety and tolerability of PMD-026, a first-in-class oral RSK inhibitor, in metastatic breast cancer patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-33.