Abstract OT-03-08: A Phase 2, open-label study to evaluate the safety and efficacy of the probody therapeutic (Pb-Tx) CX-2009 in metastatic HR-Positive/HER2-negative breast cancer (mHR+/HER2− BC) and of CX-2009 as monotherapy and in combination therapy with CX-072 in metastatic triple-negative breast cancer (TNBC)
Authors: Miller Kathy D. , Emens Leisha A. , Tolaney Sara , Hurvitz Sara A. , Hamilton Erika , Paton Virginia , Hannah Alison , Boni Valentina 
Published: February 2021

Abstract
Background: Probody® therapeutics (Pb-Tx) are masked antibodies designed to be selectively activated in the tumor microenvironment by tumor-associated proteases, while remaining largely inactive in normal tissue and in circulation. This allows Pb-Tx to address previously undruggable targets that are highly expressed in both tumor and normal tissue, such as the activated leukocyte cell adhesion molecule (ALCAM) CD166. CX-2009 is an investigational Probody drug conjugate consisting of an anti-CD166 monoclonal antibody conjugated to the microtubule inhibitor DM4. A Phase 1 study demonstrated safety and durable clinical activity in patients with mHR+/HER2− BC and in mTNBC patients who had received a median of 7 prior regimens. In the efficacy evaluable subgroup receiving doses of at least 4 mg/kg Q3W, the overall response rate (ORR; includes confirmed and unconfirmed responses) was 11% (HR+/HER2−; n=18) and 38% (TNBC; n=8), with a clinical benefit rate at 24 weeks (CBR24) of 35% in all breast cancer patients. Gr ≥3 DM4-associated ocular toxicities related to CX-2009 ≤7mg/kg were reported in 2%. In this Phase 2 study, CX-2009 monotherapy will be evaluated in patients with mHR+/HER2− BC and mTNBC. In addition, CX-2009 will be combined with CX-072, a Probody therapeutic directed against PD-L1, to evaluate the safety of the combination and whether the cytotoxic activity of the DM4 payload is additive with PD-L1 blockade via CX-072 in patients with mTNBC. CD166 expression in patients with HR+/HER2− BC was high (&gt;90%) in the Phase 1 study; this cohort will enroll without screening for CD166. CD166 expression in patients with TNBC was variable and, as such, patients will undergo screening for CD166 positivity.
Methods: This Phase 2, open-label noncomparative study with 3 parallel arms (n≈40/arm) is investigating the safety and activity of CX-2009 monotherapy (7 mg/kg Q3W) and the combination of CX-2009 (7 mg/kg Q3W) + CX-072 (1200 mg Q3W) in patients with previously treated locally advanced or metastatic HER2− BC. All patients will be adults with an ECOG status of 0-1, acceptable end-organ function, measurable disease, and willingness to receive ocular prophylaxis for DM4 related toxicities. Tumor tissue is required for CD166 expression analysis. Key eligibility criteria for the mHR+/HER2− BC cohort include 2-4 prior regimens (not including single-agent hormonal therapy). Patients with mTNBC must be CD166 positive by IHC and have received 1-3 regimens. For mTNBC patients who receive the doublet, key exclusion criteria include known PD-L1-negative tumor status, history of or active autoimmune disease, and progression within 120 days of first dose of an IO agent. Patients with active or chronic corneal disorders will be excluded from the study. All treatments will be given until disease progression or unacceptable toxicity. Radiology assessments will be done Q6W. The primary endpoint will be ORR assessed by an independent radiology committee per RECIST v1.1. Secondary endpoints will include ORR, DoR, CBR16 and CBR24, and PFS by investigator, OS will also be assessed. This study will also evaluate tolerability, pharmacokinetics, and antidrug antibodies with CX-2009 as monotherapy and in combination with CX-072. Exploratory endpoints will include potential predictive markers of response or toxicity. This trial is actively enrolling.
Email address for questions or comments: gpaton@cytomx.com
Citation Format: Kathy D. Miller, Leisha A. Emens, Sara Tolaney, Sara A. Hurvitz, Erika Hamilton, Virginia Paton, Alison Hannah, Valentina Boni. A Phase 2, open-label study to evaluate the safety and efficacy of the probody therapeutic (Pb-Tx) CX-2009 in metastatic HR-Positive/HER2-negative breast cancer (mHR+/HER2− BC) and of CX-2009 as monotherapy and in combination therapy with CX-072 in metastatic triple-negative breast cancer (TNBC) [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 OT-03-08.