Abstract P5-17-08: A phase Ib/II study of leronlimab combined with carboplatin in patients with CCR5+ metastatic triple-negative breast cancer (mTNBC)
Authors: Cristofanilli Massimo , Chittoria Namita , Ehsani Sima , Rui Hallgeir , Dolezal Milana , Stork-Sloots Lisette , de Snoo Femke , Recknor Christopher , Abramson Vandana 
Published: March 2022

Abstract
Background C-C Chemokine Ligand type-5 (CCR5) is overexpressed in &gt;95% of TNBC and has been correlated with disease progression. Moreover, enhancement of DNA repair signaling by CCR5 activation may contribute to chemotherapy resistance. Therefore, blocking CCR5 may result in increased immune response against tumor cells and synergize with chemotherapy. Leronlimab (PRO 140) is a humanized monoclonal antibody to CCR5. Preclinical data showed leronlimab binds human CCR5, blocks CCR5-mediated signaling, and CCL5-induced breast cancer cell invasion. The therapeutic antibody leronlimab has been administered to over 800 healthy and HIV-1 infected individuals with good tolerance and without obvious dose-related toxicity, making it an ideal partner for chemotherapy combinations in TNBC. Methods In this ongoing phase 1B/2 study, patients with CCR5+ mTNBC with ≤2 line of therapy in the metastatic setting (no prior carboplatin) are treated with weekly subcutaneous leronlimab (3 dose levels, 3+3 dose escalation) and a fixed dose of carboplatin AUC 5 on day 1 with a 21-day dose-limiting toxicity (DLT) window, followed by expansion in 30 patients with CCR5+ mTNBC who are naïve to chemotherapy in the metastatic setting or who have failed first-line combination of chemotherapy (excluding carboplatin) and a checkpoint inhibitor in the metastatic setting. CCR5 positivity is centrally assessed by IHC and defined as &gt;10% CCR5 staining in primary or metastatic tumor cells and/or high predominance of CCR5+ tumor-infiltrating leukocytes (TIL). Primary objectives are safety, tolerability, determination of maximum tolerated dose, and determination of the recommended phase 2 dose (RP2D). Results Fifteen patients had archived tumor tissue assessed for CCR5 expression, with 12 being CCR5 positive (median expression 20%, range 0 - 100%, and 7 out of 12 high CCR5+ TILs) . A total of ten patients (median age 51 years; median 2 prior therapies) have been enrolled at 3 dose levels (350, 525, and 700 mg). In the second cohort, 1 additional patient was inadvertently enrolled. All patients completed the DLT assessment period and no DLTs have been observed. Patients received between 3 and 27 doses of leronlimab with the number of cycles ranging from 1 to 9. Five patients remain on treatment. The most common treatment-emergent adverse events (TEAEs) by any grade were: fatigue (6/10), headache (4/10), constipation (3/10), and nausea (3/10). The following grade ≥3 TEAEs were reported: neutropenia, anemia, thrombocytopenia, hyponatremia, hypertension, diarrhea and headache. Serious Adverse Events were reported in 2 patients (grade 2 sepsis and grade 3 headache). The following leronlimab treatment related adverse events (TRAEs) occurred (all grade 1): injection site reaction in cohort 1, fatigue (n=2) and headache in cohort 2. Three carboplatin TRAEs ≥3 were reported in one patient in cohort 1: thrombocytopenia, anemia and leukopenia. Two out of seven patients eligible for response achieved a confirmed partial response, and 4 patients stable disease. Conclusions Leronlimab, in combination with carboplatin, has been well-tolerated in all 3 dose levels with early signs of anti-tumor activity in patients with CCR5+ mTNBC. The study is currently enrolling patients at the RP2D dose of leronlimab 700mg in combination with carboplatin AUC 5 in the phase 2 part of the trial. Clinical trial information: NCT03838367
Citation Format: Massimo Cristofanilli, Namita Chittoria, Sima Ehsani, Hallgeir Rui, Milana Dolezal, Lisette Stork-Sloots, Femke de Snoo, Christopher Recknor, Vandana Abramson. A phase Ib/II study of leronlimab combined with carboplatin in patients with CCR5+ metastatic triple-negative breast cancer (mTNBC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-17-08.