Phase Ib study of CNTO 888 (anti-CCL 2) in combination with chemotherapies for treatment of patients with solid tumors.

Abstract

3059 Background: CC-chemokine ligand 2 (CCL2) is expressed in various malignancies, implicated in angiogenesis, proliferation and metastasis. CNTO888 is a hIgG1κ mAb with selective high CCL2 binding affinity and showed preclinical antitumor activity. Methods: Primary objectives were safety and a recommended dose of CNTO 888 in combination with chemotherapy: Arm 1 - 15 mg/kg CNTO 888 + docetaxel 75 mg/m2 Q3W; Arm 2 - 15 mg/kg CNTO 888 + gemcitabine 1000 mg/m2 on D1 and 8 Q3W; Arm 3 - 15 mg/kg CNTO 888 + paclitaxel 175 mg/m2 and carboplatin AUC6 Q3W; Arm 4 - 10 mg/kg CNTO 888 Q2W + pegylated doxorubicin 50 mg/m2 Q4W. Two (Arms 1, 2, 3) or 4 (Arm 4) prior chemotherapies for advanced disease were allowed. Pharmacokinetic (PK) profile of CNTO 888 and chemotherapies, free and total CCL2, CTC/CEC count, and uNTX were evaluated. Adverse events (AE) and dose limiting toxicities (DLT) were evaluated after 6 subjects completed 1 cycle. Results: 53 subjects (22F/31M) were treated: Arm 1 n=15, Arm 2 n=12, Arm 3 n=12, Arm 4 n=14. Two DLTs occurred: a grade 4 febrile neutropenia (Arm 1) and a grade 3 neutropenia (Arm 2). All 4 combinations were found to be safe and tolerable and continued enrolment to a minimum of 12 subjects evaluable for safety and PK. Best overall response were partial response (PR) (1) and stable disease (18; 2 ≥ 4 months). One subject with pancreatic adenocarcinoma achieved PR, allowing for surgical resection. Most frequently reported (≥ 20%) related serious AEs are: Arm 1: Neutropenia, Stomatitis, Fatigue, Febrile neutropenia, Alopecia. Arm 2: Anemia. Arm 3: Thrombocytopenia, Alopecia, Neutropenia, Asthenia, Fatigue, Anemia, Arthralgia, Nausea, Vomiting. Arm 4: Stomatitis, Rash, Fatigue, Nausea, Anemia, Neutropenia. CNTO 888 did not affect the chemotherapy PK profile; similarly, chemotherapy did not affect the CNTO 888 PK profile. No subjects (n=38) tested positive for antibodies to CNTO 888. Free CCL2 declined 2 hrs post treatment and returned to baseline levels by 48 hrs and continued to increase with further administrations in all treatment arms. There were no consistent changes with other biomarkers. Conclusions: CNTO 888 in combination with standard chemotherapy was well tolerated but few objective responses were seen.