Anticancer targeted agent combination

Abstract

Cancer is a highly frequent disease associated to high mortality. Drug development in Oncology has shown to be inefficient, having one of the lowest success rate of drugs entering in phase I trials that finally achieves marketed authorization. The main reason for this high failure rate is lack of efficacy. Different strategies have been adopted to improved anti-cancer drug development with the aim of improving patient care. This strategies include the combinatorial use of agents, biomarker co-development, and optimization of clinical trial design with the use of pharmacokinetic-pharmacodynamic modeling. This thesis is presented as compendium of work integrating two projects; the first project preclinically evaluates the combination of two PI3K-mTOR inhibitors and chemotherapy or the pan-HER inhibitor dacomitinib in patient derived xenografts. The second project evaluates de monoclonal antibody anti-CCL2 carlumab in patient derived xenografts. Project 1: Three PDXs were selected for their lack of PTEN expression by immunohistochemistry: a triple-negative breast cancer (TNBC), a KRAS G12R low-grade serous ovarian cancer (LGSOC), and KRAS G12C and TP53 R181P lung adenocarcinoma (LADC). Two dual PI3K-mTOR inhibitors were evaluated—PF-04691502 and PF-05212384—in combination with cisplatin, paclitaxel, or dacomitinib. The addition of PI3K-mTOR inhibitors to cisplatin or paclitaxel increased the activity of chemotherapy in the TNBC and LGSOC models; whereas no added activity was observed in the LADC model. Pharmacodynamic modulation of pS6 and pAKT was observed in the group treated with PI3K-mTOR inhibitor. Our research suggests that the addition of a PI3K-mTOR inhibitor may enhance tumor growth inhibition when compared to chemotherapy alone in PTEN-deficient PDXs. However, this benefit was absent in the KRAS and TP53 mutant LADC model. The role of PTEN deficiency in the antitumor activity of these combinations should be further investigated in the clinic. Project 2 is a first-in-human phase 1b study of carlumab with one of four chemotherapy regimens (docetaxel, gemcitabine, paclitaxel+carboplatin, and pegylated liposomal doxorubicin HCl [PLD]). Fifty-three patients with advanced solid tumors for which ≥1 of these regimens was considered standard of care or for whom no other treatment options existed participated in the study: docetaxel (n=15), gemcitabine (n=12), paclitaxel or carboplatin (n=12), or PLD (n=14). Dose-limiting toxicities included one grade 4 febrile neutropenia (docetaxel arm) and one grade 3 neutropenia (gemcitabine arm). The most common drug-related grade ≥3 adverse events were docetaxel arm—neutropenia (6/15) and febrile neutropenia (4/15); gemcitabine arm—neutropenia (2/12); paclitaxel+carboplatin arm—neutropenia, thrombocytopenia (4/12 each), and anemia (2/12); and PLD arm—anemia (3/14) and stomatitis (2/14). One partial response and 18 (38 %) stable disease responses were observed. Combination treatment with carlumab had no clinically relevant pharmacokinetic effect on any of the chemotherapeutic agents tested. Free CCL2 declined immediately post-treatment with carlumab but increased with further chemotherapy administrations in all arms, suggesting that carlumab could sequester CCL2 for only a short time. Neither antibodies against carlumab nor consistent changes in circulating tumor cells (CTCs) or circulating endothelial cells (CECs) enumeration were observed. Three of 19 evaluable patients showed a 30 % decrease from baseline urinary cross-linked N-telopeptide of type I collagen (uNTx). Carlumab could be safely administered at 10 or 15 mg/kg in combination with standard-of-care chemotherapy and was well-tolerated, although no long-term suppression of serumCCL2 or significant tumor responses were observed.

Date of Award	28 Sept 2017
Original language	English
Supervisor	Jorge Luis Giralt (Director), Nhu-An Pham (Director) & Josep Maria Tabernero Caturla (Director)