CX-072 (pacmilimab), a Probody® PD-L1 inhibitor, in advanced or recurrent solid tumors (PROCLAIM-CX-072): an open-label dose-finding and first-in-human study

Background: Probody® therapeutics are antibody prodrugs that are activated in the tumor microenvironment by tumor-associated proteases, thereby restricting the activity to the tumor microenvironment and minimizing ‘off-tumor’ toxicity. We report dose-escalation and single-agent expansion phase data from the first-in-human study of CX-072 (pacmilimab), a Probody checkpoint inhibitor directed against programmed death-ligand 1 (PD-L1). / Methods: In the dose-escalation phase of this multicenter, open-label study (NCT03013491), adults with advanced solid tumors (naive to programmed-death-1/PD-L1 or cytotoxic T-lymphocyte-associated antigen 4 inhibitors) were enrolled into one of seven dose-escalation cohorts, with pacmilimab administered intravenously every 14 days. The primary endpoints were safety and determination of the maximum tolerated dose (MTD). In the expansion phase, patients with one of six prespecified malignancies (triple-negative breast cancer [TNBC]; anal squamous cell carcinoma [aSCC]; cutaneous SCC [cSCC]; undifferentiated pleomorphic sarcoma [UPS]; small bowel adenocarcinoma [SBA]; and thymic epithelial tumor [TET]); or high tumor mutational burden (hTMB) tumors were enrolled. The primary endpoint was objective response (Response Evaluation Criteria In Solid Tumors v.1.1). / Results: An MTD was not reached with doses up to 30 mg/kg. A recommended phase 2 dose (RP2D) of 10 mg/kg was chosen based on pharmacokinetic and pharmacodynamic findings in the expansion phase. Ninety-eight patients enrolled in the expansion phase: TNBC (n=14), aSCC (n=14), cSCC (n=14), UPS (n=20), SBA (n=14), TET (n=8), and hTMB tumors (n=14). Of 114 patients receiving pacmilimab at the RP2D, grade ≥3 treatment-related adverse events (TRAEs) were reported in 10 patients (9%), serious TRAEs in six patients (5%), and treatment discontinuation due to TRAEs in two patients (2%). Grade ≥3 immune-related AEs occurred in two patients (rash, myocarditis). High PD-L1 expression (ie, >50% Tumor Proportion Score) was observed in 22/144 (19%) patients. Confirmed objective responses were observed in patients with cSCC (n=5, including one complete response), hTMB (n=4, including one complete response), aSCC (n=2), TNBC (n=1), UPS (n=1), and anaplastic thyroid cancer (n=1). / Conclusions: Pacmilimab can be administered safely at the RP2D of 10 mg/kg every 14 days. At this dose, pacmilimab had a low rate of immune-mediated toxicity and showed signs of antitumor activity in patients not selected for high PD-L1 expression. / Trial registration number: NCT03013491

A model of hypertension and proteinuria in cancer patients treated with the anti-angiogenic drug E7080

Hypertension and proteinuria are commonly observed side-effects for anti-angiogenic drugs targeting the VEGF pathway. In most cases, hypertension can be controlled by prescription of anti-hypertensive (AH) therapy, while proteinuria often requires dose reductions or dose delays. We aimed to construct a pharmacokinetic–pharmacodynamic (PK–PD) model for hypertension and proteinuria following treatment with the experimental VEGF-inhibitor E7080, which would allow optimization of treatment, by assessing the influence of anti-hypertensive medication and dose reduction or dose delays in treating and avoiding toxicity. Data was collected from a phase I study of E7080 (n = 67), an inhibitor of multiple tyrosine kinases, among which VEGF. Blood pressure and urinalysis data were recorded weekly. Modeling was performed in NONMEM, and direct and indirect response PK–PD models were evaluated. A previously developed PK model was used. An indirect response PK–PD model described the increase in BP best, while the probability of developing proteinuria toxicity in response to exposure to E7080, was best described by a Markov transition model. This model may guide clinical interventions and provide treatment recommendations for E7080, and may serve as a template model for other drugs in this class

The in vivo properties of STX243: a potent angiogenesis inhibitor in breast cancer

The steroidal-based drug 2-ethyloestradiol-3,17-O,O-bis-sulphamate (STX243) has been developed as a potent antiangiogenic and antitumour compound. The objective of this study was to ascertain whether STX243 is more active in vivo than the clinically relevant drug 2-methoxyoestradiol (2-MeOE2) and the structurally similar compound 2-MeOE2-3,17-O,O-bis-sulphamate (STX140). The tumour growth inhibition efficacy, antiangiogenic potential and pharmacokinetics of STX243 were examined using four in vivo models. Both STX243 and STX140 were capable of retarding the growth of MDA-MB-231 xenograft tumours (72 and 63%, respectively), whereas no inhibition was observed for animals treated with 2-MeOE2. Further tumour inhibition studies showed that STX243 was also active against MCF-7 paclitaxel-resistant tumours. Using a Matrigel plug-based model, in vivo angiogenesis was restricted with STX243 and STX140 (50 and 72%, respectively, using a 10 mg kg−1 oral dose), thereby showing the antiangiogenic activity of both compounds. The pharmacokinetics of STX243 were examined at two different doses using adult female rats. The compound was orally bioavailable (31% after a single 10 mg kg−1 dose) and resistant to metabolism. These results show that STX243 is a potent in vivo drug and could be clinically effective at treating a number of oncological conditions

Tivozanib for the treatment of renal cell carcinoma: patient selection and perspectives

RJ Rodenburg, FALM EskensErasmus MC Cancer Institute, Department of Medical Oncology, Rotterdam, The NetherlandsAbstract: Tivozanib is an oral selective vascular endothelial growth factors receptor (VEGFR) tyrosine kinase inhibitor that is recently approved by the European Medicines Agency for the treatment of previously untreated patients with metastatic renal cell carcinoma (mRCC) as well as for those patients with disease progression during or after cytokine therapy. Nowadays, in first-line and second-line treatment of mRCC, there is an abundance of options, mainly consisting of VEGFR-directed tyrosinekinase inhibitors. This review focusses on the role of tivozanib with respect to patient selection and future perspectives in this fast-changing landscape.Keywords: tivozanib, metastatic renal cell cancer, tyrosine kinase inhibito

A phase II open-label study of DHA-paclitaxel (Taxoprexin) by 2-h intravenous infusion in previously untreated patients with locally advanced or metastatic gastric or oesophageal adenocarcinoma

Purpose Combination chemotherapy regimens can improve survival in patients with advanced gastric and oesophageal adenocarcinoma. Docosahexaenoic acid (DHA)-paclitaxel is a novel conjugate formed by the covalent linkage of the fatty acid DHA to paclitaxel and may result in increased tumour exposure to paclitaxel without increased toxicity. Patients and methods In this single arm, phase II study of DHA-paclitaxel, eligible patients with previously untreated, inoperable locally advanced or metastatic adenocarcinoma of the oesophagus, oesophago-gastric junction or stomach were treated with DHA-paclitaxel (1,100 mg/m(2)) administered by 2-h intravenous infusion every 21 days. Results Fifty-four patients were recruited of whom 53 were evaluable for toxicity, and 48 for response. There were five confirmed partial responses (9.4%) by the RECIST criteria. The median duration of response was 87 days (range 49-97 days), the median time to progression was 84 days (95% CI 78-124 days), and median overall survival was 262 days (95% CI 205-357 days). Grade >= 3 neutropaenia occurred in 93% of patients, and febrile neutropaenia in 17% of patients. Conclusions DHA-paclitaxel has modest activity in patients with oesophago-gastric cancer and with haematological toxicity that is comparable to paclitaxel and docetaxel