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In Patients with Previously Treated Solid Tumors

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In Patients with Previously Treated Solid Tumors Investigational New Drugs (2019) 37:461–472 https://doi.org/10.1007/s10637-018-0665-y PHASE I STUDIES A first-in-human phase 1a study of the bispecific anti-DLL4/anti-VEGF antibody navicixizumab (OMP-305B83) in patients with previously treated solid tumors Antonio Jimeno1 & Kathleen N. Moore2,3 & Michael Gordon4 & Rashmi Chugh5 & Jennifer R. Diamond1 & Raid Aljumaily2,3 & David Mendelson4 & Ann M. Kapoun6 & Lu Xu6 & Robert Stagg6 & David C. Smith5 Received: 18 July 2018 /Accepted: 3 September 2018 /Published online: 19 September 2018 # Springer Science+Business Media, LLC, part of Springer Nature 2018 Summary Purpose Navicixizumab (OMP-305B83) is a bispecific antibody that inhibits delta-like ligand 4 and vascular endothelial growth factor. This Phase 1a trial assessed escalating doses of navicixizumab in refractory solid tumors patients. Design A 3 + 3 dose escalation design was used followed by the treatment of additional patients in an expansion cohort. Study objectives were determination of the maximum tolerated dose, safety, pharmacokinetics, pharmacodynamics, immunogenicity and efficacy. Results Sixty-six patients were treated once every 3 weeks in 8 dose-escalation cohorts (0.5, 1, 2.5, 3.5, 5, 7.5, 10, and 12.5 mg/kg) and an expansion cohort (7.5 mg/kg). The median age was 60 years and 68% of the patients were female. The most commonly enrolled tumor types were ovarian (12), colorectal (11) and breast, pancreatic, uterine and endometrial (4 each) cancers. As only 1 dose limiting toxicity occurred, the maximum tolerated dose was not reached, but 7.5 mg/kg was chosen as the dose for the expansion cohort. The treatment related adverse events (≥15% of patients) were hypertension (57.6%), headache (28.8%), fatigue (25.8%), and pulmonary hypertension (18.2%). Pulmonary hypertension was mostly asymptomatic at doses ≤5 mg/kg (6 Gr1, 1 Gr2), but was more severe at higher doses (4 Gr2, 1 Gr3). Navicixizumab’s half-life was 11.4 days and there was a moderate (29%) incidence of anti-drug antibody formation. Four patients (3 ovarian cancer, 1 uterine carcinosarcoma) had a partial response and 17 patients had stable disease. Nineteen patients had a reduction in the size of their target lesions including 7/11 patients with ovarian cancer. Four patients remained on study for >300 days and 2 of these patients were on study for >500 days. Conclusions Navicixizumab can be safely administered with manageable toxicities and these data showed prelim- inary signs of antitumor activity in multiple tumor types, but was most promising in ovarian cancer. As a result these data justify its continued development in combination Phase 1b clinical trials. Keywords Navicixizumab . OMP-305B83 . VEGF . DLL4 pathway Prior Presentations: Presented at the 2016 AACR-NCI-EORTC, Berlin, Germany Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10637-018-0665-y) contains supplementary material, which is available to authorized users. * Antonio Jimeno 3 Sarah Cannon Research Institute, Nashville, TN, USA [email protected] 4 Pinnacle Oncology Hematology, Scottsdale, AZ, USA 5 University of Michigan, Ann Arbor, MI, USA 1 University of Colorado School of Medicine, 12801 East 17th Avenue 6 Building RC-1 South, 8111, Aurora, CO 80045, USA OncoMed Pharmaceuticals, Redwood City, CA, USA 2 The University of Oklahoma, Oklahoma City, OK, USA 462 Invest New Drugs (2019) 37:461–472 Introduction Navicixizumab is an IgG2 humanized bispecific monoclo- nal antibody directed against both DLL4 and VEGF. This The Notch pathway mediates intercellular communication and molecule was designed to enhance the anti-tumor effect that plays a key role in regulating cell fate decisions in normal is obtained with inhibiting DLL4 or VEGF alone and also to development and in many types of cancer [1]. There are four avoid the cardiac toxicity that was observed with the anti- Notch receptors and five cell surface ligands that activate DLL4 agents. Preclinically it was tested in multiple human Notch signaling. One of the key ligands of the Notch pathway tumor xenograft studies, including colon, pancreatic, ovarian is Delta-Like Ligand 4 (DLL4). DLL4 plays a central role and gastric cancer and significant single agent activity was both in embryonic development (including the formation of observed in every model tested as well as enhanced activity the vasculature) and in adult cell regulation (including stem when combined with chemotherapy, which supported explor- cell homeostasis, differentiation of the gastrointestinal tract ing navicixizumab in humans. In addition, inhibition of DLL4 and neo-angiogenesis). During neo-angiogenesis, DLL4 reg- decreases CSC frequency in human xenograft models, and has ulates the orderly formation of tip cells and sprouting and also an immunomodulatory effect by decreasing myeloid derived serves as a feedback regulator of vascular endothelial growth suppressor cells. This first-in-human Phase 1 study reports the factor (VEGF) signaling [2, 3]. Disruption of DLL4 signaling safety, tolerability, pharmacokinetics (PK), pharmacodynam- in the vasculature leads to an increase in VEGF activity, dys- ics (PD), antitumor efficacy, and recommended Phase 2 dose regulated sprouting and a VEGF-mediated hyperproliferation (RP2D) of navicixizumab administered every 3 weeks in pa- of endothelial cells that fail to form functional blood vessels, tients with advanced solid tumors. leading to disrupted angiogenesis [4, 5]. These mechanisms demonstrate a coordinated interplay between DLL4 and VEGF in neo-angiogenesis regulation. The role of DLL4 has been evaluated in detail in solid Patients and methods tumors. Preclinical data demonstrate that DLL4 blockade elicits a potent anti-tumor effect in solid tumors such as colon, Patient eligibility pancreatic, breast and lung cancers [6, 7]. The mechanisms underlying the anti-tumor activity of anti-DLL4 include the Eligible patients were ≥ 21 years old, had a histologically selective elimination of cancer stem cells (CSCs) and the in- confirmed advanced solid tumor, an Eastern Cooperative hibition of tumor angiogenesis, via mechanisms referenced Oncology Group (ECOG) performance status of 0 or 1, above [8]. Multiple anti-DLL4 agents have advanced into adequate organ and marrow function, a tumor at least clinical development [9, 10]. Single agent activity has been 1 cm in a single dimension on computerized tomography observed with anti-DLL4 therapy, but treatment duration was (CT) scan or magnetic resonance imaging (MRI) and their limited by cardiotoxicity that is believed to be due to the last chemotherapy, biologic, or investigational therapy increased vascular sprouting which occurs when DLL4 is was administered ≥4 weeks prior to enrollment. inhibited, but VEGF is not inhibited [10]. Exclusion criteria included receiving other investigational VEGF inhibition is a well-established anti-neoplastic ther- anticancer agents within 4 weeks of enrollment, receiving apy. Multiple inhibitors have been developed and approved therapeutic doses of an anticoagulant; brain metastases; for the treatment of solid tumors, including bevacizumab significant intercurrent illnesses or a history of abdominal (Avastin®) [11]. Anti-VEGF treatment reduces endothelial fistula, gastrointestinal perforation, or intra-abdominal ab- cell proliferation and thereby inhibits angiogenesis and tumor scess. In addition, patients were excluded if they had a growth. Targeting both DLL4 and VEGF would potentially tumor involving the lumen of the gastrointestinal tract; a augment the antitumor effects of DLL4 inhibition while lim- blood pressure of >140/90 mmHg, were receiving more iting the VEGF-induced vascular sprouting. than 2 antihypertensive agents, had a baseline brain natri- There has been an increased focus in the development uretic peptide (BNP) value of >100 pg/mL, had a left of agents targeting more than one pathway by a single ventricular ejection fraction (LVEF) <50%, had a peak molecule [12], given both developmental and biological tricuspid velocity > 3.0 m/s on Doppler echocardiogram; advantages including inhibition of key proteins co- had received a total cumulative dose of ≥400 mg/m2 localized in tumors. Several bispecific antibodies have doxorubicin or had a significant history of cardiac dis- been granted regulatory approval including blinatumomab ease. The study was approved by local Institutional in the USA for relapsed or refractory B cell precursor Review Boards (IRBs) and was conducted in accordance Acute Lymphoblastic Leukemia in both adults and chil- with the declaration of Helsinki, the International dren [13], and catumaxomab in Europe for treatment of Conference on Harmonization Good Clinical Practice malignant ascites in patients with EpCAM positive cancer guidelines, and all applicable local regulatory require- [13, 14] (later withdrawn by the manufacturer). ments and laws. Invest New Drugs (2019) 37:461–472 463 Study design and treatments study drug. Serum was assayed for concentrations of navicixizumab by enzyme-linked immunosorbent assay This phase 1, dose-escalation study (NCT02298387) was con- (ELISA). For pharmacokinetic analyses, non-compartmental ducted at four centers in the United States. The primary end- analysis was conducted for individual patients with evaluable point was to determine the maximum tolerated dose. pharmacokinetic data. Summary statistics including mean, Secondary endpoints were to determine safety, pharmacoki- standard deviation, median, minimum, and maximum
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