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First-in-Human Phase I Study of Aprutumab Ixadotin, a Fibroblast Growth Factor Receptor 2 Antibody–Drug Conjugate (BAY 1187982) in Patients with Advanced Cancer

First-in-Human Phase I Study of Aprutumab Ixadotin, a Fibroblast Growth Factor Receptor 2... Background Fibroblast growth factor receptor (FGFR) 2 is overexpressed in several tumor types, including triple-negative breast cancer and gastric cancer, both of which have a high unmet medical need. Aprutumab ixadotin (BAY 1187982) is the first antibody–drug conjugate (ADC) to target FGFR2 and the first to use a novel auristatin-based payload. Objective This first-in-human trial was conducted to determine the safety, tolerability, and maximum tolerated dose (MTD) of aprutumab ixadotin in patients with advanced solid tumors from cancer indications known to be FGFR2-positive. Patients and Methods In this open-label, multicenter, phase I dose-escalation trial (NCT02368951), patients with advanced solid tumors received escalating doses of aprutumab ixadotin (starting at 0.1 mg/kg body weight), administered intravenously on day 1 of every 21-day cycle. Primary endpoints included safety, tolerability, and the MTD of aprutumab ixadotin; second- ary endpoints were pharmacokinetic evaluation and tumor response to aprutumab ixadotin. Results Twenty patients received aprutumab ixadotin across five cohorts, at doses of 0.1–1.3 mg/kg. The most common grade ≥ 3 drug-related adverse events were anemia, aspartate aminotransferase increase, proteinuria, and thrombocytopenia. Dose-limiting toxicities were thrombocytopenia, proteinuria, and corneal epithelial microcysts, and were only seen in the two highest dosing cohorts. The MTD was determined to be 0.2 mg/kg due to lack of quantitative data following discontinu- ations at 0.4 and 0.8 mg/kg doses. One patient had stable disease; no responses were reported. Conclusions Aprutumab ixadotin was poorly tolerated, with an MTD found to be below the therapeutic threshold estimated preclinically; therefore, the trial was terminated early. ClinicalTrials.gov Identifier NCT02368951. Electronic supplementary material The online version of this 1 Introduction article (https ://doi.org/10.1007/s1152 3-019-00670 -4) contains supplementary material, which is available to authorized users. Fibroblast growth factor receptor (FGFR) 2 is a transmem- * Sung-Bae Kim brane receptor tyrosine kinase with a key role in tissue repair sbkim3@amc.seoul.kr and embryonic development [1, 2]. Aberrations leading to Department of Oncology, Asan Medical Center, University constitutive activation or overexpression of FGFR2, includ- of Ulsan College of Medicine, 88 Olympic-ro 43-gil, ing gene amplification, gene fusions, and single nucleotide Songpa-gu, Seoul 05505, Republic of Korea 2 polymorphisms, have been identified in many cancer types, The University of Texas MD Anderson Cancer Center, including triple-negative breast cancer, pancreatic, esopha- Houston, TX, USA 3 geal, hepatocellular, colorectal, ovarian, gastric, non-small- Northwestern University Feinberg School of Medicine, cell lung cancer (NSCLC), and glioma [3–16]. Furthermore, Chicago, IL, USA 4 FGFR2 overexpression has been associated with poor sur- Bayer AG, Berlin, Germany vival in patients with gastric cancer [7]. Although treatments Bayer Healthcare, Whippany, NJ, USA are available for gastric and other cancers overexpressing Bayer Yakuhin, Ltd., Osaka, Japan FGFR2, the generally poor prognosis for patients with these Bayer AG, Basel, Switzerland tumors suggests that a high unmet medical need remains [3–16]. In contrast to typically high expression levels in Vanderbilt University Medical Center, Nashville, TN, USA Vol.:(0123456789) 592 S.-B. Kim et al. ixadotin has low nanomolar potency and suggested that Key Points high FGFR2 expression correlates with internalization and cytotoxic effects [ 28]. In mice, pharmacokinetic studies of Aprutumab ixadotin (BAY 1187982) is a novel conjugate aprutumab ixadotin showed that concentrations of the cyto- of an anti-fibroblast growth factor receptor (FGFR) 2 toxic payload metabolite are enriched by more than 30-fold antibody linked to an innovative auristatin W derivative in FGFR2-positive tumors compared with healthy tissue toxophore. This is the first time this novel payload has [28]. Furthermore, aprutumab ixadotin treatment resulted been used in a clinical setting and the first time an anti- in dose-dependent tumor regression in patient-derived xeno- body–drug conjugate has been used to target FGFR2. graft (PDX) models of FGFR2-positive gastric cancer and triple-negative breast cancer, including reductions in tumor Toxicities were observed at doses lower than the pre- volume equivalent to partial and complete responses [28]. dicted therapeutic dose and were unexpected based on Results from PDX studies also indicated that FGFR2 ampli- the preclinical findings. The cause of these toxicities is fication or overexpression was predictive of high antitumor not yet known but may be attributed to the unique com- activity in vivo [28]. In these preclinical studies, no evidence bination of an auristatin W derivative payload with an was found to suggest that aprutumab ixadotin would exert a FGFR2-targeting antibody. bystander effect [28]. Furthermore, findings from preclini- These findings highlight the need for improved preclini- cal studies have also indicated that aprutumab ixadotin was cal models that more accurately predict the effects of stable in the circulatory system [28]. novel compounds in humans, which may increase the Based on these promising preclinical data, an open-label, efficiency of clinical development. non-randomized, first-in-human phase  I dose-escalation study of aprutumab ixadotin was conducted in adult patients with advanced, refractory solid tumor indications reported tumors, FGFR2 is generally expressed at low levels in nor- mal tissue, making it an attractive antigen for development to express FGFR2. Aprutumab ixadotin is the first ADC to target FGFR2 in the treatment of advanced tumors and is of a targeted anticancer therapy [8, 17]. Antibody–drug conjugates (ADCs) comprise a cytotoxic also the first ADC to include this novel auristatin W deriva- tive payload. The primary objectives of this study were to payload conjugated by a linker to a monoclonal antibody directed against an antigen that is selectively expressed on determine the safety, tolerability, and maximum tolerated dose (MTD) of aprutumab ixadotin. the surface of tumor cells [18, 19]. This selectivity allows ADCs to be directed at tumor cells, limiting systemic expo- sure and off-target toxicity [20, 21]. Binding of the antibody to its target antigen triggers internalization of the ADC, after 2 Materials and Methods which the linker molecule is cleaved, or the antibody moiety is degraded in the lysosome (non-cleavable linker). Cleavage 2.1 Patients or degradation of the linker molecule releases the payload metabolite within the cell, resulting in cytotoxic effects [20, Patients aged 18 years or older with advanced solid tumors from cancer indications known to be FGFR2-positive, which 21]. The ADCs brentuximab vedotin, gemtuzumab ozo- gamicin, inotuzumab ozogamicin, and trastuzumab emtan- were refractory to any standard therapy or had no standard therapy available, were eligible for enrollment. Patients were sine have been approved based on their efficacy in late-stage clinical trials [22–25]. In addition, several ADCs are cur- required to have measurable disease, Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–1, rently being investigated in clinical trials in a wide range of tumor types [26, 27]. However, ADCs targeting FGFR2 have an expected lifespan of at least 12 weeks, and a formalin- fixed paraffin-embedded (FFPE) tumor tissue sample from not yet been described in any tumor type. Aprutumab ixadotin (BAY  1187982) is a novel ADC either archival tissues or fresh biopsy for intended retrospec- tive FGFR2 expression analyses. Patients were excluded if comprising a fully human anti-FGFR2 monoclonal anti- body (BAY 1179470) conjugated by lysine side chains to they had a history of allergic reactions to monoclonal anti- body therapy, anticancer chemotherapy, immunotherapy, or a non-cleavable linker and via this an innovative aurista- tin W derivative [28]. This novel auristatin W derivative is experimental cancer therapy (including clinical trials) within 3 weeks prior to the first dose of study drug. Full eligibility a highly potent microtubule-disrupting agent used for the first time in aprutumab ixadotin [28]. Lysosomal degrada- criteria are reported in the Electronic Supplementary Mate- rial Appendix. tion of the antibody moiety releases the non-cell-permeable payload metabolite that cannot cross cell membranes due to the presence of a charged group, as previously described [28]. Results from in vitro studies indicated that aprutumab Aprutumab Ixadotin (BAY 1187982) Anti-FGFR2 ADC in Solid Tumors 593 2.2 Objectives The primary objectives were to determine the safety, toler- ability, and MTD of aprutumab ixadotin. Secondary objec- tives included evaluation of pharmacokinetics, pharmacody- namics, immunogenicity, and tumor response. 2.3 Study Design This was a phase I, open-label, first-in-human, non-rand- omized, multicenter trial. The trial was planned to include two phases, the first being a dose-escalation phase to deter - mine the MTD of aprutumab ixadotin, and the second an expansion phase to further evaluate safety, pharmacokinet- ics, and clinical activity at the MTD. Aprutumab ixadotin was administered as an intravenous infusion over 1 h on day 1 of every 21-day cycle, with the first infusion given on cycle 1, day 1. Treatment continued Fig. 1 Patient disposition and analysis population until evidence of disease progression, unacceptable toxicity, withdrawal of consent, or patient withdrawal from the trial. data available for cycle 1, or had discontinued early, before The aprutumab ixadotin dose could be reduced or delayed the next cohort was initiated. Modeling of DLTs was carried to manage dose-limiting toxicities (DLTs) or adverse events out after at least one DLT was reported or grade ≥ 2 drug- (AEs). Treatment was stopped if more than two dose reduc- related AE (except asymptomatic changes in biochemistry tions were required. laboratory values) was reported in two different patients in Dose escalation and MTD determination were conducted the first 21 days of treatment in cycle 1. The five dose-esca- using a previously described adaptive dose-escalation trial lation cohorts enrolled were 0.1, 0.2, 0.4, 0.8, and 1.3 mg/kg. design [29]. The MTD was defined as the maximum dose at which the incidence of DLTs during cycle 1 was below 2.4 Safety Assessments 20%, or the maximum dose administered, whichever was achieved first during dose escalation. DLTs were defined Patients were assessed for safety on days 1, 2, 3, 5, 8, 15, and as any of the following AEs occurring during cycle 1 and 21 of cycles 1 and 3, and days 1, 8, 15, and 21 of cycle 2, considered related to study drug: grade 4 absolute neutrophil cycle 4, and subsequent cycles. End-of-treatment visits were count decrease for ≥ 7 days; grade ≥ 3 febrile neutropenia; also conducted at the time of study drug discontinuation or grade 4 thrombocytopenia for > 1 day; grade 4 anemia or 14 days after last treatment, with an end-of-study visit or anemia requiring blood transfusion; grade ≥ 3 hemorrhage; phone call taking place 30 days after the last treatment with grade ≥ 3 thrombotic event; any other non-hematological study drug. Patients had ophthalmic evaluation prior to ini- toxicity considered to be drug-related, excluding grade ≥ 3 tiation of study drug and on day 15 of each cycle. AEs were nausea and vomiting controllable by anti-emetics within reported using the National Cancer Institute Common Ter- 3 days; grade 3 fatigue lasting ≤ 72 h; isolated change in minology Criteria for AEs (NCI-CTCAE) version 4.03. The laboratory biochemical values; and grade 3 infusion-related study protocol was amended to include dose modification as reactions resolving within 6 h and controlled by medical well as remedial treatment guidelines for corneal toxicity. management. Figure 1 shows the patient disposition of the dose-esca- 2.5 Pharmacokinetics lation cohorts. Five dose-escalation cohorts of at least three patients were enrolled (where multiple sites conducted the Serial blood samples for pharmacokinetic characteriza- dose escalation, there was an option to enroll four patients). tion of aprutumab ixadotin (total drug), total antibody, and The first four patients of each cohort were enrolled with a toxophore metabolite BAY 1159184 were collected during safety interval of at least 48 h between drug administrations cycles 1 and 3 at the following timepoints: pre-dose, 0.5, on cycle 1, day 1. The starting dose was 0.1 mg/kg body 1 (end-of-infusion sample), 1.5, 2, 3, 5, 8, 24, 48, 96, 168, weight, with doses increased in two-fold increments up to 336, and 504 h after the start of infusion, with the 504-h 0.8 mg/kg, after which the dose was escalated in 0.5 mg/kg sample being collected before the start of cycles 2 and 4, increments. All participants in a dose-level cohort must have respectively. Plasma concentrations were determined by received one complete infusion of study drug and have safety 594 S.-B. Kim et al. enzyme immunoassay (EIA) for aprutumab ixadotin and 1.3 mg/kg group, one patient had grade 3 proteinuria, one total antibody and by liquid chromatography–tandem mass patient had grade 3 proteinuria and grade 4 thrombocytope- spectrometry (LC–MS/MS) for the toxophore metabolite nia, and a third patient had grade 3 corneal epithelial micro- BAY 1159184. If a patient discontinued study after cycle 3, cysts and grade 2 blurred vision. day 21, the 504-h blood sample was collected on cycle 3, After three of five patients in the 1.3 mg/kg group and day 21. Starting with cycle 5, day 1, samples were collected one patient in the 0.8 mg/kg group experienced DLTs, it before infusion with aprutumab ixadotin and at the end of was decided that new patients should only be enrolled at a infusion, in every second cycle. Tumor tissue samples were starting dose of 0.2 mg/kg or lower due to the high degree of planned to be analyzed for FGFR2 overexpression; however, uncertainty regarding the time course and degree of revers- this was not conducted. ibility of these toxicities. Since two of the patients in the 1.3 mg/kg group experienced grade 3 proteinuria, dose lev- 2.6 T umor Response Assessment els of 0.4 and 0.8 mg/kg were not considered safe due to lack of quantitative data for protein in urine and limited exposure Tumors were evaluated using computed tomography or as the majority of patients discontinued; therefore, a dose magnetic resonance imaging; response was assessed using of 0.2 mg/kg was determined to be the MTD. At 0.2 mg/kg, Response Evaluation Criteria in Solid Tumors (RECIST), the efficacy profile of the drug did not favor further develop- version 1.1. ment; therefore, the study was discontinued by the sponsor and the dose-expansion phase was not carried out. 3 Results3.3 Safety 3.1 Patient Characteristics All patients had at least one treatment-emergent AE (TEAE) of any grade (100%), with at least one grade ≥ 3 Twenty patients were enrolled at three sites in the USA and TEAE reported in 15 patients (75%; Table  2). Grade  3 one site in Korea, and treated with aprutumab ixadotin. TEAEs occurred in 13 patients (65%), and grade 4 TEAEs The median age was 52 years (range 24–76 years) and 55% in two patients (10%). The most common grade 3 TEAEs were female (n = 11). The four most common tumor types were thrombocytopenia, increased aspartate transaminase were colorectal cancer (n = 5; 25%), cholangiocarcinoma (AST), increased blood alkaline phosphatase (ALP) levels, (n = 4; 20%), gastric cancer (n = 2; 10%), and hepatocellu- proteinuria, and anemia. The only grade 4 TEAE was throm- lar carcinoma (n = 2; 10%). Most patients had an ECOG PS bocytopenia in two patients (10%); no grade 5 TEAEs were of 1 (n = 14; 70%). The median number of prior systemic reported. therapies was eight (range 1–23). Four patients had FGFR2 TEAEs determined to be drug-related were reported amplification according to institution-led DNA copy num- by 17 patients (85%), and nine patients (45%) reported ber analysis. Patient demographics and characteristics are grade ≥ 3 drug-related TEAEs. The most common of these described in Table 1. were thrombocytopenia (15%), anemia (10%), increased AST (10%), and proteinuria (10%). Other grade  3 drug- 3.2 Dose Escalation related TEAEs were hypertension, increased alanine ami- notransferase (ALT), decreased blood albumin, increased All patients enrolled were assigned to one of five dose-esca- blood ALP levels, dehydration, decreased neutrophil count, lation cohorts (0.1 mg/kg [n = 4], 0.2 mg/kg [n = 3], 0.4 mg/ and corneal epithelial microcysts, which occurred in one kg [n = 4], 0.8 mg/kg [n = 4], or 1.3 mg/kg [n = 5]) and com- patient each (5%). Grade 4 drug-related thrombocytopenia pleted the study. Fifteen patients discontinued treatment due was reported in two patients (10%). to progressive disease (75%) and five discontinued due to Treatment-emergent serious AEs (SAEs) were reported AEs (25%). The longest treatment duration observed was in eight patients (40%), the most common being anorexia, 13 cycles, which included one dose reduction from 0.8 to thrombocytopenia, and proteinuria, each reported in two 0.4 mg/kg after the first cycle due to grade 4 thrombocyto- patients (10%). Drug-related SAEs were proteinuria and penia and one dose interruption between cycles 10 and 11 thrombocytopenia, both reported in two patients (10%), and due to reactivation of hepatitis B that was controlled. anorexia and nausea in one patient each (5%). Patients in the lower dose cohorts of 0.1, 0.2, and 0.4 mg/ One death due to colorectal cancer disease progression kg did not experience any DLTs. DLTs were observed in was reported during follow-up, after discontinuation of apru- one patient in the 0.8 mg/kg group and three of five patients tumab ixadotin. The patient experienced two occurrences of in the 1.3 mg/kg group. The patient in the 0.8 mg/kg group grade 3 ascites that were considered to be unrelated to the had grade 4 thrombocytopenia; of the three patients in the study drug. Aprutumab Ixadotin (BAY 1187982) Anti-FGFR2 ADC in Solid Tumors 595 dipstick values from previous cohorts at the 0.1, 0.2, 0.4, and Table 1 Patient demographics and characteristics 0.8 mg/kg dose levels (where available) were retrospectively CharacteristicTotal population (N= 20) reviewed and plotted to analyze intensity and kinetics. Based Age (years) on these dipstick test results, proteinuria was also observed  Median (range) 52 (24–76) in three of four patients at the 0.8 mg/kg dose level and in Sex [n (%)] all four patients at the 0.4 mg/kg dose level. However, dis-  Male 9 (45) continuation of patients in cycle 2 due to early tumor pro-  Female 11 (55) gression precluded further characterization of the observed ECOG PS [n (%)] proteinuria. Due to the lack of quantitative values, the course  0 6 (30) and clinical relevance of proteinuria in these patients could  1 14 (70) not be interpreted. Additionally, the limited drug exposure Median number of prior systemic thera- 8 (1–23) and insufficient observation period in these patients pre- pies (range) cluded assessment of the nephrotoxic potential of aprutumab b 2 Body mass inde x (kg/m ) ixadotin at dose ranges of 0.4–0.8 mg/kg. Therefore, the  Mean (SD) 25.3 ± 4.5 0.2 mg/kg dose level was regarded as non-nephrotoxic based  Median (range) 23.5 (20.1–35.4) on available data from three patients at the 0.2 mg/kg dose Tumor type [n (%)] level. No signs of hematuria were observed using a dipstick  Breast cancer 1 (5) test. Signs of recovery were observed 20 days after discon-  Cholangiocarcinoma 4 (20) tinuation of the study drug.  Colorectal cancer 5 (25) Ocular events occurred in eight patients (40%) across all  Esophageal cancer 1 (5) dose groups, and included corneal epithelial microcysts,  Gastric cancer 2 (10) blurred vision, corneal deposits, retinal hemorrhage, and  Gastrointestinal stromal tumor 1 (5) ocular discomfort. The ocular events manifested within  Hepatocellular cancer 2 (10) the first two cycles and did not typically result in dosage  Pancreatic adenocarcinoma 1 (5) changes, except in one patient for whom treatment was dis-  Parotid gland adenoid cystic carcinoma 1 (5) continued due to dose-limiting grade 3 corneal epithelial  Mouth floor cancer 1 (5) microcysts and grade 1 blurred vision. Ocular events con-  Tongue base adenoid cystic carcinoma 1 (5) sidered to be drug-related included corneal deposits in four patients (deposits of lipids or calcium that build up on the ECOG PS Eastern Cooperative Oncology Group performance status, cornea in layers resulting in blurred vision; 20%), corneal SD standard deviation epithelial microcysts in three patients (incompletely formed The total population includes all patients enrolled in the dose-escala- tion cohorts; patients with brain metastases were excluded cells in the epithelia that can cause vision hazing; 15%), N = 19 patients and blurred vision in one patient (5%). These drug-related events were reported in two patients (50%) in the 0.8 mg/ kg group (time to onset: 36 days) and in all five patients in Five patients discontinued treatment due to one or more the 1.3 mg/kg group (time to onset: 6–22 days). Remedial TEAEs (proteinuria, thrombocytopenia, dehydration, ane- treatment for ocular events consisted of carmellose ophthal- mia, fatigue, worsening chronic renal disease, corneal epi- mic drops in concert with polyacrylic acid, difluprednate, or thelial microcysts, and blurred vision). Three patients had fluorometholone drops. Ocular symptoms had fully resolved treatment interruptions due to TEAEs (proteinuria, gastro- for one patient, appeared to be improving in two patients, paresis, corneal epithelial microcysts, and blurred vision). and showed no further worsening in three patients at the Two patients had dose reductions due to thrombocytopenia. time of last study visit. A transient decrease in platelet count was observed in one 3.4 Key Safety Observations patient at the 0.1 mg/kg dose level during cycle 1. Throm- bocytopenia was subsequently observed in all patients at Proteinuria or nephrotic syndrome was reported in two of the 0.4, 0.8, and 1.3 mg/kg dose levels. Thrombocytopenia five patients after the cycle 1 at the 1.3 mg/kg dose level, was reported as a DLT in one patient each at both the 0.8 with a time to onset of approximately 20 days. Proteinuria and 1.3 mg/kg dose levels. The time to onset and time to worsened in consecutive cycles, and both patients devel- recovery of thrombocytopenia was consistent in consecutive oped nephrotic syndrome. Both patients also showed abnor- cycles at all dose levels. mally high fibrinogen and D-dimer concentrations, while Increased serum transaminase levels were detected in serum blood urea nitrogen-to-creatinine ratios were nor- cycle 1 at the 0.2 mg/kg dose level. The intensity and fre- mal. Following these findings at the 1.3 mg/kg dose level, quency of abnormally high transaminase levels tended to 596 S.-B. Kim et al. than the upper limit of normal. Elevated transaminase levels Table 2 Summary of adverse events typically resolved within the same treatment cycle. AEs Aprutumab ixadotin (N= 20) All grades [n (%)] Grade ≥ 3 [n (%)] 3.5 Pharmacokinetics Any TEAE 20 (100) 15 (75) Initial pharmacokinetic analyses of 18 patients showed that  Any drug-related TEAE 17 (85) 9 (45) the pharmacokinetic profile of the toxophore metabolite Any serious TEAE 8 (40) BAY 1159184 appeared approximately dose-proportional  Any drug-related serious 5 (25) at doses from 0.4 to 1.3 mg/kg (Fig. 2). Dose-proportional TEAE increases in exposure to aprutumab ixadotin (total drug) at TEAEs occurring in ≥ 10% of patients in the overall population doses of 0.1–1.3 mg/kg were also observed (Fig.  2). The  AST increased 12 (60) 3 (15) pharmacokinetic profiles of total antibody and FGFR2-ADC  Thrombocytopenia 10 (50) 5 (25) (aprutumab ixadotin, i.e., total drug) were similar, which  Anemia 6 (30) 2 (10) may indicate that aprutumab ixadotin would be stable in  Fatigue 6 (30) 0 plasma.  Nausea 5 (25) 0  Pyrexia 5 (25) 0 3.6 Tumor Response  ALT increased 5 (25) 1 (5)  Blood ALP increased 5 (25) 3 (15) Stable disease was observed in one patient with tongue base  Decreased appetite 5 (25) 1 (5) adenoid cystic carcinoma assigned to the 0.8 mg/kg group  Corneal deposits 4 (20) 0 whose dose was reduced after cycle 1–0.4 mg/kg (Fig. 3).  Abdominal pain 4 (20) 0 Disease progression occurred in this patient during cycle 13.  Corneal epithelial micro- 3 (15) 1 (5) cysts No partial or complete responses were observed in any  Dyspepsia 3 (15) 0 patients.  Vomiting 3 (15) 1 (5)  Urinary tract infections 3 (15) 1 (5)  Hypoalbuminemia 3 (15) 0 4 Discussion  Cough 3 (15) 0  Abdominal distension 2 (10) 0 FGFR2 has been identified as a promising drug target  Ascites 2 (10) 1 (5) because it is overexpressed in various tumor types [7–9, 11].  Blood cholesterol increased 2 (10) 0 This phase I trial was initiated to investigate the safety of the  Blood creatinine increased 2 (10) 0 anti-FGFR2 ADC aprutumab ixadotin (BAY 1187982), fol-  Blood fibrinogen increased 2 (10) 0 lowing positive in vitro and in vivo data [28], and to deter-  BNP increased 2 (10) 0 mine the MTD for subsequent dose-expansion cohorts. This  Fibrin d -dimer increased 2 (10) 0 study represented the first time an ADC had been used to  Lipase increased 2 (10) 0 target FGFR2 in the treatment of advanced tumors. Despite  WBC count decreased 2 (10) 0 promising results in preclinical studies, safety data col-  Dehydration 2 (10) 1 (5) lected during this trial suggested that in a heavily pretreated  Hypercalcemia 2 (10) 0 population of patients with advanced solid tumors, apru-  Proteinuria 2 (10) 2 (10) tumab ixadotin was poorly tolerated with a MTD of 0.2 mg/  Epistaxis 2 (10) 0 kg every 3 weeks The activity of aprutumab ixadotin has  Productive cough 2 (10) 0 been evaluated in a range of preclinical models, including assessment of antitumor activity and pharmacokinetics in AE adverse event, ALP alkaline phosphatase, ALT alanine ami- mouse xenograft tumor models [28]. The pharmacokinetics notransferase, AST aspartate aminotransferase, BNP brain natriuretic of aprutumab ixadotin were also assessed in cynomolgus peptide, TEAE treatment-emergent adverse event, WBC white blood cell monkeys after single and repeat dosing, and a rat model was Data are sorted by the incidence of TEAEs in the overall escalation used to assess the toxophore-linker metabolite [30]. Results group from preclinical mouse xenograft studies and pharmacoki- netic modeling predicated that the minimum doses required increase with the dose of aprutumab ixadotin. The highest for stable disease, partial response, and complete response levels were observed in one patient in each of the 0.8 and were 0.4, 0.5, and 1.2 mg/kg, respectively [31]. As the MTD 1.3 mg/kg cohorts, with levels that were five times higher of aprutumab ixadotin in this trial was below the predicted minimum therapeutic dose established during PDX studies, Aprutumab Ixadotin (BAY 1187982) Anti-FGFR2 ADC in Solid Tumors 597 Fig. 3 Treatment duration in patients treated with aprutumab ixado- tin. Dose reductions are indicated with a black arrow; dose reduction occurred a on day 22 from 0.8 to 0.4 mg/kg and b on day 23 from 1.3 to 0.8 mg/kg the sponsor discontinued the trial after enrollment and treat- ment of 20 patients [31]. In non-clinical safety studies in cynomolgus monkey models, aprutumab ixadotin treatment led to increased ALT and AST levels; extrapolation of these data to humans led to an estimated highest non-severely toxic dose of aprutumab ixadotin of 1.48 mg/kg when administered every 3 weeks, as was applied in this trial. The predicted therapeutic index in humans was approximately 3.5, calculated using the high- est non-severely toxic dose and the dose required to achieve stable disease [31]. These data supported the decision to Fig. 2 Geometric mean plasma concentrations of a aprutumab ixad- further investigate aprutumab ixadotin in a first-in-human otin, b total antibody, and c toxophore metabolite (BAY  1159184) during cycle  1 for the 0.1 (n = 4), 0.2, 0.4 (n = 3), 0.8 (n = 4), and phase I trial. 1.3 (n = 5) mg/kg dose cohorts. Data for the toxophore metabolite The N-terminal epitope of FGFR2 is conserved between (BAY  1159184) are only available for the 0.4, 0.8, and 1.3  mg/kg humans, monkeys, rats, and mice. The antibody moiety of dose cohorts. *Data are presented individually in the 0.2 mg/kg dose aprutumab ixadotin binds to recombinant FGFR2 protein cohort due to the low number of patients with available pharmacoki- netic data (n = 2) with a similar EC (half-maximal effective concentration) across these species, making any of them relevant for toxic- ity testing. Toxicity studies in rats and cynomolgus monkeys 598 S.-B. Kim et al. revealed effects typical of ADC-mediated toxicity related to the FGFR1–3 inhibitor BGJ398. Thus, while dry eye and toxophore activity. This was observed in the form of mor- corneal toxicity has been reported with FGFR inhibitors, phological degeneration/regeneration and inflammation in kidney toxicity has not been previously observed [42–46]. lung, liver, kidneys, cornea, and the lympho-hematopoietic The similar temporal pattern of the course of proteinuria in system at sufficient multiples of exposure compared with patients in this trial and the lack of alternative explanation the expected human efficacious exposure to suggest an for this abnormality support the causal relationship between acceptable therapeutic index; most effects were reversible observed proteinuria/nephrotic syndrome and aprutumab and no functional organ toxicity was detected. Data from ixadotin, although this association was not seen in non- cynomolgus monkeys showed that aprutumab ixadotin had clinical safety studies conducted in rats and cynomolgus a small effect on blood clot formation in the form of a small monkeys. and transient decrease in platelets that was restricted to the Ocular toxicities seem to be a class effect of ADCs with first treatment cycle; additionally, increases in thrombin microtubule-disrupting payloads, with corneal epitheliopa- time and d -dimer levels were observed. These effects were thy reported during treatment with both maytansinoid (DM4 fully reversible. Similar effects on blood clot formation payload metabolite) and auristatin-containing (monomethy- were induced by an isotype control ADC with an identical lauristatin F payload metabolite) ADCs [39–41, 47, 48]. As toxophore payload. No adverse effects were observed after observed in the current study, corneal epitheliopathy typi- administration of the payload metabolite alone, including in cally resolves with supportive care and treatment interrup- the coagulation system, indicating that the combination of tion or discontinuation. the payload-linker metabolite and an antibody moiety may Although efficacy was not formally evaluated during the be the causative factor for the coagulation effects. To our trial, one patient with tongue base adenoid cystic carcinoma knowledge, similar coagulation effects have not been seen in had a best response of stable disease and remained on treat- clinical trials of other ADCs or toxophores [32–35]. ment until disease progression during cycle 14. This patient The most common TEAEs that occurred in patients was enrolled in the 0.8 mg/kg dose cohort and had a dose treated with aprutumab ixadotin in this phase I trial included reduction to 0.4 mg/kg to manage toxicities during cycle 2. thrombocytopenia and increased levels of AST, which No other responses were observed in the four patients (two occurred in 50% and 60% of patients, respectively, with a cases of gastric cancer and one case each of cholangiocar- further eight TEAEs occurring in 25% or more of patients cinoma and colorectal cancer) with known FGFR2 ampli- across all dose cohorts. The safety data indicate the follow- fications. Most patients discontinued treatment because of ing undesirable effects of aprutumab ixadotin: proteinuria/ disease progression. nephrotic syndrome; thrombocytopenia; increased serum ALT and AST levels; and corneal epithelial microcysts. Patients treated with aprutumab ixadotin in this study were 5 Conclusion heavily pretreated, with a median number of prior therapies of eight (range 1–23), which may have contributed to the The ADC aprutumab ixadotin was found to be poorly toler- observed poor tolerance. ated in this phase I first-in-human trial, with an MTD of Patients in the 1.3 mg/kg dose cohort had d -dimer lev- 0.2 mg/kg, which is below the estimated minimum thera- els notably higher in the second cycle than during the first peutic dose predicted in preclinical studies. The safety cycle of treatment with aprutumab ixadotin. d -Dimer eleva- profile of this ADC in humans also differed markedly from tion is thought to be caused by kidney damage leading to that observed in animal models, with a high rate of pro- nephrotic syndrome [36]; during the second cycle it was teinuria and nephropathy. These results underline the need to concluded that kidney recovery did not seem to balance the develop new methods to predict the effects of investigational kidney damage. Furthermore, patients with nephrotic syn- ADCs and their metabolites in humans during preclinical drome have a significantly higher risk of thrombotic events development. and renal failure [37]. Proteinuria and nephrotic syndrome Acknowledgements The authors thank the patients, their families, and may be considered as toxicities specifically associated with all investigators involved in this study. We would also like to thank aprutumab ixadotin treatment, as similar toxicities have not Ruprecht Zierz of Bayer AG for providing the preclinical toxicology been previously reported in clinical trials of other ADCs data and for his review and feedback on this manuscript. that carry a range of payloads [38–41]. AEs reported for pan-FGFR inhibitors and FGFR1–3 specific inhibitors Author contributions Conception and design: S-BK and FR. Acquisi- tion of data (provided animals, acquired and managed patients, pro- include hyperphosphatemia, stomatitis, mucosal dryness, vided facilities, etc.): FM-B, S-BK, AK, and JB. Analysis and inter- nail changes with onycholysis, hair modifications, and ocu- pretation of data (e.g., statistical analysis, biostatistics, computational lar disorders (dry eye and keratitis); asymptomatic retinal analysis): FM-B, S-BK, and TT. Writing, review, and/or revision of the pigment epithelial detachment has also been described for manuscript: S-BK, FM-B, AK, AB, RL, TT, AS, MO, FR, DL, SW-R, Aprutumab Ixadotin (BAY 1187982) Anti-FGFR2 ADC in Solid Tumors 599 and JB. Administrative, technical, or material support (i.e., reporting 2. De Moerlooze L, Spencer-Dene B, Revest JM, Hajihosseini M, or organizing data, constructing databases): S-BK and TT. Rosewell I, Dickson C. An important role for the IIIb isoform of fibroblast growth factor receptor 2 (FGFR2) in mesenchymal– epithelial signalling during mouse organogenesis. Development. Compliance with Ethical Standards 2000;127(3):483–92. 3. Matsuda Y, Yoshimura H, Suzuki T, Uchida E, Naito Z, Ishi- Funding This study was funded by Bayer Healthcare. Medical writing wata T. Inhibition of fibroblast growth factor receptor 2 attenu- support, including assisting authors with the development of the initial ates proliferation and invasion of pancreatic cancer. Cancer Sci. draft and incorporation of comments, was provided by Karl Kemp- 2014;105(9):1212–9. https ://doi.org/10.1111/cas.12470 . O’Brien, Ph.D, and editorial support, including referencing, format- 4. Hattori Y, Itoh H, Uchino S, Hosokawa K, Ochiai A, Ino Y, et al. ting, and proofreading, was provided by Ian Norton, Ph.D and Annabel Immunohistochemical detection of K-sam protein in stomach can- Ola, MSc, all of Scion, London, UK, supported by Bayer HealthCare cer. Clin Cancer Res. 1996;2(8):1373–81. according to Good Publication Practice guidelines. The Sponsor was 5. Carter EP, Fearon AE, Grose RP. Careless talk costs lives: fibro- involved in the study design, collection, analysis, and interpretation of blast growth factor receptor signalling and the consequences of data, as well as data checking of information provided in the manu- pathway malfunction. Trends Cell Biol. 2015;25(4):221–33. https script. However, ultimate responsibility for opinions, conclusions, and ://doi.org/10.1016/j.tcb.2014.11.003. data interpretation lies with the authors. 6. Andre F, Cortes J. Rationale for targeting fibroblast growth fac - tor receptor signaling in breast cancer. Breast Cancer Res Treat. 2015;150(1):1–8. https ://doi.org/10.1007/s1054 9-015-3301-y. Conflict of interest A. Sommer, F. Reetz, A. Babich, S. Wittemer- 7. Deng N, Goh LK, Wang H, Das K, Tao J, Tan IB, et al. A com- Rump, and R.  Liu are shareholders and employees of Bayer AG. prehensive survey of genomic alterations in gastric cancer reveals T. Tanigawa is an employee of Bayer Yakuhin. M. Osada and D. Lau- systematic patterns of molecular exclusivity and co-occurrence rent were employees of Bayer AG, Berlin, Germany, during the con- among distinct therapeutic targets. Gut. 2012;61(5):673–84. https duct of the study. M. Osada now works at Merck Serono, Tokyo, Japan. ://doi.org/10.1136/gutjn l-2011-30183 9. D. Laurent now works at Berlin-Chemie, Berlin, Germany. S.-B. Kim 8. Dienstmann R, Rodon J, Prat A, Perez-Garcia J, Adamo B, reports receiving institutional research funding from Novartis, Sanofi- Felip E, et  al. Genomic aberrations in the FGFR pathway: Genzyme, Kyowa Kirin Inc., and Dongkook Pharma Co Ltd. F. Meric- opportunities for targeted therapies in solid tumors. Ann Oncol. Bernstam reports receiving commercial research grants from Novartis, 2014;25(3):552–63. https ://doi.org/10.1093/annon c/mdt41 9. AstraZeneca, Taiho, Genentech, Calithera, Debio International Group, 9. Kim S, Dubrovska A, Salamone RJ, Walker JR, Grandinetti Bayer, PUMA, Aileron, Jounce, CytoMx, Effector, Zymeworks, Curis, KB, Bonamy GM, et al. FGFR2 promotes breast tumorigenicity and Pfizer, and is a consultant/advisory board member for Dialecta, through maintenance of breast tumor-initiating cells. PLoS One. Sumitomo Dainippon, Pieris Pharmaceuticals, Darwin Health, Sam- 2013;8(1):e51671. https: //doi.org/10.1371/journal.p one.0051671 . sung Bioepis, Aduro, Spectrum, OrigiMed, Debiopharm International, 10. Martignetti JA, Camacho-Vanegas O, Priedigkeit N, Camacho Inflection Biosciences, Xencor, and Genentech. 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First-in-Human Phase I Study of Aprutumab Ixadotin, a Fibroblast Growth Factor Receptor 2 Antibody–Drug Conjugate (BAY 1187982) in Patients with Advanced Cancer

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Springer Journals
Copyright
Copyright © 2019 by The Author(s)
Subject
Medicine & Public Health; Oncology; Biomedicine, general
ISSN
1776-2596
eISSN
1776-260X
DOI
10.1007/s11523-019-00670-4
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Abstract

Background Fibroblast growth factor receptor (FGFR) 2 is overexpressed in several tumor types, including triple-negative breast cancer and gastric cancer, both of which have a high unmet medical need. Aprutumab ixadotin (BAY 1187982) is the first antibody–drug conjugate (ADC) to target FGFR2 and the first to use a novel auristatin-based payload. Objective This first-in-human trial was conducted to determine the safety, tolerability, and maximum tolerated dose (MTD) of aprutumab ixadotin in patients with advanced solid tumors from cancer indications known to be FGFR2-positive. Patients and Methods In this open-label, multicenter, phase I dose-escalation trial (NCT02368951), patients with advanced solid tumors received escalating doses of aprutumab ixadotin (starting at 0.1 mg/kg body weight), administered intravenously on day 1 of every 21-day cycle. Primary endpoints included safety, tolerability, and the MTD of aprutumab ixadotin; second- ary endpoints were pharmacokinetic evaluation and tumor response to aprutumab ixadotin. Results Twenty patients received aprutumab ixadotin across five cohorts, at doses of 0.1–1.3 mg/kg. The most common grade ≥ 3 drug-related adverse events were anemia, aspartate aminotransferase increase, proteinuria, and thrombocytopenia. Dose-limiting toxicities were thrombocytopenia, proteinuria, and corneal epithelial microcysts, and were only seen in the two highest dosing cohorts. The MTD was determined to be 0.2 mg/kg due to lack of quantitative data following discontinu- ations at 0.4 and 0.8 mg/kg doses. One patient had stable disease; no responses were reported. Conclusions Aprutumab ixadotin was poorly tolerated, with an MTD found to be below the therapeutic threshold estimated preclinically; therefore, the trial was terminated early. ClinicalTrials.gov Identifier NCT02368951. Electronic supplementary material The online version of this 1 Introduction article (https ://doi.org/10.1007/s1152 3-019-00670 -4) contains supplementary material, which is available to authorized users. Fibroblast growth factor receptor (FGFR) 2 is a transmem- * Sung-Bae Kim brane receptor tyrosine kinase with a key role in tissue repair sbkim3@amc.seoul.kr and embryonic development [1, 2]. Aberrations leading to Department of Oncology, Asan Medical Center, University constitutive activation or overexpression of FGFR2, includ- of Ulsan College of Medicine, 88 Olympic-ro 43-gil, ing gene amplification, gene fusions, and single nucleotide Songpa-gu, Seoul 05505, Republic of Korea 2 polymorphisms, have been identified in many cancer types, The University of Texas MD Anderson Cancer Center, including triple-negative breast cancer, pancreatic, esopha- Houston, TX, USA 3 geal, hepatocellular, colorectal, ovarian, gastric, non-small- Northwestern University Feinberg School of Medicine, cell lung cancer (NSCLC), and glioma [3–16]. Furthermore, Chicago, IL, USA 4 FGFR2 overexpression has been associated with poor sur- Bayer AG, Berlin, Germany vival in patients with gastric cancer [7]. Although treatments Bayer Healthcare, Whippany, NJ, USA are available for gastric and other cancers overexpressing Bayer Yakuhin, Ltd., Osaka, Japan FGFR2, the generally poor prognosis for patients with these Bayer AG, Basel, Switzerland tumors suggests that a high unmet medical need remains [3–16]. In contrast to typically high expression levels in Vanderbilt University Medical Center, Nashville, TN, USA Vol.:(0123456789) 592 S.-B. Kim et al. ixadotin has low nanomolar potency and suggested that Key Points high FGFR2 expression correlates with internalization and cytotoxic effects [ 28]. In mice, pharmacokinetic studies of Aprutumab ixadotin (BAY 1187982) is a novel conjugate aprutumab ixadotin showed that concentrations of the cyto- of an anti-fibroblast growth factor receptor (FGFR) 2 toxic payload metabolite are enriched by more than 30-fold antibody linked to an innovative auristatin W derivative in FGFR2-positive tumors compared with healthy tissue toxophore. This is the first time this novel payload has [28]. Furthermore, aprutumab ixadotin treatment resulted been used in a clinical setting and the first time an anti- in dose-dependent tumor regression in patient-derived xeno- body–drug conjugate has been used to target FGFR2. graft (PDX) models of FGFR2-positive gastric cancer and triple-negative breast cancer, including reductions in tumor Toxicities were observed at doses lower than the pre- volume equivalent to partial and complete responses [28]. dicted therapeutic dose and were unexpected based on Results from PDX studies also indicated that FGFR2 ampli- the preclinical findings. The cause of these toxicities is fication or overexpression was predictive of high antitumor not yet known but may be attributed to the unique com- activity in vivo [28]. In these preclinical studies, no evidence bination of an auristatin W derivative payload with an was found to suggest that aprutumab ixadotin would exert a FGFR2-targeting antibody. bystander effect [28]. Furthermore, findings from preclini- These findings highlight the need for improved preclini- cal studies have also indicated that aprutumab ixadotin was cal models that more accurately predict the effects of stable in the circulatory system [28]. novel compounds in humans, which may increase the Based on these promising preclinical data, an open-label, efficiency of clinical development. non-randomized, first-in-human phase  I dose-escalation study of aprutumab ixadotin was conducted in adult patients with advanced, refractory solid tumor indications reported tumors, FGFR2 is generally expressed at low levels in nor- mal tissue, making it an attractive antigen for development to express FGFR2. Aprutumab ixadotin is the first ADC to target FGFR2 in the treatment of advanced tumors and is of a targeted anticancer therapy [8, 17]. Antibody–drug conjugates (ADCs) comprise a cytotoxic also the first ADC to include this novel auristatin W deriva- tive payload. The primary objectives of this study were to payload conjugated by a linker to a monoclonal antibody directed against an antigen that is selectively expressed on determine the safety, tolerability, and maximum tolerated dose (MTD) of aprutumab ixadotin. the surface of tumor cells [18, 19]. This selectivity allows ADCs to be directed at tumor cells, limiting systemic expo- sure and off-target toxicity [20, 21]. Binding of the antibody to its target antigen triggers internalization of the ADC, after 2 Materials and Methods which the linker molecule is cleaved, or the antibody moiety is degraded in the lysosome (non-cleavable linker). Cleavage 2.1 Patients or degradation of the linker molecule releases the payload metabolite within the cell, resulting in cytotoxic effects [20, Patients aged 18 years or older with advanced solid tumors from cancer indications known to be FGFR2-positive, which 21]. The ADCs brentuximab vedotin, gemtuzumab ozo- gamicin, inotuzumab ozogamicin, and trastuzumab emtan- were refractory to any standard therapy or had no standard therapy available, were eligible for enrollment. Patients were sine have been approved based on their efficacy in late-stage clinical trials [22–25]. In addition, several ADCs are cur- required to have measurable disease, Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–1, rently being investigated in clinical trials in a wide range of tumor types [26, 27]. However, ADCs targeting FGFR2 have an expected lifespan of at least 12 weeks, and a formalin- fixed paraffin-embedded (FFPE) tumor tissue sample from not yet been described in any tumor type. Aprutumab ixadotin (BAY  1187982) is a novel ADC either archival tissues or fresh biopsy for intended retrospec- tive FGFR2 expression analyses. Patients were excluded if comprising a fully human anti-FGFR2 monoclonal anti- body (BAY 1179470) conjugated by lysine side chains to they had a history of allergic reactions to monoclonal anti- body therapy, anticancer chemotherapy, immunotherapy, or a non-cleavable linker and via this an innovative aurista- tin W derivative [28]. This novel auristatin W derivative is experimental cancer therapy (including clinical trials) within 3 weeks prior to the first dose of study drug. Full eligibility a highly potent microtubule-disrupting agent used for the first time in aprutumab ixadotin [28]. Lysosomal degrada- criteria are reported in the Electronic Supplementary Mate- rial Appendix. tion of the antibody moiety releases the non-cell-permeable payload metabolite that cannot cross cell membranes due to the presence of a charged group, as previously described [28]. Results from in vitro studies indicated that aprutumab Aprutumab Ixadotin (BAY 1187982) Anti-FGFR2 ADC in Solid Tumors 593 2.2 Objectives The primary objectives were to determine the safety, toler- ability, and MTD of aprutumab ixadotin. Secondary objec- tives included evaluation of pharmacokinetics, pharmacody- namics, immunogenicity, and tumor response. 2.3 Study Design This was a phase I, open-label, first-in-human, non-rand- omized, multicenter trial. The trial was planned to include two phases, the first being a dose-escalation phase to deter - mine the MTD of aprutumab ixadotin, and the second an expansion phase to further evaluate safety, pharmacokinet- ics, and clinical activity at the MTD. Aprutumab ixadotin was administered as an intravenous infusion over 1 h on day 1 of every 21-day cycle, with the first infusion given on cycle 1, day 1. Treatment continued Fig. 1 Patient disposition and analysis population until evidence of disease progression, unacceptable toxicity, withdrawal of consent, or patient withdrawal from the trial. data available for cycle 1, or had discontinued early, before The aprutumab ixadotin dose could be reduced or delayed the next cohort was initiated. Modeling of DLTs was carried to manage dose-limiting toxicities (DLTs) or adverse events out after at least one DLT was reported or grade ≥ 2 drug- (AEs). Treatment was stopped if more than two dose reduc- related AE (except asymptomatic changes in biochemistry tions were required. laboratory values) was reported in two different patients in Dose escalation and MTD determination were conducted the first 21 days of treatment in cycle 1. The five dose-esca- using a previously described adaptive dose-escalation trial lation cohorts enrolled were 0.1, 0.2, 0.4, 0.8, and 1.3 mg/kg. design [29]. The MTD was defined as the maximum dose at which the incidence of DLTs during cycle 1 was below 2.4 Safety Assessments 20%, or the maximum dose administered, whichever was achieved first during dose escalation. DLTs were defined Patients were assessed for safety on days 1, 2, 3, 5, 8, 15, and as any of the following AEs occurring during cycle 1 and 21 of cycles 1 and 3, and days 1, 8, 15, and 21 of cycle 2, considered related to study drug: grade 4 absolute neutrophil cycle 4, and subsequent cycles. End-of-treatment visits were count decrease for ≥ 7 days; grade ≥ 3 febrile neutropenia; also conducted at the time of study drug discontinuation or grade 4 thrombocytopenia for > 1 day; grade 4 anemia or 14 days after last treatment, with an end-of-study visit or anemia requiring blood transfusion; grade ≥ 3 hemorrhage; phone call taking place 30 days after the last treatment with grade ≥ 3 thrombotic event; any other non-hematological study drug. Patients had ophthalmic evaluation prior to ini- toxicity considered to be drug-related, excluding grade ≥ 3 tiation of study drug and on day 15 of each cycle. AEs were nausea and vomiting controllable by anti-emetics within reported using the National Cancer Institute Common Ter- 3 days; grade 3 fatigue lasting ≤ 72 h; isolated change in minology Criteria for AEs (NCI-CTCAE) version 4.03. The laboratory biochemical values; and grade 3 infusion-related study protocol was amended to include dose modification as reactions resolving within 6 h and controlled by medical well as remedial treatment guidelines for corneal toxicity. management. Figure 1 shows the patient disposition of the dose-esca- 2.5 Pharmacokinetics lation cohorts. Five dose-escalation cohorts of at least three patients were enrolled (where multiple sites conducted the Serial blood samples for pharmacokinetic characteriza- dose escalation, there was an option to enroll four patients). tion of aprutumab ixadotin (total drug), total antibody, and The first four patients of each cohort were enrolled with a toxophore metabolite BAY 1159184 were collected during safety interval of at least 48 h between drug administrations cycles 1 and 3 at the following timepoints: pre-dose, 0.5, on cycle 1, day 1. The starting dose was 0.1 mg/kg body 1 (end-of-infusion sample), 1.5, 2, 3, 5, 8, 24, 48, 96, 168, weight, with doses increased in two-fold increments up to 336, and 504 h after the start of infusion, with the 504-h 0.8 mg/kg, after which the dose was escalated in 0.5 mg/kg sample being collected before the start of cycles 2 and 4, increments. All participants in a dose-level cohort must have respectively. Plasma concentrations were determined by received one complete infusion of study drug and have safety 594 S.-B. Kim et al. enzyme immunoassay (EIA) for aprutumab ixadotin and 1.3 mg/kg group, one patient had grade 3 proteinuria, one total antibody and by liquid chromatography–tandem mass patient had grade 3 proteinuria and grade 4 thrombocytope- spectrometry (LC–MS/MS) for the toxophore metabolite nia, and a third patient had grade 3 corneal epithelial micro- BAY 1159184. If a patient discontinued study after cycle 3, cysts and grade 2 blurred vision. day 21, the 504-h blood sample was collected on cycle 3, After three of five patients in the 1.3 mg/kg group and day 21. Starting with cycle 5, day 1, samples were collected one patient in the 0.8 mg/kg group experienced DLTs, it before infusion with aprutumab ixadotin and at the end of was decided that new patients should only be enrolled at a infusion, in every second cycle. Tumor tissue samples were starting dose of 0.2 mg/kg or lower due to the high degree of planned to be analyzed for FGFR2 overexpression; however, uncertainty regarding the time course and degree of revers- this was not conducted. ibility of these toxicities. Since two of the patients in the 1.3 mg/kg group experienced grade 3 proteinuria, dose lev- 2.6 T umor Response Assessment els of 0.4 and 0.8 mg/kg were not considered safe due to lack of quantitative data for protein in urine and limited exposure Tumors were evaluated using computed tomography or as the majority of patients discontinued; therefore, a dose magnetic resonance imaging; response was assessed using of 0.2 mg/kg was determined to be the MTD. At 0.2 mg/kg, Response Evaluation Criteria in Solid Tumors (RECIST), the efficacy profile of the drug did not favor further develop- version 1.1. ment; therefore, the study was discontinued by the sponsor and the dose-expansion phase was not carried out. 3 Results3.3 Safety 3.1 Patient Characteristics All patients had at least one treatment-emergent AE (TEAE) of any grade (100%), with at least one grade ≥ 3 Twenty patients were enrolled at three sites in the USA and TEAE reported in 15 patients (75%; Table  2). Grade  3 one site in Korea, and treated with aprutumab ixadotin. TEAEs occurred in 13 patients (65%), and grade 4 TEAEs The median age was 52 years (range 24–76 years) and 55% in two patients (10%). The most common grade 3 TEAEs were female (n = 11). The four most common tumor types were thrombocytopenia, increased aspartate transaminase were colorectal cancer (n = 5; 25%), cholangiocarcinoma (AST), increased blood alkaline phosphatase (ALP) levels, (n = 4; 20%), gastric cancer (n = 2; 10%), and hepatocellu- proteinuria, and anemia. The only grade 4 TEAE was throm- lar carcinoma (n = 2; 10%). Most patients had an ECOG PS bocytopenia in two patients (10%); no grade 5 TEAEs were of 1 (n = 14; 70%). The median number of prior systemic reported. therapies was eight (range 1–23). Four patients had FGFR2 TEAEs determined to be drug-related were reported amplification according to institution-led DNA copy num- by 17 patients (85%), and nine patients (45%) reported ber analysis. Patient demographics and characteristics are grade ≥ 3 drug-related TEAEs. The most common of these described in Table 1. were thrombocytopenia (15%), anemia (10%), increased AST (10%), and proteinuria (10%). Other grade  3 drug- 3.2 Dose Escalation related TEAEs were hypertension, increased alanine ami- notransferase (ALT), decreased blood albumin, increased All patients enrolled were assigned to one of five dose-esca- blood ALP levels, dehydration, decreased neutrophil count, lation cohorts (0.1 mg/kg [n = 4], 0.2 mg/kg [n = 3], 0.4 mg/ and corneal epithelial microcysts, which occurred in one kg [n = 4], 0.8 mg/kg [n = 4], or 1.3 mg/kg [n = 5]) and com- patient each (5%). Grade 4 drug-related thrombocytopenia pleted the study. Fifteen patients discontinued treatment due was reported in two patients (10%). to progressive disease (75%) and five discontinued due to Treatment-emergent serious AEs (SAEs) were reported AEs (25%). The longest treatment duration observed was in eight patients (40%), the most common being anorexia, 13 cycles, which included one dose reduction from 0.8 to thrombocytopenia, and proteinuria, each reported in two 0.4 mg/kg after the first cycle due to grade 4 thrombocyto- patients (10%). Drug-related SAEs were proteinuria and penia and one dose interruption between cycles 10 and 11 thrombocytopenia, both reported in two patients (10%), and due to reactivation of hepatitis B that was controlled. anorexia and nausea in one patient each (5%). Patients in the lower dose cohorts of 0.1, 0.2, and 0.4 mg/ One death due to colorectal cancer disease progression kg did not experience any DLTs. DLTs were observed in was reported during follow-up, after discontinuation of apru- one patient in the 0.8 mg/kg group and three of five patients tumab ixadotin. The patient experienced two occurrences of in the 1.3 mg/kg group. The patient in the 0.8 mg/kg group grade 3 ascites that were considered to be unrelated to the had grade 4 thrombocytopenia; of the three patients in the study drug. Aprutumab Ixadotin (BAY 1187982) Anti-FGFR2 ADC in Solid Tumors 595 dipstick values from previous cohorts at the 0.1, 0.2, 0.4, and Table 1 Patient demographics and characteristics 0.8 mg/kg dose levels (where available) were retrospectively CharacteristicTotal population (N= 20) reviewed and plotted to analyze intensity and kinetics. Based Age (years) on these dipstick test results, proteinuria was also observed  Median (range) 52 (24–76) in three of four patients at the 0.8 mg/kg dose level and in Sex [n (%)] all four patients at the 0.4 mg/kg dose level. However, dis-  Male 9 (45) continuation of patients in cycle 2 due to early tumor pro-  Female 11 (55) gression precluded further characterization of the observed ECOG PS [n (%)] proteinuria. Due to the lack of quantitative values, the course  0 6 (30) and clinical relevance of proteinuria in these patients could  1 14 (70) not be interpreted. Additionally, the limited drug exposure Median number of prior systemic thera- 8 (1–23) and insufficient observation period in these patients pre- pies (range) cluded assessment of the nephrotoxic potential of aprutumab b 2 Body mass inde x (kg/m ) ixadotin at dose ranges of 0.4–0.8 mg/kg. Therefore, the  Mean (SD) 25.3 ± 4.5 0.2 mg/kg dose level was regarded as non-nephrotoxic based  Median (range) 23.5 (20.1–35.4) on available data from three patients at the 0.2 mg/kg dose Tumor type [n (%)] level. No signs of hematuria were observed using a dipstick  Breast cancer 1 (5) test. Signs of recovery were observed 20 days after discon-  Cholangiocarcinoma 4 (20) tinuation of the study drug.  Colorectal cancer 5 (25) Ocular events occurred in eight patients (40%) across all  Esophageal cancer 1 (5) dose groups, and included corneal epithelial microcysts,  Gastric cancer 2 (10) blurred vision, corneal deposits, retinal hemorrhage, and  Gastrointestinal stromal tumor 1 (5) ocular discomfort. The ocular events manifested within  Hepatocellular cancer 2 (10) the first two cycles and did not typically result in dosage  Pancreatic adenocarcinoma 1 (5) changes, except in one patient for whom treatment was dis-  Parotid gland adenoid cystic carcinoma 1 (5) continued due to dose-limiting grade 3 corneal epithelial  Mouth floor cancer 1 (5) microcysts and grade 1 blurred vision. Ocular events con-  Tongue base adenoid cystic carcinoma 1 (5) sidered to be drug-related included corneal deposits in four patients (deposits of lipids or calcium that build up on the ECOG PS Eastern Cooperative Oncology Group performance status, cornea in layers resulting in blurred vision; 20%), corneal SD standard deviation epithelial microcysts in three patients (incompletely formed The total population includes all patients enrolled in the dose-escala- tion cohorts; patients with brain metastases were excluded cells in the epithelia that can cause vision hazing; 15%), N = 19 patients and blurred vision in one patient (5%). These drug-related events were reported in two patients (50%) in the 0.8 mg/ kg group (time to onset: 36 days) and in all five patients in Five patients discontinued treatment due to one or more the 1.3 mg/kg group (time to onset: 6–22 days). Remedial TEAEs (proteinuria, thrombocytopenia, dehydration, ane- treatment for ocular events consisted of carmellose ophthal- mia, fatigue, worsening chronic renal disease, corneal epi- mic drops in concert with polyacrylic acid, difluprednate, or thelial microcysts, and blurred vision). Three patients had fluorometholone drops. Ocular symptoms had fully resolved treatment interruptions due to TEAEs (proteinuria, gastro- for one patient, appeared to be improving in two patients, paresis, corneal epithelial microcysts, and blurred vision). and showed no further worsening in three patients at the Two patients had dose reductions due to thrombocytopenia. time of last study visit. A transient decrease in platelet count was observed in one 3.4 Key Safety Observations patient at the 0.1 mg/kg dose level during cycle 1. Throm- bocytopenia was subsequently observed in all patients at Proteinuria or nephrotic syndrome was reported in two of the 0.4, 0.8, and 1.3 mg/kg dose levels. Thrombocytopenia five patients after the cycle 1 at the 1.3 mg/kg dose level, was reported as a DLT in one patient each at both the 0.8 with a time to onset of approximately 20 days. Proteinuria and 1.3 mg/kg dose levels. The time to onset and time to worsened in consecutive cycles, and both patients devel- recovery of thrombocytopenia was consistent in consecutive oped nephrotic syndrome. Both patients also showed abnor- cycles at all dose levels. mally high fibrinogen and D-dimer concentrations, while Increased serum transaminase levels were detected in serum blood urea nitrogen-to-creatinine ratios were nor- cycle 1 at the 0.2 mg/kg dose level. The intensity and fre- mal. Following these findings at the 1.3 mg/kg dose level, quency of abnormally high transaminase levels tended to 596 S.-B. Kim et al. than the upper limit of normal. Elevated transaminase levels Table 2 Summary of adverse events typically resolved within the same treatment cycle. AEs Aprutumab ixadotin (N= 20) All grades [n (%)] Grade ≥ 3 [n (%)] 3.5 Pharmacokinetics Any TEAE 20 (100) 15 (75) Initial pharmacokinetic analyses of 18 patients showed that  Any drug-related TEAE 17 (85) 9 (45) the pharmacokinetic profile of the toxophore metabolite Any serious TEAE 8 (40) BAY 1159184 appeared approximately dose-proportional  Any drug-related serious 5 (25) at doses from 0.4 to 1.3 mg/kg (Fig. 2). Dose-proportional TEAE increases in exposure to aprutumab ixadotin (total drug) at TEAEs occurring in ≥ 10% of patients in the overall population doses of 0.1–1.3 mg/kg were also observed (Fig.  2). The  AST increased 12 (60) 3 (15) pharmacokinetic profiles of total antibody and FGFR2-ADC  Thrombocytopenia 10 (50) 5 (25) (aprutumab ixadotin, i.e., total drug) were similar, which  Anemia 6 (30) 2 (10) may indicate that aprutumab ixadotin would be stable in  Fatigue 6 (30) 0 plasma.  Nausea 5 (25) 0  Pyrexia 5 (25) 0 3.6 Tumor Response  ALT increased 5 (25) 1 (5)  Blood ALP increased 5 (25) 3 (15) Stable disease was observed in one patient with tongue base  Decreased appetite 5 (25) 1 (5) adenoid cystic carcinoma assigned to the 0.8 mg/kg group  Corneal deposits 4 (20) 0 whose dose was reduced after cycle 1–0.4 mg/kg (Fig. 3).  Abdominal pain 4 (20) 0 Disease progression occurred in this patient during cycle 13.  Corneal epithelial micro- 3 (15) 1 (5) cysts No partial or complete responses were observed in any  Dyspepsia 3 (15) 0 patients.  Vomiting 3 (15) 1 (5)  Urinary tract infections 3 (15) 1 (5)  Hypoalbuminemia 3 (15) 0 4 Discussion  Cough 3 (15) 0  Abdominal distension 2 (10) 0 FGFR2 has been identified as a promising drug target  Ascites 2 (10) 1 (5) because it is overexpressed in various tumor types [7–9, 11].  Blood cholesterol increased 2 (10) 0 This phase I trial was initiated to investigate the safety of the  Blood creatinine increased 2 (10) 0 anti-FGFR2 ADC aprutumab ixadotin (BAY 1187982), fol-  Blood fibrinogen increased 2 (10) 0 lowing positive in vitro and in vivo data [28], and to deter-  BNP increased 2 (10) 0 mine the MTD for subsequent dose-expansion cohorts. This  Fibrin d -dimer increased 2 (10) 0 study represented the first time an ADC had been used to  Lipase increased 2 (10) 0 target FGFR2 in the treatment of advanced tumors. Despite  WBC count decreased 2 (10) 0 promising results in preclinical studies, safety data col-  Dehydration 2 (10) 1 (5) lected during this trial suggested that in a heavily pretreated  Hypercalcemia 2 (10) 0 population of patients with advanced solid tumors, apru-  Proteinuria 2 (10) 2 (10) tumab ixadotin was poorly tolerated with a MTD of 0.2 mg/  Epistaxis 2 (10) 0 kg every 3 weeks The activity of aprutumab ixadotin has  Productive cough 2 (10) 0 been evaluated in a range of preclinical models, including assessment of antitumor activity and pharmacokinetics in AE adverse event, ALP alkaline phosphatase, ALT alanine ami- mouse xenograft tumor models [28]. The pharmacokinetics notransferase, AST aspartate aminotransferase, BNP brain natriuretic of aprutumab ixadotin were also assessed in cynomolgus peptide, TEAE treatment-emergent adverse event, WBC white blood cell monkeys after single and repeat dosing, and a rat model was Data are sorted by the incidence of TEAEs in the overall escalation used to assess the toxophore-linker metabolite [30]. Results group from preclinical mouse xenograft studies and pharmacoki- netic modeling predicated that the minimum doses required increase with the dose of aprutumab ixadotin. The highest for stable disease, partial response, and complete response levels were observed in one patient in each of the 0.8 and were 0.4, 0.5, and 1.2 mg/kg, respectively [31]. As the MTD 1.3 mg/kg cohorts, with levels that were five times higher of aprutumab ixadotin in this trial was below the predicted minimum therapeutic dose established during PDX studies, Aprutumab Ixadotin (BAY 1187982) Anti-FGFR2 ADC in Solid Tumors 597 Fig. 3 Treatment duration in patients treated with aprutumab ixado- tin. Dose reductions are indicated with a black arrow; dose reduction occurred a on day 22 from 0.8 to 0.4 mg/kg and b on day 23 from 1.3 to 0.8 mg/kg the sponsor discontinued the trial after enrollment and treat- ment of 20 patients [31]. In non-clinical safety studies in cynomolgus monkey models, aprutumab ixadotin treatment led to increased ALT and AST levels; extrapolation of these data to humans led to an estimated highest non-severely toxic dose of aprutumab ixadotin of 1.48 mg/kg when administered every 3 weeks, as was applied in this trial. The predicted therapeutic index in humans was approximately 3.5, calculated using the high- est non-severely toxic dose and the dose required to achieve stable disease [31]. These data supported the decision to Fig. 2 Geometric mean plasma concentrations of a aprutumab ixad- further investigate aprutumab ixadotin in a first-in-human otin, b total antibody, and c toxophore metabolite (BAY  1159184) during cycle  1 for the 0.1 (n = 4), 0.2, 0.4 (n = 3), 0.8 (n = 4), and phase I trial. 1.3 (n = 5) mg/kg dose cohorts. Data for the toxophore metabolite The N-terminal epitope of FGFR2 is conserved between (BAY  1159184) are only available for the 0.4, 0.8, and 1.3  mg/kg humans, monkeys, rats, and mice. The antibody moiety of dose cohorts. *Data are presented individually in the 0.2 mg/kg dose aprutumab ixadotin binds to recombinant FGFR2 protein cohort due to the low number of patients with available pharmacoki- netic data (n = 2) with a similar EC (half-maximal effective concentration) across these species, making any of them relevant for toxic- ity testing. Toxicity studies in rats and cynomolgus monkeys 598 S.-B. Kim et al. revealed effects typical of ADC-mediated toxicity related to the FGFR1–3 inhibitor BGJ398. Thus, while dry eye and toxophore activity. This was observed in the form of mor- corneal toxicity has been reported with FGFR inhibitors, phological degeneration/regeneration and inflammation in kidney toxicity has not been previously observed [42–46]. lung, liver, kidneys, cornea, and the lympho-hematopoietic The similar temporal pattern of the course of proteinuria in system at sufficient multiples of exposure compared with patients in this trial and the lack of alternative explanation the expected human efficacious exposure to suggest an for this abnormality support the causal relationship between acceptable therapeutic index; most effects were reversible observed proteinuria/nephrotic syndrome and aprutumab and no functional organ toxicity was detected. Data from ixadotin, although this association was not seen in non- cynomolgus monkeys showed that aprutumab ixadotin had clinical safety studies conducted in rats and cynomolgus a small effect on blood clot formation in the form of a small monkeys. and transient decrease in platelets that was restricted to the Ocular toxicities seem to be a class effect of ADCs with first treatment cycle; additionally, increases in thrombin microtubule-disrupting payloads, with corneal epitheliopa- time and d -dimer levels were observed. These effects were thy reported during treatment with both maytansinoid (DM4 fully reversible. Similar effects on blood clot formation payload metabolite) and auristatin-containing (monomethy- were induced by an isotype control ADC with an identical lauristatin F payload metabolite) ADCs [39–41, 47, 48]. As toxophore payload. No adverse effects were observed after observed in the current study, corneal epitheliopathy typi- administration of the payload metabolite alone, including in cally resolves with supportive care and treatment interrup- the coagulation system, indicating that the combination of tion or discontinuation. the payload-linker metabolite and an antibody moiety may Although efficacy was not formally evaluated during the be the causative factor for the coagulation effects. To our trial, one patient with tongue base adenoid cystic carcinoma knowledge, similar coagulation effects have not been seen in had a best response of stable disease and remained on treat- clinical trials of other ADCs or toxophores [32–35]. ment until disease progression during cycle 14. This patient The most common TEAEs that occurred in patients was enrolled in the 0.8 mg/kg dose cohort and had a dose treated with aprutumab ixadotin in this phase I trial included reduction to 0.4 mg/kg to manage toxicities during cycle 2. thrombocytopenia and increased levels of AST, which No other responses were observed in the four patients (two occurred in 50% and 60% of patients, respectively, with a cases of gastric cancer and one case each of cholangiocar- further eight TEAEs occurring in 25% or more of patients cinoma and colorectal cancer) with known FGFR2 ampli- across all dose cohorts. The safety data indicate the follow- fications. Most patients discontinued treatment because of ing undesirable effects of aprutumab ixadotin: proteinuria/ disease progression. nephrotic syndrome; thrombocytopenia; increased serum ALT and AST levels; and corneal epithelial microcysts. Patients treated with aprutumab ixadotin in this study were 5 Conclusion heavily pretreated, with a median number of prior therapies of eight (range 1–23), which may have contributed to the The ADC aprutumab ixadotin was found to be poorly toler- observed poor tolerance. ated in this phase I first-in-human trial, with an MTD of Patients in the 1.3 mg/kg dose cohort had d -dimer lev- 0.2 mg/kg, which is below the estimated minimum thera- els notably higher in the second cycle than during the first peutic dose predicted in preclinical studies. The safety cycle of treatment with aprutumab ixadotin. d -Dimer eleva- profile of this ADC in humans also differed markedly from tion is thought to be caused by kidney damage leading to that observed in animal models, with a high rate of pro- nephrotic syndrome [36]; during the second cycle it was teinuria and nephropathy. These results underline the need to concluded that kidney recovery did not seem to balance the develop new methods to predict the effects of investigational kidney damage. Furthermore, patients with nephrotic syn- ADCs and their metabolites in humans during preclinical drome have a significantly higher risk of thrombotic events development. and renal failure [37]. Proteinuria and nephrotic syndrome Acknowledgements The authors thank the patients, their families, and may be considered as toxicities specifically associated with all investigators involved in this study. We would also like to thank aprutumab ixadotin treatment, as similar toxicities have not Ruprecht Zierz of Bayer AG for providing the preclinical toxicology been previously reported in clinical trials of other ADCs data and for his review and feedback on this manuscript. that carry a range of payloads [38–41]. AEs reported for pan-FGFR inhibitors and FGFR1–3 specific inhibitors Author contributions Conception and design: S-BK and FR. Acquisi- tion of data (provided animals, acquired and managed patients, pro- include hyperphosphatemia, stomatitis, mucosal dryness, vided facilities, etc.): FM-B, S-BK, AK, and JB. Analysis and inter- nail changes with onycholysis, hair modifications, and ocu- pretation of data (e.g., statistical analysis, biostatistics, computational lar disorders (dry eye and keratitis); asymptomatic retinal analysis): FM-B, S-BK, and TT. Writing, review, and/or revision of the pigment epithelial detachment has also been described for manuscript: S-BK, FM-B, AK, AB, RL, TT, AS, MO, FR, DL, SW-R, Aprutumab Ixadotin (BAY 1187982) Anti-FGFR2 ADC in Solid Tumors 599 and JB. Administrative, technical, or material support (i.e., reporting 2. De Moerlooze L, Spencer-Dene B, Revest JM, Hajihosseini M, or organizing data, constructing databases): S-BK and TT. Rosewell I, Dickson C. An important role for the IIIb isoform of fibroblast growth factor receptor 2 (FGFR2) in mesenchymal– epithelial signalling during mouse organogenesis. Development. Compliance with Ethical Standards 2000;127(3):483–92. 3. Matsuda Y, Yoshimura H, Suzuki T, Uchida E, Naito Z, Ishi- Funding This study was funded by Bayer Healthcare. Medical writing wata T. Inhibition of fibroblast growth factor receptor 2 attenu- support, including assisting authors with the development of the initial ates proliferation and invasion of pancreatic cancer. Cancer Sci. draft and incorporation of comments, was provided by Karl Kemp- 2014;105(9):1212–9. https ://doi.org/10.1111/cas.12470 . O’Brien, Ph.D, and editorial support, including referencing, format- 4. Hattori Y, Itoh H, Uchino S, Hosokawa K, Ochiai A, Ino Y, et al. ting, and proofreading, was provided by Ian Norton, Ph.D and Annabel Immunohistochemical detection of K-sam protein in stomach can- Ola, MSc, all of Scion, London, UK, supported by Bayer HealthCare cer. Clin Cancer Res. 1996;2(8):1373–81. according to Good Publication Practice guidelines. The Sponsor was 5. Carter EP, Fearon AE, Grose RP. Careless talk costs lives: fibro- involved in the study design, collection, analysis, and interpretation of blast growth factor receptor signalling and the consequences of data, as well as data checking of information provided in the manu- pathway malfunction. Trends Cell Biol. 2015;25(4):221–33. https script. However, ultimate responsibility for opinions, conclusions, and ://doi.org/10.1016/j.tcb.2014.11.003. data interpretation lies with the authors. 6. Andre F, Cortes J. Rationale for targeting fibroblast growth fac - tor receptor signaling in breast cancer. 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Published: Sep 9, 2019

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