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PDF file - 224K, Supplemental table 1: Mean (CV%) PK parameters of SAR3419 at 55 mg/m2 obtained after first and last administration. Supplemental figure 1: SAR3419 Ctrough observed during repeated intravenous infusion of SAR3419 using weekly or optimized schedules. Supplemental table 2: relationship between CD19 expression, proliferation (KI67), mitosis (pHH3) and p53 status with observed observed responses at the MTD during the optimized schedule.

Purpose: To determine recommended dose, dose-limiting toxicity, safety profile, pharmacokinetics, preliminary antitumor activity, and exploratory pharmacodynamics of SAR3419, an antibody–drug conjugate targeting CD19, administered alone by intravenous infusion weekly (qw), in a dose-escalation phase I study in patients with refractory/relapsed (R/R) non-Hodgkin lymphoma (NHL).Experimental Design: Patients with R/R CD19+ B-NHL were treated with escalating doses of SAR3419 repeated qw for eight to 12 doses. On the basis of clinical evidence of late or cumulative toxicities, the study protocol was amended to test an “optimized” administration schedule consisting of four qw doses followed by four biweekly (q2w) doses (qw/q2w) at the recommended dose with the intent of reducing drug accumulation.Results: Forty-four patients were treated on seven dose levels ranging from 5 to 70 mg/m2. SAR3419 recommended dose was determined as 55 mg/m2 qw. Twenty-five patients received the qw/q2w schedule at 55 mg/m2, which showed an improved safety profile compared with the qw schedule. Antilymphoma activity was observed with both schedules in around 30% of patients with either indolent or aggressive diseases. SAR3419 displayed a long terminal half-life (approximately 7 days) and a low clearance (approximately 0.6 L/d), with no dose effect. The qw/q2w schedule allowed limiting accumulation with a decrease in SAR3419 plasma trough and average concentrations by around 1.4-fold compared with the qw schedule.Conclusion: While administered weekly, SAR3419 is well tolerated and active. The qw/q2w schedule that shows an improved safety profile and preserves antilymphoma activity is selected for clinical phase II studies. Clin Cancer Res; 20(1); 213–20. ©2013 AACR.

PDF file - 68K, Individual median of free to VEGF-bound aflibercept Ctrough ratio observed from cycle.

Purpose: This phase I study cohort investigated aflibercept in combination with docetaxel in patients with advanced solid tumors.Materials and Methods: Eligible patients had metastatic or nonresectable cancer for which docetaxel was considered appropriate. Patients received intravenous aflibercept (either 2, 4, 5, 6, 7, or 9 mg/kg) with docetaxel (75 mg/m2) on day 1 every 3 weeks until disease progression or unacceptable toxicity. Primary objectives were to evaluate dose-limiting toxicities (DLT) during cycle 1 and to determine the aflibercept recommended phase II trial dose (RP2D) for combination with docetaxel. Pharmacokinetics, tolerability, and antitumor activity were also investigated.Results: Fifty-four patients (mean age, 56 y) were enrolled. Most had prior chemotherapy (96%) and most (24.1%) had breast cancer. In the dose-escalation phase (n = 34), there were three DLTs: grade 4 neutropenic infection (2 mg/kg), grade 3 dysphonia (7 mg/kg), and grade 2 hypertension (9 mg/kg). An excess of free-over-bound aflibercept was observed at doses of 5 mg/kg or more. The pharmacokinetics of aflibercept and docetaxel were not modified by coadministration. Aflibercept (6 mg/kg) was defined as the RP2D based on DLT and pharmacokinetic data. Overall, the most frequent grade 3/4 adverse events (AE) were neutropenia (85.2%), leukopenia (74.1%), hypertension (18.5%), and stomatitis (16.7%). AEs associated with vascular endothelial growth factor blockade included epistaxis (all grades, 83.3%), proteinuria (68.5%), dysphonia (68.5%), and hypertension (53.7%). Seven patients had partial responses, and 32 patients had stable disease (>3 months in 18 patients).Conclusion: On the basis of findings from this study, aflibercept (6 mg/kg) was the dose recommended for further clinical development. Clin Cancer Res; 18(6); 1743–50. ©2012 AACR.

Aflibercept targets vascular endothelial growth factor. The present study involved assessing the efficacy, safety and pharmacokinetics of aflibercept plus 5-fluorouracil/levofolinate/irinotecan (FOLFIRI) as a second-line treatment for metastatic colorectal cancer (mCRC) in Japanese patients. Aflibercept (4 mg/kg) plus FOLFIRI was administered every 2 weeks in 62 patients with mCRC until disease progression, unacceptable toxicity or patient withdrawal. Tumors were imaged every 6 weeks. The primary endpoint was objective response rate (ORR); secondary endpoints were progression-free survival, overall survival, safety, and pharmacokinetics of aflibercept, irinotecan and 5-fluorouracil. A total of 60 patients were evaluated for ORR; 50 had received prior bevacizumab. The ORR was 8.3% (95% confidence interval [CI]: 1.3%-15.3%), and the disease control rate (DCR) was 80.0% (69.9%-90.1%). The median progression-free survival was 5.42 months (4.14-6.70 months) and the median overall survival was 15.59 months (11.20-19.81 months). No treatment-related deaths were observed, and no significant drug-drug interactions were found. The most common treatment-emergent adverse events were neutropenia and decreased appetite. Free aflibercept had a mean maximum concentration (coefficient of variation) of 73.2 μg/mL (15%), clearance of 0.805 L/d (22%) and volume of distribution of 6.2 L (18%); aflibercept bound with vascular endothelial growth factor had a clearance of 0.162 L/d (9%) (N = 62). Aflibercept did not significantly affect the pharmacokinetics of irinotecan or 5-fluorouracil: The clearance was 11.1 L/h/m2 (28%) for irinotecan and, at steady state, 72.6 L/h/m2 (56%) for 5-fluorouracil (N = 10). Adding aflibercept to FOLFIRI was shown to be beneficial and well-tolerated in Japanese patients with mCRC. ClinicalTrials.gov Identifier: NCT01882868.

Background This study assessed the preliminary safety, pharmacokinetics (PK) and anti-tumor effects of aflibercept in combination with 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) in Chinese patients with previously-treated advanced solid malignancies. Patients and Methods This open-label single-arm Phase I study conducted at two centers in China included adult (≥18 years) patients with metastatic or unresectable solid malignancies who had received ≥1 prior treatment. Patients received aflibercept 4 mg/kg IV on Day 1 followed by FOLFIRI over Days 1 and 2 every 2 weeks, and were assessed for safety, tumor response, PK parameters and immunogenicity. Post-hoc analyses included calculation of progression-free survival (PFS) for patients with colorectal cancer (CRC). Results A total of 20 patients were enrolled. The most common Grade 3/4 adverse events included neutropenia (35%), hypertension (30%), stomatitis (20%) and proteinuria (20%), and no anti-aflibercept antibodies were detected. Six patients achieved a partial response, and in 15 patients with CRC median PFS was 5.95 months (95% CI: 5.29–8.77). Free aflibercept remained in excess of VEGF-bound aflibercept for the majority of the study treatment duration. The mean free aflibercept values for Cmax (64.8 μg/mL) AUC (291 μg.day/mL), CL (0.92 L/day) and Vss (5.9 L) were similar to those measured in Caucasian patients. The addition of aflibercept did not influence the PK of the chemotherapy agents. Conclusion For Chinese patients with pre-treated advanced solid malignancies, 4 mg/kg of aflibercept in combination with FOLFIRI was well-tolerated, demonstrated preliminary anti-tumor activity and had a PK profile consistent with that in Caucasian patients.

Purpose: To determine recommended dose, dose-limiting toxicity, safety profile, pharmacokinetics, preliminary antitumor activity, and exploratory pharmacodynamics of SAR3419, an antibody–drug conjugate targeting CD19, administered alone by intravenous infusion weekly (qw), in a dose-escalation phase I study in patients with refractory/relapsed (R/R) non-Hodgkin lymphoma (NHL). Experimental Design: Patients with R/R CD19+ B-NHL were treated with escalating doses of SAR3419 repeated qw for eight to 12 doses. On the basis of clinical evidence of late or cumulative toxicities, the study protocol was amended to test an “optimized” administration schedule consisting of four qw doses followed by four biweekly (q2w) doses (qw/q2w) at the recommended dose with the intent of reducing drug accumulation. Results: Forty-four patients were treated on seven dose levels ranging from 5 to 70 mg/m2. SAR3419 recommended dose was determined as 55 mg/m2 qw. Twenty-five patients received the qw/q2w schedule at 55 mg/m2, which showed an improved safety profile compared with the qw schedule. Antilymphoma activity was observed with both schedules in around 30% of patients with either indolent or aggressive diseases. SAR3419 displayed a long terminal half-life (approximately 7 days) and a low clearance (approximately 0.6 L/d), with no dose effect. The qw/q2w schedule allowed limiting accumulation with a decrease in SAR3419 plasma trough and average concentrations by around 1.4-fold compared with the qw schedule. Conclusion: While administered weekly, SAR3419 is well tolerated and active. The qw/q2w schedule that shows an improved safety profile and preserves antilymphoma activity is selected for clinical phase II studies. Clin Cancer Res; 20(1); 213–20. ©2013 AACR.

This work proposes a model-based approach to help select the phase 1 dosing regimen for the antibody–drug conjugate (ADC) SAR408701 leveraging the available data for 2 other ADCs of the same construct: SAR3419 and SAR566658. First, monkey and human pharmacokinetic (PK) data of SAR566658 and SAR3419 were used to establish the appropriate allometric approach to be applied to SAR408701 monkey PK data. Second, a population pharmacokinetics-pharmacodynamics (PK-PD) model was developed to describe tumor volume evolution following SAR408701 injection in mice. Third, allometric approaches identified for SAR566658 and SAR3419 were applied to SAR408701 monkey PK data to predict the human PK profile. Both SAR566658 and SAR3419 human and monkey PK were best described by a 2-compartment linear model. The relative difference was less than 10% between predicted and observed clearance using allometric exponents of 0.75 and 1, respectively. Tumor volume evolution following SAR408701 injection was best described by a full Simeoni model with a plasma concentration threshold of 4.6 μg/mL for eradication in mice. Both allometric exponents were used to predict SAR408701 PK in human from PK in monkey and to identify the potential effective dosing regimens. This translational strategy may be a valuable tool to design future clinical studies for ADCs, to support selection of the most appropriate dosing regimen, and to estimate the minimal dose required to assure antitumor activity, according to the schedule used.

Background: This phase I cohort study investigated aflibercept (vascular endothelial growth factor (VEGF) trap) plus docetaxel and cisplatin in patients with advanced solid tumours. Methods: Patients received intravenous aflibercept 4, 5, or 6 mg kg−1 with docetaxel and cisplatin (75 mg m−2 each) on day 1 of a 3-week cycle until progressive disease or unacceptable toxicity. Primary objectives were determining cycle 1 dose-limiting toxicities (DLTs) and the aflibercept recommended phase II trial dose (RP2D) for this combination. Results: During the dose-escalation phase (n=16), there were two DLTs of febrile neutropenia (at 4 and 5 mg kg−1). Granulocyte colony-stimulating factor prophylaxis was subsequently recommended. The RP2D of aflibercept was established at 6 mg kg−1 and administered to 14 additional patients. The most frequent grade 3/4 adverse events (AEs) were neutropenia (43.3%), stomatitis (20.0%), asthenia/fatigue (20.0%), and hypertension (16.7%). All-grade AEs associated with VEGF blockade included epistaxis (83.3%), dysphonia (70.0%), proteinuria (53.3%), and hypertension (50.0%). There were five partial responses (16.7%) and 18 cases of stable disease (60.0%) (lasting >3 months in 10 patients). There were no pharmacokinetic (PK) interactions between the three drugs. Conclusion: Aflibercept 6 mg kg−1 with docetaxel and cisplatin 75 mg m−2 every 3 weeks is the RP2D based on tolerability, antitumour activity, and PKs.

799 Background: Z + 5-fluorouracil/levofolinate/irinotecan (FOLFIRI) is a 2nd-line treatment for mCRC. There are no established biomarkers that predict response to this treatment. This study aimed to identify such biomarkers. Methods: 62 pts with mCRC received Z (4 mg/kg) + FOLFIRI every 2 weeks. 78 potential protein biomarkers (e.g., cytokines) were chosen for analysis based on their roles in angiogenesis, tumor progression, and tumor-stroma interaction. Plasma levels of biomarkers at baseline and pre-dose 3 (Day 1 of Cycle 3) were measured in all pts by enzyme-linked immunosorbent assays. Relationships between these levels and efficacy endpoints were assessed. PK data were calculated. Results: 10 potential biomarkers had a ±30% change from baseline to pre-dose 3 (adjusted P < .001); the greatest changes were in placental growth factor (median: 4,716%) and vascular endothelial growth factor receptor 1 (2,171%). Baseline levels of 8 potential biomarkers correlated with overall survival (OS; see table) in a univariate Cox regression analysis; none correlated with progression-free survival or maximum tumor shrinkage. Pre-dose 3 levels did not correlate with any efficacy endpoints. Conclusions: Preliminary data show that these 8 biomarkers could be associated with OS. No significant drug interactions were found. Clinical trial information: NCT01882868. [Table: see text]

2511Background: SAR566658 (SAR) is a maytansinoid-loaded ADC targeting CA6, a sialoglycotope of MUC-1 over-expressed in solid tumors and rarely in normal tissues. Methods: Phase I dose escalation and expansion study to evaluate SAR intravenous administration as single agent every 3 weeks (q3w) and 2 weeks (q2w). Primary objective included dose limiting toxicities (DLTs), maximum tolerated dose (MTD) and recommended dose (RD). Secondary objectives were PK, PD and preliminary efficacy assessment (RECIST1.1). Results: One hundred and fourteen patients (Pts) with heavily pretreated solid tumors expressing CA6 in ≥ 30% tumor cells with an intensity 2/3+ by immunohistochemistry were enrolled. SAR was administered across 11 dose levels (DLs) (10 to 240 mg/m² q3w and 120 mg/m² q2w). DLTs [1 grade (Gr) 3 diarrhea and 2 Gr3 keratitis] were observed at 240 mg/m². Initial RD was 190 mg/m² however a high incidence of keratopathy was seen mainly at cycle 2. PK/safety simulation, preserving drug exposure and limiting ke...

Purpose: This phase I study cohort investigated aflibercept in combination with docetaxel in patients with advanced solid tumors. Materials and Methods: Eligible patients had metastatic or nonresectable cancer for which docetaxel was considered appropriate. Patients received intravenous aflibercept (either 2, 4, 5, 6, 7, or 9 mg/kg) with docetaxel (75 mg/m2) on day 1 every 3 weeks until disease progression or unacceptable toxicity. Primary objectives were to evaluate dose-limiting toxicities (DLT) during cycle 1 and to determine the aflibercept recommended phase II trial dose (RP2D) for combination with docetaxel. Pharmacokinetics, tolerability, and antitumor activity were also investigated. Results: Fifty-four patients (mean age, 56 y) were enrolled. Most had prior chemotherapy (96%) and most (24.1%) had breast cancer. In the dose-escalation phase (n = 34), there were three DLTs: grade 4 neutropenic infection (2 mg/kg), grade 3 dysphonia (7 mg/kg), and grade 2 hypertension (9 mg/kg). An excess of free-over-bound aflibercept was observed at doses of 5 mg/kg or more. The pharmacokinetics of aflibercept and docetaxel were not modified by coadministration. Aflibercept (6 mg/kg) was defined as the RP2D based on DLT and pharmacokinetic data. Overall, the most frequent grade 3/4 adverse events (AE) were neutropenia (85.2%), leukopenia (74.1%), hypertension (18.5%), and stomatitis (16.7%). AEs associated with vascular endothelial growth factor blockade included epistaxis (all grades, 83.3%), proteinuria (68.5%), dysphonia (68.5%), and hypertension (53.7%). Seven patients had partial responses, and 32 patients had stable disease (>3 months in 18 patients). Conclusion: On the basis of findings from this study, aflibercept (6 mg/kg) was the dose recommended for further clinical development. Clin Cancer Res; 18(6); 1743–50. ©2012 AACR.