This phase I dose-escalation/expansion study evaluated isatuximab (anti-CD38 monoclonal antibody) monotherapy in patients with relapsed/refractory multiple myeloma (RRMM). Patients progressing on or after standard therapy received intravenous isatuximab (weekly [QW] or every 2 weeks [Q2W]). The primary objective was to determine the maximum tolerated dose (MTD) of isatuximab. Overall, 84 patients received ≥ 1 dose of isatuximab. The MTD was not reached; no cumulative adverse reactions were noted. The most frequent adverse events were infusion reactions (IRs), occurring in 37/73 patients (51%) following introduction of mandatory prophylaxis. IRs were mostly grade 1/2, occurred predominantly during Cycle 1, and led to treatment discontinuation in two patients. CD38 receptor occupancy reached a plateau of 80% with isatuximab 20 mg/kg (highest dose tested) and was associated with clinical response. In patients receiving isatuximab ≥ 10 mg/kg, overall response rate (ORR) was 23.8% (15/63), including one complete response. In high-risk patients treated with isatuximab 10 mg/kg (QW or Q2W), ORR was 16.7% (3/18). Median (range) duration of response at doses ≥ 10 mg/kg was 25 (8–30) weeks among high-risk patients versus 36 (6–85) weeks for other patients. In conclusion, isatuximab demonstrated a manageable safety profile and clinical activity in patients with RRMM.

This work described the development and the full validation of a precise, sensitive and accurate assay. After validation, this new assay was successfully applied to routine toxicological analysis.

Background: SAR566658 (SAR) is a maytansinoid-loaded ADC (huDS6-SPDB-DM4) targeting CA6, a specific glycol-epitope of MUC-1 over-expressed in solid tumors (pancreas 26%, ovary 55%, breast 30%, bladder 60%) and rarely in normal tissues. This FIH study was designed to assess the safety, dose limiting toxicities (DLTs)/recommended dose (RD) and pharmacokinetic following SAR administration in Pts with CA6-expressing STs. Trial is funded by Sanofi. Methods: This Phase I study explored escalating intravenous doses of SAR administered as single agent every 3 weeks (q3w). An accelerated dose escalation scheme was used for the two first dose levels (DL), followed by a standard 3+3 dose escalation scheme. Results: 34 heavily pretreated Pts were enrolled including: 11M/23F, median age 58 years (range, 32-77), ECOG-PS ≤1, with a variety of advanced STs including ovary (13), pancreas (10) and breast (4). A total of 114 cycles (cy), median 2, (range,1-14) of SAR was administered across 9 DLs ranging from 10 to 240 mg/m2. DLTs were observed at the highest DL of 240 mg/m2 and included grade (Gr) 3 diarrhea at cy1 in 1 Pt and Gr3 keratitis at cy2 in 2 Pts. Anticipated toxicity was cornea, peripheral neuropathy, hematological and pulmonary. So far the number of Pts with these toxicities are: keratitis (all Gr: 11 Pts, including 2 Pts with Gr3), peripheral neuropathy (5 Pts, no Gr≥3), neutropenia (Gr3, 2 Pts), interstitial pneumonitis (1 Pt). Other than late occurrence of reversible corneal adverse events (AE) at 150 mg/m2, no dose-dependent AE was observed. Exposure to SAR (Cmax and AUC) increased with no major deviation from dose proportionality over doses of 20 to 240 mg/m2. Clearance was roughly constant over the doses with a low to moderate total variability. SAR 190 mg/m2 fulfills the criteria for RD: no DLT and manageable ocular AE versus highest DL. Clinical benefit was observed at doses ≥120 mg/m2: 1 partial response (breast), 1 PR to be confirmed (ovary), 3 stable disease (SD)>6months and 11 SDs were noted. A significant decrease in tumor marker was noted in 1 Pt. Conclusions: SAR has a favorable safety profile and encouraging antitumor activity. SAR at 190mg/m2 q3w was selected as the RD and is being confirmed in an ongoing extension cohort. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A73. Citation Format: Valentina Boni, Olivier Rixe, Drew Rasco, Carlos Gomez-Roca, Emiliano Calvo, John C. Morris, Anthony W. Tolcher, Sylvie Assadourian, Helene Guillemin, Jean-Pierre Delord. A Phase I first-in-human (FIH) study of SAR566658, an anti CA6-antibody drug conjugate (ADC), in patients (Pts) with CA6-positive advanced solid tumors (STs) (NCT01156870). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A73.

Adrenocortical carcinoma (ACC) is an aggressive malignancy of the adrenal gland. Mitotane (o,p'-DDD) is the most effective chemotherapy for ACC. According to the literature, mitotane plasma trough concentrations within 14-20 mg L are correlated with a higher response rate with acceptable toxicity. Therapeutic drug monitoring (TDM) of mitotane is therefore recommended. The aim of this study was to propose a robust and simple method for mitotane quantification in plasma. The validation procedures were based on international guidelines. Sample preparation consisted of a single protein precipitation with methanol using 100 μL of plasma. The supernatant was submitted to liquid chromatography coupled with ultra-violet detection at 230 nm. Mitotane retention time was 7.1 min. The limit of detection was 0.1 mg L and the limit of quantification was 0.78 mg L . The assay demonstrated a linear range of 0.78-25 mg L with correlation coefficients (r ) at 0.999. Inter- and intra-assay precision was <4.85%. Evaluation of accuracy showed a deviation <13.69% from target concentration at each quality control level. This method proved easy and rapid to perform mitotane TDM and required a small volume of sample. It was successfully applied to routine TDM in our laboratory.

No abstract