Final results of a phase 1b study of isatuximab short-duration fixed-volume infusion combination therapy for relapsed/refractory multiple myeloma

Part B of this phase 1b study (ClinicalTrials.gov number, NCT02283775) evaluated safety and efficacy of a fixed-volume infusion of isatuximab, an anti-CD38 monoclonal antibody, in combination with pomalidomide and dexamethasone (Pd) in relapsed/refractory multiple myeloma patients. Isatuximab (10 mg/kg weekly for 4 weeks, then every other week) was administered as a fixed-volume infusion of 250 mL (mL/h infusion rate) with standard doses of Pd on 28-day cycles. Patients (N = 47) had a median of three prior treatment lines (range, 1–8). Median duration of exposure was 36.9 weeks and median duration of first, second, and 3+ infusions were 3.7, 1.8, and 1.2 h, respectively. The most common non-hematologic treatment-emergent adverse events were fatigue (63.8%), infusion reactions (IRs), cough, and upper respiratory tract infection (40.4% each). IRs were all grade 2 and occurred only during the first infusion. The overall response rate was 53.2% in all patients (55.5% in response-evaluable population, 60.0% in daratumumab-naïve patients). Efficacy and safety findings were consistent with data from the isatuximab plus Pd infusion schedule in Part A of this study and also from the phase 3 ICARIA-MM study, and these new data confirm the safety, efficacy, and feasibility of fixed-volume infusion of isatuximab.

P724 Delaying an infliximab infusion by more than 3 days is associated with a significant reduction in trough levels

Background An association between higher infliximab-trough-levels (TL) and better outcomes has been demonstrated among IBD patients. Although standard scheduled infliximab therapy regimen consists of infusions at pre-defined time-points (weeks 0, 2, 6 and every 8 weeks), short-period deviations from therapeutic schedule are common in ‘real life’, especially during maintenance period (due to weekends, holidays, concurrent illnesses, etc.). We aimed to determine whether short-period deviations from infusion-schedule affect infliximab-TL and therapy outcome. Methods This was a retrospective study, analysing sera from all IBD patients receiving infliximab maintenance-therapy every 8 weeks in a tertiary medical centre. Associations between time since last infusion and TL were analysed. Clinical scores were recorded prospectively on infusion days and baseline demographic parameters were derived from patients’ charts. Statistical analysis was performed using generalised estimating equations. Results In total, 2088 sera of 302 maintenance-period infliximab-therapy-patients were included (median TL 4.1 μg/ml, IQR 2.3–6.5 μg/ml). A delay beyond 3 days in infusion (n > 59 days since last infusion) was demonstrated as significantly affecting TL (mean difference in TL 1 μg/ml, 95% CI 0.03–1.9 μg/ml, p < 0.04). A sub-analysis was performed for 60 maintenance-period infliximab-therapy-patients with >10 consecutive TL measurements (1226 measurements in total), with adjustment for background parameters (gender, infliximab dose, disease type, concomitant immunomodulator, age and weight). A delay of >4 days from scheduled infusion resulted in a statistically significant decline in infliximab trough levels (mean difference in TL 1.45 μg/ml, 95% CI 0.61–2.2 μg/ml, p < 0.001). Finally, deviation from infusion schedule was analysed in association with clinical remission status. Patients that were in clinical remission were more likely to arrive late, rather than early, for scheduled therapy, compared with patients with active disease (OR 2.92 CI 1.75–4.85, p < 0.0001). Conclusion Real life delays of <4 days from infusion protocol can probably be allowed. Delays beyond that would significantly decrease TL and might negatively affect therapy outcome. As patients arriving late for an infusion had higher rates of clinical remission than those arriving early, we assume clinical factors mainly drive patients to receive an earlier-then-scheduled infusion.

Pembrolizumab for Unresectable or Metastatic Melanoma in Patients Older than 85 Years of Age

Background: Programmed cell death protein-1 (PD-1) inhibitors (pembrolizumab and nivolumab) have been approved for the treatment of advanced melanoma. Over the past decades, patients older than 85 years represent an expanding group of patients in developed countries. In France, 25% of melanomas are diagnosed in patients older than 75 years. Objective: To perform a monocentric retrospective study of patients older than 85 years and treated with pembrolizu­mab for unresectable or metastatic melanoma in order to evaluate tolerance and potential benefits of this immunotherapy. Methods: Medical records of patients treated with the PD-1 inhibitor pembrolizumab between January 2015 and January 2018 were reviewed. Results: Nine patients (6 women and 3 men) older than 85 years were included in the study. The mean age was 89.6 (85–97) years at inclusion. All patients were PS 0 or 1. The mean number of infusions was 4 (1–12). However, most patients were not able to tolerate the 4-infusion schedule. One patient refused the second infusion for personal reasons. Seven patients had grade 3 or 4 treatment-related adverse events. Conclusion: These results indicate that pembrolizumab treatment in patients older than 85 years may induce responses but is associated with a high risk of toxicity and impaired autonomy.

Deflexifol (a novel formulation of 5FU): Pharmacokinetics in a phase 1 trial in comparison to 5FU.

2530 Background: Simultaneous administration of 5-fluorouracil (5FU) and leucovorin (LV) is generally not feasible as 5FU and LV are chemically incompatible (CaPO4 crystals), so the maximum possible interaction for benefit is not achieved. Deflexifol, an all in one formulation of 5FU/LV with cyclodextrin (HP-β-CD 100mg/ml, 5-FU 15mg/ml & LV 1mg/ml) at pH 7, was developed to overcome this problem. Methods: Limited sampling PK was done with dose 1 and 6 in a standard 3+3 phase I trial of Deflexifol given in two schedules (46-h infusion Q2W or bolus weekly x6) with no intrapatient dose escalation, at doses shown in Table. Sample times were infusion: 0, 2, 46h; bolus: 0, 0.2, 0.4, 1, 24h. 5FU and dihydroFU were measured as per Ackland et al, Anal Biochem 1997. 5FU AUC, clearance (CLR) and t1/2 were estimated for each patient to assess PK variability and adequacy of dosing compared to previous reports. Results: 40 patients were treated (21 infusion, 19 bolus, median age 67, 19 M, 21 F). The MTD(bolus) was 575 mg/m2, with no DLT in infusion schedule to 3600 mg/m2. PK showed substantial inter-patient variability – CLR(bolus) 21-900 L/h, t1/2 0.11-0.52 h, with intra-patient dose 6 CLR = 54-117% of dose 1, and a trend to increased AUC (mg/L.h) with dose (Table). Infusion CLR and AUC estimates were highly variable (CLR range 2-1200), with many cases with insufficient data. Compared to historical data with 5FU alone, AUC was likely subtherapeutic until 475mg/m2 bolus and for many patients with infusion <3000mg/m2. Conclusions: 5FU PK with Deflexifol is similar to 5FU alone. No evidence of saturation of kinetics over this dose range was seen, or induction of metabolism with repeated dosing. In each schedule AUC data supports the clinical impression of reduced toxicity at the same dose of 5FU. Accurate estimation of infusion PK requires more than 2 timepoints. PK in a phase II study is planned. Clinical trial information: 044867. [Table: see text]

Safety, pharmacology, and preliminary clinical activity of MM-151: An oligocolnal anti-EGFR theraputic in patients with cetuximab-resistant CRC and other refractory solid tumors.

647 Background: MM-151 is an oligoclonal anti-EGFR antibody combination designed to provide enhanced targeting of the EGFR network. This work describes the first in human experience of MM-151 alone and in combination with irinotecan. Methods: A standard 3+3 design was used to assess safety and tolerability of MM-151 monotherapy (QW, Q2W, Q3W) and MM-151 (QW) in combination with irinotecan 180mg/m2 (Q2W). A monotherapy expansion cohort has begun in cetuximab-resistant CRC. Results: Results presented are based on preliminary data as of September 2, 2014, for MM-151 monotherapy (n=65; QW/Q2W) and MM-151 in combination with irinotecan (n=10). The most common tumor types were CRC (29 [39%]), NSCLC (9 [12%]), HNSCC (8 [11%]). The monotherapy RP2D has been defined as 10.5 mg/kg QW and dosing continues at 18 mg/kg Q2W. Most adverse events were CTCAE grades 1 and 2. The most common AEs were toxicities related to the EGFR-pathway, including rash (70%), hypomagnesemia (24%), fatigue, dry skin, and diarrhea (21%). IRR was initially observed at high frequencies; however, standardized pre-medication and a modified infusion schedule significantly decreased this frequency. At doses >9 mg/kg QW, trough total antibody levels at steady state were in the expected therapeutic range. Of the CRC patients enrolled, 3 experienced Partial Responses (PRs) per RECIST criteria and a total of 8 (31%) pts had SD for >4 months. Initial biomarker data suggests particular clinical activity in triple-wildtype, EGFR-ligand positive CRC patients. Combination therapy with irinotecan continues with MM-151 at 9 mg/kg QW and 3 PRs have been observed (CRC, HNSCC, melanoma). Initial safety data is consistent with known toxicities of MM-151 and irinotecan. Preliminary results from the monotherapy expansion cohort (10.5 mg/kg QW) in CTX-refractory CRC will also be presented. Conclusions: These results demonstrate that MM-151 monotherapy has an acceptable tolerability profile and objective clinical activity alone and in combination with irinotecan. Results also support further clinical evaluation in triple-wildtype, EGFR-ligand positive CRC and other EGFR dependent cancers. Clinical trial information: NCT01520389.