This randomized controlled trial confirmed the efficacy of chemotherapy (mGEMOX) compared with BSC and FUFA in improving OS and PFS in unresectable GBC.

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BackgroundOral mucositis is a common inflammatory complication in patients undergoing high-dose chemotherapy and radiation followed by haematopoietic stem cell transplantation (HSCT). Lactobacillus brevis CD2 has been proven efficacious in preventing chemoradiotherapy-induced oral mucositis in squamous cell carcinoma of head and neck.MethodsThis phase II study aimed to evaluate the safety and efficacy of L. brevis CD2 lozenges in preventing oral mucositis in patients undergoing HSCT. Eligible patients received four to six lozenges of L. brevis CD2 per day, beginning from 4 to 7 days before initiation of chemotherapy and continuing until resolution of mucositis or till day +24.ResultsOf 31 patients enrolled, 7 (22.6%) patients did not develop any mucositis, 6 (19.4%) patients developed grade 1, 12 (38.7%) patients developed grade 2, 4 (12.9%) and 2 (6.5%) patients developed grade 3 and grade 4 mucositis, respectively. Median time to onset and for resolution of mucositis were 6 days and 8 days, respectively. No adverse events were reported with usage of study drug. However, one patient died of Klebsiella sepsis.ConclusionPromising results from the study encourage the use of L. brevis CD2 lozenges as a supportive care treatment option; however, a randomised, double-blind, multicentric trial in a larger population is warranted.Trials registration numberNCT01480011 at https://www.clinicaltrials.gov/ (Registered on Nov 04, 2011).

4500 Background: More than 70% of patients receiving high dose chemotherapy and haematopoietic stem cell transplantation (HSCT) are likely to develop grade III or IV mucositis causing significant morbidity. Palifermin, which helps in reducing duration and severity, is expensive and not available in many countries. Probiotic Lactobacillus CD 2 has been shown to reduce incidence and severity of chemo-radiotherapy induced mucositis in squamous cell carcinoma of head and neck (Sharma A, et al. Eur J Cancer 2012: 875–81). The objective of this study was to determine the efficacy of this probiotic in preventing grade III/IV mucositis in patients undergoing HSCT. Methods: Lozenges containing not less than 2×109 viable cells of Lactobacillus CD2 as active ingredient were started 4–7 days prior to commencing conditioning regimen of HSCT and continued till resolution of mucositis or Day+24 post stem cell infusion, whichever was earlier. The lozenges were supposed to be kept in mouth for it to be dissolved by itself. Mucositis (NCI-CTCAE V 4.03) was assessed daily till recovery; number of lesions, localization in the oral cavity, bleeding, erythema and ulceration were recorded. Photographs of the mucosal lesions (oral cavity) were taken once a week and saliva samples of patients was collected weekly till complete recovery or day +24 of the treatment to analyze the levels of pro-inflammatory cytokines. Results: Twenty-one patients (17 autologous and 4 RIC-allogeneic) in the age group of 10–70 years undergoing high dose chemotherapy and HSCT were enrolled. Median age was 29 years (range11–64 yrs). Multiple myeloma constituted 9 (43%) of cases. Others included HL (5), NHL (3), AML (3), and RMS (1). Fourteen patients had received at least 2 lines of prior therapy. Conditioning regimens used were high dose melphalan, BEAM, CBV, or melphalan treosulfan. Four patients received RIC (fludarabine with melphalan). One patient could not continue study drug beyond one day because of nausea, however, rest tolerated lozenges well. Eighteen patients took at least 3 or 4 lozenges daily for an average duration of 8 days. Six patients (28.6%) had no mucositis, 4 (19%) had grade I, 7 (33.3%) had grade II, and 2 (9.5%) patients each had grade III or IV mucositis (one of these was post autologous HSCT and another one was on long term methotrexate for rheumatoid arthritis). Seventeen patients had < grade 2 dysphagia. Median duration of IV antibiotic use was 8 days (range 5–18). Median days to onset of mucositis and time to recovery were 6 (range 3–8) and 8 days (range 5–40), respectively. No adverse events except occasional grade I/II nausea due to study drug were noted. Conclusion: This study suggests that the use of Lactobacillus CD2 significantly reduced events of severe mucositis in patients undergoing HSCT as only 19% developed grade III or IV mucositis compared to the expectation of >60%. This needs confirmation in randomized studies. ClinicalTrials.gov Identifier: NCT01480011 Disclosures: No relevant conflicts of interest to declare.

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BackgroundBintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β ”trap”) fused to a human IgG1 mAb blocking PD-L1. Here we report cumulative safety and pharmacokinetic (PK) results from the global, phase 1b/2 INTR@PID LUNG 024 study (NCT03840915), which evaluated bintrafusp alfa in combination with chemotherapy (CT) in patients with stage IV NSCLC.MethodsAdult patients with stage IV nonsquamous or squamous NSCLC and an ECOG PS ≤1 were included. Cohorts A, B, and C included patients with no prior systemic therapy; patients in cohort D had disease that progressed with previous anti–PD-(L)1 therapy. Cohorts received bintrafusp alfa 2400 mg every 3 weeks intravenously in combination with CT for 4 cycles (A [nonsquamous only]: cisplatin or carboplatin + pemetrexed; B: carboplatin + nab-paclitaxel or paclitaxel; C: cisplatin or carboplatin + gemcitabine; D: docetaxel) followed by bintrafusp alfa maintenance (monotherapy or in combination with pemetrexed in cohort A) for up to 31 cycles. The primary objective of this study was to evaluate the safety of bintrafusp alfa in combination with CT. Dose-limiting toxicities (DLTs) were assessed during a 3-week observation period. Serial samples were drawn to assess serum concentration and calculate PK parameters by noncompartmental analysis.ResultsAs of the May 5, 2021, data cutoff, 70 patients received bintrafusp alfa in combination with CT. Of 35 patients included in the DLT analysis, 4 experienced 1 DLT according to a safety monitoring committee (data cutoff May 5, 2021; A: n=1/8; B: n=1/8; C: n=0/8; D: n=2/11). Cumulative safety data are reported in table 1. PK data were available for 67 patients (A: n=38; B: n=9; C: n=8; D: n=12). PK profiles were similar across cohorts and between patients who did and did not experience a DLT. Observed bintrafusp alfa first-cycle exposures (Cmax, AUC, and Ctrough) were consistent with the published population PK (popPK) model.1Abstract 465 Table 1Safety results from the INTR@PID LUNG 024 studyConclusionsThe safety profile of bintrafusp alfa in combination with CT was manageable and similar to that reported for ICIs in combination with CT, with the exception of TGF-β–related skin lesions known to occur with TGF-β inhibition. No new safety signals were identified and there were no treatment-related deaths. The PK profile was consistent with the predicted monotherapy popPK model, suggesting no victim DDI potential for bintrafusp alfa with CT.AcknowledgementsThe authors thank the patients and their families, investigators, co-investigators, and the study teams at each of the participating centers, at the healthcare business of Merck KGaA, Darmstadt, Germany, and at EMD Serono, Billerica, Massachusetts, USA.Trial RegistrationNCT03840915ReferenceWilkins JJ, Vugmeyster Y, Dussault I. Population pharmacokinetic analysis of bintrafusp alfa in different cancer types. Adv Ther 2019;36:2414–2433.Ethics ApprovalThe trial was approved by each site’s independent ethics committee.

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