Phase I dose-escalation study of plitidepsin in combination with bevacizumab in patients with refractory solid tumors

This phase I trial evaluated the toxicity profile and maximum tolerated dose of the combination between the marine derived cyclodepsipeptide plitidepsin and bevacizumab in advanced cancer patients. Thirteen patients were enrolled and treated with plitidepsin at three dose levels (2.8 mg/m2, n=3; 3.8 mg/m2, n=4; and 4.8 mg/m2, n=6) with a fixed dose of bevacizumab (10 mg/kg). Both agents were administered intravenously at D1 and D15 of a 28-day cycle. All 13 patients were evaluable for safety and toxicity. Doselimiting toxicities occurred in two out of six patients treated at the maximum dose tested (plitidepsin 4.8 mg/m2 and bevacizumab 10 mg/kg) and consisted of grade 3 fatigue, grade 3 myalgia, and two grade 2/3 alanine aminotransferase increases lasting for more than 7 days or leading to subsequent cycle delay greater than 2 weeks (n=1 each). The recommended dose for the combination of plitidepsin with bevacizumab was 3.8 mg/m2 for plitidepsin and 10 mg/kg for bevacizumab every 2 weeks. Most frequent treatment-related adverse events were nausea, vomiting, fatigue, epistaxis, and headache. Relevant hematological toxicity was minimal. Objective disease responses were not observed; however, stable disease (>3 months) was observed in four patients with colorectal cancer, renal cancer, and cervical cancer. Combining plitidepsin with bevacizumab combination is feasible. Stable disease was the best response obtained.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

An open-label, dose-escalation study to evaluate the safety and pharmacokinetics of CEP-9722 (a PARP-1 and PARP-2 inhibitor) in combination with gemcitabine and cisplatin in patients with advanced solid tumors

Poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors may potentiate chemotherapy by hindering DNA damage repair pathways. CEP-9722 is the prodrug of CEP-8983, a selective inhibitor of PARP-1 and PARP-2. Preclinical studies and a prior phase 1 study suggested that CEP-9722 may cause less myelosuppression than has been observed with other oral PARP inhibitors. The primary objective of this study was to determine the maximum-tolerated dose of CEP-9722 in combination with gemcitabine and cisplatin in patients with advanced solid tumors. All patients received cisplatin 75 mg/m2 on day 1 and gemcitabine 1250 mg/m2 on days 1 and 8 of a 21-day cycle. Patients who completed one cycle of chemotherapy alone continued chemotherapy in combination with CEP-9722 150, 200, 300, or 400mg orally twice daily on days 2-7, with dose-limiting toxicity assessed in cycle 2. Patients experiencing clinical benefit could continue treatment until disease progression or unacceptable toxicity. Thirty-two patients enrolled; 18 patients completed cycle 1 and received chemotherapy plus CEP-9722. The median (range) treatment administration with CEP-9722 was five (1-12) cycles. No patient experienced dose-limiting toxicity with CEP-9722 treatment. Grade 3/4 hematologic adverse events included neutropenia (28%) and leukopenia (11%); adverse events led to discontinuation in 33% of patients. One patient achieved complete response, three had partial responses, and 11 had stable disease; however, the relative contribution of CEP-9722 and/or the chemotherapeutic agents cannot be determined from this single-arm design. This study was discontinued before determination of the maximum-tolerated dose because of highly variable CEP-8983 exposure in all cohorts and toxicity, particularly chemotherapy-induced myelosuppression.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Systemic Therapy in Advanced Pleomorphic Liposarcoma: a Comprehensive Review

International audienceThe therapeutic approach of pleomorphic liposarcoma (PLPS), a rare high-grade subgroup of soft tissue sarcoma, is commonly extrapolated from the management of other LPS subtypes. Only published retrospective data on PLPS currently serve as a guide for oncologists without clear recommendations or specific guidelines. In the advanced setting, specific systemic therapy such as eribulin and trabectedin showed promising activity in comparison to conventional therapy (doxorubicin- and gemcitabine-based protocols), which currently remains the current standard of care at initial stages of the disease. The better understanding of soft tissue sarcoma (STS) pathophysiology and disease course has led to the development of adapted clinical trial designs for rare STS histotypes with specific treatment approach

PemBOv trial: Pembrolizumab plus bevacizumab with or without pegylated liposomal doxorubicin-based chemotherapy in patients with platinum-resistant ovarian cancer.

5575 Background: Few platinum resistant ovarian cancer (PROvC) patients respond to anti-PD1 monotherapy (ORR 7.6%) with little impact on survival (OS 10.1 mo). Among responders the median duration of response is impressive (18.7 mo) (Hamanishi 2021). Methods: We have evaluated the combination of pembrolizumab (200mg), with bevacizumab (400mg) for 6 cycles plus minus peglyated liposomal doxorubicin (PLD) q3w in PROvC patients with no limit in previous treatment lines, allowed to be previously treated with bevacizumab. An initial safety run evaluated the dual combination of pembrolizumab plus PLD (cohort A). The triple combination was evaluated at MTD-1 and at MTD of PLD (30mg/m 2 q3w) (cohort C). The dual combination of pembrolizumab + bevacizumab was run in parallel (cohort B). This is an open label phase I trial with a modified toxicity probability interval design. The evaluation criteria endpoints were safety and efficacy. Pharmacokinetics of bevacizumab were evaluated. NCT03596281 Results: A total of 47 patients (pts) were enrolled between January 2019 and February 2021. Median age was 70 years (38-77). 30/12 pts (63.8/25.5%) had an initial FIGO stage III/IV, 44 pts (93.6%) had a HGSOC. 40 pts (85.1%) underwent surgery, out of which 13 pts (32.5%) had a primary debulking. BRCA mutations were present in 9 pts (19.1%). Pts had a median of 3 previous treatment lines (0-13), including pretreatment with antiangiogenic agents in 36 (76.6%) and PARP inhibitors in 21 pts (44.7%). No DLT was reported. Grade 3/4 treatment-related adverse events were reported in 2 pts (30%), 4 (20%) and 11 (50%) in cohorts A, B and C respectively. The ORR was 0, 26.3 (95% CI 6.5-46.1) and 30% (9.9-50.1) with a DCR of 0, 78.9 and 75% in cohorts A, B and C respectively. According to investigator assessment, the median PFS was 2.1, 4.7 and 4.8 mo (table). The blinded independent central review is currently under evaluation. A large inter-patient variability in bevacizumab plasma concentrations was observed among patients. The 400 mg flat dosing achieved residual concentrations similar to that of 5 mg/kg Q2W or 7.5 mg/kg q3w (51± 30 μg/ml in cohort B and 63 ± 55 μg/ml in cohort C (p>0.05) after C1). Overall, 22 % of pts of cohort B and 18 % of cohort C showed trough levels below the targeted threshold (i.e. < 25 μg/ml). Correlative studies are ongoing. Conclusions: Short-term flat dose bevacizumab potentiates the response to anti-PD1 therapy even in the absence of chemotherapy in heavily pre-treated PROvC patients. The long-term treatment with bevacizumab could potentially improve the outcome. The combination of anti-PD-1 plus anti-angiogenic agents should be a backbone for the treatment of PROvC patients. Clinical trial information: NCT03596281. [Table: see text

TP53 Mutation as a Prognostic and Predictive Marker in Sarcoma: Pooled Analysis of MOSCATO and ProfiLER Precision Medicine Trials

(1) Background: locally resected high-grade sarcomas relapse in 40% of cases. There is no prognostic or predictive genomic marker for response to peri-operative chemotherapy. (2) Methods: MOSCATO and ProfiLER are pan-tumor prospective precision medicine trials for advanced tumors. Molecular analysis in both trials comprised targeted next-generation sequencing and comparative genomic hybridization array. We investigated if molecular alterations identified in these trials in sarcomas were associated with disease-free survival (DFS) and response to anthracyclines. (3) Results: this analysis included 215 sarcomas, amongst which 53 leiomyosarcomas, 27 rhabdomyosarcomas, 20 undifferentiated pleomorphic sarcomas, and 17 liposarcomas. The most frequently altered gene was TP53 (46 mutations and eight deletions). There were 149 surgically resected localized sarcomas. Median DFS in TP53 wild type (WT), deleted, and mutated sarcomas was 16, 10, and 10 months, respectively (p = 0.028; deletions: HR = 1.55; 95% CI = 0.75–3.19; mutations: HR = 1.70; 95%CI = 1.13–2.64). In multivariate analysis, TP53 mutations remained associated with shorter DFS (p = 0.027; HR = 2.30; 95%CI = 1.10–4.82). There were 161 localized and advanced sarcomas evaluable for response to anthracyclines. Objective response rates were 35% and 55% in TP53 WT and mutated sarcomas, respectively (OR = 2.24; 95%CI = 1.01–5.03; p = 0.05). In multivariate analysis, TP53 mutations remained associated with increased response (OR = 3.24; 95%CI = 1.30–8.45; p = 0.01). (4) Conclusions: TP53 mutations are associated with shorter DFS and increased response to anthracyclines. Post-validation, these findings could assist in decision-making for peri-operative treatments

A phase IB dose-escalation study of the safety and pharmacokinetics of pictilisib in combination with either paclitaxel and carboplatin (with or without bevacizumab) or pemetrexed and cisplatin (with or without bevacizumab) in patients with advanced non-small cell lung cancer

Aim: The phosphatidylinositol 3-kinase (PI3K) pathway is a potential therapeutic target in non-small cell lung cancer (NSCLC). This study aimed to evaluate the pan-PI3K inhibitor pictilisib in combination with first-line treatment regimens that were the standard of care at the time of study, in patients with NSCLC. Patients and methods: A 3 + 3 dose-escalation study was performed using a starting daily dose of 60 mg pictilisib on days 1-14 of a 21-day cycle. Depending on bevacizumab eligibility and NSCLC histology, patients also received either paclitaxel + carboplatin or pemetrexed + cisplatin, +/- bevacizumab every 3 weeks. The primary objectives of the study were to assess safety and tolerability and to identify dose-limiting toxicities (DLTs), the maximum tolerated dose (MTD) and a recommended phase II dose (RP2D), for each combination. Results: All 66 treated patients experienced at least one adverse event (AE). Grade >= III AEs, serious AEs and deaths occurred in 57 (86.4%), 56 (84.8%) and 9 (13.6%) patients, respectively. Three patients reported DLTs across the four arms of the study. The MTD was not reached in any arm and the RP2D of pictilisib was determined to be 330 mg (capsules) or 340 mg (tablets) on a '14 days on, 7 days off' schedule. The best confirmed response was partial response in 29 (43.9%) patients and stable disease in 20 (30.9%) patients. Conclusion: Combining pictilisib with various standard-of-care first-line treatment regimens is feasible from a safety perspective in patients with NSCLC, and encouraging preliminary antitumour activity was observed

Expression patterns of RelA and c-mip are associated with different glomerular diseases following anti-VEGF therapy.

International audienceRenal toxicity constitutes a dose-limiting side effect of anticancer therapies targeting vascular endothelial growth factor (VEGF). In order to study this further, we followed up 29 patients receiving this treatment, who experienced proteinuria, hypertension, and/or renal insufficiency. Eight developed minimal change nephropathy/focal segmental glomerulopathy (MCN/FSG)-like lesions and 13 developed thrombotic microangiopathy (TMA). Patients receiving receptor tyrosine kinase inhibitors (RTKIs) mainly developed MCN/FSG-like lesions, whereas TMA complicated anti-VEGF therapy. There were no mutations in factor H, factor I, or membrane cofactor protein of the complement alternative pathway, while plasma ADAMTS13 activity persisted and anti-ADAMTS13 antibodies were undetectable in patients with TMA. Glomerular VEGF expression was undetectable in TMA and decreased in MCN/FSG. Glomeruli from patients with TMA displayed a high abundance of RelA in endothelial cells and in the podocyte nuclei, but c-mip was not detected. Conversely, MCN/FSG-like lesions exhibited a high abundance of c-mip, whereas RelA was scarcely detected. RelA binds in vivo to the c-mip promoter and prevents its transcriptional activation, whereas RelA knockdown releases c-mip activation. The RTKI sorafenib inhibited RelA activity, which then promoted c-mip expression. Thus, our results suggest that c-mip and RelA define two distinct types of renal damage associated with VEGF-targeted therapies

Bevacizumab exposure and tumor response in patients with platinum resistant epithelial ovarian cancer.

International audience There is a high unmet medical need for disease control in platinum resistant epithelial ovarian cancer patients (PROC). PemBOv trial (NCT03596281) showed promising results with the combination of pembrolizumab plus short-term flat dose bevacizumab with or without pegylated liposomal doxorubicin (PLD) based chemotherapy. However, overall, 20 % of pts showed trough levels for bevacizumab below the targeted threshold of plasma levels associated with efficacy. Based on the PemBOv data, the current analysis aimed to develop a pharmacometric model to characterize the tumor growth early kinetics and quantify the effect of treatment in the study cohorts. A focus was made on the association between bevacizumab exposure and tumor response. Methods: Tumor growth kinetic was studied to predict the clinical outcome. Population pharmacodynamic non-linear mixed-effects modeling approach was used to characterize tumor size evolution in patients. The Kkill parameter expressed as week-1 was defined to best describe the shrinkage in tumor size depending on the treatments. In addition, Exposure-Response relationships was performed to evaluate whether bevacizumab plasma levels were associated with the previously determined Kkill parameter. The exposure to bevacizumab was defined by the trough level at the second treatment cycle (PreC2, µg/ml). Results: A strong difference in Kkill values was found between cohort A (pembrolizumab plus PLD, n=6, Kkill = 0.00091 week-1) and either cohorts B (pembrolizumab + bevacizumab, n=19, Kkill = 0.002) and C (pembrolizumab + bevacizumab + PLD, n=19, Kkill = 0.02 week-1) respectively, whereas little difference was observed between cohorts B and C. This difference indicates higher tumor shrinkage in cohorts B and C as compared to cohort A. No clear Exposure-Response relationship was evidenced between bevacizumab plasma levels and tumor shrinkage. Still, in patients treated with bevacizumab plus pembrolizumab (cohorts B and C), mean bevacizumab exposure was higher in patients with an ORR and Stable disease of at least 4 months as compared with patients with no clinical benefit (i.e., 69.4 VS. 48 ug/ml). Association between bevacizumab levels and clinical outcome deserves further investigations. Because Kkill can be estimated in an early fashion through in silico modeling, this could be evaluated as a surrogate marker to forecast clinical outcome. Conclusions: Bevacizumab exposure correlated with ORR and clinical benefit in PROC patients treated with bevacizumab plus pembrolizumab plus minus PLD, since higher plasma trough levels were associated with better clinical outcome. The early Kkill in silico modeling could pave the way for the development of prediction models for personalized treatments of PROC patients. Clinical trial information: NCT03596281 . </jats:p