Dose-limiting Toxicity Research Articles

First-In-Human Phase 1/2a Study of the First-In-Class CDK2/4/6 Inhibitor PF-06873600 Alone or with Endocrine Therapy in Patients with Breast Cancer.

The discovery that cyclin E overexpression is a key CDK4/6 inhibitor resistance mechanism has reinvigorated interest in targeting CDK2, and simultaneous inhibition of CDK2/4/6 as a novel therapeutic approach. This first-in-human study assessed safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of PF-06873600, the first-in-class inhibitor of CDK2/4/6. Dose escalation included 78 patients with advanced breast cancer, triple negative breast cancer, or ovarian cancer who received oral PF-06873600 1-50 mg twice daily (BID) (Part 1A, n=51), or PF-06873600 with endocrine therapy (Part 1B, n=16; Part 1C n=11) to determine the recommended dose for expansion (RDE). Dose expansion (Part 2A, n=45; Part 2C, n=28) assessed preliminary antitumor activity, safety and tolerability at the RDE in combination with fulvestrant in patients with HR+/HER2- mBC. Pharmacodynamics and translational readouts were assessed by phosphorylated Rb and Ki67 in tumor biopsies and circulating tumor DNA (ctDNA). The RDE of PF-06873600 was 25mg BID. During dose escalation, six of 42 (14.3%) evaluable patients had treatment-related dose-limiting toxicities. Most common all-causality adverse events (N=151) were nausea (62.9%), anemia (44.4%) and fatigue (43.7%). Reductions in Ki67-positive cells, pRb H-score, and ctDNA levels were observed. Three RECIST partial responses (PRs) were observed in Part 1. In Part 2A there were three PRs (objective response rate [ORR] 6.7%, 95% CI: 1.4-18.3%) and, in Part 2C, five PRs (ORR 22.7%, 95% CI: 7.8-45.4%). PF-06873600 demonstrated a benefit-risk profile consistent with the CDK4/6 inhibitor class of drugs, with preliminary clinical activity in HR+/HER2- mBC. gov identifier: NCT03519178.

Identification of low-toxicity DNA topoisomerase I inhibitors with potential blood-brain barrier penetrability for glioblastoma therapy: structure-based virtual screening reveals promising novel Scaffolds.

Due to the blood-brain barrier (BBB), DNA topoisomerase I (Topo I) inhibitors often cause dose-limiting toxicity in glioblastoma (GBM) treatment. Therefore, developing low-toxicity Topo I inhibitors with enhanced BBB permeability holds a significant promise for improving GBM treatment outcomes. In this study, structure-based virtual screening methods combined with biological evaluations successfully identified three potent Topo I inhibitors, which exhibited IC50 values of approximately 25µM against A172 cells. Structural similarity analysis showed that these compounds have novel scaffolds. Compounds F1260-0895 and F2557-0012 exhibited negligible cytotoxicity on HK-2 cells. The most active compound, F2557-0012, directly targets human Topo I. Clonal formation assays and growth inhibition curves demonstrated the sustained inhibitory effects of F2557-0012 on A172 cells. The flow cytometric analysis showed that F2557-0012 effectively inhibits cell proliferation with minimal effect on apoptosis. Molecular dynamic simulations demonstrated that compound F2557-0012 exhibits stable binding to the Topo I-DNA complex. Two new easily synthesized compounds, demonstrating improved BBB permeability and reduced hematotoxicity, were derived from F1260-0895 and F2557-0012 through structural optimization utilizing the OptADMET platform. Molecular docking analyses indicated that the two novel compounds exhibited a significantly stronger interaction with the Topo I-DNA complex. Further investigations are warranted to synthesize optimized compounds and evaluate their anti-GBM activity both in vitro and in vivo.

Expansion of a bacterial operon during cancer treatment ameliorates fluoropyrimidine toxicity.

Dose-limiting toxicities remain a major barrier to drug development and therapy, revealing the limited predictive power of human genetics. Here, we demonstrate the utility of a more comprehensive approach to studying drug toxicity through longitudinal profiling of the human gut microbiome during colorectal cancer (CRC) treatment (NCT04054908) coupled to cell culture and mouse experiments. Substantial shifts in gut microbial community structure during oral fluoropyrimidine treatment across multiple patient cohorts, in mouse small and large intestinal contents, and in patient-derived ex vivo communities were revealed by 16S rRNA gene sequencing. Metagenomic sequencing revealed marked shifts in pyrimidine-related gene abundance during oral fluoropyrimidine treatment, including enrichment of the preTA operon, which was sufficient for the inactivation of active metabolite 5-fluorouracil (5-FU). preTA+ bacteria depleted 5-FU in gut microbiota grown ex vivo and in the mouse distal gut. Germ-free and antibiotic-treated mice experienced increased fluoropyrimidine toxicity, which was rescued by colonization with the mouse gut microbiota, preTA+ Escherichia coli, or preTA-high stool from patients with CRC. Last, preTA abundance was negatively associated with fluoropyrimidine toxicity in patients. Together, these data support a causal, clinically relevant interaction between a human gut bacterial operon and the dose-limiting side effects of cancer treatment. Our approach may be generalizable to other drugs, including cancer immunotherapies, and provides valuable insights into host-microbiome interactions in the context of disease.

Efficacy and Toxicity Analysis of Selective BET Bromodomain Inhibitors in Models of Inflammatory Liver Disease.

BET bromodomain inhibitors demonstrate significant promise as anti-inflammatory agents. However, clinical data demonstrated that nonselective BET bromodomain inhibitors led to significant dose-limiting toxicity in clinical settings. Here, we use three orally bioavailable inhibitors, 1-3, that are either BRD4-D1 selective or pan-D1-biased + BRD4-D2, for assessing their cellular and in vivo efficacy and safety profile compared to known BET inhibitors in two inflammatory disease models. Our results show that pan-D1-biased + BRD4-D2 inhibitor, 3, is as efficacious as pan-BET inhibitor, I-BET151, in reducing inflammation in both models, whereas pan-D2 inhibitors are less effective. BRD4-D1 selective inhibitors are also efficacious; however, inhibitors with improved cellular engagement will be necessary to better assess their effects. Finally, BRD4-D1 selective inhibitors are better tolerated in a preclinical thrombocytopenia model than 3, while gastrointestinal toxicity may be a BRD4-driven effect. These results highlight the importance of assessing specific BET bromodomain functions due to their diverse roles in disease models.

A phase I/II trial evaluating the safety of increased-dose S- 1 with oxaliplatin and nivolumab in HER2-negative advanced gastric cancer

BackgroundWe developed and refined an S-1 dosage formula based on renal function, sex, and body surface area (BSA) to achieve the target area under the concentration–time curve of 5-fluorouracil in two prospective pharmacokinetic studies. The clinical validity of the refined formula (BBT formula) was evaluated using data from the two phase III trials of fist-line chemotherapy including S-1 for advanced gastric cancer, which demonstrated that overall survival and progression-free survival tended to be shorter in patients whose S-1 standard dose, based on BSA alone, was lower than that determined using the BBT formula.MethodsChemo-naïve patients with HER2-negative advanced gastric or gastroesophageal junction cancer, whose standard S-1 dose is lower than that determined using the BBT formula, receive S-1 at an increased dose based on the BBT formula plus oxaliplatin (130 mg/m2) and nivolumab (360 mg/body). The primary endpoint is the incidence of dose-limiting toxicity in six patients in the phase I part and the proportion of patients requiring S-1 dose reduction in a total of 20 patients, expecting 30% and rejecting 50% with an alpha error of 0.1 and beta error of 0.2. The secondary endpoints are adverse events, relative dose intensity, response rate, disease control rate, progression-free survival, and overall survival. A correlation study is conducted to investigate the immune profiles associated with efficacy.DiscussionThis phase I/II trial evaluates the safety and efficacy of S-1 at increased doses, determined by the BBT formula, in combination with oxaliplatin and nivolumab in patients with HER2-negative advanced gastric cancer, whose standard dose of S- 1 is lower than the dose recommended dose by the BBT formula.Trial registrationThis study was approved by the University of Tokyo Clinical Research Review Board (URL: https://www.ut-crescent.jp/patients/chiken_jisshi/, review number: 2022529SP) and was initiated at 19 institutions in June 2023 (registered as jRCTs031230127).

CMOEP regimen in the treatment of untreated peripheral T-cell lymphoma: a multicenter, single-arm, phase I study

The current first-line treatment for peripheral T-cell lymphoma (PTCL) has a typically poor prognosis. Developing a new regimen is urgently needed. This phase I study evaluated the maximum tolerated dose (MTD), safety, and efficacy of mitoxantrone hydrochloride liposome (Lipo-MIT) plus cyclophosphamide, vincristine, etoposide, and prednisone (COEP) in untreated PTCL. Patients with untreated PTCL were enrolled and received Lipo-MIT (15, 18, and 20 mg/m2) following a 3 + 3 dose-escalation design plus standard doses of COEP (750 mg/m2 cyclophosphamide, 1.4 mg/m2 vincristine, 60 mg/m2 etoposide, and 100 mg prednisone) every 3 weeks for 6 cycles. Primary endpoint was MTD; secondary endpoints were safety, overall response rate (ORR), complete response (CR) rate, progression-free survival (PFS), and overall survival (OS). As of the cut-off date (October 29, 2024), 13 patients received the Lipo-MIT plus COEP (CMOEP) regimen. No patients experienced dose-limiting toxicities (DLT); MTD was 20 mg/m2 and the recommended phase 2 dose was 18 mg/m2. Common ≥grade 3 hematologic toxicities included neutrophil count decreased (76.9%), white blood cell decreased (76.9%), and lymphocyte count decreased (46.2%). Most common ≥grade 3 non-hematologic toxicity was lung infection (15.4%). No deaths due to toxicities were reported. Among 12 patients evaluated for best response, ORR (95% CI, 73.5-100.0), and the CR rate was 66.7% (95% CI, 34.9-90.1). At a median follow-up of 8.5 months, the median PFS and OS were both not reached. The CMOEP regimen had a manageable safety profile and an encouraging clinical efficacy for PTCL patients, which warrants further investigation.Clinical trial registrationClinicalTrials.gov, identifier NCT05458180.

Exposure-response relationship of niraparib in maintenance therapy for recurrent ovarian cancer: ancillary analysis of the French GINECO-NiQoLe study.

Exposure-response relationship of niraparib in maintenance therapy for recurrent ovarian cancer: ancillary analysis of the French GINECO-NiQoLe study.

Evorpacept plus rituximab for the treatment of relapsed or refractory non-Hodgkin lymphoma: results from the phase I ASPEN-01 study.

CD47 overexpression has been associated with tumor cell survival. We present the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of evorpacept, a novel fusion protein comprising a high-affinity CD47-SIRPα immune checkpoint inhibitor to promote tumor-cell phagocytosis and inactive Fc domain to spare healthy cells, plus rituximab in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL) from the phase I ASPEN-01 study. Thirty-three patients received intravenous evorpacept (10 mg/kg [n=22] or 15 mg/kg [n=11] once weekly) until disease progression, in combination with fixed-duration intravenous rituximab (375 mg/m2 once weekly for 4 weeks, then every 4 weeks for 8 months). Evorpacept plus rituximab was well tolerated, with no doselimiting toxicities; no maximum tolerated dose was identified. The most common treatment-related adverse events (TRAE) were rash (24.2%) and fatigue (15.2%); most TRAE (70.0%) were mild-tomoderate in severity. Four (12.1%) patients reported grade 3 TRAE: anemia, neutropenia, decreased neutrophil count, increased alanine aminotransferase, decreased lymphocyte count, and decreased platelet count (one of each). Two (6.1%) patients experienced grade 4 TRAE (neutropenia, decreased neutrophil count). Six (18.2%) patients experienced serious AE (not treatment-related): asthma, dyspnea, respiratory failure, gastrointestinal infection, pneumonia, cardiac failure, and disease progression (one of each). Two (6.1%) deaths occurred (not treatment-related). Pharmacokinetics/pharmacodynamics were consistent with previous studies, with complete CD47 target occupancy (85%) achieved at both doses. In response-evaluable patients (n=32), objective response rate was 50.0% (95% confidence interval 33.1%- 69.8%). The safety, tolerability, and promising antitumor activity of evorpacept plus rituximab support continued evaluation of this combination in NHL (ClinicalTrials.gov identifier: NCT03013218).

A Phase Ia/b study of MEK1/2 inhibitor binimetinib with MET inhibitor crizotinib in patients with RAS mutant advanced colorectal cancer (MErCuRIC)

BackgroundTargeting RAS mutant (MT) colorectal cancer (CRC) remains a difficult challenge, mainly due to the pervasiveness of RAS/MEK-mediated feedback loops. Preclinical studies identified MET/STAT3 as an important mediator of resistance to KRAS-MEK1/2 blockade in RASMT CRC. This dose escalation/expansion study assessed safety and initial efficacy of the MEK1/2 inhibitor binimetinib with MET inhibitor crizotinib in RASMT advanced CRC patients.MethodsIn the dose escalation phase, patients with advanced solid tumours received binimetinib with crizotinib, using a rolling- 6 design to determine the maximum tolerable dose (MTD) and safety/tolerability. A subsequent dose expansion in RASMT CRC patients assessed treatment response. Blood samples for pharmacokinetics, MET biomarker and ctDNA analyses, and skin/tumour biopsies for pharmacodynamics, c-MET immunohistochemistry (IHC), MET in situ hybridisation (ISH) and MET DNA-ISH analyses were collected.ResultsTwenty patients were recruited in 3 cohorts in the dose escalation. The MTD was binimetinib 30 mg B.D, days 1–21 every 28 days, with crizotinib 250 mg O.D continuously. Dose-limiting toxicities included grade ≥ 3 transaminitis, creatinine phosphokinase increases and fatigue. Thirty-six RASMT metastatic CRC patients were enrolled in the dose expansion. Pharmacokinetic and pharmacodynamic parameters showed evidence of target engagement.Across the entire study, the most frequent treatment-related adverse events (TR-AE) were rash (80.4%), fatigue (53.4%) and diarrhoea (51.8%) with grade ≥ 3 TR-AE occurring in 44.6%. Best clinical response within the RASMT CRC cohort was stable disease in seven patients (24%). Tumour MET super-expression (IHC H-score > 180 and MET ISH + 3) was observed in 7 patients (24.1%), with MET-amplification only present in 1 of these patients. This patient discontinued treatment early during cycle 1 due to toxicity. Patients with high baseline RASMT allele frequency had a significant shorter median overall survival compared with that seen for patients with low baseline KRASMT allele frequency.ConclusionsCombination binimetinib/crizotinib showed a poor tolerability with no objective responses observed in RASMT advanced CRC patients.EudraCT-Number: 2014–000463 - 40 (20/06/2014: A Sequential Phase I study of MEK1/2 inhibitors PD- 0325901 or Binimetinib combined with cMET inhibitor Crizotinib in RAS Mutant and RAS Wild Type with aberrant c-MET).

Synergy of Body Composition, Exercise Oncology, and Pharmacokinetics: A Narrative Review of Personalizing Paclitaxel Treatment for Breast Cancer

Background/Objectives: Paclitaxel is a type of small molecule chemotherapy widely used for breast cancer, but its clinical efficacy is often hindered by dose-limiting toxicities such as chemotherapy-induced peripheral neuropathy and neutropenia. Traditional dosing based on body surface area does not account for variations in body composition, which may influence paclitaxel metabolism, toxicity, and treatment outcomes. This review explores the interplay between body composition, physical activity, and paclitaxel pharmacokinetics, emphasizing the potential for personalized dosing strategies. Methods: A comprehensive narrative review was conducted by analyzing the literature on body composition, small molecule chemotherapy-related toxicities, pharmacokinetics, and exercise oncology. Studies examining the role of skeletal muscle mass, adipose tissue, and physical activity in modulating paclitaxel metabolism and side effects were included. Results: Evidence suggests that patients with low skeletal muscle mass are at a higher risk of paclitaxel-induced toxicities due to altered drug distribution and clearance. Sarcopenic obesity, characterized by low muscle and high-fat levels, further exacerbates these risks. Exercise, particularly resistance and aerobic training, has been shown to improve muscle mass, mitigate toxicities, and enhance chemotherapy tolerance. However, the precise mechanisms by which exercise influences paclitaxel pharmacokinetics remain underexplored. Conclusions: Personalized chemotherapy dosing, considering body composition and physical activity, may optimize paclitaxel treatment outcomes. Future research should focus on integrating exercise interventions into oncology care and refining dosing models that account for interindividual differences in drug metabolism. These advancements could improve treatment efficacy while minimizing toxicities in breast cancer patients.

Final results from the phase Ia/Ib study of the novel bromodomain and extra-terminal domain inhibitor, BI 894999, in patients with advanced solid tumors or diffuse large B-cell lymphoma.

Final results from the phase Ia/Ib study of the novel bromodomain and extra-terminal domain inhibitor, BI 894999, in patients with advanced solid tumors or diffuse large B-cell lymphoma.

Using body composition to predict treatment-related adverse events and disease-free survival in patients with gastrointestinal stromal tumors treated with imatinib: a retrospective cohort study

BackgroundImatinib (IM) is the primary treatment for Gastrointestinal stromal tumor (GIST), but it faces significant challenges with resistance and a high incidence of adverse events. This study aims to assess the predictive value of baseline body composition parameters on treatment-related adverse events and disease-free survival (DFS) in GIST patients treated with imatinib.Materials and MethodsA single-center retrospective analysis was conducted on 107 moderate or high-risk stratification GIST patients diagnosed from 2014 to 2020 at the First Affiliated Hospital of Nanjing Medical University. Body composition parameters, including skeletal muscle index (SMI), myosteatosis, cachexia index (CXI), and Fat-Free Mass (FFM), etc. were obtained using abdominal CT images and clinical data. Logistic and COX regression models were used to analyze the relationship between these indicators and treatment-related adverse events and DFS.ResultsMultivariate analysis revealed that myosteatosis (OR=7.640, P<0.001) and drug dose (OR=1.349, P=0.010) were independent risk factors for adverse events, while a higher CXI (OR=0.983, P=0.017) was protective. Additionally, LAMA/SMA% (OR=1.072, P=0.028) was identified as an independent risk factor for dose-limiting toxicity (DLT). Independent predictors of DFS included sarcopenia (HR=3.067, P=0.013), myosteatosis (HR=6.985, P=0.024), risk stratification (HR=9.562, high-risk vs. moderate-risk, P=0.003), and C-KIT mutation (HR=3.615, C-KIT exon 9 mutation vs. 11, P=0.013).ConclusionsBaseline body composition parameters, particularly myosteatosis, effectively predict the adverse events and DFS in patients taking imatinib. Personalized treatment, such as targeted nutritional and exercise interventions, and close monitoring of patients with myosteatosis or sarcopenia can enhance compliance and improve survival rates.

Sequential combination with ropeginterferon alfa-2b and anti-PD-1 treatment as adjuvant therapy in HBV-related HCC: a phase 1 dose escalation trial

Abstract Background/purpose Post-operative recurrence is a major clinical challenge with hepatocellular carcinoma (HCC). While currently unapproved, anti-programmed cell death 1 (PD-1) and anti-vascular endothelial growth factor combination adjuvant therapy showed promise. We initiated a phase I trial using sequential treatment with ropeginterferon alfa-2b (ropeg), a novel interferon-based antiviral and antitumor agent, followed by anti-PD-1 therapeutic antibody nivolumab as an adjuvant therapy for hepatitis B virus (HBV)-related HCC. Methods Patients who underwent surgical resection of HBV-related HCC with curative intent received sequential therapy with six doses of ropeg every two weeks at 450 μg, followed by three doses of nivolumab escalating from 0.3 to 0.75 mg/kg every two weeks. Safety, HBV surface antigen (HBsAg) loss or decrease, anti-HBV surface (HBs) antibodies, cancer recurrence, and survival were evaluated. Results Fifteen eligible patients were enrolled. Most adverse events (AEs) were mild or moderate and no severe or serious AEs were observed. Alanine transaminase flares, including one grade 3 event as dose-limiting toxicity, were noted in five cases and the final recommended dose for anti-PD1 was determined at 0.75 mg/kg. Interestingly, all five cases had HBsAg clearance or reduction. All patients in the study were alive without cancer recurrence during a median follow-up of 1024 days with six patients surviving > 4 years and three for > 5 years. Conclusions This phase I trial supports the safety and clinical efficacy of sequential treatment with ropeg and nivolumab in post-resection HBV-related HCC. This regimen holds promise for further adjuvant therapy trials in HCC, both HBV-related and other types. Graphic abstract

A Phase I study targeting the APE1/Ref-1 redox signaling protein with APX3330: First clinical agent targeting APE1/Ref-1 in Cancer.

APX3330 is an oral agent targeting the redox signaling activity of Ape1/Ref-1 (Ref-1), a key regulator of transcription factors involved in inflammation and tumorigenesis. APX3330 selectively inhibits Ref-1's redox function without affecting its DNA repair role. This Phase 1, multicenter, open-label, dose-escalation study in advanced solid tumor was aimed at determining the recommended Phase 2 dose (RP2D) while assessing safety, pharmacokinetics, and biomarker evidence of target engagement. Clinical trial: NCT03375086 . Nineteen cancer patients were treated, with eight completing follow-up. Subjects received APX3330 orally twice daily in 21-day cycles, starting at 240 mg/day and escalating in 120 mg/day increments. Adverse event (AE) monitoring followed a 1 pt/cohort approach until a >G2 toxicity event, after which a 3+3 design was implemented. Treatment continued until disease progression, consent withdrawal, or intolerable toxicity. Antitumor activity was assessed using RECIST 1.1, and pharmacodynamic markers included serum Ref-1 levels and circulating tumor cells. Six subjects had stable disease for >4 cycles, with four remaining on study for 252- 421 days. No treatment-related serious adverse events occurred. One subject (720 mg cohort) withdrew due to Grade 3 maculopapular rash (dose-limiting toxicity). Laboratory assessments and ECGs showed no clinically significant abnormalities. APX3330 demonstrated clinical benefit by stabilizing disease in ∼33% of subjects. Ref-1 target engagement was confirmed via biomarker analyses, with reduced serum Ref-1 and circulating tumor cells. The RP2D is 600 mg daily, with APX3330 showing a favorable safety profile and target-mediated effects.

First-in-Human Phase I Study of a CD16A Bispecific Innate Cell Engager, AFM24, Targeting EGFR-Expressing Solid Tumors.

Innate immune cell-based therapies have shown promising antitumor activity against solid and hematologic malignancies. AFM24, a bispecific innate cell engager, binds CD16A on NK cells/macrophages and EGFR on tumor cells, redirecting antitumor activity toward tumors. The safety and tolerability of AFM24 were evaluated in this phase I/IIa dose-escalation/dose-expansion study in patients with recurrent or persistent, advanced solid tumors known to express EGFR. The main objective in phase I was to determine the MTD and/or recommended phase II dose. The primary endpoint was the incidence of dose-limiting toxicities during the observation period. Secondary endpoints included the incidence of treatment-emergent adverse events and pharmacokinetics. In the dose-escalation phase, 35 patients received AFM24 weekly across seven dose cohorts (14-720 mg). One patient experienced a dose-limiting toxicity of grade 3 infusion-related reaction. Infusion-related reactions were mainly reported after the first infusion; these were manageable with premedication and a gradual increase in infusion rate. Pharmacokinetics was dose-proportional, and CD16A receptor occupancy on NK cells approached saturation between 320 and 480 mg. Paired tumor biopsies demonstrated the activation of innate and adaptive immune responses within the tumor. The best objective response was stable disease in 10/35 patients; four patients had stable disease for 4.3 to 7.1 months. AFM24 was well tolerated, with 480 mg established as the recommended phase II dose. AFM24 could be a novel therapy for patients with EGFR-expressing solid tumors, with suitable tolerability and appropriate pharmacokinetic properties for further development in combination with other immuno-oncology therapeutics.

IL-12-producing cytokine factories induce precursor exhausted T cells and elimination of primary and metastatic tumors

BackgroundCurative responses to immunotherapy require the generation of robust systemic immunity with limited toxicity. Recruitment of T cell populations such as precursor exhausted T cells (Tpex) from lymphoid tissues to...

Irreversible Electroporation and Beta-Glucan-Induced Trained Innate Immunity for Treatment of Pancreatic Ductal Adenocarcinoma: A Phase II Study.

Irreversible electroporation (IRE) has augmented the effects of certain immunotherapies in pancreatic ductal adenocarcinoma (PDA). Yeast-derived particulate beta-glucan induces trained innate immunity and successfully reduced murine pancreatic cancer burden. This is a phase II study to test the hypothesis that IRE may augment beta-glucan-induced trained immunity in patients with PDA. In this phase II clinical trial (NCT03080974), surgical ablative IRE was performed on clinical stage III PDA followed by oral beta-glucan administration for 12 months or until disease recurrence. Peripheral blood was taken preoperative, 14 days, and every 3 months and was evaluated by mass cytometry and compared with patients who received IRE alone. Thirty consecutive patients with preoperative clinical stage III PDA were treated with IRE and then initiated on oral beta-glucan postoperatively were compared with 20 patients treated with IRE alone. There were no dose-limiting toxicities with oral beta-glucan, and compliance with therapy was 96% in all patients. Seven patients (23%) developed grade 3 or 4 treatment-related adverse events at 90 days; none required a dose modification of oral beta-glucan. A median disease-free interval (DFI) was 18 months (range 6 to 48 months), with a median overall survival (OS) of 32.5 months (range 4 to 53 months). At 12 months post-IRE, immunophenotyping was demonstrated a significant effect with improvement in the IRE-beta-glucan-treated group. This also resulted in a significant decrease on naive CD4 and CD8 T cells with increased CD4 and CD8 terminal effector cells in the IRE-beta-glucan-treated group, which correlated with a significant improvement in DFI and OS (p = 0.001). Combined beta-glucan with IRE-ablated PDA tumor cells elicited a potent trained response and augmented antitumor functionality at 12 months post-IRE, which translated into an improved DFI and OS.

Boswellia serrata for the Management of Radiation-Induced Cerebral Edema and Necrosis: A Systematic Meta-Narrative Review of Clinical Evidence.

Boswellia serrata for the Management of Radiation-Induced Cerebral Edema and Necrosis: A Systematic Meta-Narrative Review of Clinical Evidence.

Cathepsin B dependent activatable trigger fluorophore (CAT-Fluor) for in situ functional imaging of antibody-drug conjugates.

Cathepsin B dependent activatable trigger fluorophore (CAT-Fluor) for in situ functional imaging of antibody-drug conjugates.

Olaparib, Temozolomide, and Concomitant Radiotherapy for Partially Resected or Biopsy-Only Glioblastoma First-Line Treatment: Results from the OLA-TMZ-RTE-01 Phase I Study.

Radiochemotherapy remains the mainstay of glioblastoma (GBM) first-line treatment after extended surgery, but the prognosis is still poor. PARP inhibitors like olaparib may improve GBM outcomes. We implemented a phase I to IIa trial to assess the safety and efficacy of olaparib combined with standard radiochemotherapy as a first-line treatment in patients with unresected GBM. We herein present results of phase I. Based on the Stupp regimen, two sequential dose escalations of olaparib were performed to distinguish the radiotherapy period and the maintenance period for assessing the MTD of olaparib separately for each treatment period. Dose escalations were performed by a Time-to-Event Continual Reassessment Method. A total of 30 patients were enrolled: 20 (66.7%) men, median age 59 years (range, 25-70), and 12 patients (42.9%) with Eastern Cooperative Oncology Group performance status of 0. Among them, 16 and 11 patients were assessable for determining MTD in each period. Hematologic dose-limiting toxicities were experienced by four and one patients in each sequential dose escalation, respectively. The MTD was olaparib 100 mg twice daily for 3 days a week in concomitant during both the radiochemotherapy and maintenance periods of the standard treatment. The median progression-free and overall survival were 6.2 and 19.8 months, respectively. The 2-year survival rate was 36.7% (22.9-58.7). Intermittent dosing of olaparib at radiosensitizing concentrations in concomitant with the Stupp protocol has an acceptable safety profile with promising outcomes in patients with unresectable GBM. Further efficacy determination is ongoing in the phase IIa step.