Frequent prophylactic intravitreal anti-vascular endothelial growth factor injections can reduce risk of progression to vision-threatening complications in nonproliferative diabetic retinopathy (NPDR). A refillable drug delivery system for continuous intraocular ranibizumab release could offer less frequent treatment regimens.

This open-label, investigator-initiated, phase II study was conducted to evaluate the safety, survival, and neoadjuvant outcomes of neoadjuvant chemotherapy (NAC) combined with dual immune checkpoint inhibitors in advanced-stage epithelial ovarian cancer (EOC).

Mutations or silencing of the von Hippel-Lindau tumor suppressor gene accumulate hypoxia-inducible factors (HIF). HIF-2α is implicated in the oncogenesis of ∼50% of patients with clear-cell renal cell carcinoma (ccRCC) but has been considered "undruggable." DFF332, an orally administered novel allosteric inhibitor of HIF-2α, showed dose-dependent antitumor efficacy in preclinical models of ccRCC.

SL-279252 is a bifunctional hexameric fusion protein adjoining the extracellular domains of PD-1 and OX40L via an inert IgG4 derived Fc domain. A Phase 1 dose escalation study was conducted in patients (pts) with advanced solid tumors or lymphomas. SL-279252 was administered intravenously across 12 dose levels (range: 0.0001-24 mg/kg). Objectives included evaluation of safety, dose-limiting toxicity (DLT), recommended phase 2 dose, pharmacokinetic and pharmacodynamic (PD) parameters, and anti-tumor activity. Forty-nine pts (48 with solid tumor and 1 with lymphoma) were enrolled (median age 64 years; 53% male; median [range] of 3 [0-5] prior systemic therapies; 61% had been previously treated with PD-1/L1 inhibitors). Most common treatment-related adverse events (AEs) were infusion-related reaction (16%), maculopapular rash (10%), fatigue (6%), and neutropenia (6%). Treatment-related Grade (G) 3 AE was neutropenia (4%). There were no G4 or G5 AEs or DLTs. SL-279252 Cmax and area under the curve (AUC) increased proportionally with dose. T½ was ~ 20 h. Baseline anti-drug antibodies (ADA) were observed in 11/42 pts who had received a PD-1 inhibitor within 250 days. 7/31 pts had a persistent SL-279252 induced ADA response. PD effects consistent with OX40 engagement included dose dependent egress of CD4 + OX40 + cells and increases in Ki67 + CD4 and CD8 central and effector memory cells in the blood. Best response by iRECIST [1] in 46 response evaluable subjects was 1 iPR and 15 iSD. SL-279252 was well tolerated. PD effects consistent with OX40 activation were observed, however, efficacy was limited which may have been due to the disease characteristics, prior treatment with PD-1/L1 inhibitors, neutralization of the PD-1 domain of SL-279252 by circulating PD-1 inhibitors, limited SL-279252 penetration into tumors or other variables. Trial register number NCT03894618. Trial registration date 28-March-2019.

Experimental studies have shown that dietary isothiocyanates reduced cellular proliferative marker Ki-67 and increased apoptotic markers caspase-3 and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) in animals, but human data are lacking. The present study was to assess whether sulforaphane would stop/reverse the progression of bronchial histopathology, reduce the Ki-67 index, and/or increase caspase-3 and TUNEL indices in humans. A randomized clinical trial (NCT03232138) was conducted in former smokers. Forty-three subjects were randomly assigned to the placebo or the treatment with a potential daily dose of 95 μmol sulforaphane for 12 months. The endpoints were the changes in histopathology scores and Ki-67, caspase-3, and TUNEL indices in post- versus pretreatment bronchial biopsies. Thirty-seven participants (17 in the sulforaphane and 20 in the placebo group) completed the study. Supplementation of sulforaphane did not show significant impact on bronchial histopathology but significantly reduced the Ki-67 index with a 20% decrease in the sulforaphane group and a 65% increase in the placebo (P = 0.014). The difference was even greater in high-density (3+) positive Ki-67, with a 44% decrease in the sulforaphane group compared with a 71% increase in the placebo (P = 0.004). Higher bioavailability of sulforaphane was correlated with greater reduction of the Ki-67 index (P for trend = 0.019). Sulforaphane treatment had no impact on the caspase-3 or TUNEL index in bronchial biopsies. No severe adverse event was observed in the study participants. The findings of oral sulforaphane that significantly reduced the Ki-67 index in bronchial tissue support further development as a potential chemopreventive agent against lung cancer development. Prevention Relevance: High intake of cruciferous vegetables and their sulforaphane is associated with lower incidence of lung cancer in humans and animal models. This clinical trial has demonstrated that oral supplementation of sulforaphane for 12 months significantly reduced the Ki-67 index, a potential surrogate endpoint of biomarkers for lung cancer risk.

Chemotherapy-related cognitive changes following breast cancer are commonly reported; however, changes in brain dynamics of large-scale neural networks remain unclear. Using data from the Aerobic exercise and CogniTIVe functioning in women with breAsT cancEr (ACTIVATE) trial, we conducted exploratory analyses to compare self-reported and objective measures of cognition and applied microstate analysis to resting state (RS) electroencephalography (EEG) data of women with breast cancer before and following chemotherapy treatment.

Although successful treatment of papillary craniopharyngiomas (PCPs) with BRAFv600e inhibitors has been reported in clinical trials, studies have shown that approximately 10% of PCPs lack the BRAFv600e mutation and that BRAFv600e inhibitors may not be significantly effective against these tumors. However, no studies have focused specifically on BRAFv600e- PCPs.

Tarlatamab demonstrated a durable response and promising survival outcomes in patients with previously treated small cell lung cancer (SCLC) in the phase 2, open-label DeLLphi-301 trial. Patient-reported outcomes (PROs) were evaluated to assess the benefit-risk profile of tarlatamab.

Immune checkpoint inhibitors (ICIs), particularly PD-1/PD-L1 inhibitors, have demonstrated significant survival benefits in treating recurrent or metastatic nasopharyngeal carcinoma (R/M-NPC). While baseline peripheral blood lymphocyte subsets have been identified as prognostic biomarkers in various cancers treated with ICIs, their relevance in R/M-NPC has not been extensively studied.

Higher levels of tumor-infiltrating lymphocytes (TILs) in breast cancers are associated with increased likelihood of pathologic complete response (pCR) to chemotherapy. DNA methyltransferase inhibitors (DNMTi) can augment immune responses to cancers, decreasing myeloid-derived suppressor cells (MDSCs) and increasing T lymphocyte responsiveness. We have shown that the DNMTi decitabine augments the effectiveness of immunotherapy using murine triple-negative breast cancer (TNBC) models. The primary objective was to determine whether DNMTi+immune checkpoint blockade would increase stromal TIL (sTIL) in primary breast cancers before neoadjuvant chemotherapy (NCT).

To estimate in humans, in vivo, drug retention in the subretinal space following either 1- or 2-step subretinal injection (SRI).

Trastuzumab rezetecan (also known as SHR-A1811) is a novel antibody-drug conjugate consisting of a humanised HER2-directed monoclonal antibody, cleavable tetrapeptide-based linker, and DNA topoisomerase I inhibitor. In the phase 1 portion of this phase 1/2 study, trastuzumab rezetecan showed preliminary anti-tumour activity and a favourable safety profile in patients with HER2-mutant non-small-cell lung cancer (NSCLC). We present phase 2 results from the study, which aimed to further evaluate the activity and safety of trastuzumab rezetecan at the recommended dose.

SY-2101 is a novel oral formulation of arsenic trioxide (ATO). Although IV ATO in combination with all trans retinoic acid is highly efficacious in treating acute promyelocytic leukemia (APL), there remains a significant unmet need due to the treatment burden associated with receiving daily ATO infusions for nearly a year and the risk of complications associated with indwelling central catheters. The pharmacokinetics (PK), safety, and tolerability of SY-2101 and ATO IV after single- and multiple-dose administration and the impact of food on PK for SY-2101 were evaluated in this phase 1 study in 15 participants with APL. SY-2101 in the fasted state demonstrated comparable systemic exposure to ATO IV based on the active metabolite arsenious acid [As(III)], with geometric mean ratios (GMRs) of SY-2101 to ATO IV of 1.00 for area under the plasma concentration (AUC) from 0 hour to last time point (AUC0-last) and from 0 hour to infinity (AUC0-inf). The GMR of SY-2101 to ATO IV maximum concentration (Cmax) was 0.76, as was expected due to the different routes of administration. Comparisons of SY-2101 in fed to fasted states demonstrated similar exposure with GMRs of AUC0-last, AUC0-inf, and Cmax at 1.08, 1.12, and 0.85, respectively, allowing for SY-2101 administration with or without food. SY-2101 was well tolerated. Most adverse events were of low grade. This study provides the first intrapatient PK crossover results directly comparing SY-2101 with ATO IV and supports the likelihood of clinical equivalence between the 2 formulations. This trial was registered at www.ClinicalTrials.gov as #NCT04996030.

This phase I trial aimed to assess the feasibility and toxicity of combining the poly(adenosine diphosphate-ribose) polymerase inhibitor olaparib with 177Lu-DOTATATE in patients with somatostatin receptor-positive tumors, with the goal of enhancing treatment efficacy through the inhibition of tumor cell DNA repair mechanisms. Methods: Eighteen patients were enrolled, mostly with pancreatic or small intestinal neuroendocrine tumors or atypical lung carcinoids. Patients received a standard dose of 177Lu-DOTATATE (7,400 MBq) for up to 4 cycles, combined with escalating doses of olaparib (50-300 mg twice a day [BID]). The primary objective was to evaluate toxicity using National Cancer Institute Common Toxicity Criteria version 5.0. Secondary objectives included time to progression, overall survival, response rate, and dosimetry variables. Results: The combination of olaparib and 177Lu-DOTATATE was generally well tolerated. Five patients did not complete the 4 cycles because of progression, noncompliance, and carcinoid crisis after the first 177Lu-DOTATATE infusion. Among the remaining patients, thrombocytopenia was the primary dose-limiting toxicity, observed in 3 patients at the 300-mg dose level. Other toxicities were mild, predominantly low-grade bone marrow suppression, nausea, and fatigue. Conclusion: This study demonstrates that combining olaparib with 177Lu-DOTATATE is feasible, with toxicity primarily related to thrombocytopenia. On the basis of the findings, we recommend a starting dose of 200 mg BID for future studies, with the potential to escalate to 300 mg BID depending on patient tolerance. Further investigation in larger, randomized trials is warranted to assess the clinical efficacy of this combination and optimize dosing strategies.

Peripheral neuropathy is a major adverse effect of Vincristine (VCR) in pediatric acute lymphoblastic leukemia (ALL) patients. Curcumin can prevent the development of many neurological diseases.

LOXO-338 is a novel, orally bioavailable small-molecule inhibitor of Bcl-2, designed to achieve selectivity for Bcl-2 over Bcl-xL, thus avoiding dose-limiting thrombocytopenia associated with Bcl-xL inhibition. This first-in-human, open-label, Phase 1 study investigated LOXO-338 in patients with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or B-cell non-Hodgkin lymphoma (NHL) (NCT05024045).

The purpose of this study was to evaluate the angiographic predictors of response to the anti-vascular endothelial growth factor-C/-D agent, sozinibercept.

The aim of this study was to assess differences between Chinese and White patients in pharmacokinetics (PK) of, and clinical response to, acalabrutinib and its pharmacologically active major metabolite, ACP-5862, to support recommended dosing in Chinese patients with B-cell malignancies.

PREDICT-5FU aimed to document 5-fluorouracil (5FU) exposure in a cancer population and to evaluate the feasibility of 5FU and capecitabine therapeutic drug monitoring (TDM) in patients receiving standard doses and schedules.

KO-947, a potent, intravenously administered, extracellular signal-regulated kinase (ERK) inhibitor, has demonstrated activity in preclinical models. This phase I trial of KO-947 evaluated maximum tolerated dose (MTD), safety, and pharmacokinetics in patients with relapsed/refractory solid tumors.