Investigational New Drugs最新文献

Acute myeloid leukemia (AML) carries a poor prognosis in elderly or medically unfit patients, with median overall survival (OS) of only 7-8 months for those ineligible for intensive chemotherapy. While venetoclax (VEN) combined with azacitidine (AZA) has become a standard therapy, real-world evidence indicates that Asian patients experience higher VEN exposure and toxicity with the standard 400 mg/day dose. This retrospective study aimed to evaluate the efficacy and safety of a reduced-dose regimen (VEN 200 mg/day + AZA) in frail/elderly Chinese AML patients deemed unfit for intensive therapy. We analyzed 14 patients (13 newly diagnosed, 1 relapsed; median age 71.5 years) treated at Zhejiang University Hospital (May 2020-May 2024). All had ECOG status ≥ 3 (64.3%) or comorbidities (71.4%), and 57.1% were classified as adverse-risk by ELN 2022 criteria. Treatment comprised AZA (75 mg/m², days 1-7) and VEN (200 mg/day, days 1-28, in absence of CYP3A4 inducer). Response to treatment was evaluated by bone marrow biopsy for minimal residual disease (MRD). Toxicity was graded per CTCAE v5.0. Survival and trough VEN concentrations were analyzed using Kaplan-Meier and descriptive statistics. All patients (100%) achieved CR/CRi, with a median time to MRD negativity of 1.45 months. Median OS was not reached (> 24.6 months), with 2-year OS and EFS rates of 61.5% and 53.8%, respectively. Adverse-risk patients (42.9%) showed 50.0% survival beyond 21.8 months. Trough VEN concentrations (median 487.7 ng/mL) exceeded therapeutic thresholds (~ 500 ng/mL), confirming adequate exposure. Hematologic toxicity was reduced versus historical full-dose data: grade ≥ 3 thrombocytopenia (21.4% vs. 24-89.5%), febrile neutropenia (35.7% vs. 42.9-78.9%), and anemia (50.0% vs. 70-100%). No VEN dose modifications, tumor lysis syndrome, or 60-day mortality occurred. The semi-dosed VEN-AZA regimen (200 mg/day) demonstrated unprecedented efficacy (100% CR/CRi, median OS > 24.6 months) and a favorable safety profile in frail Chinese AML patients. Reduced toxicity without compromised efficacy supports its use in this population, likely due to optimized pharmacokinetics in Asian patients. These findings challenge the necessity of standard VEN dosing and highlight 200 mg/day as a viable, potentially superior strategy for this demographic.

The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is the first-line regulator of a plethora of cytoprotective pathways, such as inflammation, redox metabolism, and proteostasis. Besides its protective role in oxidative stress, several recent advances suggested that the Nrf2 pathway is extensively involved in cancer pathogenesis and confers a survival advantage and malignant transformation. Therefore, pharmacological inhibition of Nrf2 is a potential therapeutic approach for cancer that is related to oxidative stress and inflammation. In this review, we first describe the molecular regulatory mechanisms of Nrf2 and its biological function in cancer. Then, we discuss the recent progress of blocking Nrf2 activity, comprising novel chemical molecules, and the advance in preclinical or clinical trials in cancer therapy.

This study aimed to develop gemcitabine-loaded nanocapsules for pancreatic cancer treatment, optimizing their formulation before evaluating them through in vivo studies. The researchers selected gemcitabine as the model drug because it has established clinical relevance and known pharmacokinetic shortfalls (short half-life and poor bioavailability) with toxic dose limits which suit the evaluation of nanoparticle drug delivery systems. The researchers conducted a 3² factorial design to optimize the formulation through adjustments of PLGA concentration and Tween 80 concentration. The optimal characteristics of F5 among nine formulations included particles of 160 ± 3 nm with 87 ± 2% encapsulation efficiency and - 27.8 ± 1.2 mV zeta potential. The in vitro drug release testing alongside pharmacokinetic results established that nanoparticle gemcitabine caused extended drug delivery and dramatically better bioavailability in addition to achieving longer systemic circulation than free gemcitabine alone. Evaluation of biodistribution revealed that the product displayed tumor-targeting property and had improved antitumor effect and less side effect compared with the other groups. The findings demonstrate that gemcitabine works as an ideal model chemotherapy drug to measure nanocarrier delivery platforms for treating pancreatic cancer solid tumors.

In China, many solid tumor drugs have been approved via the accelerated approval (AA) pathway. We extracted data regarding indications for solid tumor-treating drugs approved by the National Medical Products Administration (NMPA) between 2015 and 2023, along with their corresponding Chinese Society of Clinical Oncology (CSCO) guideline recommendation levels and inclusion data. Descriptive statistics, Fisher's exact tests, and t-tests were used to examine associations between NMPA approval pathways and CSCO guideline recommendation levels. The study included 92 solid tumor drugs comprising 191 indications. Sixty-three indications were approved via the regular approval (RA), and 128 were approved via the AA. One hundred fifty-seven indications obtained CSCO guideline recommendation level I, 28 obtained level II, and 6 obtained level III. No significant difference in the recommendation level was observed between the approval pathways. The average time for the indications approved via the RA to obtain the recommendation level was 2.03 months before NMPA approval. The average time for the indications approved via the AA to obtain the level was 6.66 months after NMPA approval. Compared with initial levels, 57 indications had their recommendation levels upgraded. Most indications obtain the CSCO guideline recommendation level I, with similar likelihoods across obtaining different approval pathways. Indications approved via the RA tended to obtain the CSCO guideline recommendation earlier than those via the AA. Given the limitations in data completeness and CSCO guideline coverage, these findings should be interpreted with caution. Clearer criteria for evaluating recommendation levels and standardizing rating procedures will enable CSCO guidelines to better support clinicians and patients.

The ability of tumor cells to survive under low-oxygen conditions is largely attributed to the hypoxia-inducible factor-1 (HIF-1) pathway, in which HIF-1α forms a functional complex with the transcriptional co-activators p300/CBP. This interaction drives the expression of genes that promote angiogenesis, metabolic reprogramming, and immune evasion and correlates with advanced disease and poor outcomes in diverse cancer types. In recent years, extensive efforts have sought to disrupt the HIF-1α-p300/CBP axis, leveraging strategies that include blocking protein-protein binding, inhibiting acetyltransferase activity, and modulating post-translational modifications that stabilize HIF-1α. A range of small-molecule inhibitors, derived either synthetically or from natural sources such as fungal metabolites and plant polyphenols, have demonstrated efficacy in preclinical cancer models by attenuating tumor hypoxia adaptations and sensitizing malignant cells to chemotherapies and radiotherapies. Although many of these compounds exhibit favorable anti-tumor activity, issues of specificity, drug delivery, toxicity, and potential resistance mechanisms remain. This review highlights the current understanding of HIF-1α-p300/CBP biology, examines small-molecule compounds that target this critical transcriptional interface, and evaluates preclinical evidence validating their therapeutic promise. We also discuss emerging challenges in translating these findings to clinical practice, emphasizing combination treatment strategies, biomarker-driven patient selection, and refined drug formulations to optimize efficacy and safety. By offering a detailed overview of the HIF-1α-p300/CBP landscape, this review underscores the potential of disabling tumor hypoxia responses as an innovative approach to combat cancer progression.

Palbociclib combined with fulvestrant is a standard treatment for hormone receptor-positive, human epidermal growth factor receptor 2 (HER2) -negative metastatic breast cancer. Both agents are mainly eliminated by hepatic metabolism, and it is recognized that no dose adjustment is required for patients with renal impairment according to their prescribing information. However, their pharmacokinetics in patients with end-stage renal disease (ESRD) undergoing hemodialysis (HD) were not studied in their development phases. We here report a case of 62-year-old female with ESRD on HD who was treated with palbociclib and fulvestrant. Palbociclib was initiated at a reduced dose of 100 mg/day (standard dose of 125 mg/day) and fulvestrant at a standard dose of 500 mg/body for multiple metastases. Along with dose adjustment of palbociclib due to hematologic toxicities, stable disease (SD) was maintained for 18 months. We also assessed the pharmacokinetics of palbociclib and fulvestrant at the first dose with HD and at steady state. Although the starting dose of palbociclib was reduced, the area under the concentration-time curve from 0 to 24 h (AUC_0-24) and the maximum concentration (C_max) at steady state were higher than those observed in patients with normal renal function receiving 125 mg/day in a Phase I study. Plasma concentrations of fulvestrant at steady state were almost within the range from the mean minimum concentration (C_min) to the mean C_max in patients receiving 500 mg/body in a Phase II study. This report suggests that palbociclib and fulvestrant combination therapy is manageable and effective in patients with ESRD.

Introduction: No correlation between the dose, adverse events, and efficacy was detected in clinical trials of anti-PD-1 antibodies across a range of solid and hematological malignancies. Given that dose reduction with potentially comparable clinical efficacy may improve access to treatment, particularly in low-income regions, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety of low-dose PD-1 inhibitor monotherapy in relapsed/refractory (r/r) classic Hodgkin lymphoma (cHL).

Materials and methods: Relevant reports were identified through PUBMED, MEDLINE, Cochrane, ScienceDirect databases, and major international conference proceedings, from inception till December 1, 2024. The risk of bias was assessed independently by two authors using the Joanna Briggs's critical appraisal checklist for studies reporting prevalence data. Heterogeneity was assessed using Cochran's Q test, with statistical significance defined as p < 0.05; I² statistic was used to quantify heterogeneity. Random effects models (Der-Simonian method) was used to pool results from primary studies in the presence of significant heterogeneity.

Results: After screening, 13 reports including 148 patients were included in the systematic review. After exclusion of duplicated reports, studies with less than 5 patients, and studies with unextractable data, five studies with a total of 84 patients were included in the meta-analysis. The pooled objective response rate (ORR) with low-dose PD-1 inhibition in r/r cHL, as determined by meta-analysis, was 87% (95% CI, 71.9%-100%), with a corresponding complete response (CR) rate of 53.9% (95% CI, 34.7%-73.1%). The ORR with low-dose nivolumab was 83.8% (95% CI, 64.2%-100%), with a CR rate of 43.3% (95% CI, 29.7%-56.9%). The pooled rate of any-grade adverse events after low-dose PD-1 inhibition was 55.7% (95% CI, 36.1%-75.3%), with a grade 3-4 adverse event rate of 7.5% (95% CI, 1.7%-13.3%).

Conclusions: This systematic review and meta-analysis demonstrated the high efficacy and acceptable toxicity of low-dose PD-1 inhibition in r/r cHL.

This study explored the impact of hepatic impairment on the safety and pharmacokinetics (PK) of FCN-437c, a novel dual CDK4/6 inhibitor for potential breast cancer treatment. In an open-label trial, 25 subjects (8 with mild hepatic impairment, 8 with moderate hepatic impairment, and 8 healthy controls matched for age, sex, and body weight) received a single 200-mg dose of FCN-437c. Results showed that FCN-437c was generally well-tolerated, with no serious adverse events. In mild hepatic impairment group, total FCN-437c C_max increased by 9.5%, while AUC_0-t and AUC_0-∞ decreased by 4.8%. Free drug exposure increased by 24.7%, 8.4%, and 8.4%. In moderate hepatic impairment group, total FCN-437c C_max, AUC_0-t, and AUC_0-∞ decreased by 16.7%, 17.1%, and 15.7%, and free drug exposure increased by 47.8%, 47.0%, and 49.6%. Overall, no clinically relevant differences in FCN-437c exposure were found between subjects with mild or moderate hepatic impairment and normal controls, but moderate hepatic impairment increased free drug exposure. Thus, no dose adjustment is needed for patients with mild hepatic impairment, but a reduced dose may be necessary for those with moderate hepatic impairment. Trial Registration: www.clinicaltrials.gov identifier NCT06620731 (retrospectively registered).

As monotherapy, PARP inhibitors have little cytotoxic effect in tumors without homologous recombinant repair (HRR) alterations. Supported by preclinical models, we hypothesized that the PARP inhibitor talazoparib in combination with temozolomide chemotherapy could induce DNA damage leading to cell death and tumor response in patients with metastatic castration-resistant prostate cancer (mCRPC) without HRR alterations. In this phase 1b/2 trial (NCT04019327; registration date July 11, 2019), patients with progressive mCRPC without HRR mutations who failed at least one androgen receptor signaling inhibitor were enrolled in escalating doses of intermittent talazoparib plus temozolomide to determine the maximum tolerated dose and recommended phase 2 dose (RP2D) in Phase 1b. Phase 2 used a composite endpoint of overall response per RECIST v1.1, 50% decline in prostate-specific antigen (PSA), and/or circulating tumor cells (CTC) conversion from ≥ 1 cell/7.5 mL to 0. Sixteen patients were enrolled across 4 dose levels. The most common adverse events were thrombocytopenia, neutropenia, anemia, fatigue, and nausea. In phase 1b, one patient receiving talazoparib 1 mg and temozolomide 75 mg/m² had a dose-limiting toxicity (grade 3 neutropenic fever, grade 4 thrombocytopenia). The RP2D was talazoparib 1 mg once daily (QD) (D1-6) and temozolomide 75 mg/m² QD (D2-8) in 28D cycles. The phase 2 portion was terminated early. Across dose levels, three (18.8%) patients met the efficacy endpoint. Hematologic toxicity was dose-limiting in this combination strategy using intermittent dosing of talazoparib and temozolomide in patients with mCRPC without HRR alterations. The risk/benefit profile did not support further evaluation.

Osteosarcoma (OS), chondrosarcoma (CHS), and Ewing sarcoma (EwS) are the most common primary bone cancers (BCs). Among primary malignant tumors of the bones, OS is the most common, mainly affecting young people (4.8 per 1,000,000). The treatment of bone cancer (BC) is challenging for current medicine owing to its substantial incidence and the vast heterogeneity of malignant lesions within bone tissue. Due to the limitations of current therapies, researchers developed new strategies to treat BC. Exosomes (EXOs) play a crucial role in the development, progression, metastasis, and drug delivery of BCs, such as OS, EwS, and CHS. Hierarchical translation via tissue-specific reactions and cell-specific molecular signaling pathways accounts for the various therapeutic effects of EXOs produced from stem cells. The aim of this review is to highlight the critical role of EXOs derived from multiple cells, such as mesenchymal stem cells, immune cells, and tumor cells, in BCs, including OS, CHS, and EwS. Additionally, we provide a concise overview of how tumor-derived EXOs induce BCs. To lessen the adverse effects of EXOs on patients with BC and to provide more effective and focused treatments, it is necessary to understand these pathways. Moreover, we reviewed the potential of using EXOs as drug delivery systems for the treatment of BCs. Finally, we discussed the pros and cons of this therapeutic approach for BCs.