Investigational New Drugs最新文献

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).

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.

This study aims to systematically analyze the clinical features of cystitis induced by anti-PD-1/PD-L1 drugs, with a view to providing a basis for early warning, diagnosis, and standardized management of this adverse reaction in clinical practice. In this study, we comprehensively searched multiple databases to systematically collect all case reports involving cystitis induced by anti-PD-1/PD-L1 drugs from the initiation of relevant research up to May 20, 2025, and conducted an in-depth retrospective analysis of these cases. The clinical characteristics of 43 patients with cystitis induced by anti-PD-1/PD-L1 agents in this study showed a median age of 57 years (27-78 years), with 26 cases (60.5%) being male. The median time from the initiation of these agents to cystitis onset was 96 days (9-510 days). Diagnosis confirmed that 81.4% cases were non-infectious cystitis, and antibiotic treatment was often ineffective or showed suboptimal efficacy. After discontinuing the relevant drugs and administering appropriate steroids, patients generally had a favorable prognosis. Notably, reinitiating anti-PD-1/PD-L1 therapy was associated with a significantly increased risk of cystitis recurrence. Cystitis is a rare adverse reaction during PD-1/PD-L1 immune checkpoint inhibitor therapy, which can impact patients' quality of life. It is notable that nearly all cases can be effectively managed through timely intervention and standardized pharmacotherapy. Therefore, early identification of cystitis induced by these drugs and the implementation of appropriate management strategies are crucial for improving patient outcomes.

Multidrug resistance (MDR) appears to be a major challenge in cancer treatment, frequently leading to suboptimal clinical results and treatment failure. A transmembrane efflux pump called P-glycoprotein (P-gp) is essential to multidrug resistance because it actively transports various chemotherapeutic drugs out of cancer cells, lowering their intracellular concentrations and efficacy. To improve treatment approaches, it is essential to comprehend the structural and functional dynamics of P-glycoprotein and the genetic and epigenetic processes controlling its expression. From the early-generation drugs with poor clinical outcomes to the creation of new medications with enhanced selectivity, potency, and safety profiles, this article thoroughly summarizes the development of P-glycoprotein inhibitors. Enhancing medication bioavailability and overcoming P-glycoprotein-mediated efflux may be possible through the integration of sophisticated drug delivery methods, such as micellar formulations, liposomes, nanoparticles, and polymer-based carriers. Meanwhile, the rise of personalized medicine provides a revolutionary way to manage multidrug resistance through identifying biomarkers, genetic and proteomic characterization, and medication modification for each patient. Advanced tactics such as RNA interference, CRISPR-mediated gene editing, immunotherapeutic therapies, and tumor microenvironment modulation significantly broaden the options to counter multidrug resistance. While highlighting current difficulties, case studies and clinical examples also illustrate translational achievements. In addition to highlighting recent advancements, the present research points out important constraints and suggests potential paths for more potent, focused multidrug resistance cancer treatments.

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.

Recently, comprehensive genomic profiling (CGP)-matched therapy and antibody-drug conjugates (ADCs) have garnered increased attention. However, their response rates and prognoses in early-phase clinical trials are not yet widely appreciated in clinical practice. We conducted a retrospective chart review of patients with advanced solid tumors who enrolled in clinical trials as a late-line treatment in our department between January 2020 and December 2023. This study aimed to evaluate clinical outcomes, including overall response rate (ORR), disease control rate (DCR), overall survival (OS), and associated prognostic factors. A total of 574 cases were referred, including 173 in the late-line setting. The ADCs group achieved the highest ORR and DCR (31.9% and 68.1%, respectively). ADCs also demonstrated a longer median progression-free survival (PFS) compared to CGP-matched and other trials (median PFS: ADCs 4.0 months vs. CGP-matched trials 1.9 months vs. others 1.7 months; p = 0.001). Multivariate analysis identified ADCs as significantly associated with improved PFS, while CGP-matched therapy was associated with better OS. The findings suggest that, even in early phase clinical trials for the late-line setting, ADCs can enhance therapeutic responses. These results underscore the need to avoid overreliance on CGP outcomes and instead prioritize early referral to Phase 1 facilities, timely intervention, and the appropriate inclusion of patients to achieve optimal clinical outcomes.

Acute myeloid leukemia (AML) is a malignant clonal hematological tumor originating from immature myeloid cells and is the most prevalent type of leukemia in adults. Traditional chemotherapy regimens based on cytarabine and anthracycline agents are associated with a high relapse rate. Therefore, investigation of novel targeted therapies is crucial for improving AML treatment outcomes. In this study, we found that CTI-2, a novel inhibitor of perinucleolar compartment (PNC), has potential anti-AML activity with a favorable safety profile. CTI-2 induced a greater degree of apoptosis in FLT3-ITD mutant AML cells compared to AML cells with wild-type FLT3 mainly through the intrinsic apoptotic pathway. Furthermore, MK2 and Pim-1 were identified as potential targets of CTI-2 through molecular docking analysis. CTI-2 decreased both the overall expression level and the phosphorylation of c-Myc, which are regulated by MK2 and Pim-1, respectively. Notably, CTI-2 exhibited a more substantial inhibitory effect on c-Myc in FLT3-ITD mutant cells, which may contribute to the enhanced efficacy of CTI-2 in this specific subset of AML. In summary, we have conducted a preliminary investigation into the anti-AML activity and underlying mechanisms of CTI-2. These results provide clues for the targeting of PNC in the treatment of AML.

We report a phase 1/2 study evaluating EDP1503 (capsule containing Bifidobacterium animalis lactis) ± pembrolizumab in participants with microsatellite-stable colorectal cancer (MSS CRC), triple-negative breast cancer (TNBC), or other tumor types that relapsed after responding to immunotherapy (KEYNOTE-939/EDP1503-101; NCT03775850). Participants (≥ 18 years) had confirmed advanced/metastatic tumors and progressive disease (PD), were intolerant/nonresponsive to recommended treatment, and had measurable disease (RECIST v1.1). Cohorts were: MSS CRC (Cohort A), metastatic/locally advanced TNBC (Cohort B), and PD following partial response/stable disease for ≥ 6 months during anti‒PD-(L)1 therapy (≥ 8 months during anti‒PD-(L)1 therapy plus chemotherapy for non-small-cell lung cancer) (Cohort C). Participants received oral EDP1503 (2 or 4 capsules twice daily [BID]) for 2 weeks, then EDP1503 (2 or 4 capsules BID) plus intravenous pembrolizumab 200 mg every 3 weeks until PD, participant withdrawal, investigator decision, intolerable toxicity, or completion of 35 cycles. Primary endpoints were safety/tolerability, objective response rate (RECIST v1.1), and immune-response rate. Secondary endpoints included duration of clinical benefit, progression-free survival (PFS), and overall survival (OS). Of 69 participants, objective responses were observed in 3 (2 in Cohort B and 1 in Cohort C with partial responses received 4 capsules BID). For participants receiving 4 capsules BID, median duration of clinical benefit (95% CI) was 8.7 months (5.5 months‒not evaluable), median PFS was 1.8 (1.7‒1.9) months, and median OS was 7.8 (2.5‒13.5) months. Grade ≥ 3 adverse events occurred in 28 participants (40.6%), with no new safety signals. EDP1503 plus pembrolizumab had manageable safety but limited clinical activity.Trial registration: KEYNOTE-939, EDP1503-101 trial: ClinicalTrials.gov NCT03775850.