Investigational New Drugs最新文献

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.

Lurbinectedin and irinotecan showed synergistic antitumor activity when combined in preclinical studies, and have non-completely overlapping toxicity profiles. A two-stage phase I/II trial was designed to evaluate the combination. The first (dose escalation) stage of the trial assessed two schedules, lurbinectedin on Day (D)1 plus irinotecan on D1,D8 or D1 every three weeks in 83 patients with relapsed advanced solid tumors. Two recommended doses (RDs) were defined for lurbinectedin on D1 plus irinotecan on D1,D8: lurbinectedin 2.0 mg/m² plus irinotecan 75 mg/m², and lurbinectedin 3.0 mg/m² plus irinotecan 40 mg/m², both with primary growth factor prophylaxis. No RD was defined for lurbinectedin on D1 plus irinotecan on D1. Lurbinectedin on D1 plus irinotecan on D1,D8 q3wk showed a manageable safety profile at the RDs, with most common toxicities being myelosuppression, fatigue and gastrointestinal disorders. No toxic deaths occurred. Thirteen confirmed partial responses and 24 disease stabilizations ≥ 4 months were found at all dose levels, including the RDs. Compared to other tumor types, antitumor activity was higher in small cell lung cancer (SCLC), soft tissue sarcoma (synovial), endometrial carcinoma, glioblastoma and pancreatic adenocarcinoma. No major pharmacokinetic interaction was found between lurbinectedin and irinotecan. The second (expansion) stage of the trial is evaluating the RD of lurbinectedin 2.0 mg/m² plus irinotecan 75 mg/m² with primary growth factor prophylaxis in selected advanced solid tumors. An ongoing phase III trial is also evaluating the combination in second-line SCLC after prior platinum-containing chemotherapy. Trial registration number: NCT02611024 (Nov 20, 2015).

Mitochondrial dynamics, particularly the balance between fission and fusion, are critical in regulating cellular metabolism, apoptosis, and cancer progression. Dysregulation of this balance contributes to tumor survival and therapeutic resistance in castration-resistant prostate cancer (CRPC). Rucaparib, a clinically approved poly (ADP-ribose) polymerase (PARP) inhibitor, is primarily known for its role in DNA damage repair; however, its impact on mitochondrial function remains largely unexplored. In this study, we demonstrate that Rucaparib induces significant cytotoxicity and apoptosis in PC-3 CRPC cells in a time- and concentration-dependent manner, characterized by increased Bax/Bcl-2 ratio, cytochrome c release, and caspase-3 activation. Mechanistically, Rucaparib disrupts mitochondrial integrity by reducing mitochondrial membrane potential (MMP), inhibiting Complex IV activity, and depleting ATP levels. Confocal imaging and biochemical assays reveal that Rucaparib triggers mitochondrial fragmentation by promoting phosphorylation of dynamin-related protein 1 (Drp1) at Ser616 and enhancing its translocation to mitochondria. This process is accompanied by elevated intracellular Ca²⁺ levels and activation of calcium/calmodulin-dependent protein kinase II (CaMKII), suggesting a Ca²⁺/CaMKII/Drp1 signaling axis. Importantly, pharmacological inhibition of CaMKII with KN-93 reverses Drp1 mitochondrial translocation, restores mitochondrial morphology, and partially rescues ATP production, confirming the functional role of CaMKII in Rucaparib-induced mitochondrial dysfunction. These findings uncover a previously unrecognized mechanism of Rucaparib action beyond DNA repair inhibition, highlighting its ability to target mitochondrial dynamics and bioenergetics through Ca²⁺/CaMKII/Drp1 signaling. Our results provide new insights into the multifaceted anticancer mechanisms of Rucaparib and suggest that modulation of mitochondrial fission may offer a promising therapeutic avenue for CRPC.

Lung cancer remains the leading cause of cancer-related deaths worldwide, with immune evasion posing a major therapeutic challenge. One key mechanism involves the 'don't eat me' signal mediated by the interaction between CD47 and signal regulatory protein alpha (SIRPα), which inhibits macrophage phagocytosis and natural killer (NK) cell cytotoxicity, facilitating tumor escape. To overcome this immune evasion, we developed a tri-specific killer engager (TriKE) targeting CD47, termed anti-CD47 TriKE, designed to enhance NK cell-mediated cytotoxicity against lung cancer cells. The activity of anti-CD47 TriKE was evaluated for its ability to induce NK cell proliferation and its binding affinity to NK cells and lung cancer cell lines (A549, NCI-H460, and NCI-H1975). At a concentration of 30 nM, anti-CD47 TriKE effectively promoted NK cell proliferation and exhibited strong binding to both NK cells and lung cancer cells. Functional assays in 2D and 3D co-culture models demonstrated that anti-CD47 TriKE significantly enhanced NK cell specificity and cytotoxicity. Notably, NK cell-mediated cytotoxicity correlated with the basal level of CD47 expression in target cells. In NCI-H1975 cells, which exhibit the highest CD47 expression, target cell viability was reduced by approximately 40%-a significantly greater reduction than in control groups. These findings highlight the potential of anti-CD47 TriKE as a promising immunotherapeutic strategy for lung cancer, particularly in targeting high-CD47-expressing tumor cells and overcoming immune evasion mechanisms.

Kinesin family member 15 (KIF15), a kinesin superfamily motor protein, is known to be involved in mitotic spindle formation and chromosome movement during cell division. Recent research has determined KIF15 to be a crucial regulator in several oncogenic pathways and proposed that its role may extend beyond mere cell mechanics. Aberrant KIF15 expression has also been found to be involved in the onset of numerous cancers by promoting the proliferation, migration, and invasive abilities of cancer cells, thereby leading to increased metastatic capability. This review summarizes knowledge of the complex roles of KIF15 in cancer biology, highlighting its regulatory functions and interactions with key signaling pathways that control cell cycle kinetics and mechanisms for tumorigenesis. Moreover, the elevated levels of KIF15 in certain types of cancer make it an amenable target for therapy. New directions toward inhibiting activity or reducing the levels of KIF15 promise to restrict tumor growth, offering new hope for cancer treatment. This combined understanding of KIF15 functions stresses its importance not only in the fundamental processes of cell division but also in the developing field of cancer treatment, highlighting the ongoing necessity for extensive research into creating effective treatments targeted against KIF15 in oncology.

Drug lag in rare pediatric diseases remains a significant challenge in Japan despite its sophisticated healthcare system. We examined this issue through a case study of isotretinoin, an established standard drug for high-risk neuroblastoma (affecting 45-60 new patients annually in Japan) since the 2000s that has not been granted regulatory approval in Japan as of 2025. Analysis of regulatory documents and clinical practices revealed that while isotretinoin has demonstrated improved event-free survival rates in international trials when used as maintenance therapy for high-risk neuroblastoma, multiple barriers have hindered its domestic approval. These include the challenges of conducting clinical trials in limited pediatric populations, substantial development costs, diminishing market attractiveness due to Japan's demographic shift, and restrictions on "mixed billing system" which means combining covered insurance treatments with uncovered treatments under the universal health insurance system in Japan. Currently, patients must rely on costly private imports or clinical trial participation to access the drug, leading to financial burdens and treatment discontinuation risks. Recent regulatory reforms, including the establishment of the Evaluation Committee on Unapproved or Off-labeled Drugs with High Medical Needs in 2009 and amendments enabling investigator-led trials, have facilitated progress. An investigator-led Phase II clinical trial evaluating isotretinoin's safety and efficacy is ongoing since 2023, with expected completion in 2026. However, the lengthy timeline of approximately 25 years from global adoption to potential approval highlights persistent challenges in pediatric drug development and Japan's isolation from global drug development networks. This case demonstrates the need for innovative policy approaches to ensure sustainable drug development for rare pediatric diseases in an aging society.

Previous research shows that the benefits of phase-I oncology trials increased from 5 to 18% between 2000 and 2019 globally. However, the risk-benefit profile of phase-I trials in China is unclear. This study aims to analyze the risk-benefit profile of phase-I oncology trials in China and explore their correlation. We included adult phase-I oncology trials registered on the Chinese Clinical Trial Registry and Information Disclosure Platform between September 2013 and December 2021. Data on response rates and grade-3/4 adverse events were retrieved from PubMed, Google Scholar, and CNKI to assess their correlation. A total of 189 trials with 9591 patients were analyzed. The median response rate was 25.4% (IQR, 9.4-41.4%), and the overall incidence of grade-3/4 adverse events was 29.3% (IQR, 15.0-43.8%). No significant trends were observed over time. Subgroup analysis showed higher response rates in lymphoma (45.8%), cell therapies (80.0%), and biomarker trials (38.0%). Higher adverse event rates were seen in breast cancer (55.0%), chemical drugs (33.3%), cytotoxic drugs (73.3%), and combination therapies (35.7%). A weak correlation was found between response rates and grade-3/4 adverse events (ρ = 0.217; p = 0.003), with a moderate correlation in immunotherapy (ρ = 0.417; p < 0.001). This is the first assessment of early efficacy and safety signals of phase-I oncology trials in China. No significant temporal trends were identified. However, the correlation in immunotherapy suggests that higher benefits may be accompanied by greater risks.

Recent progress in cancer treatment has led to the development of advanced therapies targeting specific oncogenic drivers, with, for instance, new small molecule-targeted agents, antibody-drug conjugates, peptide drugs, cell-based, or gene therapies. The key target may be either the mutated/fused protein itself or a protein whose expression is directly dysregulated and involved in proliferation, resistance to cell death, or other cellular processes associated with the oncogenic process. Identifying the best therapeutic strategy requires evaluating both inhibitors of the altered protein and the dysregulated oncogene linked to the pathology. Within this context, the MLL-rearranged subtype (MLL-r) of acute myeloid leukemia (AML) poses significant challenges due to unfavorable prognosis, frequent relapses, and treatment resistance. MLL-r AMLs are known to be addicted to the oncogene transcription factor HOXA9, with a differentiation blockade that relies on its ability to bind DNA. Recently, several MLL-r epigenetic complex inhibitors have been developed, some entering clinical trials. We identified and optimized two HOXA9 functional inhibitors, DB818 and DB1055, operating at the DNA-binding level. The present study compares the cellular effects of both indirect (epigenetic MLL inhibitors) and direct (DNA binding) HOXA9 inhibitors in two distinct pediatric MLL-r cell models, THP-1 and MV4-11. Our findings indicate that direct DNA-binding inhibition of HOXA9 by DB818 and DB1055 resulted in more favorable outcomes in facilitating leukemic cell differentiation, impairing uncontrolled proliferation, and promoting cell death. Thus, a direct DNA-binding inhibition of the addiction oncogene HOXA9 could represent an interesting opportunity for MLL-r therapy.