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Abstract Background Preclinical models demonstrated promising anti-tumor activity of SPH4336, a novel oral, highly selective cyclin-dependent kinase (CDK) 4/6 inhibitor. Methods This phase I study enrolled patients who received SPH4336 orally in 6 dose-escalation cohorts (50-600 mg) in a 3 + 3 design. Based on tolerability, pharmacokinetics (PK) and activity data from the dose-escalation phase, 2-3 dose cohorts were expanded. Dose-limiting toxicity (DLT), maximum tolerated dose (MTD), recommended phase II dose (RP2D), efficacy, safety, tolerability, and pharmacokinetics (PK) were investigated. Results A total of 29 patients with breast cancer (BC) (n = 14), sarcoma (n = 8), non-small cell lung cancer (n = 2) and others (n = 5) were enrolled. Neither DLT nor MTD were reached. All patients had at least one treatment-related adverse events (TRAEs), most of which were grade 1/2. Grade ≥ 3 TRAEs occurred in 51.7% of patients. One patient died from disease progression and five reported serious adverse events. Plasma concentrations increased dose-dependently, except at 600 mg, and steady state was reached at 2 weeks for 400 mg. One BC patient in the 600-mg cohort had a confirmed partial response. The disease control rate was 59.3% (95% CI, 38.8-77.6). Conclusion SPH4336 demonstrated an acceptable safety profile and dose-dependent plasma exposure in patients with various advanced solid tumors. (ClinicalTrials.gov Identifier: NCT05905614; IRB Approved.)

Background: Targeting factor XI (FXI) is a promising therapeutic strategy for the treatment and prevention of thrombosis without increasing the risk of bleeding. Here, we assessed the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of SHR2285, a novel FXIa inhibitor, in healthy subjects. Methods: In this randomized, double-blinded, placebo-controlled, dose-ascending single-dosing trial (NCT03769831), eligible volunteer subjects receive either SHR2285 or placebo in a 3:1 ratio. Subjects assigned to the SHR2285 group received a single oral dose of SHR2285 at 50 mg, which was subsequently escalated to 100 mg, 200 mg, and 400 mg. Safety, pharmacokinetics, and pharmacodynamics parameters were assessed. All subjects were followed for 6 days. Results: SHR2285 was well tolerated. All adverse events were grade 1, and there was no evidence of bleeding events. The PK results revealed a rapid onset of action of SHR2285 (median time to maximum plasma concentration [T max ] in different dose groups ranged 3.0–4.0 h) and the mean half-life ranged from 7.6 to 15.8 h. The metabolite SHR164471 had a slightly longer T max than the parent SHR2285, reaching a peak at a median of 6.0–7.0 h, and its mean half-life were 10.1–14.7 h in different dose groups. The sums of the area under the concentration–time curve from zero to time infinity of SHR2285 and SHR164471 in the 200 and 400 mg groups were similar, indicating the sum pharmacological activity of SHR2285 and SHR164471 showed a saturation trend between 200 and 400 mg. PD analysis showed that the inhibition of FXI activity was synchronized with prolonged activated partial thromboplastin time after SHR2285 administration, but the serum prothrombin time and international normalized ratio levels were not affected by SHR2285. Conclusion: SHR2285 demonstrated favorable safety, PK, and PD profiles in the dose range of 50 mg–400 mg. This first-in-human study supports the further development of SHR2285 for indications requiring anticoagulation. Clinical Trial Registration : https://clinicaltrials.gov/ct2/show/NCT03769831 , identifier [NCT03769831].

The discovery of immune checkpoint inhibitors (ICIs) has now been universally acknowledged as a significant breakthrough in tumor therapy after the targeted treatment of checkpoint molecules: anti-programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) and anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) on several cancer types achieved satisfying results. However, there are still quite a lot of patients suffering from severe side effects and ineffective treatment outcomes. Although the current ICI therapy is far from satisfying, a series of novel immune checkpoint molecules with remarkable preclinical and clinical benefits are being widely investigated, like the V-domain Ig suppressor of T cell activation (VISTA), which can also be called PD-1 homolog (PD-1H), and ectonucleotidases: CD39, CD73, and CD38, which belong to the ribosyl cyclase family, etc. In this review, we systematically summarized and discussed these molecules' biological structures, molecular features, and the corresponding targeted drugs, aiming to help the in-depth understanding of immune checkpoint molecules and promote the clinical practice of ICI therapy.

Background BCMA-specific chimeric antigen receptor-T cells (CAR-Ts) have exhibited remarkable efficacy in refractory or relapsed multiple myeloma (RRMM); however, primary resistance and relapse exist with single-target immunotherapy. Bispecific CARs are proposed to mitigate these limitations. Methods We constructed a humanized bispecific BM38 CAR targeting BCMA and CD38 and tested the antimyeloma activity of BM38 CAR-Ts in vitro and in vivo. Twenty-three patients with RRMM received infusions of BM38 CAR-Ts in a phase I trial. Results BM38 CAR-Ts showed stronger in vitro cytotoxicity to heterogeneous MM cells than did T cells expressing an individual BCMA or CD38 CAR. BM38 CAR-Ts also exhibited potent antimyeloma activity in xenograft mouse models. In the phase I trial, cytokine release syndrome occurred in 20 patients (87%) and was mostly grade 1–2 (65%). Neurotoxicity was not observed. Hematologic toxicities were common, including neutropenia in 96% of the patients, leukopenia in 87%, anemia in 43% and thrombocytopenia in 61%. At a median follow-up of 9.0 months (range 0.5 to 18.5), 20 patients (87%) attained a clinical response and minimal residual disease-negativity (≤ 10 –4 nucleated cells), with 12 (52%) achieving a stringent complete response. Extramedullary plasmacytoma was eliminated completely in 56% and partially in 33% and of 9 patients. The median progression-free survival was 17.2 months. Two relapsed patients maintained BCMA and CD38 expression on MM cells. Notably, BM38 CAR-Ts cells were detectable in 77.8% of evaluable patients at 9 months and 62.2% at 12 months. Conclusion Bispecific BM38 CAR-Ts were feasible, safe and significantly effective in patient with RRMM. Trial registration : Chictr.org.cn ChiCTR1800018143.

Background We developed a 13-mer locked nucleic acid (LNA) inhibitor of miR-221 (LNA-i-miR-221) with a full phosphorothioate (PS)-modified backbone. This agent downregulated miR-221, demonstrated anti-tumor activity against human xenografts in mice, and favorable toxicokinetics in rats and monkeys. Allometric interspecies scaling allowed us to define the first-in-class LNA-i-miR-221 safe starting dose for the clinical translation. Methods In this first-in-human, open-label, dose-escalation phase 1 trial, we enrolled progressive cancer patients (aged ≥ 18 years) with ECOG 0–2 into 5 cohorts. The treatment cycle was based on a 30-min IV infusion of LNA-i-miR-221 on 4 consecutive days. Three patients within the first cohort were treated with 2 cycles (8 infusions), while 14 patients were treated with a single course (4 infusions); all patients were evaluated for phase 1 primary endpoint. The study was approved by the Ethics Committee and Regulatory Authorities (EudraCT 2017-002615-33). Results Seventeen patients received the investigational treatment, and 16 were evaluable for response. LNA-i-miR-221 was well tolerated, with no grade 3–4 toxicity, and the MTD was not reached. We recorded stable disease (SD) in 8 (50.0%) patients and partial response (PR) in 1 (6.3%) colorectal cancer case (total SD + PR: 56.3%). Pharmacokinetics indicated non-linear drug concentration increase across the dose range. Pharmacodynamics demonstrated concentration-dependent downregulation of miR-221 and upregulation of its CDKN1B/p27 and PTEN canonical targets. Five mg/kg was defined as the recommended phase II dose. Conclusions The excellent safety profile, the promising bio-modulator, and the anti-tumor activity offer the rationale for further clinical investigation of LNA-i-miR-221 (ClinTrials.Gov: NCT04811898).

9MW1911 is a high-affinity human IgG4 monoclonal antibody targeting ST2, the human IL-33 receptor. It may have anti-inflammatory effects by blocking the IL-33/ST2 pathway. This first-in-human trial (NCT05803902) aimed to evaluate the safety, tolerability, pharmacokinetics, immunogenicity and pharmacodynamics of 9MW1911 in healthy participants. This phase I, randomized, double-blind, placebo-controlled study enrolled 48 healthy adults. After a screening period of up to 28 days, they received a single ascending intravenous dose (ranging from 25 to 1200 mg) of 9MW1911 (n = 6 per dose) or matched placebo (n = 2 per dose). Parameters of safety, pharmacokinetics, immunogenicity and pharmacodynamics were evaluated, with follow-up visits until day 113 post-dosing. 9MW1911 was safe and well-tolerated across various doses. Most AEs were of mild to moderate, resolved without treatments. No dose-related AEs were observed, and the only serious AE (fetal malformation) was deemed unrelated to the study drug. No deaths or discontinuations due to AEs occurred. 9MW1911 ranging from 25 mg to 1,200 mg demonstrated a non-linear increase in exposure, while a linear PK profile was observed in the dose range from 100 mg to 1200 mg. No anti-drug antibodies were detected in any participants. Total sST2 in serum increased and stabilized at higher dose levels, demonstrating sustained target binding. The study demonstrates that 9MW1911 was safe and well-tolerated in healthy participants. As 9MW1911 concentrations increased,the sustained elevation of sST2 in the higher dose levels (100mg-1200 mg) suggested that the target-mediated drug disposition (TMDD) elimination became saturated, leading to the observed linear PK profile. These data support the continued development of 9MW1911 for the therapeutic use in the relevant disease.

Background Synovial Sarcomas (SS) are rare tumors occurring predominantly in adolescent and young adults with a dismal prognosis in advanced phases. We report a first-in-human phase I of monoclonal antibody (OTSA-101) targeting FZD10 , overexpressed in most SS but not present in normal tissues, labelled with radioisotopes and used as a molecular vehicle to specifically deliver radiation to FZD10 expressing SS lesions. Methods Patients with progressive advanced SS were included. In the first step of this trial, OTSA-101 in vivo bio-distribution and lesions uptake were evaluated by repeated whole body planar and SPECT-CT scintigraphies from H1 till H144 after IV injection of 187 MBq of 111 In-OTSA-101. A 2D dosimetry study also evaluated the liver absorbed dose when using 90 Y-OTSA-101. In the second step, those patients with significant tumor uptake were randomized between 370 MBq (Arm A) and 1110 MBq (Arm B) of 90 Y-OTSA-101 for radionuclide therapy. Results From January 2012 to June 2015, 20 pts. (median age 43 years [21–67]) with advanced SS were enrolled. Even though 111 In-OTSA-101 liver uptake appeared to be intense, estimated absorbed liver dose was less than 20 Gy for each patient. Tracer intensity was greater than mediastinum in 10 patients consistent with sufficient tumor uptake to proceed to treatment with 90 Y-OTSA-101: 8 were randomized (Arm A: 3 patients and Arm B: 5 patients) and 2 were not randomized due to worsening PS. The most common Grade ≥ 3 AEs were reversible hematological disorders, which were more frequent in Arm B. No objective response was observed. Best response was stable disease in 3/8 patients lasting up to 21 weeks for 1 patient. Conclusions Radioimmunotherapy targeting FZD10 is feasible in SS patients as all patients presented at least one lesion with 111 In-OTSA-101 uptake. Tumor uptake was heterogeneous but sufficient to select 50% of pts. for 90 Y-OTSA-101 treatment. The recommended activity for further clinical investigations is 1110 MBq of 90 Y-OTSA-101. However, because of hematological toxicity, less energetic particle emitter radioisopotes such as Lutetium 177 may be a better option to wider the therapeutic index. Trial registration The study was registered on the NCT01469975 website with a registration code NCT01469975 on November the third, 2011.

Background The mammalian target of rapamycin (mTOR) kinase, a central component of the PI3K/AKT/mTOR pathway, plays a critical role in tumor biology as an attractive therapeutic target. We conducted this first-in-human study to investigate the safety, pharmacokinetics (PK), and pilot efficacy of LXI-15029, an mTORC1/2 dual inhibitor, in Chinese patients with advanced malignant solid tumors. Methods Eligible patients with advanced, unresectable malignant solid tumors after failure of routine therapy or with no standard treatment were enrolled to receive ascending doses (10, 20, 40, 60, 80, 110, and 150 mg) of oral LXI-15029 twice daily (BID) (3 + 3 dose-escalation pattern) until disease progression or intolerable adverse events (AEs). The primary endpoints were safety and tolerability. Results Between June 2017 and July 2021, a total of 24 patients were enrolled. LXI-15029 was well tolerated at all doses. Only one dose-limiting toxicity (grade 3 increased alanine aminotransferase) occurred in the 150 mg group, and the maximum tolerated dose was 110 mg BID. The most common treatment-related AEs were leukocytopenia (41.7%), increased alanine aminotransferase (20.8%), increased aspartate aminotransferase (20.8%), prolonged electrocardiogram QT interval (20.8%), and hypertriglyceridemia (20.8%). No other serious treatment-related AEs were reported. LXI-15029 was absorbed rapidly after oral administration. The increases in the peak concentration and the area under the curve were greater than dose proportionality over the dose range. Eight patients had stable disease. The disease control rate was 40.0% (8/20; 95% CI 21.7–60.6). In evaluable patients, the median progression-free survival was 29 days (range 29–141). Conclusions LXI-15029 demonstrated reasonable safety and tolerability profiles and encouraging preliminary antitumor activity in Chinese patients with advanced malignant solid tumors, which warranted further validation in phase II trials. Trial registration NCT03125746(24/04/2017), http://ClinicalTrials.gov/show/NCT03125746

Relapsed or refractory (R/R) acute myeloid leukemia (AML) has a poor prognosis. In this study, we evaluated chimeric antigen receptor (CAR) T cell therapy targeting CLL-1 in adults with R/R AML patients. Patients received conditioning chemotherapy with cyclophosphamide (500 mg/m 2 ) and fludarabine (30 mg/m 2 ) for 3 days and an infusion of a dose of 1–2 × 10 6 CAR-T cells/kg. The incidence of dose-limiting toxicity was the primary endpoint. Ten patients were treated, and all developed cytokine release syndrome (CRS); 4 cases were low-grade, while the remaining 6 were considered high-grade CRS. No patient developed CAR-T cell-related encephalopathy syndrome (CRES). Severe pancytopenia occurred in all patients. Two patients died of severe infection due to chronic agranulocytosis. The complete response (CR)/CR with incomplete hematologic recovery (CRi) rate was 70% ( n  = 7/10). The median follow-up time was 173 days (15–488), and 6 patients were alive at the end of the last follow-up. CAR-T cells showed peak expansion within 2 weeks. Notably, CLL-1 is also highly expressed in normal granulocytes, so bridging hematopoietic stem cell transplantation (HSCT) may be a viable strategy to rescue long-term agranulocytosis due to off-target toxicity. In conclusion, this study is the first to demonstrate the positive efficacy and tolerable safety of CLL-1 CAR-T cell therapy in adult R/R AML.

Purpose: To evaluate the safety, tolerability, pharmacokinetics and immunogenicity of DS002 injection, an anti-nerve growth factor (anti-NGF) monoclonal antibody for treating pain conditions, in healthy Chinese subjects. Methods: This study was a single-center, randomized, double-blind, single-dose escalation, placebo-controlled design (CTR20210155). A total of 53 healthy subjects, 27 male and 26 female, were enrolled in this study, and one subject withdrew from the study before administration. Seven dose groups were set up, which were 0.5 mg, 1.0 mg, 2.0 mg, 4.0 mg, 7.0 mg, 12.0 mg and 20.0 mg, respectively. The drug was administered by single subcutaneous injection. Four subjects were enrolled in the first dose group (0.5 mg) received DS002. Other dose groups enrolled eight subjects each, six of whom received DS002 while the other two received a placebo. Safety, tolerability, pharmacokinetic parameters and immunogenicity of DS002 were assessed. Results: DS002 was well tolerated; all adverse events were Grade 1–2, and did not reach the termination standard of dose increment within the range of 0.5–20.0 mg. Adverse event rates were generally similar across treatments. After a single subcutaneous injection, the median T max in different dose groups ranged 167.77–337.38 h; mean t 1/2 ranged 176.80–294.23 h, the volume of distribution (V z ) ranged 5265.42–7212.00 ml, and the clearance rate (CL) ranged 12.69–24.75 ml/h. In the dose range of 0.5–20.0 mg, C max ranged from 51.83 ± 22.74 ng/ml to 2048.86 ± 564.78 ng/ml, AUC 0-t ranged from 20615.16 ± 5698.28 h·ng/mL to 1669608.11 ± 387246.36 h·ng/mL, and AUC 0-inf ranged from 21852.45 ± 5920.21 h·ng/mL to 1673504.66 ± 389106.13 h·ng/mL. They all increased with dose escalation, and C max and AUC 0-t did not have a significant dose-linear relationship, whilst AUC 0-t was not dose-dependent at all. anti-drug antibody test results of each group of all subjects in this trial were negative. Conclusion: DS002 showed satisfactory safety within the dose range of 0.5 mg–20.0 mg. The absorption and metabolism of DS002 were slow, it exhibited a low volume of distribution and the clearance rate was low. These data suggest that DS002, by blocking nerve growth factor, is expected to become a novel, safe and non-addictive treatment for pain conditions.