Oral Small Molecule Inhibitor Research Articles

Phase I study of BTK inhibitor ibrutinib with temozolomide and radiation in newly-diagnosed glioblastoma (EQUILIBRIUM): Final trial report.

2067 Background: Novel therapeutic strategies are urgently needed in newly-diagnosed glioblastoma (GBM). Ibrutinib, an oral small molecule inhibitor of BTK, is currently being investigated for several B-cell malignancies and solid tumors. Preclinical evidence suggests ibrutinib in inhibiting cancer stem cell in glioblastoma. We sought to investigate the safety and tolerability of ibrutinib in nGBM. Methods: A non-randomized, prospective phase I trial was conducted in nGBM patients with Karnofsky performance status ≥70% and normal organ function, who received standard of care chemoradiation plus ibrutinib in a 3+3 dose-escalation design (level 1: 420 mg daily, level 2: 560 mg daily, level -1: 280 mg daily). Primary study objective was to determine maximum tolerated dose (MTD) of ibrutinib in combination with radiotherapy (RT) of 60 Gy over 6 weeks with/without 75 mg/m2 of temozolomide (TMZ). Secondary objective was to determine safety, overall survival (OS), and progression-free survival. Results: 26 patients were enrolled, with 12 (46%) females. Median age was 61.5 years (range 76-22). 15 (58%) patients were MGMT methylated and 11 (42%) were unmethylated. Dose-limiting toxicities (DLTs) were observed at all dose levels of ibrutinib plus RT (ibru+RT) cohort. MTD of ibrutinib was noted to be 420 mg daily with RT+TMZ. All MGMT methylated and 2 unmethylated patients received ibrutinib+RT+TMZ. Remaining 9 unmethylated received ibru+RT. In ibru+RT+TMZ, median cycles of TMZ were 4 (range 0-6) and of ibrutinib were 3 (range 0-26). EGFR amplification status was available for 22 patients, of which 8 (36%) were amplified. Survival outcomes are described, stratified using log-rank test. Conclusions: 420 mg of Ibrutinib daily is safe and feasible in combination with TMZ and radiation in nGBM. Outcomes of ibrutinib appears promising compared to historical survival data in the MGMT methylated cohorts. Further trials are planned. Clinical trial information: NCT03535350 . [Table: see text]

ENHANCER OF ZESTE HOMOLOG 2 (EZH2) INHIBITOR SHR2554 IN RELAPSED OR REFRACTORY (R/R) PERIPHERAL T‐CELL LYMPHOMA (PTCL): UPDATED OUTCOMES FROM THE FIRST‐IN‐HUMAN PHASE 1 STUDY

Introduction: Inhibition of histone methyltransferase EZH2 represents a rational therapeutic strategy for lymphomas. SHR2554 is an oral small-molecule inhibitor exhibiting potent selectivity for EZH2. The multicenter, 2-part, phase 1 study was initiated to assess SHR2554 in patients (pts) with r/r lymphomas (NCT03603951). In part I, 350 mg BID was established as the recommended phase 2 dose (RP2D) based on the findings in the dose-escalation and expansion phases; subsequently, pts with selected lymphoma subtypes were recruited in the clinical expansion phase to receive SHR2554 at RP2D (Y Song et al. Lancet Haematol, 2022). Here we report the updated results of part I focusing on PTCL pts at RP2D. The prognosis of PTCL is extremely poor due to low response to chemotherapy regimens and limited treatment options thereafter, highlighting an urgent, unmet medical need. Methods: Pts with histologically confirmed PTCL that had relapsed or were refractory to ≥1 line of prior systemic therapy were eligible for inclusion in part I of this study. Efficacy and safety were assessed in PTCL pts who received at least one dose of SHR2554 at 350 mg BID. Results: Totally, 28 pts were included in this analysis: median age, 56 y (range 30–70); ECOG PS 1, 64.3% (18/28); median lines of prior systemic therapies, 2 (range 1–14). At data cutoff on 31 August 2022, the median follow-up duration was 11.9 mo (range 0.9–23.9). 17 pts achieved complete or partial response, resulting in a confirmed objective response rate (ORR) of 60.7% (95% CI 40.6–78.5). Responses were still ongoing in 58.8% (10/17) of the responders; estimated median duration of response (DoR) was 12.3 mo (95% CI 7.4–NR). 16 (57.1%) pts had disease progression or died; median progression-free survival (PFS) was 11.1 mo (95% CI 5.3–22.0). 4 (14.3%) deaths occurred; 1-y overall survival rate was 92.2% (95% CI 72.1–98.0). Of the 28 pts, 17 were diagnosed with angioimmunoblastic T-cell lymphoma (AITL), and 11 had PTCL not otherwise specified (PTCL-NOS). AITL pts showed better outcomes than PTCL-NOS pts: ORR, 76.5% versus 36.4%; median DoR, 20.3 versus 3.3 mo; median PFS, 22.1 versus 5.0 mo (Table). Grade ≥3 treatment-related adverse events (TRAEs) occurred in 14 of the 28 pts (50.0%), with the most common being decreased platelet count (32.1%), decreased white blood cell count (14.3%), decreased neutrophil count (14.3%), and anemia (14.3%). One (3.6%) pt discontinued treatment due to TRAE (interstitial lung disease). No treatment-related deaths were reported. Conclusions: This extended follow-up analysis further provides evidence of potent anti-tumor activity, durable response, and acceptable safety of SHR2554 in pts with r/r PTCL. The research was funded by: The study was sponsored by Jiangsu Hengrui Pharmaceuticals Co., Ltd. Keywords: aggressive T-cell non-Hodgkin lymphoma, molecular targeted therapies Conflicts of interests pertinent to the abstract Y. Shen Employment or leadership position: Jiangsu Hengrui Pharmaceuticals J. Shen Employment or leadership position: Jiangsu Hengrui Pharmaceuticals Z. Xiao Employment or leadership position: Jiangsu Hengrui Pharmaceuticals

Effects of ALZ-801, an Oral Amyloid Oligomer Inhibitor, on Biomarkers of Alzheimer’s Disease (AD): 12-Month Results of Phase 2 Biomarker Study in Early AD (S26.007)

<h3>Objective:</h3> To evaluate effects of ALZ-801 on plasma and imaging biomarkers of AD pathology. <h3>Background:</h3> ALZ-801 (valiltramiprosate) is an oral small molecule inhibitor of amyloid oligomer formation. Fully enrolled Phase 2 study in APOE4 carriers is evaluating effects on plasma biomarkers, including hyperphosphorylated tau (p-tau₁₈₁) and beta amyloid (Aβ42 and Aβ40). Plasma p-tau₁₈₁ is elevated in AD and reduced by efficacious doses of lecanemab and aducanumab. APOLLOE4 Phase 3 trial is ongoing in Early AD patients with APOE4/4 genotype. <h3>Design/Methods:</h3> Phase 2 study enrolled subjects with MMSE ≥ 22 and CDR-G 0.5/1, and amyloid positive by CSF or PET scans who received ALZ-801 265 mg BID over 2 years (7 European sites). Biomarker analyses were conducted with Lumipulse (CSF) and Simoa (plasma) assays at Dr. Kaj Blennow’s laboratory. Hippocampal volume (HV) atrophy was assessed by Clario. Changes from baseline were analyzed in mITT population on observed data with paired t-tests and 2-sided p-values. <h3>Results:</h3> mITT population included 84 subjects with 75 completing 52 weeks. Mean age was 69 years, 51% female, MMSE 26.0, 70/30% MCI/Mild AD. Significant plasma p-tau₁₈₁ reduction started at 13 weeks and reached −41% at 52 weeks (p=0.016), with significant reduction in plasma Aβ42 and Aβ40 at 52 weeks (−5%, p=0.002 &amp; p=0.005). Hippocampal atrophy was reduced by 25% compared to matched ADNI controls. Composite cognitive Z-score improved significantly at 13 and 26 weeks and remained above baseline at 52 weeks. Common adverse events were mild nausea and COVID infection, with no drug-related serious events or ARIA-E. <h3>Conclusions:</h3> ALZ-801 produced a significant reduction of plasma p-tau₁₈₁, a marker of amyloid-induced neuronal injury in AD, as well as slowing of hippocampal atrophy at 1 year and cognitive stabilization, suggesting a disease modifying effect in AD patients. These biomarker and clinical effects are being confirmed in the Phase 3 trial. <b>Disclosure:</b> Dr. Hey has received personal compensation for serving as an employee of Alzheon. Dr. Hey has stock in Alzheon. Dr. Hey has stock in Alzheon. Dr. Hey has received intellectual property interests from a discovery or technology relating to health care. Dr. Abushakra has received personal compensation for serving as an employee of Alzheon Inc. Dr. Abushakra has stock in Alzheon Inc. The institution of Dr. Abushakra has received research support from NIA. Dr. Abushakra has received intellectual property interests from a discovery or technology relating to health care. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen, Axon, JOMDD, Roche, Siemens. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis, Julius Clinical. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for MagQu. Dr. Scheltens has nothing to disclose. Dr. Hort has received personal compensation in the range of $0-$499 for serving as a Consultant for Alzheimerchain. Dr. Hort has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Hort has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Schwabe. Dr. Hort has stock in Alzheon. Dr. Sheardova has stock in Alzheon. Niels Prins has nothing to disclose. Mrs. Rutgers has received personal compensation for serving as an employee of Brain Research Center Amsterdam B.V.. Dr. Dautzenberg has nothing to disclose. Dr. Pazdera has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Pazdera has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Teva. Patrick Kesslak has nothing to disclose. Rosalind Mandelbaum has nothing to disclose. Dr. Power has received personal compensation for serving as an employee of Alzheon. Dr. Power has stock in Pfizer. Dr. Power has stock in Alzheon. Dr. Tolar has received personal compensation for serving as an employee of Alzheon. Dr. Tolar has received intellectual property interests from a discovery or technology relating to health care.

Abstract LB329: A potent and selective small molecule inhibitor of CSF-1R ABSK021 demonstrates strong efficacy in preclinical models of osteosarcoma

Abstract Introduction: Osteosarcoma is the most common primary malignant bone tumor in children and young adults. Surgery combined with multimodal chemotherapy remains as the standard treatment for osteosarcoma patients. However, patients with osteosarcoma metastasis have a five-year survival rate of less than 30%, and their long-term outcomes have not improved over the last 30 years. CSF-1/CSF-1R signaling is crucial for the survival, function, proliferation and differentiation of myeloid lineage cells, including osteoclasts and monocytes/macrophages. Targeting CSF-1R either on tumor cells or tumor-associated macrophages has been reported to limit osteosarcoma progression in preclinical models. ABSK021, an oral, highly potent and selective small molecule inhibitor of CSF-1R discovered by Abbisko, has entered into Phase I trial (NCT04192344) and showed significant anti-tumor activity and favorable safety profile in patients with advanced tenosynovial giant cell tumor. Here, we conducted a series of preclinical in vitro and in vivo experiments, as well as human osteosarcoma profiling, to investigate the treatment potential of ABSK021 for osteosarcoma patients. Methods: Cellular potency of ABSK021 was evaluated by Celltiter-Glo assay in osteosarcoma cell lines and CSF-1R expression was evaluated by western blot. In vivo efficacy studies were conducted in murine osteosarcoma models and pharmacodynamics changes were measured. CSF-1R IHC staining was conducted in tissue microarray samples from osteosarcoma patients. Results: ABSK021 potently inhibited the proliferation of K7M2, a murine osteosarcoma cell line with high expression of CSF-1R. In animal, ABSK021 showed strong anti-tumor activity on K7M2 syngeneic model and SA4094 osteosarcoma PDX model without causing significant body weight loss. Pharmacodynamics analysis displayed robust inhibition of macrophage infiltration and CSF-1R signaling by ABSK021, confirming its effective target engagement in vivo. Parallel IHC analysis of human tissue microarray samples revealed high prevalence of positive CSF-1R staining in osteosarcoma patients. Conclusion: Taken together, these results demonstrate that ABSK021 has strong inhibition of CSF-1R activity and corresponding anti-tumor activity in preclinical osteosarcoma models. High prevalence of CSF-1R expression was also found in osteosarcoma patients, suggesting great potential of utilizing ABSK021 as a novel therapy to treat osteosarcoma patients in clinic. Citation Format: Nannan Zhang, Cheng Dai, Jiacheng Zhang, Shuqun Yang, Jie Wang, Jie Zhang, Manqi Liu, Zhui Chen. A potent and selective small molecule inhibitor of CSF-1R ABSK021 demonstrates strong efficacy in preclinical models of osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB329.

Abstract CT118: A phase I/II trial of a CXCR1/2 inhibitor in combination with anti-PD-1 for circulating tumor DNA (ctDNA) positive &amp; refractoryRAS-mutated microsatellite stable (MSS) colorectal cancer

Abstract Background: Preclinical CRC models reveal KRAS mutations activate the CXCR2 axis promoting an immunosuppressive tumor microenvironment (TME). This occurs via KRAS repression of interferon regulatory factor 2 (IRF2) resulting in upregulation of CXCL3 chemokines, which bind CXCR2 and recruit myeloid-derived suppressor cells (MDSC; Liao et al, Cancer Cell 2019). MDSCs also accelerate metastases by ‘priming’ the premetastatic niche via promoting egress of tumors cells into the circulation, inhibiting killing by immune cells and promoting extravasation into the tissues (Veglia et al. Nature 2021). SX-682 is a novel oral small-molecule inhibitor of CXCR1/2 chemokine receptors involved in MDSC-recruitment to TME. This proof-of-concept study investigates whether a CXCR1/2 antagonist in combination with anti-PD-1 therapy can overcome de novo immunotherapy resistance in MSS RAS mutated mCRC and eradicate micrometastatic disease in ctDNA positive CRC post definitive therapy. Methods: STOPTRAFFIC-1 is a phase I/II, open-label, dose-escalation/dose expansion study of SX-682 plus nivolumab for patients (pts) with RAS mutated MSS mCRC or ctDNA positive CRC. Key eligibility criteria - Arm A: pts with MSS mCRC with progression or intolerance to 2 prior lines of therapy, ECOG 0/1; Arm B: ctDNA positive post completion of definitive therapy (adjuvant chemotherapy for stage III or metastasectomy for stage IV CRC). Pts will receive SX-682 (5 dose levels: 25 mg, 50 mg, 100mg, 200mg, or 400 mg PO twice daily) in an 8-week cycle with intravenous nivolumab (480 mg) on days 1 and 29. Adverse events per CTCAE v5.0. RECIST assessments every 8 weeks. In dose escalation, pts enter a 3-week monotherapy safety run-in of SX-682 followed by 3-week combination with nivolumab for a six-week dose-limiting toxicity (DLT) period. Cohorts 1-4 have been completed without DLT. Enrollment to Cohort 5 is completed with expansion arms to open February 2023. Dose expansion is a Simon's optimal two-stage design for Arm A. Efficacy will be assessed in the first 15 pts with a requirement of 2 responses in order to enroll 14 additional pts (N=29). Pre- and on-treatment tissue biopsies will be collected. Arm B will enroll 15 pts with positive ctDNA post definitive therapy. Pts will be screened with CLIA certified ctDNA test for minimal residual disease (MRD) and if positive, enrolled for treatment for up to 6 months (m). Pts will undergo radiographic evaluation at 3 and 6m and then every 3-6m for at least 3 years. The primary objectives are to determine safety profile, recommended phase 2 dose, clinical activity &amp; 6m ctDNA clearance rate in CRC pts with MRD following 6m of SX-682 + Nivolumab on Arm B. Translational analyses include correlations of clinical outcomes with genomic and immune biomarkers from paired tissue and plasma samples. Clinical trial information: NCT04599140. Citation Format: Benny Johnson, Cara Haymaker, Van K. Morris, Arvind Dasari, Victoria Serpas Higbie, John Paul Shen, Christine Parseghian, Maria Pia Morelli, Ryan Huey, Michael S. Lee, Jason Willis, Kanwal P. Raghav, Ying Yuan, John Zebala, Ronald A. DePinho, Scott Kopetz, Michael Overman. A phase I/II trial of a CXCR1/2 inhibitor in combination with anti-PD-1 for circulating tumor DNA (ctDNA) positive &amp; refractoryRAS-mutated microsatellite stable (MSS) colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT118.

A single-arm phase II clinical trial of anlotinib combined with chemotherapy for the treatment of metastatic triple-negative breast cancer.

Anlotinib is a novel oral small-molecule tyrosine kinase inhibitor (TKI), which can inhibit angiogenesis. The purpose of this study was to evaluate the efficacy and safety of anlotinib combined with chemotherapy in patients with metastatic triple-negative breast cancer (TNBC). This phase II clinical trial included 40 patients with metastatic TNBC who had previously received anthracycline and/or taxane treatment. All patients received anlotinib combined with chemotherapy. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), disease control rate (DCR) and safety. During May 1, 2019 and April 30, 2022, there were 40 patients enrolled in this study. The median PFS and median OS were 8.8 months (95% confidence interval [CI] 6.5-11.1 months) and 19.0 months (95% CI, 12.1-25.9 months), respectively. The ORR, CBR and DCR were 40.0% (16/40), 85.0% (34/40) and 95.0% (38/40), respectively. Cox univariate and multivariate analyses demonstrated that having more than 3 metastatic sites (p = 0.001; p = 0.020) was an independent and meaningful unfavorable prognostic factor for PFS. 37.5% of patients had grade 3 to 4 treatment-related adverse events (TRAEs). The grade 3 to 4 TRAEs included neutropenia (22.5%), leukopenia (20.0%), secondary hypertension (10.0%), hand-foot syndrome (5.0%), vomiting (5.0%), proteinuria (5.0%) and thrombocytopenia (2.5%). None of the patients withdrew from the study or died due to TRAEs. In this single-arm study, the treatment of metastatic TNBC with anlotinib combined with chemotherapy showed certain efficacy, and its toxicity was acceptable.

Abstract 6268: TT125-802 is a potent and highly selective CBP/p300 bromodomain inhibitor for the treatment of castration resistant prostate cancer and haematological malignancies

Abstract The paralogous lysine acetyltransferases CREB-binding protein (CBP) and p300 are key epigenetic regulators involved in diverse signaling pathways in cancer. The bromodomain (BRD) of CBP/p300 serves as an acetyl-lysine “reader” that allows CBP/p300 to bind chromatin at acetylated histone and non-histone proteins leading to the regulation of gene transcription. Indeed, CBP/p300 are critical co-activators of nuclear receptors, including the androgen receptor (AR) in castration resistant prostate cancer (CRPC). Thus, inhibition of CBP and p300 is an emerging therapeutic strategy to block the transactivation activity of the AR in CRPC. In addition, inhibition of the CBP/p300 BRD has been described as a potential therapeutic strategy to treat multiple myeloma (MM) through transcriptional suppression of interferon regulatory factor 4 (IRF4) and concomitant repression of its target genes MYC and MYB. TT125-802 is a highly selective and potent, oral small molecule inhibitor of the BRD of CBP/p300. In a BROMOscan assay against a panel of 40 BRD-containing proteins, TT125-802 revealed the unique selectivity to the BRD of CBP/p300 with a minimal off-target binding to all other BRDs, including BET proteins.TT125-802 shows selective anti-proliferative activity in AR-dependent prostate cancer cell lines (22Rv-1, C4-2, and LNCaP) and inhibits AR target gene expression (KLK2, KLK3, TMPRSS2, and MYC) in a dose-dependent manner (IC50 of 2 to 33 nM). AR-negative prostate cancer cell lines (DU-145 and PC-3) are insensitive to TT125-802 in vitro, pointing to an AR-selective mode of action. In an in vivo model of CRPC, TT125-802 inhibited tumor growth when administered orally to human C4-2 xenograft-bearing mice. Daily dosing of TT125-802 was well tolerated with stable bodyweights and platelet counts. In addition, preclinical studies in CRPC patient-derived xenograft (PDX)-bearing mice showed that the combination treatment of TT125-802 and enzalutamide had a synergistic effect on tumor growth inhibition compared to single agent treatments. TT125-802 reduced mRNA expression of the AR-target genes in tumor samples and decreased plasma PSA levels compared to enzalutamide alone, and the combination reduced levels even further. In a preclinical model of MM (OPM2), TT125-802 had a dose-dependent effect on tumor growth, inducing tumor regressions at the highest dose. Target genes such as MYC, MYB, and IRF4 were potently downregulated in tumors. We conclude that TT125-802 is a novel, highly selective inhibitor of the BRD of CBP/P300. It has therapeutic potential as monotherapy in prostate cancer and multiple myeloma and in combination with next-generation AR inhibitors for patients with lethal prostate cancer. A FIH study of TT125-802 in cancer patients is on track to start in 2023. Citation Format: Sara Laudato, Dorothea Gruber, Thomas Bohnacker, Martin Schwill, Charles-Henry Fabritius, Raquel Herrador, Katrin Westritschnig, Thushara Pattupara, Vikram Ayinampudi, Stefanie Flückiger-Mangual. TT125-802 is a potent and highly selective CBP/p300 bromodomain inhibitor for the treatment of castration resistant prostate cancer and haematological malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6268.

Antithrombotic Effects of the Novel Small-Molecule Factor XIa Inhibitor Milvexian in a Rabbit Arteriovenous Shunt Model of Venous Thrombosis

Background Factor XIa (FXIa) is an emerging therapeutic target, and FXIa inhibition is a promising mechanism to improve therapeutic index over current anticoagulants. Milvexian (BMS-986177/JNJ-70033093) is an oral small-molecule FXIa inhibitor. Objective Milvexian's antithrombotic efficacy was characterized in a rabbit arteriovenous (AV) shunt model of venous thrombosis and compared with the factor Xa inhibitor apixaban and the direct thrombin inhibitor dabigatran. Methods The AV shunt model of thrombosis was conducted in anesthetized rabbits. Vehicle or drugs were administered as intravenous bolus plus a continuous infusion. Thrombus weight was the primary efficacy endpoint. Ex vivo activated partial thromboplastin time (aPTT), prothrombin time (PT), and thrombin time (TT) were measured as the pharmacodynamic responses. Results Milvexian dose dependently reduced thrombus weights by 34.3 ± 7.9, 51.6 ± 6.8 ( p < 0.01; n = 5), and 66.9 ± 4.8% ( p < 0.001; n = 6) versus vehicle at 0.25 + 0.17, 1.0 + 0.67, and 4.0 ± 2.68 mg/kg bolus + mg/kg/h infusion, respectively. Ex vivo clotting data supported a dose-dependent prolongation of aPTT (with 1.54-, 2.23-, and 3.12-fold increases from baseline upon the AV shunt start), but no changes in PT and TT. Dose-dependent inhibition in thrombus weight and clotting assays was also demonstrated for both apixaban and dabigatran as the references for the model validation. Conclusion Results demonstrate that milvexian is an effective anticoagulant for prevention of venous thrombosis in the rabbit model, which supports the utility of milvexian in venous thrombosis, as seen in the phase 2 clinical study.

Efficacy and safety of fruquintinib as third- or further-line therapy for patients with advanced bone and soft tissue sarcoma: a multicenter retrospective study.

Fruquintinib is an oral small-molecule angiogenesis inhibitor, markedly specifically inhibited vascular endothelial growth factor 2 (VEGFR2). This retrospective study aimed to evaluate the safety and efficacy of fruquintinib, or in combination with immunotherapy or chemotherapy in patients with bone and soft tissue sarcoma (STS), who have failed at least secondary-line treatment. We performed a retrospective analysis of advanced bone and STS patients who received fruquintinib containing third- or further-line therapy in Shanghai Jiao Tong University Affiliated Sixth People's and the Affiliated Hospital of Jiangxi University of Traditional Chiese Medicine from September 2019 to February 2022. All of them had accepted at least anthracyclines-based chemotherapy. For the experimental group, 25 cases, the patients took a basic dose of fruquintinib 3-5 mg once a day for 21 days per 4 weeks as a cycle until the disease progression or intolerable toxicity. The other 20 patients in the control group received the best supportive care. The patients were evaluated by computed tomography (CT) or MRI once 2 months or symptoms worse. The DCR, progression-free survival (PFS), and adverse reactions of the drug were recorded and reviewed. The DCR in patients receiving fruquintinib therapy was 80.0%. The median PFS (mPFS) in the fruquintinib-containing therapy group was significantly longer than that in the control group (4.8 vs. 1.4 months; P < 0.001). The mPFS in the fruquintinib group, the fruquintinib-OI group and the fruquintinib-chemotherapy group were 3.2 months [95% confidence interval (CI), 2.0-7.9], 4.9 months (95% CI, 3.0-9.9) and 4.2 months (95% CI, 2.6-6.6) respectively, all of them were longer than the mPFS of 1.4 months (95% CI, 0.3-2.5) in the control group (P < 0.001). Fruquintinib was reported for the first time to have favorable efficacy and safety as an optional treatment for patients with advanced bone and STS who failed in multi-line therapies.

Dosing Recommendation Based on the Effects of Different Meal Types on Pexidartinib Pharmacokinetics in Healthy Subjects: Implementation of Model-informed Drug Development Strategy.

Pexidartinib, an oral small molecule inhibitor of the colony-stimulating factor 1 receptor, is approved for treatment of adults with symptomatic tenosynovial giant cell tumor associated with severe morbidity or functional limitations and not amenable to improvement with surgery. The original dosing regimen is 400mg of pexidartinib (2×200-mg capsules) twice daily, administered on an empty stomach at least 1hour before or 2hours after a meal or snack. Because pexidartinib is likely to be taken over an extended period of time, the ability to take pexidartinib with a meal would simplify timing of administration and potentially improve compliance. Since administering 400mg of pexidartinib with alow-fatmeal increases exposure by ≈60% relative to the fasted state, administering 250mg of pexidartinib with a low-fatmeal (low-fat meal dosing regimen) was predicted to achieve an exposure similar to 400mg administered during a fasted state (original dosing regimen). Based on clinical trial simulations with two one-sided t-tests and bootstrapping (ie, resampling) analyses, a bioequivalence study (n=24) would have >90% power to conclude that the original dosing regimen (400mg fasted twice daily) and thelow-fatmeal dosing regimen (250mg with alow-fatmeal twice daily) are bioequivalent. This report provides the outcome of the implementation of the model-informed drug development strategy to recommend and justify alow-fatmeal dosing regimen for pexidartinib that has the potential to improve patient compliance while maintaining drug exposure.

Quantitative determination of plasma cabozantinib concentration using HPLC-UV and its application to patients with renal cell carcinoma.

Cabozantinib is an oral small-molecule tyrosine kinase inhibitor that has become a standard of care for advanced renal cell carcinoma (RCC). However, cabozantinib is associated with a high rate of adverse events. Therefore, individualised cabozantinib administration and monitoring could help maximise its therapeutic efficacy and avoid serious adverse events. This study developed and validated a method to determine cabozantinib concentration in plasma using HPLC-UV. Sorafenib, an internal standard, was added to the plasma sample containing cabozantinib. A calibration curve for cabozantinib showed good linearity (R2 = 1.00), between 25 and 4,000 ng/ml. The recovery rate was above 92.1%, and the intra- and inter-day coefficients of variation were smaller than 5.2 and 6.8%, respectively. Then, we applied the method for monitoring cabozantinib blood levels in three patients with advanced RCC who were taking cabozantinib at a dose of 20, 40 or 60 mg/day. Grade 3 adverse events were more likely to occur in patients with high dosing and blood level of cabozantinib. Owing to its simplicity, the developed method can be used in general hospitals, and is expected to help maximise drug efficacy and minimise serious adverse events in many patients with RCC undergoing cabozantinib treatment.

First-in-class oral innate immune activator BXCL701 combined with pembrolizumab in patients with metastatic, castration-resistant prostate cancer (mCRPC) of small cell neuroendocrine (SCNC) phenotype: Phase 2a final results.

176 Background: BXCL701 (talabostat), oral small molecule inhibitor of dipeptidyl peptidases (DPP)—primarily DPP8/9 &amp; DPP4—triggers inflammasome to alert and prime immune cells, leading to induction of IL-18 &amp; IL-1ß, bridging innate &amp; adaptive immunity. BXCL701 is evaluated in a Phase 2 study in combination with pembrolizumab, in mCRPC patients with SCNC phenotype. SCNC is highly proliferative and aggressive with limited duration of response to platinum-based chemotherapy. Here are reported the results of the Phase 2a after enrollment of 32 patients for the SCNC cohort. The final results will be presented at the Symposium. Methods: Phase 2a patients with any SCNC histopathological features, either de novo or treatment-emergent including mixed SCNC, required to have progression by PCWG3 on ≥1 prior line of cytotoxic chemotherapy (patients who either have refused chemotherapy or are considered unsuitable for chemotherapy also permitted entry with prior approval by sponsor). Patients receive pembrolizumab (200 mg IV q3week) + BXCL701 0.2 mg BID on days 1-7 with step-up to 0.3 mg BID on days 8-14, and 0.3 mg BID on days 1-14 of subsequent cycles. Primary endpoint is Composite Response, either objective response by RECIST 1.1 or PSA50 or CTC count conversion from ≥5/7.5 mL to &lt;5/7.5 mL from baseline. Study uses a Simon 2-stage minimax design with 15 evaluable patients in stage 1 and 13 in stage 2. Baseline markers and changes in relevant immune effector cells also evaluated. Results: As of 10/11/2022, 32 patients have been accrued, 27 of which are evaluable. 16 patients (59%) are treatment-emergent SCNC and 11 (41%) are de novo SCNC. 19 patients (70%) received prior platinum chemotherapy. BXCL701 in combination with pembrolizumab continues to demonstrate acceptable tolerability without evidence of increased immune-related AEs compared to historic controls with checkpoint inhibitors. Adverse Events consistent with cytokine activation were observed (hypotension, fever, fatigue). In the previously reported 15 evaluable SCNC patients, 5 were composite responders, including 4 RECIST responders with a median duration of response of 39 weeks (range 9-45 weeks). 2/5 responders still actively receiving treatment and median duration of follow up is 48.3 weeks (range 1.9-88 weeks). All responders are MSS and/or low TMB. Enrollment is ongoing and 9 patients are actively receiving treatment at abstract submission. Final data for 28 evaluable patients will be presented at the Symposium. Conclusions: Oral BXCL701 in combination with pembrolizumab demonstrates encouraging anti-tumor activity with durability of response in late-line, refractory mCRPC SCNC for which there is currently no standard of care. BXCL701 BID dosing continues to demonstrate an acceptable safety profile. Clinical trial information: NCT03910660 .

Efficacy of THB001, a Potent and Selective Oral Small Molecule Inhibitor of Wild Type KIT Receptor Tyrosine Kinase, in a Rat Passive Cutaneous Anaphylaxis Model

Mast cells play a central role in the pathophysiology of allergic inflammation. Mast cell activation, migration, proliferation and survival are dependent on KIT (CD117) signaling. THB001 is a potent and selective inhibitor of wild type KIT being studied clinically as a therapy for mast cell driven diseases. The current study correlated target engagement, mast cell depletion and efficacy in an in vivo model of anaphylaxis.

Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated KRAS G12C

BackgroundAdagrasib, an oral small-molecule inhibitor of mutant KRAS G12C protein, has shown clinical activity in pretreated patients with several tumor types, including colorectal cancer. Preclinical studies suggest that combining a KRAS G12C inhibitor with an epidermal growth factor receptor antibody could be an effective clinical strategy.MethodsIn this phase 1–2, open-label, nonrandomized clinical trial, we assigned heavily pretreated patients with metastatic colorectal cancer with mutant KRAS G12C to receive adagrasib monotherapy (600 mg orally twice daily) or adagrasib (at the same dose) in combination with intravenous cetuximab once a week (with an initial loading dose of 400 mg per square meter of body-surface area, followed by a dose of 250 mg per square meter) or every 2 weeks (with a dose of 500 mg per square meter). The primary end points were objective response (complete or partial response) and safety.ResultsAs of June 16, 2022, a total of 44 patients had received adagrasib, and 32 had received combination therapy with adagrasib and cetuximab, with a median follow-up of 20.1 months and 17.5 months, respectively. In the monotherapy group (43 evaluable patients), a response was reported in 19% of the patients (95% confidence interval [CI], 8 to 33). The median response duration was 4.3 months (95% CI, 2.3 to 8.3), and the median progression-free survival was 5.6 months (95% CI, 4.1 to 8.3). In the combination-therapy group (28 evaluable patients), the response was 46% (95% CI, 28 to 66). The median response duration was 7.6 months (95% CI, 5.7 to not estimable), and the median progression-free survival was 6.9 months (95% CI, 5.4 to 8.1). The percentage of grade 3 or 4 treatment-related adverse events was 34% in the monotherapy group and 16% in the combination-therapy group. No grade 5 adverse events were observed.ConclusionsAdagrasib had antitumor activity in heavily pretreated patients with metastatic colorectal cancer with mutant KRAS G12C, both as oral monotherapy and in combination with cetuximab. The median response duration was more than 6 months in the combination-therapy group. Reversible adverse events were common in the two groups. (Funded by Mirati Therapeutics; KRYSTAL-1 ClinicalTrials.gov number, NCT03785249.)

Pharmacokinetics of the Multi-kinase Inhibitor Pexidartinib: Mass Balance and Dose Proportionality.

Pexidartinib is an oral small-molecule tyrosine kinase inhibitor that selectively targets colony-stimulating factor 1 receptor. Two phase 1 single-center trials were conducted in healthy subjects to determine the absorption, distribution, metabolism, and excretion of pexidartinib using radiolabeled drug and to assess the dose proportionality of pexidartinib following single oral doses. In the mass balance study, eight male subjects received a single oral dose of [14 C]-pexidartinib 400mg with radioactivity assessed in plasma, urine, and feces samples taken at various timepoints postdose. In the dose-proportionality study, 18 subjects received single doses of pexidartinib 200, 400, and 600mg using randomization sequences. Peak pexidartinib and total radioactivity were observed at 1.75-2.0hours after the oral dose and then declined in a multiphasic manner. The overall mean recovery of administered radioactivity was 92.2% over 240hours with 64.8% in the feces and 27.4% in the urine. Major components detected in plasma were pexidartinib and glucuronide (M5, ZAAD-1006a), with M5 and pexidartinib detected in urine and feces, respectively. A glucuronide of dealkylated form (M1) in the urine and multiple oxidized forms (M2, M3, and M4) in feces were detected. The dose-proportionality study found dose-proportional drug exposure between the 200- and 400-mg doses and slightly less than proportional exposure between the 400- and 600-mg doses. These results from these studies provide insight into pexidartinib disposition after oral administration and support the development of dosing guidance in subjects with renal or hepatic impairment or subjects taking cytochrome P450 3A and uridine disphosphate-glucuronosyl transferase inhibitors and inducers.

Research Progress of Oral BCL-2 Inhibitor Venetoclax in the Treatment of Non-Hodgkin's Lymphoma --Review

Abnormal cell apoptosis is closely related to the occurrence of hematologic tumors, B-cell lymphoma-2 (BCL-2), as a key anti-apoptotic protein in intrinsic programmed cell death, has become a hot spot in the treatment of hematologic tumors in recent years. Venetoclax is an oral small-molecule selective BCL-2 inhibitor approved by the Food and Drug Administration (FDA） for the treatment of chronic lymphocytic leukemia (CLL) patients or small lymphocytic lymphoma (SLL) patients and for the treatment of elderly acute myeloid leukemia (AML) patients that is not suitable for aggressive chemotherapy. In addition, it also showed a promising clinical application in treatment of non-Hodgkin's lymphoma (NHL) patients, which is a new expansion of the clinical indications for venetoclax. In this review, the role of BCL-2 protein family played in the regulation of NHL cell apoptosis, the development of BCL-2 inhibitors and the recent research progress of venetoclax in the treatment of NHL are reviewed.

345 (PB125) - STC-15, an oral small molecule inhibitor of the RNA methyltransferase METTL3, inhibits tumour growth through activation of anti-cancer immune responses associated with increased interferon signalling, and synergises with T cell checkpoint blockade

Background: METTL3 is an RNA methyltransferase responsible for the deposition of N-6-methyladenosine (m6A) modification on mRNA and long non-coding RNA (lncRNA) targets, to regulate their stability, splicing, transport and translation. Small molecule inhibitors of METTL3 catalytic activity have previously demonstrated direct anti-tumour efficacy in models of acute myeloid leukemia (AML). Here we present pre-clinical data showing that the orally bioavailable small molecule METTL3 inhibitor STC-15 inhibits cancer growth and induces anti-cancer immunity.

Influence of esomeprazole on the bioavailability of afatinib: A pharmacokinetic cross-over study in patients with non-small cell lung cancer

Afatinib is an oral small-molecule kinase inhibitor (SMKI) approved for treatment of metastatic non-small cell lung cancer (NSCLC) with an epidermal growth factor receptor (EGFR) driver mutation. Although oral administration is convenient, most SMKIs experience pH-dependent solubility. A drug-drug interaction between afatinib and proton-pump inhibitors (PPIs) has, however, never been studied in humans. Hence, we performed a randomized, three-period cross-over study. Afatinib (30 mg or 40 mg) was administered without PPI (period A), concomitantly with esomeprazole (period B) and three hours after esomeprazole intake (period C). Primary objective was the area under the curve (AUC0–24 h) comparing period A to period B and period A to period C. Secondary objectives were other pharmacokinetic parameters and toxicity. Linear mixed effect modelling was performed for differences in AUC0–24 h and Cmax between periods A and B and periods A and C. In 18 evaluable NSCLC patients, concomitant use of 40 mg esomeprazole decreased the steady-state afatinib AUC0–24 h with 10.2% (95% CI −29.2 to +14.0%; p = 0.564) compared to afatinib administration without PPI. Esomeprazole intake three hours prior to afatinib did not significantly influence afatinib AUC0–24 h (−0.6%; 95% CI −14.9 to +16.1%; p = 1.0). No differences in toxicity were observed. To conclude, esomeprazole did not change the exposure to afatinib in patients with NSCLC. Since there is no clinically relevant drug-drug interaction, esomeprazole can safely be co-administered with afatinib. This is important for clinical practice, because other EGFR-SMKIs (e.g. erlotinib and gefitinib) do experience clinically relevant drug-drug interactions with acid-suppressive agents.

Rationale and design of the AXIOMATIC-SSP phase II trial: Antithrombotic treatment with factor XIa inhibition to Optimize Management of Acute Thromboembolic events for Secondary Stroke Prevention

BackgroundIndividuals with ischemic stroke or transient ischemic attack (TIA) have a high early risk of ischemic stroke despite dual antiplatelet therapy. The risk of ischemic stroke, and associated disability, represents a significant unmet clinical need. Genetic variants resulting in reduced factor XI levels are associated with reduced risk for ischemic stroke but are not associated with increased intracranial bleeding. Milvexian is an oral small-molecule inhibitor of FXIa that binds activated factor XI with high affinity and selectivity and may reduce the risk of stroke when added to antiplatelet drugs without significant bleeding. We aimed to evaluate the dose-response relationship of milvexian in participants treated with dual antiplatelets. MethodsWe began a phase II, double-blinded, randomized, placebo-controlled trial at 367 sites in 2019. Participants (N = 2366) with ischemic stroke (National Institutes of Health Stroke Scale score ≤7) or high-risk TIA (ABCD2 score ≥6) were randomized to 1 of 5 doses of milvexian or placebo for 90 days. Participants also received clopidogrel 75 mg daily for the first 21 days and aspirin 100 mg for 90 days. The efficacy endpoint was the composite of ischemic stroke or incident infarct on magnetic resonance imaging. Major bleeding, defined as type 3 or 5 bleeding according to the Bleeding Academic Research Consortium, was the safety endpoint. Participant follow-up will end in 2022. ConclusionThe AXIOMATIC-SSP trial will evaluate the dose-response of milvexian for ischemic stroke occurrence in participants with ischemic stroke or TIA.

Pimitespib: First Approval.

Pimitespib (Jeselhy®) is an oral small molecule inhibitor of the α and β isoforms of heat shock protein 90 (HSP90). HSP90α and HSP90β regulate the stability and activity of a number of proteins that are crucial for tumour development. Pimitespib is being developed by Taiho Pharmaceutical for the treatment of solid tumours, including gastrointestinal stromal tumour (GIST), and in June 2022 it received its first approval in Japan for GIST that has progressed after chemotherapy. Pimitespib is undergoing phase I development for the treatment of solid tumours in the EU and the USA. This article summarizes the milestones in the development of pimitespib leading to this first approval for GIST that has progressed after chemotherapy.