Abstract Background: Advanced angiosarcoma is a rare and aggressive sarcoma which is most often fatal, with a median progression free survival of 4-6 months on standard therapy. Therefore, innovative treatment regimens are urgently needed. Methods: Endpoints: Primary: Progression Free Survival; Secondary: Best overall response; Overall Survival; Incidence and severity of adverse events. Eligibility: > 18 years, confirmed diagnosis of advanced angiosarcoma, acceptable hematologic and organ function. Treatment Schedule: Gemcitabine (600 mg/m2; max:1000 mg), doxorubicin (18 mg/m2; max: 32 mg), docetaxel (25 mg/m2; max:42 mg) on Days 1 and 8, and nivolumab (240 mg) on Day 1 of a 3-week cycle. Results: Median prior regimens = 1 (range 0-9). Efficacy: 7 of 9 patients who completed at least 2 treatment cycles and follow-up imaging (modified ITT population) were evaluated for: Median PFS: 9.4 months (95% CI: 8.224 to 9.441; 7 events, 0 censored); Best response: Confirmed 1 CR, 3 PR, 3 SD; ORR = 57%; DCR = 100%. Nine patients who received at least one dose of each chemotherapy agent (ITT population) were evaluated for: Median OS: 28.4 months (95% CI: 0.724 to 31.217; 5 events, 4 censored). Safety: 8 of 9 (89%) patients experienced a ≥ Grade 3 TRAE: leukopenia (n=6), thrombocytopenia (n=4), neutropenia (n=5), anemia (n=2), lymphopenia (n=2), fatigue (n=1), dec. LVEF (n=1), periorbital edema (n=1), limb edema (n=1) and worsening hypothyroidism (n=1). There were no Grade 5 nor unexpected adverse events. Conclusion: This metronomic chemo/immunotherapy regimen may be a synergistic and effective therapy for advanced angiosarcoma with manageable toxicity. Citation Format: Samantha Jeffrey, Piya Mann, Oliver Davidorf, Anmol Dia Agarwal, Sarah Lande, Mihir Chawla, Neal Chawla, Ania Moradkhani, Ted Kim, Victoria Chua-Alcala, Sant Chawla, Erlinda Gordon. A Phase II chemo/immunotherapy study using metronomic gemcitabine, doxorubicin, docetaxel and nivolumab for advanced angiosarcoma (NCT04535713): An interim analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT256.
In the phase III placebo-controlled DeFi trial (ClinicalTrials.gov identifier: NCT03785964) primary analysis, nirogacestat showed significant improvement versus placebo in progression-free survival (PFS), objective response rate (ORR), and patient-reported outcomes (PRO) in adult patients with progressing desmoid tumors (DT; median [range] exposure: 20.6 [0.3-33.6] months). Here, long-term nirogacestat efficacy and safety were evaluated in patients randomly assigned to nirogacestat and followed through the final data cutoff date of December 19, 2024. End points included PFS and ORR per RECIST v1.1, PRO, and safety. The median (range) duration of exposure was 33.6 (0.3-61.8) months. Median PFS was not reached. The ORR with up to 4 years of nirogacestat treatment was 45.7% (32 of 70), with three additional partial and three additional complete responses since the primary analysis. Further target tumor size reduction occurred in most patients. Benefits in PROs were sustained while on treatment. Frequently reported treatment-emergent adverse events (TEAEs) decreased in incidence and severity over time. Since the primary analysis, four patients discontinued nirogacestat because of TEAEs between years 2 and 4. In conclusion, long-term continuous nirogacestat treatment was associated with further tumor size reductions, durable objective responses, sustained PRO benefits, and a manageable safety profile consistent with the primary analysis.
PURPOSE:Achieving precise drug activation without associated toxicities is a significant challenge in developing cancer therapeutics. Click Activated Protodrugs Against Cancer is a pretargeting approach that uses bioorthogonal click chemistry in vivo to selectively capture and activate drugs at tumors and can be applied to a wide variety of targeted therapeutics. The first-in-class Click Activated Protodrugs Against Cancer-based cancer therapeutic SQ3370 uses a clickable pretargeting agent that reacts with a chemically attenuated clickable payload of doxorubicin (Dox) and releases the active cytotoxic drug in situ. PATIENTS AND METHODS:We describe the preclinical development and translation of SQ3370 to a first-in-human dose-escalation clinical trial in adult patients with advanced solid tumors (NCT04106492). RESULTS:SQ3370 inhibited tumor progression across several mouse tumor models through the safe and selective release of Dox in tumors at concentrations unachievable by conventional treatment. SQ3370 exhibited safety when administered at 8.9 times the veterinary Dox dose in dogs and 15 times the conventional Dox dose in patients, with no reported protocol-defined dose-limiting toxicities. In patients, SQ3370 modulated active Dox pharmacokinetics and enabled T-cell-dependent immune responses, including cytotoxic CD8+ T-cell expansion and activation in tumors and systemically. CONCLUSIONS:SQ3370, the first demonstration of click chemistry within the human body in a clinical setting, facilitated the delivery of chemotherapy to tumors and unlocked additional biological effects such as favorable immune responses that may benefit patients with metastasis. Consistent safety, toxicology, pharmacokinetic, and immune activation results observed across species highlight the translatability of the technology and position click chemistry as a powerful new modality for the development of targeted cancer therapeutics.
TPS4217 Background: IL-27 is a heterodimerized cytokine, a member of the IL-12/IL-23 cytokine family, and an immunoregulatory cytokine expressed by myeloid cells that dampens T and NK effector function. IL-27 is highly expressed by tumor-associated macrophages in several cancers, including hepatocellular carcinoma (HCC) and non-small cell lung cancer (NSCLC), and suppresses antitumor immune responses. Casdozokitug (Casdozo) is the only clinical-stage IL-27 targeting antibody and it increases IFN-g and T and NK cell activation in preclinical/clinical studies. A phase 1 study (NCT04374877) demonstrated a favorable safety profile and antitumor activity of casdozo as monotherapy and in combination with PD-1 blockade in indications, including HCC, with known high levels of IL-27 activation signature (Marron T, et al. Ann Oncol . 2023). A phase 3 study of toripalimab (tori) + bevacizumab (bev) demonstrated significant improvements in efficacy (overall survival [OS], progression-free survival [PFS], and objective response rate [ORR]) compared to sorafenib (Yinghong S, et al. CSCO 2024) in HCC. A phase 2 study of casdozo + atezolizumab + bev showed an acceptable safety profile and antitumor activity (ORR 38%, CR 17.2%, mPFS 8.1 mo) (Li D, et al. ASCO GI 2025). CHS-388-202 (NCT06679985) will evaluate the efficacy, safety, and biomarkers of tori + bev ± casdozo and optimize the dose for casdozo in combination with tori + bev as first-line treatment for patients (pts) with unresectable and/or locally advanced/metastatic HCC. Methods: CHS-388-202 is a Phase 2, open-label, randomized study and will enroll up to 72 pts randomized (1:1:1) to 1 of 3 treatment arms (IV Q3W): Arm A (tori 240 mg + bev 15 mg/kg + casdozo 700 mg), Arm B (tori 240 mg + bev 15 mg/kg + casdozo 1400 mg), Arm C (tori 240 mg + bev 15 mg/kg). Key eligibility criteria include treatment-naïve unresectable metastatic HCC with ≥1 measurable lesion; not suitable for surgical or local therapy; Child-Pugh A; ECOG PS 0 or 1; controlled hepatitis B virus or cured hepatitis C virus. Pts will be stratified by geographic region (Asia excluding Japan vs the rest of the world) and macrovascular invasion or extrahepatic spread of disease (presence vs absence). Primary endpoints are ORR by investigator review according to RECIST v1.1 and safety. Secondary endpoints are ORR by investigator review according to HCC modified RECIST (mRECIST) criteria; duration of response, PFS, and disease control rate by investigator review according to RECIST v1.1 and mRECIST criteria; OS, pharmacokinetics. A safety run-in evaluation will be conducted after the first ~6 pts are enrolled in Arms A and B, with ≥3 from each arm completing 1 cycle of treatment. Pts will remain on study treatment for ≤2 years or until documented disease progression or unacceptable toxicity. Enrollment is ongoing. Clinical trial information: NCT06679985 .
2013 Background: Isocitrate dehydrogenase (IDH) 1 or IDH2 mutations or co-mutations have been associated with various tumors, including glioma. HMPL-306 (’306) is a novel, small-molecule, orally available, highly selective, and potent dual inhibitor of both mIDH1 and mIDH2. This is a phase 1 study of ’306 in pts with locally advanced or metastatic solid tumors with mIDH. Here, we report the results of the dose escalation stage. Methods: Pts with locally advanced or metastatic solid tumors with any mIDH were enrolled to receive ’306 once daily (QD) for 28-day cycles. The mTPI-2 design was used for dose escalation, having explored in 8 successive cohorts (50-400 mg). The study aims to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), evaluate safety, tolerability, preliminary efficacy and pharmacokinetics/ pharmacodynamics (PK/PD). Results: As of Aug 9, 2024, 42 pts were administered ’306 across 8 doses (n = 3, 3, 5, 12, 6, 4, 4, 5 in 50, 100, 150, 200, 250, 300, 350, 400 mg QD cohorts, respectively), with 17 (40.5%) lower-grade glioma (LGG, grade 2 and grade 3 glioma) pts, 3 (7.1%) grade 4 glioma pts and 22 (52.4%) non glioma pts. The median age was 55 years, and 25 (59.5%) pts were male. During the dose escalation from 50 mg to 400 mg QD cohort, 1 pt given 250 mg QD experienced a dose-limiting toxicity (DLT) of grade 3 lipase increased. MTD was not reached. 12 (28.6%) pts reported grade ≥3 adverse events (AEs), which reported in ≥ 2 pts was abdominal pain. Efficacy signals were observed especially in LGG pts, in the efficacy evaluated set (N = 14), objective response rate (ORR) was 7.1%, disease control rate was 100%; in the safety analysis set (N = 17), median progression-free survival (PFS) was 20.5 months (95% confidence interval [CI]; 5.5-not estimable). One grade 2 glioma pt with multiple previous treatment on the 200 mg QD achieved minor response lasting 16.8 months. The ORR of grade 4 glioma pts and non glioma pts were not reached, the disease control rate were 33.3% and 25%, respectively. Drug exposures were dose-proportional from 50 mg to 400 mg. Steady-state with ~5-fold accumulation was reached after ~28 days of repeated daily dosing. In non-glioma pts, 2-HG inhibition plateaued after ~28 days, increasing with dose, reaching ~90% at ≥150 mg at C2D1. Conclusions: ’306 was well-tolerated in pts with mIDH1/2 solid tumors, showing target inhibition and durable responses in LGG. Clinical trial information: NCT04762602 .
