JAKaL: Phase Ib study of itacitinib, a selective JAK1 inhibitor, for the management of advanced stage hepatocellular cancer after failure of first line therapy.
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE283218 | GEO | 2025/01/01
REPOSITORIES: GEO
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Project description:Immune checkpoint inhibitor (ICI) resistance in advanced hepatocellular carcinoma (HCC)poses a major therapeutic challenge. Here, we report a phase 2 trial evaluating stereotactic bodyradiotherapy (SBRT) combined with the anti-PD-1 antibody sintilimab and bevacizumabbiosimilar (lBI305) to re-sensitize ICI-refractory HCC. Twenty-one patients with progressiveHCC after prior ICI therapy received SBRT (25-50 Gy in 5 fractions) followed by sintilimab(200 mg) and IBl305 (15 mgkg) every 3 weeks. The primary endpoint, objective response rate(ORR) in non-irradiated lesions, was 33.3% (7/21), with a disease control rate of66.7%(14/21)Median progression-free survival (PFS) was 6.2 months (95% CI 3.7-15.1), and estimatedmedian overall survival (OS) was 24.4 months (95% CI 9.2-NA). SBRT achieved 100% localcontrol, while grade >3 treatment-related adverse events occurred in 33.3% of patientsLongitudinal proteomic profiling revealed that responders exhibited lower baseline IFN-y (p0.025) and elevated IL-6 (p=0.002), with post-SBRT increases in IFN-y, IL-2, and IL-6correlating with improved outcomes. These findings demonstrate that SBRT synergizes withdual PD-1/VEGF blockade to overcome ICI resistance, potentially through radiation-inducedimmune remodeling. Biomarker dynamics highlight actionable targets for optimizingcombination therapies in anti-PD-1-refractory HCC.
2025-10-15 | PAD000004 | Pride
Project description:While patients with microsatellite instable, metastatic colorectal cancer (CRC) benefit from immune checkpoint blockade, chemotherapy with targeted therapies remains the only therapeutic option for microsatellite stable (MSS) tumors. The single arm, phase IB/II MEDITREME trial evaluates safety and efficacy of durvalumab plus tremelimumab in combination with mFOLFOX6 chemotherapy in first line, in 57 patients with RAS-mutant unresectable mCRC. Safety was primary objective of phase IB and no safety issue was observed. The primary objective of phase II was efficacy in terms of 3-month PFS in MSS patients, which was met with a 3 month PFS of 90.7% [95% CI: 79.2-96%]. For secondary objective, response rate was 64.5%, median PFS was 8.2 months [95% CI: 5.9–8.6] and overall survival was not reached in MSS patients. Higher tumor mutational burden and a lower degree of genomic instability in responder patients. Integrated transcriptomic analysis underlined that high immune signature, and low epithelio-mesenchymal transition were associated with better outcome. Immunomonitoring showed induction of neoantigen and NY-ESO1 and TERT blood tumor specific T cell response associated with better PFS. The combination of durvalumab-tremelimumab with mFOLFOX6 was tolerable with promising clinical activity in MSS mCRC.
2023-07-05 | GSE235919 | GEO
Project description:While patients with microsatellite instable, metastatic colorectal cancer (CRC) benefit from immune checkpoint blockade, chemotherapy with targeted therapies remains the only therapeutic option for microsatellite stable (MSS) tumors. The single arm, phase IB/II MEDITREME trial evaluates safety and efficacy of durvalumab plus tremelimumab in combination with mFOLFOX6 chemotherapy in first line, in 57 patients with RAS-mutant unresectable mCRC. Safety was primary objective of phase IB and no safety issue was observed. The primary objective of phase II was efficacy in terms of 3-month PFS in MSS patients, which was met with a 3 month PFS of 90.7% [95% CI: 79.2-96%]. For secondary objective, response rate was 64.5%, median PFS was 8.2 months [95% CI: 5.9–8.6] and overall survival was not reached in MSS patients. Higher tumor mutational burden and a lower degree of genomic instability in responder patients. Integrated transcriptomic analysis underlined that high immune signature, and low epithelio-mesenchymal transition were associated with better outcome. Immunomonitoring showed induction of neoantigen and NY-ESO1 and TERT blood tumor specific T cell response associated with better PFS. The combination of durvalumab-tremelimumab with mFOLFOX6 was tolerable with promising clinical activity in MSS mCRC.
2023-07-05 | GSE235917 | GEO
Project description:Importance: Autophagy has been identified as a resistance mechanism to BRAF and MEK inhibition in BRAF mutant melanoma. In the BAMM trial, hydroxychloroquine (HCQ) was used to inhibit autophagy in combination with dabrafenib and trametenib in BRAF mutant melanoma patients. Objective: To a) determine safety and maximal tolerated dose (MTD) of hydroxychloroquine when combined with dabrafenib and trametinib and b) determine antitumor activity of the combination. Design: Open label non-randomized phase I/II clinical trial Setting: Prospective therapeutic clinical trial conducted in 4 centers Participants: Unresectable Stage III or Stage IV BRAF mutant melanoma patients Intrevention: HCQ twice daily, dabrafenib 150 mg twice daily and trametinib 2 mg daily (D+T) Main Outcome: Primary outcomes were safety and 1-year progression-free survival (PFS) rate Results: Between December 2014 and January 2020, 50 patients were screened, 38 patients were enrolled and evaluable for toxicity and 34 patients were evaluable for 1-year PFS rate. Patient demographics were: 29% were ECOG PS 1, 47% had elevated LDH, 52% were Stage IV M1c or M1d and 53% had previously received therapy for advanced melanoma. In the phase I trial there was no dose limiting toxicity of HCQ at either 400 (n=3) or 600 (MTD) mg po bid combined with D+T. For the entire study population, the 1-year PFS rate was 41% (95% CI = ), median PFS was 11.9 months (95% CI = ), overall response rate (ORR) was 85% (95% exact CI=64-95%)and complete response rate of 41% (95% exact CI=25-59%). In a prespecificed subgroup analysis in 18 patients with elevated LDH, the ORR was 88% and median PFS was 8 months Conlusion and Relevance: The combination of HCQ, dabrafenib and trametinib was well tolerated and produced a high response rate but did not meet the prespecified criteria for success with respect to the 1-year PFS rate. In patients with elevated LDH , the response rate and PFS were encouraging. A randomized placebo controlled trial of dabrafenib and trametinib with/without HCQ in advanced BRAF mutant melanoma patients with elevated LDH and previously treated with immunotherapy is being conducted through the National Clinical Trial Network.
2022-01-07 | GSE193157 | GEO
Project description:Inhibition of the B-cell receptor pathway, and specifically of Bruton tyrosine kinase (BTK), is a leading therapeutic strategy in chronic lymphocytic leukemia (CLL). Target occupancy has been measured as a pharmacodynamic parameter in clinical studies of covalent BTK inhibitors. However, the kinetics of BTK turnover, which determines occupancy, and the relationship between occupancy, pathway inhibition and clinical outcomes remains undefined. This randomized phase 2 study investigated the safety, efficacy, and pharmacodynamics of a selective BTK inhibitor acalabrutinib at 100 mg twice daily or 200 mg once daily in 48 patients with relapsed/refractory or high-risk treatment naïve CLL. Acalabrutinib was well tolerated and yielded an overall response rate (ORR) of partial response or better of 95.8% (95% CI 78.9%, 99.9%) and an estimated progression-free survival (PFS) rate at 24 months of 91.5% (95% CI 70.0%, 97.8%) with twice daily dosing and an ORR of 79.2% (95% CI 57.9%, 92.9%) and an estimated PFS rate at 24 months of 87.2% (95% CI 57.2%, 96.7%) with once daily dosing. BTK resynthesis was faster in CLL than in healthy volunteers. Twice daily dosing maintained higher BTK occupancy and achieved more potent pathway inhibition compared to once daily dosing. Additional follow-up is required to address the impact of dosing schedule and BTK occupancy on long-term clinical outcomes.
2020-04-07 | GSE136634 | GEO
Project description:CAMILLA is a basket trial (NCT03539822) evaluating cabozantinib plus the ICI durvalumab in chemorefractory gastrointestinal cancer. Herein, are the phase II colorectal cohort results. 29 patients were evaluable. 100% had confirmed pMMR/MSS tumors. Primary endpoint was met with ORR of 27.6% (95% CI 12.7-47.2%). Secondary endpoints of 4-month PFS rate was 44.83% (95% CI 26.5-64.3%); and median OS was 9.1 months (95% CI 5.8-20.2). Grade≥3 TRAE occurred in 39%. In post-hoc analysis of patients with RAS wild type tumors, ORR was 50% and median PFS and OS were 6.3 and 21.5 months respectively. Exploratory spatial transcriptomic profiling of pretreatment tumors showed upregulation of VEGF and MET signaling, increased extracellular matrix activity and pre-existing anti-tumor immune responses coexisting with immune suppressive features like T cell migration barriers in responders versus non-responders. Cabozantinib plus durvalumab demonstrated anti-tumor activity, manageable toxicity, and have led to the activation of the phase III STELLAR-303 trial.
2024-01-27 | GSE254054 | GEO
Project description:Metastatic pancreatic cancer (mPC) has a dismal prognosis, with first line systemic therapy relying primarily on FOLFIRINOX (5FU/irinotecan/oxaliplatin) or AG (Gemcitabine/Nab-Paclitaxel). Therapeutic options for mPC refractory to these regimens remain poorly-defined, and data on later lines options are scare. This prospective, single-arm study (NCT05481463) evaluated the safety and preliminary efficacy of combining the anti-angiogenic agent surufatinib with the cytotoxic drug TAS-102 (Trifluridine/Tipiracil) in mPC patients who had progressed on ≥ 2 prior lines of therapy. Primary and secondary endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Among 20 patients analyzed for efficacy, median PFS was 2.35 months (95% CI: 1.91-3.94) and median OS was 6.34 months (95% CI: 3.81-10.09). The ORR and DCR were 20% (4/20; all partial response) and 30% (6/20), respectively. All patients experienced treatment emergent adverse events (TEAEs), with anemia (59.1%), neutropenia (54.6%), leukopenia (50.0%), and lymphopenia (45.5%) as the most common any-grade events. Grade ≥3 TEAEs including neutropenia (31.8%), lymphopenia (13.6%), and anemia (9.1%), were observed in 50.0% (11/22) of patients. Subgroup analysis identified metastases involving > 2 organs or hepatic sites as potential predicative biomarkers for inferior efficacy. Proteomic screening revealed that overexpressed OCIAD2 correlated with poor prognosis, a finding validated in two publicly available external cohorts (CPTAC database and RuiJin cohort). In conclusion, combination of TAS-102 and surufatinib demonstrates clinically meaningful efficacy and manageable toxicity as a later line therapeutic option for refractory mPC. The biomarkers identified in this study may hold the potential to guide patient stratification and warrant further investigation to optimize precision application of this regimen.
2025-10-02 | PXD064308 | Pride
Project description:Purpose: This phase II study evaluated the efficacy and tolerability of onvansertib, a polo-like kinase 1 (PLK1) inhibitor, combined with FOLFIRI + bevacizumab for the second-line treatment of KRAS-mutant metastatic colorectal cancer (mCRC). Patients and Methods: This multicenter, open-label, single-arm study enrolled KRAS-mutated mCRC patients previously treated with oxaliplatin and 5-fluorouracil with or without bevacizumab. Patients received onvansertib 15 mg/m2 (days 1-5 and 15-19 of a 28-day cycle) and FOLFIRI + bevacizumab (days 1 and 15). The primary endpoint was the objective response rate (ORR), and secondary endpoints included progression-free survival (PFS), duration of response (DOR), and tolerability. Translational and preclinical studies were conducted in KRAS-mutant CRC. Results: Among the 53 patients treated, the confirmed ORR was 26.4% (95% CI, 15.3 to 40.3). The median DOR was 11.7 months (95% CI, 9.4 to not reached). Grade 3/4 adverse events were reported in 62% of patients. A post hoc analysis revealed that patients with no prior bevacizumab treatment had a significantly higher ORR and longer PFS compared to patients with prior bevacizumab treatment: ORR of 76.9% versus 10.0% (odds ratio of 30.0, p<0.001) and median PFS of 14.9 months versus 6.6 months (hazard ratio of 0.16, p<0.001). Our translational findings support that prior bevacizumab exposure contributes to onvansertib resistance. Preclinically, we showed that onvansertib inhibited the hypoxia pathway and exhibited robust antitumor activity in combination with bevacizumab through the inhibition of angiogenesis. Conclusion: Onvansertib combined with FOLFIRI + bevacizumab showed significant activity in the second-line treatment of KRAS-mutant mCRC patients, particularly in patients with no prior bevacizumab treatment. These findings led to the evaluation of the combination in the first line setting (ClinicalTrails.gov identifier: NCT06106308).
2025-11-25 | GSE273769 | GEO
Project description:There are many treatment options available for men with metastatic castration-resistant prostate cancer (mCRPC). Yet, biomarkers predictive of differential response to treatment are currently available. A recent translational study suggested that SLCO2B1 genotype could predict response to abiraterone acetate (AA) for men with advanced prostate cancer. Here, we investigate whether germline variants in SLCO2B1 are predictive of response to first-line AA in men with new mCRPC. Clinical data and samples were analyzed from a prospective prostate cancer registry at the University of Utah. Genotyping was performed using the Illumina OmniExpress genotyping platform. Primary endpoint was progression-free survival (PFS) on first-line AA in men with mCRPC. We performed a pre-specified multivariate Cox regression analysis to assess the independent predictive value of rs12422149 and rs1789693 on PFS on AA. Of 401 men with advanced prostate cancer genotyped, 323 were homozygous wild type for rs12422149 (80.5%), 74 were heterozygous (18.5%), and 4 were homozygous variant (1.0%). In a multivariate analysis of 79 men treated with first-line AA for mCRPC, men heterozygous for rs12422149 had significantly improved median PFS compared to the homozygous wild-type group (8.9 months vs. 6.3 months, HR 0.46, 95% CI 0.23-0.94, p=0.03). No significant difference in median PFS was seen by rs1789693 genotype. In this first clinical validation of translational data reported by Mostaghel and colleagues, germline variant alleles in rs12422149 of SLCO2B1 are common and predict improved response to first-line AA In men with mCRPC.
2018-12-13 | GSE123695 | GEO
Project description:Immune checkpoint inhibitors (ICIs) targeting PD-1/L1 have modest efficacy in hepatocellular carcinoma (HCC) as single agents, but combination regimens have demonstrated increased clinical benefit at the expense of treatment toxicities. Exposed phosphatidylserine suppresses the innate immune response in the tumor microenvironment (TME). Targeting phosphatidylserine does not induce tumor responses in the clinical setting when used as monotherapy or in combination with cytotoxic and targeted therapies, but may induce pro-inflammatory and –immune stimulating effects that enhance ICI activity. This hypothesis was tested in a single-arm phase 2 trial evaluating bavituximab, a phosphatidylserine targeting antibody, plus pembrolizumab in patients with unresectable HCC who had not received prior systemic treatments (ClinicalTrials.gov ID: NCT03519997). The primary end point was investigator-assessed objective response rate (ORR) among evaluable patients, and secondary end points included progression-free survival (PFS) and the incidence of adverse events. Among 28 evaluable patients, the ORR was 32.1%, including 2 complete responses, and a disease control rate of 64.3%. Median PFS was 6.3 months (95% CI, 1.3-11.3 months). Treatment related adverse events of any grade occurred in 45.7% of patients with grade 3 or 4 adverse events occurring in 14.3% of patients. Exploratory analyses of baseline tumor specimens showed that a depletion of B cells, and the expression of smooth muscle actin and immune checkpoints in stroma was associated with tumor response. An RNA-based TME assay which distinguishes immune-rich of inflammatory tumors was also shown to be predictive of ORR. These results suggest that targeting phosphatidylserine may lead to synergistic effects with ICIs without increasing toxicity rates, and future studies on this therapeutic strategy may be guided by biomarkers characterizing the TME.
2024-02-08 | GSE242154 | GEO