^
    5ms
    XL888 + Vemurafenib + Cobimetinib for Unresectable BRAF Mutated Stage III/IV Melanoma (clinicaltrials.gov)
    P1, N=26, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute
    Trial completion date
    |
    BRAF (B-raf proto-oncogene)
    |
    BRAF mutation • BRAF V600
    |
    Zelboraf (vemurafenib) • Cotellic (cobimetinib) • XL888
    5ms
    Pembrolizumab and XL888 in Patients With Advanced Gastrointestinal Cancer (clinicaltrials.gov)
    P1, N=49, Completed, Emory University | Active, not recruiting --> Completed
    Trial completion
    |
    Keytruda (pembrolizumab) • XL888
    8ms
    Combined BRAF, MEK, and heat-shock protein 90 (HSP90) inhibition in advanced BRAF V600-mutant melanoma. (PubMed, Cancer)
    Combined vemurafenib and cobimetinib plus XL888 had significant toxicity, requiring frequent dose reductions, which may have contributed to the relatively low progression-free survival despite a high tumor response rate. Given overlapping toxicities, caution must be used when combining HSP90 inhibitors with BRAF and MEK inhibitors.
    Journal • Metastases
    |
    BRAF (B-raf proto-oncogene) • CD8 (cluster of differentiation 8) • CD4 (CD4 Molecule) • HSP90AA1 (Heat Shock Protein 90 Alpha Family Class A Member 1Heat Shock Protein 90 Alpha Family Class A Member 1)
    |
    BRAF mutation • BRAF V600 • CD8 positive • CD4 positive
    |
    Zelboraf (vemurafenib) • Cotellic (cobimetinib) • XL888
    over1year
    Study of XL888 With Vemurafenib for Patients With Unresectable BRAF Mutated Stage III/IV Melanoma (clinicaltrials.gov)
    P1, N=21, Completed, H. Lee Moffitt Cancer Center and Research Institute | Active, not recruiting --> Completed
    Trial completion
    |
    BRAF (B-raf proto-oncogene)
    |
    BRAF mutation • BRAF V600
    |
    Zelboraf (vemurafenib) • XL888
    over1year
    Study of XL888 With Vemurafenib for Patients With Unresectable BRAF Mutated Stage III/IV Melanoma (clinicaltrials.gov)
    P1, N=21, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Dec 2022 --> Dec 2023
    Trial completion date
    |
    BRAF (B-raf proto-oncogene)
    |
    BRAF mutation • BRAF V600
    |
    Zelboraf (vemurafenib) • XL888
    over1year
    XL888 + Vemurafenib + Cobimetinib for Unresectable BRAF Mutated Stage III/IV Melanoma (clinicaltrials.gov)
    P1, N=26, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Oct 2022 --> Oct 2023
    Trial completion date
    |
    BRAF (B-raf proto-oncogene)
    |
    BRAF mutation • BRAF V600
    |
    Zelboraf (vemurafenib) • Cotellic (cobimetinib) • XL888
    almost2years
    Study of XL888 With Vemurafenib for Patients With Unresectable BRAF Mutated Stage III/IV Melanoma (clinicaltrials.gov)
    P1, N=21, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Jul 2022 --> Dec 2022
    Trial completion date
    |
    BRAF (B-raf proto-oncogene)
    |
    BRAF mutation • BRAF V600
    |
    Zelboraf (vemurafenib) • XL888
    2years
    XL888 + Vemurafenib + Cobimetinib for Unresectable BRAF Mutated Stage III/IV Melanoma (clinicaltrials.gov)
    P1, N=26, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Apr 2022 --> Oct 2022
    Trial completion date
    |
    BRAF (B-raf proto-oncogene)
    |
    BRAF mutation • BRAF V600
    |
    Zelboraf (vemurafenib) • Cotellic (cobimetinib) • XL888
    over2years
    XL888 + Vemurafenib + Cobimetinib for Unresectable BRAF Mutated Stage III/IV Melanoma (clinicaltrials.gov)
    P1, N=26, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Dec 2021 --> Apr 2022
    Clinical • Trial completion date
    |
    BRAF (B-raf proto-oncogene)
    |
    BRAF mutation • BRAF V600
    |
    Zelboraf (vemurafenib) • Cotellic (cobimetinib) • XL888
    over2years
    Correlative analysis of blood and biopsy samples from a clinical trial of Hsp90 inhibition in combination with pembrolizumab reveals increased intratumoral myeloid cell accumulation after treatment (SITC 2021)
    Methods Based on these data, we are conducting a Phase Ib/II clinical trial to evaluate the combination of XL888 (Hsp90 inhibitor) and pembrolizumab in patients with metastatic pancreatic cancer. As clinical data matures, changes in soluble and cellular biomarkers will be correlated with response to elucidate mechanisms of response or resistance to this combination therapy. Trial Registration This clinical trial is underway and registered with the ID NCT03095781
    Clinical • Combination therapy • PD(L)-1 Biomarker • IO biomarker
    |
    HSP90AA1 (Heat Shock Protein 90 Alpha Family Class A Member 1Heat Shock Protein 90 Alpha Family Class A Member 1)
    |
    Keytruda (pembrolizumab) • XL888
    over2years
    Study of XL888 With Vemurafenib for Patients With Unresectable BRAF Mutated Stage III/IV Melanoma (clinicaltrials.gov)
    P1, N=21, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Jul 2021 --> Jul 2022
    Clinical • Trial completion date
    |
    BRAF (B-raf proto-oncogene)
    |
    BRAF mutation • BRAF V600
    |
    Zelboraf (vemurafenib) • XL888
    almost3years
    The HSP90 inhibitor, XL888, enhanced cell apoptosis via downregulating STAT3 after insufficient radiofrequency ablation in hepatocellular carcinoma. (PubMed, Life Sci)
    We implied that XL888 promoted apoptosis of HCC cells induced by heat via disrupting the binding of HSP90 and STAT3, providing theoretical basis for a novel combination strategy for HCC.
    Journal
    |
    MCL1 (Myeloid cell leukemia 1) • STAT3 (Signal Transducer And Activator Of Transcription 3) • CASP3 (Caspase 3) • HSP90AA1 (Heat Shock Protein 90 Alpha Family Class A Member 1Heat Shock Protein 90 Alpha Family Class A Member 1)
    |
    MCL1 expression
    |
    XL888
    over3years
    Study of XL888 With Vemurafenib for Patients With Unresectable BRAF Mutated Stage III/IV Melanoma (clinicaltrials.gov)
    P1, N=21, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Dec 2020 --> Jul 2021
    Clinical • Trial completion date
    |
    BRAF (B-raf proto-oncogene)
    |
    BRAF mutation • BRAF V600
    |
    Zelboraf (vemurafenib) • XL888
    over3years
    Heat shock protein-90 inhibition alters activation of pancreatic stellate cells and enhances the efficacy of PD-1 blockade in pancreatic cancer. (PubMed, Mol Cancer Ther)
    Tumors from mice treated with both XL888 and anti-PD-1 had a significantly increased CD8+ and CD4+ T cell infiltrate and a unique transcriptional profile characterized by upregulation of genes associated with immune response and chemotaxis. These data demonstrate that Hsp90 inhibition directly impacts PSC/CAF in vitro and enhances the efficacy of anti-PD-1 blockade in vivo.
    Clinical • Journal • PD(L)-1 Biomarker
    |
    CD8 (cluster of differentiation 8) • IL6 (Interleukin 6)
    |
    XL888
    almost4years
    Study of XL888 With Vemurafenib for Patients With Unresectable BRAF Mutated Stage III/IV Melanoma (clinicaltrials.gov)
    P1, N=21, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Apr 2020 --> Dec 2020
    Clinical • Trial completion date
    |
    BRAF (B-raf proto-oncogene)
    |
    BRAF mutation • BRAF V600
    |
    Zelboraf (vemurafenib) • XL888
    4years
    [VIRTUAL] Anti-tumor effect and HIF1α inhibition by combining CDK4 inhibitor with HSP90 inhibitor in various cancer types including Rb-deficient tumor cells (AACR-II 2020)
    Using the FDA-approved CDK4/6 inhibitors (palbociclib & abemaciclib), we observed that dual inhibition of CDK4 and HSP90 synergistically inhibits cancer viability in colorectal cancer cell lines (eg. HCT116, SW480, DLD1) under both normoxia and hypoxia. Multiple HSP90 inhibitors have been tested, including ganetespib, onalespib, XL888 and TAS116, which indicates such combinational inhibition as a class effect...Hypoxia sensitizes the Rb-deficient MDA-MB-468 breast cancer cell line to abemaciclib treatment. Our findings suggest a therapeutic potential for utilizing the combination of CDK4 and HSP90 inhibitors in cancer treatment.
    PARP Biomarker
    |
    CDK4 (Cyclin-dependent kinase 4) • HIF1A (Hypoxia inducible factor 1, alpha subunit) • CDK1 (Cyclin-dependent kinase 1)
    |
    HIF1A expression
    |
    Ibrance (palbociclib) • Verzenio (abemaciclib) • ganetespib (ADX-1612) • Jeselhy (pimitespib) • onalespib (AT13387) • XL888
    4years
    XL888 + Vemurafenib + Cobimetinib for Unresectable BRAF Mutated Stage III/IV Melanoma (clinicaltrials.gov)
    P1, N=26, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial primary completion date: Feb 2020 --> Oct 2019
    Clinical • Trial primary completion date
    |
    BRAF (B-raf proto-oncogene)
    |
    BRAF mutation • BRAF V600
    |
    Zelboraf (vemurafenib) • Cotellic (cobimetinib) • XL888
    over4years
    Study of XL888 With Vemurafenib for Patients With Unresectable BRAF Mutated Stage III/IV Melanoma (clinicaltrials.gov)
    P1, N=21, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Dec 2019 --> Apr 2020
    Clinical • Trial completion date
    |
    BRAF (B-raf proto-oncogene)
    |
    BRAF mutation • BRAF V600
    |
    Zelboraf (vemurafenib) • XL888