XL888 / Exelixis, Merck (MSD) - LARVOL DELTA

XL888 + Vemurafenib + Cobimetinib for Unresectable BRAF Mutated Stage III/IV Melanoma (clinicaltrials.gov) - P1 | N=26 | Active, not recruiting | Sponsor: H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Mar 2025 ➔ Nov 2025

Trial completion date • Genetic Disorders • Melanoma • Oncology • Skin Cancer • Solid Tumor • BRAF • CDC37

XL888 and pembrolizumab modulate the immune landscape of colorectal tumors in a phase Ib/II clinical trial. (PubMed, Oncoimmunology) - "These findings suggest local and systemic immune activation by the combination of pembrolizumab and XL888. While clinical activity was modest in treatment-refractory CRC patients, there were notable effects on the tumor immune environment and systemic immune modulation."

Journal • P1/2 data • Colorectal Cancer • Immune Modulation • Immunology • Oncology • Solid Tumor • CD68 • CDC37 • IL6

Molecular Dynamics of Adenomatous Polyposis Coli (APC) Protein and Its Inhibitors: A Special Insight to Colorectal Cancer. (PubMed, Crit Rev Oncog) - "A combinatorial computational approach identified the potential anti-cancerous drug among XL888, 5-bromouracil, 5-fluorouracil, and Ganetespib against APC which is often treated as gatekeeper of CRC. This in silico investigation revealed Ganetespib as a potential anti-cancerous drug against APC for CRC therapeutics, which will be an alternative to chemotherapy. In vitro and in vivo studies are needed further to confirm the efficiency and evaluate potency of Ganetespib against the target."

Journal • Review • Colon Cancer • Colorectal Cancer • Oncology • Solid Tumor • APC

XL888 + Vemurafenib + Cobimetinib for Unresectable BRAF Mutated Stage III/IV Melanoma (clinicaltrials.gov) - P1 | N=26 | Active, not recruiting | Sponsor: H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Dec 2024 ➔ Mar 2025

Trial completion date • Genetic Disorders • Melanoma • Oncology • Skin Cancer • Solid Tumor • BRAF • CDC37

Design, Synthesis, and Docking of Novel Tropane Hybrids as Potent Hsp90 Inhibitors with Potential Anti-Breast Cancer Activity. (PubMed, Curr Med Chem) - "We have succeeded in synthesizing novel tropane hybrids exhibiting significant anti-Hsp90 action, similar to XL888 analogues."

Journal • Breast Cancer • Oncology • Solid Tumor • CDC37

Senescent fibroblasts in the tumor stroma rewire lung cancer metabolism and plasticity. (PubMed, bioRxiv) - "Our ex vivo senolytic screening platform identified XL888, a HSP90 inhibitor, that cleared p16 Ink4a + cancer- associated fibroblasts in vivo . XL888 administration after establishment of advanced lung adenocarcinoma significantly reduced tumor burden concurrent with the loss of plastic tumor cells. Our study identified a druggable component of the tumor stroma that fulfills the metabolic requirement of tumor cells to acquire a more aggressive phenotype."

Journal • Stroma • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CDC37 • CDKN2A • KRAS • TP53

Phase Ib study of pembrolizumab and XL888 in patients with advanced colorectal cancer (ESMO-GI 2024) - P1 | "The combination Pembro and XL888 had an acceptable safety profile but did not elicit responses in heavily treated advanced CRC pts. Correlative studies using paired biopsies and blood are ongoing to determine how dual HSP90/PD-1 blockade impacts stromal and immune biomarkers in relationship to the clinical outcome measures."

Clinical • IO biomarker • Metastases • P1 data • Anorexia • Back Pain • Colorectal Cancer • Constipation • Cough • Fatigue • Gastroenterology • Gastrointestinal Cancer • Gastrointestinal Disorder • Musculoskeletal Pain • Oncology • Pain • Respiratory Diseases • Solid Tumor • BRAF • CDC37 • HER-2 • HSP90AA1

A pipeline for senolytics. (PubMed, J Clin Invest) - "In this issue of the JCI, Lee et al. describe a pipeline for high-throughput drug screening of senolytic compounds where senescence was induced in vivo and identify the HSP90 inhibitor XL888 as a candidate senolytic to treat idiopathic pulmonary fibrosis."

Journal • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • CDC37

Selective targeting of Plasmodium falciparum Hsp90 disrupts the 26S proteasome. (PubMed, Cell Chem Biol) - "Herein, we identify BX-2819 and XL888 as potent P. falciparum (Pf)Hsp90 inhibitors...Subsequent biochemical and cellular studies suggest that PfHsp90 directly promotes proteasome hydrolysis by chaperoning the active 26S complex. These findings expand our knowledge of the PfHsp90-dependent proteome and protein quality control mechanisms in these pathogenic parasites, as well as further characterize this chaperone as a potential antimalarial drug target."

Journal • Infectious Disease • Malaria • CDC37 • HSP90AA1

An in vivo screening platform identifies senolytic compounds that target p16INK4a+ fibroblasts in lung fibrosis. (PubMed, J Clin Invest) - "Finally, XL888 preferentially targeted p16INK4a-high human lung fibroblasts isolated from patients with idiopathic pulmonary fibrosis (IPF), and reduced p16INK4a+ fibroblasts from IPF PCLS ex vivo. This study provides proof of concept for a platform where p16INK4a+ cells are directly isolated from diseased tissues to identify compounds with in vivo and ex vivo efficacy in mouse and human respectively and provides a senolytic screening platform for other age-related diseases."

Journal • Preclinical • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • CDC37 • CDKN2A

XL888 + Vemurafenib + Cobimetinib for Unresectable BRAF Mutated Stage III/IV Melanoma (clinicaltrials.gov) - P1 | N=26 | Active, not recruiting | Sponsor: H. Lee Moffitt Cancer Center and Research Institute

Trial completion date • Genetic Disorders • Melanoma • Oncology • Skin Cancer • Solid Tumor • BRAF

Pembrolizumab and XL888 in Patients With Advanced Gastrointestinal Cancer (clinicaltrials.gov) - P1 | N=49 | Completed | Sponsor: Emory University | Active, not recruiting ➔ Completed

Trial completion • Cholangiocarcinoma • Colorectal Adenocarcinoma • Colorectal Cancer • Gastric Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

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 • Acute Kidney Injury • Melanoma • Nephrology • Oncology • Renal Disease • Solid Tumor • BRAF • CD4 • CD8 • HSP90AA1

[VIRTUAL] Investigating the clinical safety, efficacy, and immune modulation of combined XL888 and pembrolizumab in metastatic gastrointestinal malignancies (SITC 2020) - P1 | "Conclusions Our correlative analysis of paired biopsies and peripheral blood from a novel clinical trial of XL888 and pembrolizumab will allow for further mechanistic insight into treatment-induced immune modulation. These data will also serve to validate whether alterations of CAF phenotype, cytokine and chemokine release, and T cell infiltration observed preclinically are mirrored in patients."

Clinical • IO biomarker • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • IL6

Study of XL888 With Vemurafenib for Patients With Unresectable BRAF Mutated Stage III/IV Melanoma (clinicaltrials.gov) - P1 | N=21 | Completed | Sponsor: H. Lee Moffitt Cancer Center and Research Institute | Active, not recruiting ➔ Completed

Trial completion • Melanoma • Oncology • Solid Tumor • BRAF

Study of XL888 With Vemurafenib for Patients With Unresectable BRAF Mutated Stage III/IV Melanoma (clinicaltrials.gov) - P1 | N=21 | Active, not recruiting | Sponsor: H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Dec 2022 ➔ Dec 2023

Trial completion date • Melanoma • Oncology • Solid Tumor • BRAF

Pembrolizumab and XL888 in Patients With Advanced Gastrointestinal Cancer (clinicaltrials.gov) - P1 | N=49 | Active, not recruiting | Sponsor: Emory University | Trial completion date: Nov 2023 ➔ Nov 2024 | Trial primary completion date: Nov 2022 ➔ Nov 2023

Trial completion date • Trial primary completion date • Cholangiocarcinoma • Colorectal Adenocarcinoma • Colorectal Cancer • Gastric Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

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) - P1 | "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 • IO biomarker • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • HSP90AA1

XL888 + Vemurafenib + Cobimetinib for Unresectable BRAF Mutated Stage III/IV Melanoma (clinicaltrials.gov) - P1 | N=26 | Active, not recruiting | Sponsor: H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Oct 2022 ➔ Oct 2023

Trial completion date • Genetic Disorders • Melanoma • Oncology • Skin Cancer • Solid Tumor • BRAF

Study of XL888 With Vemurafenib for Patients With Unresectable BRAF Mutated Stage III/IV Melanoma (clinicaltrials.gov) - P1 | N=21 | Active, not recruiting | Sponsor: H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Jul 2022 ➔ Dec 2022

Trial completion date • Melanoma • Oncology • Solid Tumor • BRAF

XL888 + Vemurafenib + Cobimetinib for Unresectable BRAF Mutated Stage III/IV Melanoma (clinicaltrials.gov) - P1 | N=26 | Active, not recruiting | Sponsor: H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Apr 2022 ➔ Oct 2022

Trial completion date • Genetic Disorders • Melanoma • Oncology • Skin Cancer • Solid Tumor • BRAF

Pembrolizumab and XL888 in Patients With Advanced Gastrointestinal Cancer (clinicaltrials.gov) - P1; N=49; Active, not recruiting; Sponsor: Emory University; Recruiting ➔ Active, not recruiting; Trial primary completion date: Nov 2021 ➔ Nov 2022

Clinical • Enrollment closed • Trial primary completion date • Cholangiocarcinoma • Colorectal Adenocarcinoma • Colorectal Cancer • Gastric Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • MRI

XL888 + Vemurafenib + Cobimetinib for Unresectable BRAF Mutated Stage III/IV Melanoma (clinicaltrials.gov) - P1; N=26; Active, not recruiting; Sponsor: H. Lee Moffitt Cancer Center and Research Institute; Trial completion date: Dec 2021 ➔ Apr 2022

Clinical • Trial completion date • Genetic Disorders • Melanoma • Oncology • Skin Cancer • Solid Tumor • BRAF

Phase Ib trial of pembrolizumab and XL888 in patients with advanced gastrointestinal malignancies: Results of the dose-escalation phase. (ASCO-GI 2020) - P1; "Eligible patients included stage IV or locally advanced unresectable gastrointestinal adenocarcinomas with at least one prior therapy (patients with colorectal (CRC) adenocarcinoma must have received oxaliplatin, irinotecan, and fluoropyrimidine), age ≥18 years, ECOG PS 0-1, adequate organ function, no prior anti-PD-1 or anti-PD-L1 agent. The XL888 and pembrolizumab combination had an acceptable safety profile and the RP2D of XL888 was 90 mg twice weekly combined with P 200 mg, every 3 weeks. The dose expansion portion and a robust series of immunologic correlative laboratory studies for this study is ongoing. Clinical trial information: NCT03095781."

Clinical • P1 data • Biliary Cancer • Cholangiocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • HSP90AA1

[VIRTUAL] Investigating the clinical safety, efficacy, and immune modulation of combined XL888 and pembrolizumab in metastatic gastrointestinal malignancies (SITC 2020) - P1 | "Conclusions Our correlative analysis of paired biopsies and peripheral blood from a novel clinical trial of XL888 and pembrolizumab will allow for further mechanistic insight into treatment-induced immune modulation. These data will also serve to validate whether alterations of CAF phenotype, cytokine and chemokine release, and T cell infiltration observed preclinically are mirrored in patients."

Clinical • IO biomarker • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • IL6