Pravitinib (carboxyamidotriazole orotate) / Tactical Therap - LARVOL DELTA

A Sequence-Dependent Combination of Photodynamic Therapy and Carboxyamidotriazole Orotate for Enhanced Treatment of Glioblastoma. (PubMed, Int J Mol Sci) - "Mechanistically, the sequential approach was associated with enhanced mitochondrial depolarization and reduced expression of glycolysis-related genes, suggesting a potential metabolic "dual-hit" involving disturbance of mitochondrial function and compensatory glycolytic adaptation. These results highlight treatment sequence as a critical determinant of PDT-CTO interaction and provide a basis for further preclinical investigation of PDT followed by metabolic intervention as a combination strategy with potential translational relevance."

Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor

Mitochondrial Complex I Inhibition Remodels the PDAC Fibrotic Microenvironment via LOXL2 Suppression to Potentiate Chemo-Immunotherapy. (PubMed, Eur J Pharmacol) - "Mitochondrial metabolic inhibition represents a feasible strategy to modulate CAF-mediated fibrosis in PDAC. CTO-mediated stromal reprogramming may enhance responses to chemo- and immunotherapy, providing a translational rationale for metabolism-based combination strategies."

IO biomarker • Journal • Fibrosis • Immunology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CAFs • LOXL2

Targeting mitochondrial α-ketoglutarate sequestration disables dual oncogenic drivers and metabolic adaptability in pancreatic ductal adenocarcinoma. (PubMed, Cell Death Dis) - "Targeting mitochondrial respiration with the complex I inhibitor carboxyamidotriazole orotate (CTO) redirected α-KG flux from mitochondrial sequestration, and increased α-KG-dependent m6A demethylation of MYC mRNA and HIF-1α hydroxylation. Combining CTO or α-KG dehydrogenase complex inhibitor devimistat with an α-KG analog (dimethyl α-KG) amplified c-Myc/HIF-1α suppression...Our work first identify a novel mechanism whereby mitochondrial metabolism drives systemic metabolic dysregulation in PDAC through the sequestration of α-KG, and establishes "redirecting α-KG flux from mitochondrial sequestration" as a strategy to disable PDAC's metabolic adaptability. The orotate salt form of carboxyamidotriazole effectively disrupts mitochondrial α-KG sequestration to suppresses PDAC growth at a dose equivalent to the clinically tested level."

Journal • Metabolic Disorders • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • HIF1A • MYC

Carboxyamidotriazole orotate (CTO) with temozolomide (TMZ) for recurrent high-grade gliomas (rHGG) and in combination with TMZ/RT->TMZ in newly diagnosed glioblastoma (ndGBM): Long term follow-up of phase IB trial (AACR 2025) - "Background: CTO, an oral brain penetrant inhibitor of calcium signaling pathways was evaluated in rHGG and ndGBM. Addition of CTO to TMZ or TMZ/RT respectively was safe with no DLT. Survival in both recurrent HGG and newly diagnosed GBM patients compares favorably with historical controls. Phase 2 randomized trials are planned.Overall Survival Summary-rHGG and ndGBM: CTO vs Historical ControlsCohortStatusNPercent censoredrHGGFailed23Censored311.54%ndGBMFailed10Censored533.33%------------------------------------------------------------------------------------------------------------------Time (months)rHGG N=26%Alive#at riskndGBM N=15% Alive#at risk010026100156882292.9131247.41092.9121819.0477.492414.2368.88360051.664843.036028.72Median OSmonths 95% Ct10.5(8.0, 14.8)37.8 (20.9,51.9)------------------------------------------------------------------------------------------------------------------Group rHGGDeadTotalMedianOS(months)95% CIp-value..."

Combination therapy • Late-breaking abstract • P1 data • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • High Grade Glioma • Oncology • Solid Tumor • EGFR • MGMT

Safety and Tolerability of Carboxyamidotriazole Orotate (CTO) in Solid Tumors or With Temodar® in Glioblastoma or Other Recurrent Malignant Gliomas or in Combination With Temodar® and Radiation Therapy for Patients With Newly Diagnosed Glioblastoma and Malignant Gliomas (clinicaltrials.gov) - P1 | N=100 | Active, not recruiting | Sponsor: Tactical Therapeutics, Inc. | Trial completion date: Jan 2024 ➔ Jan 2026 | Trial primary completion date: Jan 2024 ➔ Jan 2025

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oligodendroglioma • Oncology • Solid Tumor

Safety and Tolerability of Carboxyamidotriazole Orotate (CTO) in Solid Tumors or With Temodar® in Glioblastoma or Other Recurrent Malignant Gliomas or in Combination With Temodar® and Radiation Therapy for Patients With Newly Diagnosed Glioblastoma and Malignant Gliomas (clinicaltrials.gov) - P1 | N=100 | Active, not recruiting | Sponsor: Tactical Therapeutics, Inc. | Unknown status ➔ Active, not recruiting | Trial primary completion date: Jun 2018 ➔ Jan 2024

Combination therapy • Enrollment closed • Metastases • Trial primary completion date • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oligodendroglioma • Oncology • Solid Tumor

Multicenter Phase IB Trial of Carboxyamidotriazole Orotate and Temozolomide for Recurrent and Newly Diagnosed Glioblastoma and Other Anaplastic Gliomas. (PubMed, J Clin Oncol) - "Signals of activity in cohort 1 (n = 27) included partial (n = 6) and complete (n = 1) response, including in O-methylguanine-DNA methyltransferase unmethylated and bevacizumab-refractory tumors. Gene sequencing disclosed a high rate of responses among EGFR-amplified tumors ( P = .005), with mechanisms of acquired resistance possibly involving mutations in mismatch-repair genes and/or downstream components TSC2, NF1, NF2, PTEN, and PIK3CA. Conclusion CTO can be combined safely with TMZ or chemoradiation in GBM and anaplastic gliomas, displaying favorable brain penetration and promising signals of activity in this difficult-to-treat population."

Clinical • Journal • P1 data