- |||||||||| evofosfamide (TH 302) / Molecular Templates
Journal: In-silico screening for identification of potential inhibitors against SARS-CoV-2 transmembrane serine protease 2 (TMPRSS2). (Pubmed Central) - Jun 22, 2021
These hit compounds were subjected to stability checks between the protein-ligand complex through the dynamics simulation (MD), and binding free energy was calculated through the Molecular Mechanics energies combined with Poisson-Boltzmann (MM/PBSA) method. We hope that hit compounds would be an efficient inhibitor that can block the TMPRSS2 activity and resist the entry of the SARS-CoV-2 virus into targeted human cells by reducing the virus's infectivity and transmissibility.
- |||||||||| evofosfamide (TH 302) / Molecular Templates
Journal: A self-activating nanovesicle with oxygen-depleting capability for efficient hypoxia-responsive chemo-thermo cancer therapy. (Pubmed Central) - May 25, 2021
Herein, a novel self-activating nanovesicle, TH-302@BR-Chitosan NPs, is constructed by assembling bilirubin-chitosan conjugate (named as BR-Chitosan) with a HAP, TH-302...Moreover, as the oxidation derivatives of BR-Chitosan, BV-Chitosan exhibits intense absorbance at the range from long wavelength of visible region to near-infrared region, which can be acted as an effective photothermal agent for photothermal therapy (PTT). This biodegradable and self-activating nanovesicle with concise formulation demonstrates greatly enhanced synergistic therapeutic outcome in the activatable chemo-thermo combined therapy, showing much promising in future clinical transformation.
- |||||||||| evofosfamide (TH 302) / Molecular Templates
Review, Journal: The Hypoxia-Activated Prodrug TH-302: Exploiting Hypoxia in Cancer Therapy. (Pubmed Central) - May 7, 2021
Although many such agents have been developed, we will focus here on TH-302. TH-302 has been extensively studied, and we discuss its mechanism of action, as well as its efficacy in preclinical and clinical studies, with the aim of identifying future research directions.
- |||||||||| evofosfamide (TH 302) / Molecular Templates
[VIRTUAL] Imaging-based patient inclusion model for clinical trial performance optimization. () - Apr 28, 2021 - Abstract #ASCO2021ASCO_2314;
The study presents a first of its kind radiomic approach for patient enrichment in clinical trials based on a quantitative score . In particular, we have shown that had the novel model been used for selective patient inclusion into the SARC021 trial, it would have met its primary survival objective for patients with metastatic STS.
- |||||||||| doxorubicin hydrochloride / Generic mfg., evofosfamide (TH 302) / Molecular Templates
Targeting hypoxic habitats with hypoxia pro-drug evofosfamide in preclinical models of sarcoma (Virtual Meeting II: E-Posters) - May 16, 2020 - Abstract #AACRII2020AACR-II_2804;
In conclusion, the use of HAPs to target hypoxic tumor habitats shows superiority over conventional chemotherapy in rhabdomyosarcoma, but was without effect in RIF-1. Imaging habitats have the potential to classify different microenvironments within a tumor, and this concept may allow the choice of therapy to be based on habitat distribution.
- |||||||||| Avastin (bevacizumab) / Roche, evofosfamide (IMGS-101) / Molecular Templates, ImmunoGenesis
Trial completion, Trial completion date, Combination therapy: TH-302 in Combination With Bevacizumab for Glioblastoma (clinicaltrials.gov) - Apr 10, 2020
P2, N=35, Completed,
Research Funding: Pfizer, Inc and Molecular Templates, Inc., GRUPO ESPAÑOL DE TUMORES ENDOCRINOS Y NEUROENDOCRINOS Active, not recruiting --> Completed | Trial completion date: Jul 2019 --> Dec 2019
- |||||||||| Sutent (sunitinib) / Pfizer, evofosfamide (IMGS-101) / Molecular Templates, ImmunoGenesis
Trial completion, Trial completion date, Combination therapy, Metastases: SUNEVO: A Study to Assess the Safety and the Efficacy of the Combination of TH-302 and Sunitinib in Neuroendocrine Pancreatic Tumours (clinicaltrials.gov) - Mar 24, 2020
P2, N=16, Completed,
Active, not recruiting --> Completed | Trial completion date: Jul 2019 --> Dec 2019 Active, not recruiting --> Completed | Trial completion date: Jun 2019 --> Jan 2020
- |||||||||| netupitant (Ro 67-3189) / Helsinn, Otsuka, doxorubicin hydrochloride / Generic mfg., Sovaldi (sofosbuvir) / Gilead
Clinical, Journal: Successes, failures, and future prospects of prodrugs and their clinical impact. (Pubmed Central) - Mar 4, 2020
For example, newer platelet aggregation inhibitors could signal the end of the warfarin era with their demanding treatment follow-up...This strategy employs the design of artificial enzymes to activate prodrugs at specific sites. Agents designed for use in DEPT medicine can be directed at antibodies, genes, viruses, and clostridia.
- |||||||||| evofosfamide (TH 302) / Molecular Templates
Biomarker, Journal: Impact of Tumour Hypoxia on Evofosfamide Sensitivity in Head and Neck Squamous Cell Carcinoma Patient-Derived Xenograft Models. (Pubmed Central) - Feb 25, 2020
Overall, these data confirm that evofosfamide has antitumour activity in clinically-relevant PDX tumour models of HNSCC and support further clinical evaluation of this drug in HNSCC patients. Further research is required to identify those factors that, alongside hypoxia, can influence sensitivity to evofosfamide and could act as predictive biomarkers to support its use in precision medicine therapy of HNSCC.
- |||||||||| evofosfamide (TH 302) / Molecular Templates
Biomarker, Journal, IO biomarker: Evofosfamide for the treatment of human papillomavirus-negative head and neck squamous cell carcinoma. (Pubmed Central) - Dec 21, 2019
Of 5 advanced HNSCC patients treated with evofosfamide, 2 showed partial responses while 3 had stable disease. In conclusion, evofosfamide shows promising efficacy in aggressive HPV-negative HNSCC, with predictive biomarkers in development to support further clinical evaluation in this indication.
- |||||||||| evofosfamide (TH 302) / Molecular Templates
Journal: Functional CRISPR and shRNA screens identify involvement of mitochondrial electron transport in the activation of evofosfamide. (Pubmed Central) - Dec 20, 2019
In UT-SCC-74B cells, evofosfamide oxidised cytochromes a, b and c and inhibited respiration at complexes I, II and IV without quenching ROS production. Our results suggest that the mitochondrial electron transport chain contributes to evofosfamide activation and that predicting evofosfamide sensitivity in patients by measuring the expression of canonical bioreductive enzymes such as P450 oxidoreductase (POR) is likely to be futile.
- |||||||||| evofosfamide (TH 302) / Molecular Templates
Biomarker, Clinical, Journal: Administration of Hypoxia-Activated Prodrug Evofosfamide after Adjuvant Therapy Enhances Therapeutic Outcome and Targets Cancer-Initiating Cells in Colorectal Cancer. (Pubmed Central) - Nov 19, 2019
Hypoxia was sufficient to drive the formation of CC-ICs and cells surviving conventional therapy were more hypoxic and C-IC-like. Using a novel approach to combination therapy, we show that sequential treatment with 5-FU or CRT followed by Evo not only inhibits tumor growth of xenografts compared to 5-FU or CRT alone, but also significantly decreases the CC-IC fraction. Furthermore, non-invasive FAZA-PET hypoxia imaging was predictive of a tumor's response to Evo. Our data demonstrate a novel means to target the CC-IC fraction by adding a HAP sequentially after conventional adjuvant therapy, as well as the use of FAZA-PET as a biomarker for hypoxia to identify tumors that will benefit most from this approach.
- |||||||||| Avastin (bevacizumab) / Roche, doxycycline / Generic Mfg.
Targeting metabolic pathways in hypoxia for Glioblastoma (Ballroom Lawn) - Oct 29, 2019 - Abstract #SNO2019SNO_987;
Peroxisomal FAO and other metabolic pathways may be essential to target in order combat metabolic resistance during anti-angiogenic therapy. Better understanding differences in metabolism in different tumor environments will help determine which targets will be most therapeutically useful.
- |||||||||| Avastin (bevacizumab) / Roche, evofosfamide (TH 302) / Molecular Templates
Biomarker, P1 data, Journal: Hypoxia Activated Evofosfamide for Treatment of Recurrent Bevacizumab-Refractory Glioblastoma: A phase I surgical study. (Pubmed Central) - Oct 20, 2019
The ratio of enhancement to non-enhancement was significant on log rank analysis with time to progression (p=0.023), with patients having a ratio of less than 0.37 showing a median progression free survival (PFS) of 98 days vs 56 days for those with more enhancement. Evo plus Bev was well tolerated in patients with Bev refractory glioblastoma, with preliminary evidence of activity that merits further investigation.
- |||||||||| DC101 / Eli Lilly, evofosfamide (TH 302) / Molecular Templates
Disrupting hypoxic tumor niches to sensitize pancreatic cancer to immunotherapy (Prince George's Exhibition Halls AB) - Oct 2, 2019 - Abstract #SITC2019SITC_1193;
This is in part associated with re-activation of tumor endothelium to a pro-inflammatory state favoring T cell adhesion and extravasation. These results indicate that combining TH-302 mediated tissue remodeling with VEGFR-2 blockade can enhance both reduction of hypoxia and induction of tumor immunity in a refractory model of pancreatic cancer.
- |||||||||| evofosfamide (TH 302) / Molecular Templates
Journal: Targeted hypoxia reduction restores T cell infiltration and sensitizes prostate cancer to immunotherapy. (Pubmed Central) - Sep 14, 2019
We demonstrated that the hypoxia-activated prodrug TH-302 reduces or eliminates hypoxia in these tumors...Survival of Pb-Cre4, Ptenpc-/-Smad4pc-/- mice with highly aggressive prostate adenocarcinoma is also significantly extended by the combination of hypoxia-prodrug and checkpoint blockade. This combination of hypoxia disruption and T cell checkpoint blockade may render some of the most therapeutically resistant cancers sensitive to immunotherapy.
- |||||||||| evofosfamide (TH 302) / Molecular Templates
Journal: Cellular pharmacology of evofosfamide (TH-302): A critical re-evaluation of its bystander effects. (Pubmed Central) - May 29, 2019
We identify, in NfsA-expressing cells, the hydroxylamine metabolite of TH-302, and downstream products resulting from rearrangement or hydration of the imidazole ring, and demonstrate that formation of these candidate bystander effect mediators is suppressed by hypoxia. This characterisation of the cellular pharmacology of TH-302 implies that bystander effects from hypoxic activation of TH-302 are unlikely to contribute to its anticancer activity.
- |||||||||| evofosfamide (TH 302) / Molecular Templates
Journal: ONECUT2 is a driver of neuroendocrine prostate cancer. (Pubmed Central) - Mar 22, 2019
Treatment with hypoxia-activated prodrug TH-302 potently reduces NEPC tumor growth. Collectively, these results highlight the synergy between ONECUT2 and hypoxia in driving NEPC, and emphasize the potential of hypoxia-directed therapy for NEPC patients.
- |||||||||| Sutent (sunitinib) / Pfizer, evofosfamide (IMGS-101) / Molecular Templates, ImmunoGenesis
Trial primary completion date, Combination therapy, Metastases: SUNEVO: A Study to Assess the Safety and the Efficacy of the Combination of TH-302 and Sunitinib in Neuroendocrine Pancreatic Tumours (clinicaltrials.gov) - Feb 8, 2019
P2, N=16, Active, not recruiting,
Collectively, these results highlight the synergy between ONECUT2 and hypoxia in driving NEPC, and emphasize the potential of hypoxia-directed therapy for NEPC patients. Trial primary completion date: Jan 2019 --> Jun 2019
- |||||||||| Avastin (bevacizumab) / Roche, evofosfamide (IMGS-101) / Molecular Templates, ImmunoGenesis
Trial completion date, Trial primary completion date, Combination therapy: TH-302 in Combination With Bevacizumab for Glioblastoma (clinicaltrials.gov) - Oct 26, 2018
P2, N=35, Active, not recruiting,
Trial primary completion date: Jan 2019 --> Jun 2019 Trial completion date: Jul 2018 --> Jul 2019 | Trial primary completion date: Jul 2018 --> Jul 2019
- |||||||||| evofosfamide (IMGS-101) / Molecular Templates, ImmunoGenesis
Trial completion, Enrollment change, Trial completion date, Trial primary completion date, Monotherapy, Metastases: Study of TH-302 Monotherapy as Second-line Treatment in Advanced Biliary Tract Cancer (clinicaltrials.gov) - Sep 10, 2018
P2, N=24, Completed,
Trial completion date: Jul 2018 --> Jul 2019 | Trial primary completion date: Jul 2018 --> Jul 2019 Recruiting --> Completed | N=36 --> 24 | Trial completion date: Jun 2016 --> Oct 2017 | Trial primary completion date: Jun 2016 --> Oct 2017
- |||||||||| Sutent (sunitinib) / Pfizer, evofosfamide (IMGS-101) / Molecular Templates, ImmunoGenesis
Enrollment closed, Enrollment change, Combination therapy, Metastases: SUNEVO: A Study to Assess the Safety and the Efficacy of the Combination of TH-302 and Sunitinib in Neuroendocrine Pancreatic Tumours (clinicaltrials.gov) - Jun 11, 2018
P2, N=16, Active, not recruiting,
Recruiting --> Completed | N=36 --> 24 | Trial completion date: Jun 2016 --> Oct 2017 | Trial primary completion date: Jun 2016 --> Oct 2017 Recruiting --> Active, not recruiting | N=43 --> 16
- |||||||||| Avastin (bevacizumab) / Roche, evofosfamide (IMGS-101) / Molecular Templates, ImmunoGenesis
Trial primary completion date, Combination therapy: TH-302 in Combination With Bevacizumab for Glioblastoma (clinicaltrials.gov) - May 2, 2018
P2, N=35, Active, not recruiting,
Recruiting --> Active, not recruiting | N=43 --> 16 Trial primary completion date: Dec 2017 --> Jul 2018
- |||||||||| evofosfamide (IMGS-101) / Molecular Templates, ImmunoGenesis
Enrollment closed, Enrollment change, Trial primary completion date, Surgery, Metastases: Sorafenib Tosylate and Hypoxia-Activated Prodrug TH-302 in Treating Patients With Advanced Kidney Cancer or Liver Cancer That Cannot Be Removed By Surgery (clinicaltrials.gov) - Feb 27, 2018
P2, N=24, Active, not recruiting,
Trial primary completion date: Dec 2017 --> Jul 2018 Suspended --> Active, not recruiting | N=48 --> 24 | Trial primary completion date: Jan 2018 --> Jan 2016
- |||||||||| Avastin (bevacizumab) / Roche, evofosfamide (IMGS-101) / Molecular Templates, ImmunoGenesis
Trial primary completion date, Combination therapy: TH-302 in Combination With Bevacizumab for Glioblastoma (clinicaltrials.gov) - Oct 13, 2017
P2, N=35, Active, not recruiting,
N=165 --> 214 Trial primary completion date: Sep 2017 --> Dec 2017
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