MAESTRO: A randomized, double-blind phase III study of evofosfamide (Evo) in combination with gemcitabine (Gem) in previously untreated patients (pts) with metastatic or locally advanced unresectable pancreatic ductal adenocarcinoma (PDAC).

Cutsem, Éric Van; Lenz, Heinz‐Josef; Furuse, Junji; Tabernero, Josep; Heinemann, Volker; Ioka, Tatsuya; Bazin, I.; Ueno, Makoto; Csőszi, Tibor; Wasan, Harpreet; Melichar, Bohuslav; Karásek, Petr; Macarulla, Teresa; Guillén, Carmen; Kalinka-Warzocha, Ewa; Horváth, Zsolt; Prenen, Hans; Schlichting, Michael; Ibrahim, Ayman; Bendell, Johanna C.

doi:10.1200/jco.2016.34.15_suppl.4007

Cited by 50 publications

(33 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Evofosfamide has been the subject of 26 clinical trials, most notably failing in 2 phase 3 studiesin combination with doxorubicin for unresectable or metastatic soft-tissue sarcoma (SARC021 trial) and with gemcitabine for first-line treatment of unresectable or metastatic pancreatic adenocarcinoma (PDAC; MAESTRO trial). While SARC021 was definitively negative (65) -potentially owing in part to unanticipated antagonism between evofosfamide and doxorubicin caused by intermolecular electron transfer (66) -MAESTRO only narrowly missed primary endpoint (P = 0.059 for OS) (41). Interestingly, recent data show that an ethanol-based formulation newly implemented for MAESTRO resulted in unexpected pharmacokinetics of evofosfamide, with systemic exposure at the 340 mg/m 2 MAESTRO dose equivalent to those achieved at 240 mg/m 2 in the preceding randomized phase 2 PDAC trial (53,67).…”

Section: Discussionmentioning

confidence: 99%

“…Evofosfamide is a clinical-stage hypoxia-activated prodrug designed to target the DNA-crosslinking nitrogen mustard bromo-iso-phosphoramide (Br-IPM) to regions of hypoxia (37), leading to DNA damage, γH2AX phosphorylation, cell cycle arrest, and cleavage of caspase-3 and -6 (38)(39)(40). Despite narrowly missing its primary phase 3 overall survival (OS) endpoint with gemcitabine for advanced pancreatic adenocarcinoma (41), evofosfamide shows abundant evidence of preclinical (40,(42)(43)(44)(45)(46)(47)(48)(49)(50)(51) and clinical activity (52,53). However, evofosfamide has not been comprehensively investigated for HNSCC.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Evofosfamide for the treatment of human papillomavirus-negative head and neck squamous cell carcinoma

Jamieson¹,

Tsai²,

Kondratyev³

et al. 2018

JCI Insight

View full text Add to dashboard Cite

Evofosfamide (TH-302) is a clinical-stage hypoxia-activated prodrug of a DNA-crosslinking nitrogen mustard that has potential utility for human papillomavirus (HPV) negative head and neck squamous cell carcinoma (HNSCC), in which tumor hypoxia limits treatment outcome. We report the preclinical efficacy, target engagement, preliminary predictive biomarkers and initial clinical activity of evofosfamide for HPV-negative HNSCC. Evofosfamide was assessed in 22 genomically characterized cell lines and 7 cell line-derived xenograft (CDX), patient-derived xenograft (PDX), orthotopic, and syngeneic tumor models. Biomarker analysis used RNA sequencing, whole-exome sequencing, and whole-genome CRISPR knockout screens. Five advanced/metastatic HNSCC patients received evofosfamide monotherapy (480 mg/m2 qw × 3 each month) in a phase 2 study. Evofosfamide was potent and highly selective for hypoxic HNSCC cells. Proliferative rate was a predominant evofosfamide sensitivity determinant and a proliferation metagene correlated with activity in CDX models. Evofosfamide showed efficacy as monotherapy and with radiotherapy in PDX models, augmented CTLA-4 blockade in syngeneic tumors, and reduced hypoxia in nodes disseminated from an orthotopic model. 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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Evofosfamide for the treatment of human papillomavirus-negative head and neck squamous cell carcinoma

Jamieson¹,

Tsai²,

Kondratyev³

et al. 2018

JCI Insight

View full text Add to dashboard Cite

show abstract

“…The results demonstrated no OS benefit from combining TH-302 with gemcitabine (median of 8.7 months compared to 7.6 months for gemcitabine alone) [32]. However, the treatment combination demonstrated favourable signs of antitumour activity regarding patient PFS (median of 5.5 months compared to 3.7 months for gemcitabine alone) and higher objective response rate [33]. Ideally, TH-302 and gemcitabine should not be used alone but in combination with XRT to enhance the biological damage.…”

Section: Hypoxia Activated Prodrugmentioning

confidence: 95%

“…Although not pancreatic, the similar anatomical location of the oesophageal adenocarcinoma (at the oesophago-gastric junction) had potential to give insight demonstrating the NTCP effects of the trimodality therapy on radiosensitive gastric OAR. However, due to the previous failure of TH-302 to reach its primary endpoint when combined with chemotherapy alone in trials for soft tissue sarcoma (NCT01440088) and pancreatic cancer (MAESTRO), the study was eventually withdrawn [33,35].…”

Section: Hypoxia Activated Prodrugmentioning

confidence: 99%

Clinical Limitations of Photon, Proton and Carbon Ion Therapy for Pancreatic Cancer

Dell’Oro

Short

Wilson

et al. 2020

Cancers

View full text Add to dashboard Cite

Introduction: Despite improvements in radiation therapy, chemotherapy and surgical procedures over the last 30 years, pancreatic cancer 5-year survival rate remains at 9%. Reduced stroma permeability and heterogeneous blood supply to the tumour prevent chemoradiation from making a meaningful impact on overall survival. Hypoxia-activated prodrugs are the latest strategy to reintroduce oxygenation to radioresistant cells harbouring in pancreatic cancer. This paper reviews the current status of photon and particle radiation therapy for pancreatic cancer in combination with systemic therapies and hypoxia activators. Methods: The current effectiveness of management of pancreatic cancer was systematically evaluated from MEDLINE® database search in April 2019. Results: Limited published data suggest pancreatic cancer patients undergoing carbon ion therapy and proton therapy achieve a comparable median survival time (25.1 months and 25.6 months, respectively) and 1-year overall survival rate (84% and 77.8%). Inconsistencies in methodology, recording parameters and protocols have prevented the safety and technical aspects of particle therapy to be fully defined yet. Conclusion: There is an increasing requirement to tackle unmet clinical demands of pancreatic cancer, particularly the lack of synergistic therapies in the advancing space of radiation oncology.

show abstract

“…[ 13 ] Unfortunately, the results of the subsequent Phase III trial were disappointing and did not confirm preliminary results. [ 14 ] The role of other drugs targeting tumor stroma, such as PEGPH 20 which regulates the expression of hyaluronic acid and ibrutinib that inhibits stroma-producing cells, is currently explored in Phase III clinical trials (ClinicalTrials.gov Identifier: NCT02715804 and NCT02436668).…”

Section: Microenvironmentmentioning

confidence: 99%

The personalized medicine for pancreatic ductal adenocarcinoma patients: The oncologist perspective

2017

View full text Add to dashboard Cite

MAESTRO: A randomized, double-blind phase III study of evofosfamide (Evo) in combination with gemcitabine (Gem) in previously untreated patients (pts) with metastatic or locally advanced unresectable pancreatic ductal adenocarcinoma (PDAC).

Cited by 50 publications

References 0 publications

Evofosfamide for the treatment of human papillomavirus-negative head and neck squamous cell carcinoma

Evofosfamide for the treatment of human papillomavirus-negative head and neck squamous cell carcinoma

Clinical Limitations of Photon, Proton and Carbon Ion Therapy for Pancreatic Cancer

The personalized medicine for pancreatic ductal adenocarcinoma patients: The oncologist perspective

Contact Info

Product

Resources

About