Randomized phase II study of the efficacy and safety of gemcitabine plus TH-302 versus gemcitabine alone in previously untreated patients with advanced pancreatic cancer.

Borad, Mitesh J.; Sigal, Darren; Uronis, Hope E.; Stephenson, Joseph; Bahary, Nathan; Rarick, Mark U.; DeMarco, Linda C.; Finnegan, Thomas; Chiorean, E. Gabriela; Ryan, D. P.; Cohn, Allen Lee; Ulrich, Brian; Harish, Vallathucherry; Anderes, E.; W., W.; Yu, Peter Paul; Sinicrope, Frank A.; Eng, Charis; Sunkara, Usha; Reddy, Snigdha

doi:10.1200/jco.2011.29.15_suppl.tps176

Cited by 4 publications

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“…15,23 TH-302 is a pro-drug that is activated specifically in hypoxic cells, and has demonstrated promising results both in preclinical studies and in early clinical trials. [11][12][13]25,26 However, since TH-302 is non-fluorescent, its direct visualization in tumor tissue is not possible. Therefore, we extended our techniques of assessing biomarker distribution following drug treatment to evaluate the effects of TH-302 in hypoxic and vascular regions of solid tumors.…”

Section: Discussionmentioning

confidence: 99%

“…11 Traditional chemotherapy combined with TH-302 can lead to greater cell kill and growth delay of various rodent tumors and human xenografts, 12 and promising results have been reported from early clinical trials evaluating TH-302 combined with gemcitabine for treatment of pancreatic carcinoma. 13 However, there have been few studies evaluating the microenvironmental distribution of activity of TH-302 within solid tumors and the mechanisms which lead to antitumor effects remain uncertain.…”

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confidence: 99%

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Activity of the hypoxia‐activated pro‐drug TH‐302 in hypoxic and perivascular regions of solid tumors and its potential to enhance therapeutic effects of chemotherapy

Saggar

Tannock

2013

Intl Journal of Cancer

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Many chemotherapy drugs have poor therapeutic activity in regions distant from tumor blood vessels because of poor tissue penetration and low cytotoxic activity against slowly-proliferating cells. The hypoxia-activated pro-drug TH-302 may have selective toxicity for hypoxic and neighboring cells in tumors. Here we characterize the spatial distribution and ability of TH-302 to selectively target hypoxic regions and complement the effect of doxorubicin and docetaxel by modifying biomarker distribution. Athymic nude mice bearing human breast MCF-7 or prostate PC-3 tumors were treated with doxorubicin or docetaxel respectively and TH-302 alone or in combination. Biomarkers of drug effect including cH2aX (a marker of DNA damage), cleaved caspase-3 or -6 (markers of apoptosis) and reduction in Ki-67 (a marker of cell proliferation) were quantified in tumor sections in relation to functional blood vessels (recognized by DiOC7) and hypoxia (recognized by EF5) using immunohistochemistry. cH2aX expression at 10 min and cleaved caspase-3 or -6 at 24 hr after doxorubicin or docetaxel decreased with increasing distance from tumor blood vessels, with minimal expression in hypoxic regions; maximum reduction in Ki67 levels was observed in regions closest to vasculature at 24 hr. TH-302 induced maximal cell damage in hypoxic and neighboring regions, but was also active in tumor regions closer to blood vessels. TH-302 given 4 hr before doxorubicin or docetaxel increased DNA damage and apoptosis throughout the tumor compared to chemotherapy alone. When given with doxorubicin or docetaxel, TH-302 complements and enhances anticancer effects in both perivascular and hypoxic regions but also increases toxicity.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Activity of the hypoxia‐activated pro‐drug TH‐302 in hypoxic and perivascular regions of solid tumors and its potential to enhance therapeutic effects of chemotherapy

Saggar

Tannock

2013

Intl Journal of Cancer

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“…24 The addition of TH-302 to gemcitabine in a randomized Phase 2 PDAC clinical trial demonstrated a significant increase in progression-free survival compared with gemcitabine only (NCT01144455). 25 A Phase 3 trial of the gemcitabine and TH-302 combination compared to gemcitabine and placebo is currently underway (NCT01746979). Nab-paclitaxel is a human serum nanoparticle albumin-bound formulation of paclitaxel designed to overcome solubility problems associated with paclitaxel.…”

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of the hypoxia-activated prodrug TH-302 in combination with gemcitabine and nab-paclitaxel in human tumor xenograft models of pancreatic cancer

Sun

Liu

Ahluwalia

et al. 2015

Cancer Biology & Therapy

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The Tumor Microenvironment and Strategies to Improve Drug Distribution

Saggar¹,

Yu²,

Tan³

et al. 2013

Front. Oncol.

102

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The microenvironment within tumors is composed of a heterogeneous mixture of cells with varying levels of nutrients and oxygen. Differences in oxygen content result in survival or compensatory mechanisms within tumors that may favor a more malignant or lethal phenotype. Cells that are rapidly proliferating are richly nourished and preferentially located close to blood vessels. Chemotherapy can target and kill cells that are adjacent to the vasculature, while cells that reside farther away are often not exposed to adequate amounts of drug and may survive and repopulate following treatment. The characteristics of the tumor microenvironment can be manipulated in order to design more effective therapies. In this review, we describe important features of the tumor microenvironment and discuss strategies whereby drug distribution and activity may be improved.

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Randomized phase II study of the efficacy and safety of gemcitabine plus TH-302 versus gemcitabine alone in previously untreated patients with advanced pancreatic cancer.

Cited by 4 publications

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Activity of the hypoxia‐activated pro‐drug TH‐302 in hypoxic and perivascular regions of solid tumors and its potential to enhance therapeutic effects of chemotherapy

Activity of the hypoxia‐activated pro‐drug TH‐302 in hypoxic and perivascular regions of solid tumors and its potential to enhance therapeutic effects of chemotherapy

Efficacy and safety of the hypoxia-activated prodrug TH-302 in combination with gemcitabine and nab-paclitaxel in human tumor xenograft models of pancreatic cancer

The Tumor Microenvironment and Strategies to Improve Drug Distribution

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