A key driver behind the poor response seen with many chemotherapies and targeted agents evaluated in this setting is thought to be the stroma, which acts as a mechanical barrier to stop drug penetration and also hinder neovascularization, creating a hypoxic microenvironment. The study results of a clinical trial including TH-302, a novel anticancer agent that is converted to bromo-isophosphoramide mustard (Br-IPM), presented at ESMO 2012, the meeting of the European Society for Medical Oncology in Vienna (September 28 – October 2, 2012), showed a reduced drugassociated toxicity to surrounding healthy tissue.

At the forefront of current research in pancreatic cancer is the need to better understand both the tumor and stroma, and to identify and evaluate agents capable of mounting a dual-pronged attack. Presentations at this year?s ESMO include the latest research findings in pancreatic cancer, some of which look set to bring a glimmer of hope to advancing treatment in this field.

Among these, Mitesh J. Borad M.D., from the Mayo Clinic, Scottsdale, Arizona, USA,presented findings from an openlabel, multi-center study evaluating the efficacy and safety of adding TH-302 to gemcitabine in patients with previously untreated, advanced pancreatic cancer.

Solid tumors are generally starved of oxygen, as new blood vessel formation typically can’t keep pace with rapid cell division. But rather than suffocating cancer tissue, this ‘tumor hypoxia’ usually renders cancer cells resistant to standard therapies.

A novel anticancer agent
The novel anticancer agent TH-302 (Treshold Pharmaceuticals, South San Francisco, CA, USA), a 2-nitroimidazole triggered hypoxia-activated prodrug, isconverted to the cytotoxin bromo-isophosphoramide mustard (Br-IPM), a potent DNA alkylator, under hypoxic conditions. The drug selectively targets hypoxic tumor cells. The observed clinical benefit of TH-302 is a reduced drugassociated toxicity to surrounding healthy tissue because TH-302 remains inactive under normoxic conditions.

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Trial
In this 3-arm study, the efficacy and safety of two different doses of TH-302 in combination with gemcitabine was compared with gemcitabine alone. Key outcomes, including progression-free survival and overall survival, will be presented by Dr Borad in his presentation.

Superior efficacy
An unrelated study showed that the antitumor activity of seven chemotherapeutic drugs, including docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide was increased when combined with TH-302 in nine out of eleven models tested.

Administration of TH-302 2-8 h prior to the other chemotherapeutics yielded superior efficacy versus other sequences tested. Simultaneous administration of TH-302 and chemotherapeutics increased toxicity versus schedules with dosing separations. In a dosing optimization study, TH-302 administered daily at 50 mg/kg intraperitoneally for 5 days per week in the H460 NSCLC model showed the optimal response with minimal toxicity.

TH-302 was also evaluated for antitumor activity and changes in dynamic contrast-enhanced (DCE) and diffusion-weighted (DW) magnetic resonance imaging (MRI) in a mouse model of pancreatic cancer. This study showed that TH-302 monotherapy was associated with a significant delay in tumor growth compared to vehicle-treated controls.

The new drug treatment was also associated with a significant decrease in the volume transfer constant (K(trans)) compared to vehicle-treated controls 1 day following the first dose measured using DCE-MRI. This early decrease in K(trans) following the first dose as measured is consistent with selective killing of the hypoxic fraction of cells which are associated with enhanced expression of hypoxia inducible transcription factor-1 alpha that regulates expression of permeability and perfusion factors including vascular endothelial growth factor-A. No changes were observed in DW-MRI following treatment with TH-302. This may suggest that this technique is not sensitive enough to detect changes in small hypoxic fractions of the tumor targeted by TH-302. However, the these results seem to indicate that changes in tumor permeability and/or perfusion may be an early imaging biomarker for response to TH-302 therapy.

For more information:
Session: Proffered Papers, gastrointestinal tumors, non-colorectal
Abstract # 666O: TH-302 + gemcitabine (G+T) vs gemcitabine (G) in patients with previously untreated advanced pancreatic cancer (pac)
Presenter: Mitesh Borad, Mayo Clinic, Scottsdale, Arizona, USA
Moderators: Professor Emmanuel Mitry and Gunnar Folprecht
Day/Date:Saturday, September 29, 2012 Time: 09:15 ? 10:45

Additional reading:
– C?rdenas-Rodr?guez J, Li Y, Galons JP, Cornnell H, Gillies RJ, Pagel MD, Baker AF.Imaging biomarkers to monitor response to the hypoxia-activated prodrug TH-302 in the MiaPaCa2 flank xenograft model.Magn Reson Imaging. 2012 Sep;30(7):1002-9. Epub 2012 May 1
– Liu Q, Sun JD, Wang J, Ahluwalia D, Baker AF, Cranmer LD, et al. TH-302, a hypoxia-activated prodrug with broad in vivo preclinical combination therapy efficacy: optimization of dosing regimens and schedules. Cancer Chemother Pharmacol. 2012 Jun;69(6):1487-98. Epub 2012 Mar 2.

Study information:
– TH-302 Plus Gemcitabine vs. Gemcitabine in Patients with Untreated Advanced Pancreatic Adenocarcinoma.[PDF]
– Supplemental Information on Study TH-CR-404 Overall Survival Analysis [PDF]

Illustration:Chemical structure of TH-302

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