TH-302

TH-302 is a 2-nitroimidazole triggered hypoxia-activated prodrug of bromo-isophosphoramide mustard [1].
Hypoxia is a prevailing feature of tumors due to the abnormal aspects and structure of tumor vasculatures. It is found that hypoxic tumors usually show resistance to the traditional chemo- and radiation therapies and hypoxic tumors are more metastatic and invasive. Since the hypoxic tumors are not hyperproliferative, the traditional anti-proliferation drugs are not suitable. As a hypoxia-activated prodrug, TH-302 can release the cytotoxic agent Br-IPM and selectively deliver it the to the tumor cells under the anoxic condition [1 and 2].
The activity of TH-302 is dependent on the degree of anoxia and the exposure time of the drug under hypoxia. Higher activity requires lower oxygen concentration. Different with tirapazamine (another HAP), TH-302 needed much severer hypoxia (about 0.1%) to keep high potency. When treated in a panel of 32 kinds of tumor cells, TH-302 showed modest cytotoxicity with IC50 values all above 40 μM under the normal air condition. In contrast, TH-302 exerted elevated anti-tumor potency under the hypoxic condition. The IC50 values of it were in a range from 0.1 to 90 μM. Among these tumor cells, the non-small cell lung cancer H460 cells were most sensitive against TH-302 treatment with IC50 value of 0.1±0.03 μM. Besides that, TH-302 also showed potent efficacies in many other tumor cells, including Caki-1 (renal), SK-MEL-5 (melanoma), DU145 (prostate) and HCT116 (colon), with IC50 values of 0.4, 0.7, 0.7 and 0.8 μM, respectively [1].
In mice bearing H460 xenografts, administration of TH-302 at doses of 6.25 to 50 mg/kg dose-dependently caused tumor growth inhibition (TGI) with 43% to 89% and 50 mg/kg TH-302 administration showed no hematologic toxicity. Apart from this, TH-302 was found to induce DNA damage. TH-302 at dose of 100 mg/kg for 6 hours resulted in notable increase of γH2AX-positive cells [2].
References:
[1] Meng F, Evans J W, Bhupathi D, et al. Molecular and cellular pharmacology of the hypoxia-activated prodrug TH-302. Molecular cancer therapeutics, 2012, 11(3): 740-751.
[2] Sun J D, Liu Q, Wang J, et al. Selective tumor hypoxia targeting by hypoxia-activated prodrug TH-302 inhibits tumor growth in preclinical models of cancer. Clinical cancer research, 2012, 18(3): 758-770.

Phase I study of pazopanib plus TH-302 in advanced solid tumors.[Pubmed:28238078]

Cancer Chemother Pharmacol. 2017 Mar;79(3):611-619.

PURPOSE: To define the maximum tolerated dose (MTD), recommended phase II dose (RPTD), and assess safety and tolerability for the combination of pazopanib plus TH-302, an investigational hypoxia-activated prodrug (HAP), in adult patients with advanced solid tumors. METHODS: This was an open-label, non-randomized, single-center, phase I trial consisting 2 stages. Stage 1 was a standard "3 + 3" dose escalation design to determine safety and the RPTD for TH-302 plus pazopanib combination. Stage 2 was an expanded cohort to better describe the tolerability and toxicity profile at the MTD. Pazopanib was orally dosed at 800 mg daily on days 1-28 for all cohorts. TH-302 was administered intravenously on days 1, 8 and 15 of a 28-day cycle at doses of 340 mg/m(2) (cohort 1) or 480 mg/m(2) (cohort 2). Dose limiting toxicity (DLT) was assessed in the first 28-day cycle. Efficacy was assessed every 2 cycles. RESULTS: Thirty patients were enrolled between December 2011 and September 2013. In the dose escalation stage, 7 patients were enrolled in the 340 mg/m(2) TH-302 cohort and 6 patients in the 480 mg/m(2) TH-302 cohort. Ten patients were evaluable for DLT. DLTs included grade 2 intolerable esophagitis (n = 1) in the 340 mg/m(2) TH-302 cohort, and grade 3 vaginal inflammation (n = 1) and grade 3 neutropenia with grade 3 thrombocytopenia (n = 1, same patient) in the 480 mg/m(2) TH-302 cohort. The 340 mg/m(2) TH-302 cohort was determined to be MTD and RPTD. The most common treatment-related adverse events were hematologic (anemia, neutropenia, and thrombocytopenia), nausea/vomiting, palmar-plantar erythrodysesthesia syndrome, constipation, fatigue, mucositis, anorexia, pain, and hypertension. Partial response (PR) was observed in 10% (n = 3) of patients, stable disease (SD) in 57% (n = 17), and progressive disease (PD) in 23% (n = 7). Due to toxicity, 3 patients were discontinued from study drug prior to first radiographic assessment but were included in these calculations. Disease control >/=6 months was observed in 37% of patients (n = 11). CONCLUSIONS: The RPTD for this novel combination is pazopanib 800 mg daily on days 1-28 plus TH-302 340 mg/m(2) on days 1, 8 and 15 of each 28-day cycle. Preliminary activity was seen in treatment-refractory cancers and supports potential value of co-targeting tumor angiogenesis and tumor hypoxia.

Hypoxia Imaging With PET Correlates With Antitumor Activity of the Hypoxia-Activated Prodrug Evofosfamide (TH-302) in Rodent Glioma Models.[Pubmed:27752544]

Tomography. 2016 Sep;2(3):229-237.

High-grade gliomas are often characterized by hypoxia, which is associated with both poor long-term prognosis and therapy resistance. The adverse role hypoxia plays in treatment resistance and disease progression has led to the development of hypoxia imaging methods and hypoxia-targeted treatments. Here, we determined the tumor hypoxia and vascular perfusion characteristics of 2 rat orthotopic glioma models using 18-fluoromisonidozole positron emission tomography. In addition, we determined tumor response to the hypoxia-activated prodrug evofosfamide (TH-302) in these rat glioma models. C6 tumors exhibited more hypoxia and were less perfused than 9L tumors. On the basis of these differences in their tumor hypoxic burden, treatment with evofosfamide resulted in 4- and 2-fold decreases in tumor growth rates of C6 and 9L tumors, respectively. This work shows that imaging methods sensitive to tumor hypoxia and perfusion are able to predict response to hypoxia-targeted agents. This has implications for improved patient selection, particularly in clinical trials, for treatment with hypoxia-activated cytotoxic prodrugs, such as evofosfamide.

Targeting hypoxic microenvironment of pancreatic xenografts with the hypoxia-activated prodrug TH-302.[Pubmed:27248663]

Oncotarget. 2016 Jun 7;7(23):33571-80.

Previous reports have suggested that the hypoxic microenvironment provides a niche that supports tumor stem cells, and that this might explain clinical observations linking hypoxia to metastasis. To test this, we examined the effects of a hypoxia-activated prodrug, TH-302, on the tumor-initiating cell (TIC) frequency of patient-derived pancreatic xenografts (PDX).The frequencies of TIC, measured by limiting dilution assay, varied widely in 11 PDX models, and were correlated with rapid growth but not with the levels of hypoxia. Treatment with either TH-302 or ionizing radiation (IR), to target hypoxic and well-oxygenated regions, respectively, reduced TIC frequency, and the combination of TH-302 and IR was much more effective in all models tested. The combination was also more effective than TH-302 or IR alone controlling tumor growth, particularly treating the more rapidly-growing/hypoxic models. These findings support the clinical utility of hypoxia targeting in combination with radiotherapy to treat pancreatic cancers, but do not provide strong evidence for a hypoxic stem cell niche.

A phase 1 'window-of-opportunity' trial testing evofosfamide (TH-302), a tumour-selective hypoxia-activated cytotoxic prodrug, with preoperative chemoradiotherapy in oesophageal adenocarcinoma patients.[Pubmed:27535748]

BMC Cancer. 2016 Aug 17;16:644.

BACKGROUND: Neo-adjuvant chemoradiotherapy followed by surgery is the standard treatment with curative intent for oesophageal cancer patients, with 5-year overall survival rates up to 50 %. However, patients' quality of life is severely compromised by oesophagectomy, and eventually many patients die due to metastatic disease. Most solid tumours, including oesophageal cancer, contain hypoxic regions that are more resistant to chemoradiotherapy. The hypoxia-activated prodrug evofosfamide works as a DNA-alkylating agent under these hypoxic conditions, which directly kills hypoxic cancer cells and potentially minimizes resistance to conventional therapy. This drug has shown promising results in several clinical studies when combined with chemotherapy. Therefore, in this phase I study we investigate the safety of evofosfamide added to the chemoradiotherapy treatment of oesophageal cancer. METHODS/DESIGN: A phase I, non-randomized, single-centre, open-label, 3 + 3 trial with repeated hypoxia PET imaging, will test the safety of evofosfamide in combination with neo-adjuvant chemoradiotherapy in potentially resectable oesophageal adenocarcinoma patients. Investigated dose levels range from 120 mg/m2 to 340 mg/m2. Evofosfamide will be administered one week before the start of chemoradiotherapy (CROSS-regimen) and repeated weekly up to a total of six doses. PET/CT acquisitions with hypoxia tracer (18)F-HX4 will be made before and after the first administration of evofosfamide, allowing early assessment of changes in hypoxia, accompanied with blood sampling to measure hypoxia blood biomarkers. Oesophagectomy will be performed according to standard clinical practice. Higher grade and uncommon non-haematological, haematological, and post-operative toxicities are the primary endpoints according to the CTCAEv4.0 and Clavien-Dindo classifications. Secondary endpoints are reduction in hypoxic fraction based on (18)F-HX4 imaging, pathological complete response, histopathological negative circumferential resection margin (R0) rate, local and distant recurrence rate, and progression free and overall survival. DISCUSSION: This is the first clinical trial testing evofosfamide in combination with chemoradiotherapy. The primary objective is to determine the dose limiting toxicity of this combined treatment and herewith to define the maximum tolerated dose and recommended phase 2 dose for future clinical studies. The addition of non-invasive repeated hypoxia imaging ('window-of-opportunity') enables us to identify the biologically effective dose. We believe this approach could also be used for other hypoxia targeted drugs. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02598687 .

Evofosfamide (TH-302) is a hypoxia-activated prodrug with IC50 of 10 μM and 1000 μM in hypoxia (N2) and normoxia (21% O2), respectively.

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