This is a phase I trial that will seek to determine the acute toxicity that occurs when the anti-angiogenic copper reduction agent Tetrathiomolybdate (TM), is combined with standard radiotherapy treatment in patients with stages II, IlIA, or IllB non-small cell lung cancer (NSCLC). TM is a copper reduction agent shown to be anti-angiogenic in humans, and to affect multiple proteins involved in angiogenesis via the copper depletion mechanism. Preclinical experiments demonstrate that TM can be successfully combined with radiotherapy to improve the treatment of local tumors in mice, and that the effect is additive and non-toxic. This trial will test whether a multi-target anti-angiogenic agent can be combined with radiotherapy in the treatment of cancer.
The specific aims of this proposal are: 1) to determine the acute toxicity that occurs when anti-angiogenic copper reduction therapy with tetrathiomolybdate (TM) is combined with standard radiotherapy in stage II-IIIB NSCLC. 2) To determine whether non-invasive markers of the effect of TM on angiogenesis can be found in these irradiated patients. The measurement of biological markers (VEGF, bFGF, TGF-?, IL-6, IL-8), and imaging studies with 99mTc-MIBI scanning will be used for this. Both have previously been shown to be important in angiogenesis. 3) To assess the late toxicity that occurs when TM is combined with standard radiotherapy in stage II-IIIB NSCLC. 4) To record the tumor response, recurrence, and survival data. Patients will begin on an induction regimen of TM that will rapidly deplete their copper down to ranges where angiogenesis is inhibited. The patients will be placed into one of four possible pre-assigned ranges of copper depletion and then standard radiotherapy will then be delivered. They will then continue at their assigned range of copper reduction for a total of one year using maintenance dosages of TM. The dose of TM will be determined by empiric (ceruloplasmin, Cp) measurements of each individual's copper chelation state. Serum collection and measurements of pro-angiogenic factors (shown to be affected by TM or radiotherapy), and 99mTc-MIBI scanning (shown to correlate with angiogenesis in tumors) will be done to non-invasively assess angiogenesis at different time points. Chest CT and Chest x-ray will be taken to record tumor response, and to compare with 99mTc-MIBI scans.
| Khan, Mohamed K; Mamou, Fatema; Schipper, Matthew J et al. (2006) Combination tetrathiomolybdate and radiation therapy in a mouse model of head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 132:333-8 |
