Clinical Trials with RSR13 A total

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of 17 Phase I-III clinical studies making use of RSR13 have been completed or are ongoing in patients with cancer (including studies specifically enrolling patients with brain metastases, newly diagnosed and recurrent GBM, and NSCLC), surgical patients, patients with cardiovascular disease, and healthy subjects. Phase II studies in patients with brain metastases, GBM, and NSCLC have been completed. One randomized phase III study in patients with brain metastases is ongoing and, in addition, a phase I/II study is ongoing to evaluate RSR13 as an adjunct to BCNU chemotherapy in patients with recurrent malignant glioma.

The RSR13 dosing in clinical trials, using the drug in combination with radiotherapy, is based on a phase I trial that studied escalation of both drug dosing and frequency of administration (525). According to this open-label study in patients undergoing palliative irradiation to 20-40 Gy in 1015 fractions, RSR13 could be administered daily in doses of up to 100 mg/kg for 10 consecutive treatments through central venous access and supplemental nasal oxygen at 4 L/min. The tolerance of the drug was supported by clinical monitoring of oxygen saturation and associated pharmacokinetic and pharmacodynamic studies. At 100 mg/kg the peak increase in p50 averaged 8.1 mmHg, consistent with the targeted physiological effect (525).

2.6.1.4.1 Brain Metastases. Nearly one-third of patients with systemic cancer develop brain metastases, a complication that profoundly affects the patients' quality of life and survival. In early studies, untreated patients with brain metastases had a median survival time of about 1 month. Without more aggressive treatment, nearly all patients died as a direct result of the brain metastases (526). Even with contemporary treatment, specifically earlier diagnosis, radiation therapy, and systemic chemotherapy, approximately 30-50% of brain metastases patients die as a direct result of the brain metastases (527). Expanding intracranial tumor masses lead to intractable headaches, nausea and vomiting, serious cognitive dysfunction, and one or more focal neurological deficits, including hemiparesis, seizures, visual, speech, and gait disturbances (528). Acute, catastrophic neurological com plications, such as intracerebral hemorrhage and brainstem herniation, occur in 5-10% of brain metastases patients (529).

Study RT-008 was a phase II, open-label, multicenter study to assess the effect of on enhancing radiation therapy in patients with brain metastases. Patients received a standard 10-day course of whole-brain radiation therapy (WBRT) (3 Gy in 10 fractions = 30 Gy) within 30 min of receiving administered through a central venous access device. RSR13 administration began on the first day of WBRT and continued daily for a total of 10 doses.

Patient eligibility was based on histologically or cytologically confirmed breast, NSCLC, melanoma, genitourinary, or gastrointestinal primary carcinoma. Patients were stratified by recursive partitioning analysis (RPA), Class I or Class II, as previously described (529). A more recent analysis by the RTOG (Study 91-04) showed similar median survival times (MST) in each class. The analysis also indicated that no major change in the prognosis of brain metastases patients has been observed in the last 25 years, even with the advent of more aggressive multiagent CT regimens directed at both the primary tumor and extracranial metastases (530). At the time the study was closed there were 57 Class II patients enrolled.

The objective of the study was to compare MST in the study population to that from the RTOG Brain Metastases Database (BMD) through use of both the overall RTOG database and controls case-matched by prognostic factors. Exact case-matched controls were obtained for 38 patients [matching 5 of 5 criteria: age, Karnofsky Performance Status (KPS), extent of metastases, status of primary cancer, and location of primary tumor). RSR13-treated patients had significantly superior overall survival (6.4 months) compared to the historical BMD control group (4.1 months) ty Kaplan-Meier estimates of MST (P = 0.0269 compared to the overall database) (Fig. 4.5) (531, 532). One-year survival was 23% for RSR13-treated patients compared to 15% for the overall BMD population, and 9% for all case-matched BMD controls.

Further improvements in survival were observed for RSR13-treated patients compared

RTOG ]VBT= 4.1 mos --- RT-008M3T = 6.4mos P = 0.0269

RTOG ]VBT= 4.1 mos --- RT-008M3T = 6.4mos P = 0.0269

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