A Trial for Treatment of Cancer Patients With Multiple Brain Metastases Undergoing Whole-Brain Radiotherapy

A Safety Lead-In/Randomized Phase 2 Study of BMX-001 as a Therapeutic Agent for Treatment of Cancer Patients With Multiple Brain Metastases Undergoing Whole-Brain Radiotherapy

This protocol is for a lead-in safety study of 5 patients followed by a randomized Phase 2 clinical trial of BMX-001, a new class of pharmaceutical, in 64 patients with multiple brain metastases (MBM) undergoing whole brain radiation therapy (WBRT). Preliminary studies have demonstrated that BMX-001 provides protection of normal tissues from radiation-induced injury and augments tumor growth inhibition.

This protocol is for a Phase 1 safety lead-in clinical trial of BMX-001 in combination with WBRT in 5 patients with MBM. Demonstrating safety of the selected MTD of BMX-001 in patients with MBM undergoing standard protocol WBRT will be the "go/no-go" criteria for proceeding to Phase 2.

Phase 2 is a randomized open-label Phase 2 clinical trial of 64 patients with MBM, half receiving BMX-001 in combination with WBRT and half receiving WBRT alone.

Subjects are treated with BMX-001 for a total of 19 days, during which time they receive radiation therapy. Following completion of radiation therapy, subjects will be followed for an additional one year.

Inclusion Criteria:

• Subjects must have histologically confirmed diagnosis of a non-small cell lung cancer, breast cancer, melanoma or renal cell cancer primary
• Subjects must have >5 contrast-enhancing lesions, never previously treated with SRS and/or surgical resection, on a contrast-enhanced T1-weighted brain MRI performed within two weeks of enrollment, with at least one lesion >0.5cm in greatest dimension
• Physical examination by a radiation oncologist or medical oncologist within 14 days of the start of WBRT
• Plan to be treated with WBRT to a dose of 30 Gy in 10 fractions
• Age * 18 years
• Karnofsky Performance Status (KPS) ≥ 70
• Hemoglobin ≥ 9.0 g/dl, ANC ≥ 1,500 cells/*l, platelets ≥ 125,000 cells/*l
• Serum creatinine ≤ 1.5 mg/dl, serum SGOT and bilirubin ≤ 1.5 times upper limit of normal
• Signed informed consent approved by the Institutional Review Board
• If sexually active, patients must agree to use appropriate contraceptive measures for the duration of the study and for 6 months afterwards as stated in the informed consent
• Able to provide study specific informed consent
• Willing to follow study procedures, complete QOL questionnaires and neurocognitive testing as described in the protocol
• Negative serum pregnancy test for women of child bearing potential within 48 hours of first dose of BMX

Exclusion Criteria:

• Active infection requiring IV antibiotics 7 days before enrollment
• Hypertension requiring 3 or more anti-hypertensive medications to control
• Requirement for concurrent treatment with nitrates or other drugs that may, in the judgment of the treating investigator, create a risk for a precipitous decrease in blood pressure
• History of syncope within the last 6 months
• Subjects receiving prohibited medications listed in Section 6.4.2 of this protocol are not eligible. Subjects who can safely stop taking a prohibited medication at least 7 days prior to the first dose of BMX may participate at the discretion of the treating physician.
• Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic
• Women who are breast feeding
• Known hypersensitivity to compounds of similar chemical composition to BMX-001
• Prior surgical resection for brain metastases and/or stereotactic radiosurgery for up to 5 brain metastases in total are permitted if performed at least 1 month prior to planned WBRT under this protocol.
• Prior whole brain radiation therapy
• Patients with diffuse leptomeningeal disease (carcinomatous meningitis)
• A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval >480 milliseconds (ms) (CTCAE grade 1)
• A history of additional risk factors for TdP (e.g., congestive heart failure, hypokalemia, known family history of Long QT Syndrome)