A Trial of Concurrent Radiation Therapy, Cisplatin, and BMX-001 in Locally Advanced Head and Neck Cancer

Inclusion criteria

• Pathologically confirmed diagnosis of squamous cell carcinoma of the oropharynx, larynx, hypopharynx, or oral cavity with clinical or pathologic high-risk features for whom cisplatin and radiation would be considered appropriate care.
• Treatment plan to receive a continuous course of IMRT delivered as single daily fractions of 2.0 to 2.1 Gy with a cumulative radiation dose between 60 Gy and 70 Gy depending on whether patients are considered post-operative high risk or unresectable/organ preservation high risk. Planned radiation treatment fields must include at least two oral sites buccal mucosa, retromolar trigone, floor of mouth, oral tongue, soft palate, hard palate) with a portion of each site receiving a minimum total of 50 Gy.
• Patients who are to undergo definitive chemoradiation must have clinically or radiographically evident measurable disease at the primary site and/or at nodal stations. Tonsillectomy or local excision of the primary without removal of nodal disease is permitted.
• Limited neck dissections retrieving ≤ 4 nodes are permitted and considered as non-therapeutic nodal excisions. Fine needle aspirations of the neck that are positive for squamous cell carcinoma are sufficient for diagnosis pending pathology review at participating institutions.
• For patients undergoing curative intent resection the following criteria are required:

• Pathologically (histologically or cytologically) proven diagnosis of head and neck squamous cell carcinoma
• Patients must have undergone gross total surgical resection within 42 days prior to registration and beginning of therapy under the clinical trial. Note: Patients may have biopsy under general anesthesia in an operating room followed by definitive ablative cancer surgery representing gross total resection.
• Clinical or pathologic stage Stage III-IVb per the American Joint Committee on Cancer (AJCC), 7th edition.
• General history and physical examination by a radiation oncologist and medical oncologist within 4 weeks prior to enrollment.
• Examination by an ear/nose/throat (ENT) or head and neck surgeon, including laryngopharyngoscopy (mirror and/or fiberoptic and/or direct procedure) within 8 weeks prior to enrollment.
• Zubrod Performance Status 0-2 within 4 weeks prior to enrollment
• Complete blood count (CBC)/differential obtained within 7 days prior to starting the study drug with adequate bone marrow function, defined as follows:

• Hemoglobin ≥ 9.0 g/dl;
• Platelets ≥ 100,000 cells/mm3;
• Absolute neutrophil count (ANC) > 1,500 cell/mm3.
• Adequate hepatic function as defined as follows:

• Total bilirubin < 2x institutional upper limit of normal (ULN) within 7 days prior to starting the study drug;
• Aspartate aminotransferase (AST) and AST <3x institutional ULN within 7 days prior to starting the study drug.
• Adequate renal function defined as follows:

• Serum creatinine < 1.5 mg/dl within 7 days prior to starting the study drug or creatinine clearance rate (CCr) ≥ 50 mL/min within 7 days prior to starting the study drug determined by 24-hour collection or estimated by Cockcroft-Gault formula:

CCr male = [(140 - age) x (wt in kg)]/[(Serum Cr mg/dl) x (72)] CCr female = 0.85 x (CrCl male)

• Negative pregnancy test for women of child-bearing potential within 48 hours prior to first dose of BMX-001.
• Women of childbearing potential and male participants must agree to use a medically effective means of birth control throughout their participation in the treatment phase of the study and until 12 months following the last study treatment.

Exclusion criteria

• Stage I or II; T1N1 and T2N1 stage III presentations per AJCC 7th edition
• Distant metastasis
• Hypertension requiring 3 or more anti-hypertensive medications to control
• Grade ≥2 hypotension at screening
• 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
• Patients receiving, or unable to stop use at least 1 week prior to receiving the first dose of BMX-001, medications listed in Section 12.2 of the protocol are not eligible.
• 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 are not eligible
• Prior allergic reaction to cisplatin
• Known hypersensitivity to compounds of similar chemical composition to BMX-001
• Grade 3-4 electrolyte abnormalities (CTCAE v 4.03) except sodium, which must be ≥126 mmol/L.
• Prior unrelated malignancy requiring current active treatment with the exception of cervical carcinoma in situ, basal cell carcinoma of the skin, resected T1-2N0M0 differentiated thyroid cancers, invasive cancers with a 3-year disease-free interval, Ta bladder cancers, or low and favorable intermediate risk prostate cancer.
• Prior history of HNSCC receiving radiation or chemo-radiation.
• Prior systemic chemotherapy for the study cancer (including neoadjuvant chemotherapy); note that prior chemotherapy for a different cancer is allowable.
• Prior radiotherapy that would result in overlap of radiation treatment fields with planned treatment for study cancer.
• Severe, active co-morbidity, defined as follows:

• Cardiovascular disease or cerebrovascular disease, for example cerebrovascular accidents or myocardial infarction ≤ 6 months prior to study enrollment, unstable angina, New York Heart Association (NYHA) Grade II or greater congestive heart failure (CHF), or serious cardiac arrhythmia uncontrolled by medication or with the potential to interfere with protocol treatment;
• Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months prior to enrollment;
• History or evidence upon physical/neurological examination of central nervous system disease (e.g., seizures) unrelated to cancer unless adequately controlled by medication;
• Acute bacterial or fungal infection requiring intravenous antibiotics within 7 days of enrollment;
• Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days of registration;
• Patients known to be HIV positive or have active viral hepatitis.