Phase 2a Study to Evaluate Suppression of Methotrexate-induced Mucositis by TK112690

Patients will receive methotrexate at a dose of 45 mg/m2 administered weekly for 4 consecutive weeks as an iv infusion along with a nutritional supplement administered two hours before the methotrexate. One hour before the methotrexate treatment the patients will be administered the first infusion of the day of either TK112690 or placebo depending on randomization infusion. Five hours after the methotrexate treatment the patients will be administered the second treatment of either TK112690 or placebo depending on randomization. The TK112690 dose will be 45 mg/kg.

• A total of 22 patients will be enrolled into one of 2 different dose groups: TK-112690 treated or placebo treated.
• Screening must be within 15 days of subject enrollment.
• Patients will remain for observation at the clinical site for a minimum of 25 hours post initial TK112690 or placebo dose.
• Study follow-up will occur on Week 6, two weeks after the last dosing of methotrexate.
• Blinding: The study will be partially blinded. The patient and investigator will be blinded as to whether TK112690 or placebo is administered. The CRO, sponsor, and site pharmacist will know whether the patient was administered active drug or placebo.

Inclusion criteria

• Male and female subjects over 18 years old with a histologically or cytological confirmed diagnosis of locally residual, recurrent or metastatic SCCHN.
• Subject must have failed at least one courses of non-MTX chemotherapy, or one course of non-MTX chemotherapy and chemo radiation for treating their SCCHN.
• No prior systemic treatments for cancer (chemotherapy and/or radiotherapy) 4 weeks prior to screening.
• No other concurrent, active, invasive malignancies.
• An Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
• Must have a life expectancy of at least 6 months.
• History of brain metastases allowed if disease has stabilized or improved after radiation and/or craniotomy.
• No active angina or uncontrolled arrhythmia.
• No detectable infection including hepatitis B/C and HIV.
• Not pregnant or nursing. Women of childbearing potential must have a negative urine pregnancy test at screening and on the day before dosing and must use medically acceptable methods of birth control. Acceptable methods of birth control include oral or transdermal contraceptives, condoms, spermicidal foam, IUD, progestin implant or injection, abstinence, vaginal ring, or sterilization of partner. The reason for non-childbearing potential, such as bilateral tubal ligation, bilateral oophorectomy, hysterectomy, or post-menopausal for ≥ 1 year, must be specified in the patient's medical history file and CRF.
• Must have adequate organ and immune function as indicated by the following laboratory values:

Parameter Laboratory Values Serum creatinine ≤1.5 x ULN Est. creatinine clearance ≥45 mL/min Total bilirubin ≤2.0 mg/dL (≤34.2 μmol/L) AST & ALT ≤3 x ULN Absolute granulocytes ≥1.5 x 109 cells/L Platelets ≥100,000/µL

● Be able to read and understand, and provide a signature or thumb impression on the Informed Consent Form (ICF) before entering the study.

Exclusion criteria

• Subject has not failed at least one courses of non-MTX chemotherapy or one course of non-MTX chemotherapy and chemo radiation for treating their SCCHN.
• Uncontrolled active infection.
• Current mucositis (>Grade 1).
• Pregnant or nursing mother.
• Prior history of a cerebrovascular accident or hemorrhage.
• Congestive heart failure, as defined by New York Heart Association class III or IV.
• Uncontrolled hypertension.
• Active psychiatric/mental illness making informed consent or useful clinical follow-up unlikely.
• Subjects who have previously been enrolled into this study and subsequently withdrew.
• Subject receiving other investigational agent(s).
• Any systemic immunosuppressive medication/therapy (eg, other chemotherapy, steroids).
• Any significant systemic illness, unstable or severe medical condition(s) that could put the subject at risk during the study, interfere with outcome measures, or affect compliance with the protocol procedures such as intercurrent infection and/or autoimmune disease, ie, any condition that compromises the immune system.
• Known or suspected intolerance or hypersensitivity to the study materials (TK-112690 and/or excipients or closely related compounds).
• Subjects, who have received, or plan to receive, radiation or chemotherapy within 4 weeks of screening.
• Subjects that have a history of poor compliance in clinical research studies.
• Subjects that have participated in any other investigative clinical trial in the past 4 weeks.