Phase I Study of CUDC-101 With Cisplatin and Radiation in Subjects With Head & Neck Cancer

A Phase I Dose Escalation Study to Investigate the Safety and Pharmacokinetics of Intravenous CUDC-101 With Concurrent Cisplatin and Radiation Therapy in Subjects With Locally Advanced Head and Neck Cancer

This is a phase I dose escalation study of CUDC-101 in combination with concurrent cisplatin and radiation therapy in patients with locally advanced head and neck cancer. CUDC-101 is a multi-targeted agent designed to inhibit epidermal growth factor receptor (EGFR), human epidermal growth factor receptor Type 2 (Her2) and histone deacetylase (HDAC). The study is designed to establish the safety, tolerability and maximum tolerated dose (MTD) of CUDC-101 when administered in combination with concurrent cisplatin and radiation over an 8-week treatment course, consisting of a one week run-in period of CUDC-101 administered alone, followed by seven weeks of combination treatment with CUDC-101, cisplatin and radiation therapy.

Inclusion Criteria:

• Subjects with locally advanced, pathologically confirmed diagnosis of squamous cell carcinoma of the head and neck at the following sites: oral cavity, oropharynx, hypopharynx and larynx with either:

  • Stage IV p16 positive tumors and >10 pack-years smoking history.
  • Stage III/IV p16 negative tumors, regardless of smoking history.

• At least evaluable disease; one measurable site of disease according to RECIST (Version 1.1) criteria (at least 10 mm for conventional CT/MRI or spiral CT scan) is desirable.

• Subjects enrolled in the MTD expansion cohort must have at least 1 tumor lesion that is suitable for repeat biopsy (pre- and post-CUDC-101 infusion).

• Age ≥ 18 years

• ECOG performance < 2

• Life expectancy ≥ 3 months

• If female, neither pregnant nor lactating

• If of child bearing potential, must use adequate birth control throughout the participation in the treatment phase and for 60 days following the last study treatment.

• Absolute neutrophil count ≥ 1,800/µL; platelets ≥ 100,000/µL; hemoglobin ≥ 8.0 g/dL, creatinine ≤ 1.5x upper limit of normal (ULN); total bilirubin ≤ 1.5x ULN; AST/ALT ≤ 2 x ULN.

• Serum magnesium and potassium within normal limits (may be supplemented to achieve normal values)

• Able to render informed consent and to follow protocol requirements.

Exclusion Criteria:

• Prior radiotherapy to the region of the study cancer or adjacent anatomical sites, or > 25% of marrow-bearing area.
• Prior chemotherapy for the current indication.
• Prior therapy that specifically and directly targets EGFR, HER2 or HDAC.
• Use of investigational agent(s) within 30 days prior to study treatment.
• Primary tumor site of nasopharynx, sinuses, or salivary gland.
• History of cardiac disease with a New York Heart Association (NYHA) Class II or greater congestive heart failure (CHF), myocardial infarction (MI) or unstable angina in the past 6 months prior to Day 1 of treatment, serious arrhythmias requiring medication for treatment.
• Patients with prolonged QTc Interval >450 msec.
• Acquired Immune Deficiency Syndrome (AIDS) or known infection with human immunodeficiency virus (HIV). Testing is not required.
• Known history of gastrointestinal bleeding, ulceration, or perforation within 6 months prior to study treatment.
• Known history of stroke or cerebrovascular accident within 6 months prior to study treatment.
• Symptomatic cardiac conduction abnormality within 12 months prior to study treatment.
• Prior history of hearing impairment.
• Known history of renal disease or ongoing renal impairment.
• Any uncontrolled condition (such as active systemic infection, diabetes, hypertension), which in the opinion of the investigator, could affect the subjects participation in the study.
• Prior allergic reaction to cisplatin, carboplatin or other platinum-containing compounds.
• Central nervous system metastases.