Platinum-based Chemoradiotherapy and Rigosertib in Head and Neck Cancer

This is a multicenter, dose-escalating study of oral rigosertib administered with concurrent cisplatin and Radiotherapy in patients with intermediate- and high-risk Head and Neck Squamous Cell Carcinoma.

Three rigosertib escalating cohorts (up to 6 patients per cohort) will be sequentially evaluated: 70 mg 3 times a day (TID), 140 mg TID and 280 mg TID. The total treatment course will be 8 weeks: 1 week of oral rigosertib alone (70 mg TID, 140 mg TID or 280 mg TID) followed by 7 weeks of concurrent administration of rigosertib, cisplatin and radiation therapy.

After completion of treatment, patients will be followed for up to 36 months to document Progression-free Survival and Overall Survival.

Inclusion criteria

• Pathologically confirmed diagnosis of Squamous Cell Carcinoma of the oropharynx (tonsil, base of tongue, soft palate, or oropharyngeal wall), hypopharynx, or larynx.
• Patient is an appropriate candidate for definitive chemoradiotherapy.
• Intermediate-risk Head and Neck Squamous Cell Carcinoma (HNSCC), defined as follows:

• Clinical stage T2-4, N2a-N3 or T3-4, N0-N3
• P16 (+) by immunohistochemistry (IHC) or HPV (+) by in situ hybridization (ISH)
• Smoking status of ≥ 10 pack-years, or < 10 pack-years and T4 or N2c-N3.
• If not intermediate-risk HNSCC, is high-risk HNSCC, defined as follows:

• Clinical stage T2-4, N2a-N3 or T3-4, N0-N3.
• P16 (-) by IHC or HPV (-) by ISH.
• No evidence of distant metastases.
• Clinically or radiographically evident measurable disease (as defined by RECIST v 1.1) at the primary site or nodal stations.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Adequate hematologic function as defined by absolute neutrophil count (ANC) ≥ 1800/μL; platelet (PLT) ≥ 100,000/μL; Hgb ≥ 8.0 g/dL.
• Adequate renal function, as defined by serum creatinine ≤ 1.5 x upper limit of normal (ULN) or calculated creatinine clearance ≥ 60 mL/min.
• Adequate liver function as defined by total bilirubin ≤ 1.5 x ULN; aspartate transaminase (AST)/alanine transaminase (ALT) ≤ 2.5 x ULN; and prothrombin time ≤ 1.5 x ULN, unless receiving therapeutic anticoagulation.
• Ability to understand the nature of the study and any hazards of study participation, to communicate satisfactorily with the Investigator, and to follow the requirements of the entire protocol.
• Willingness to adhere to the prohibitions and restrictions specified in this protocol.
• The patient must sign an informed consent form (ICF) indicating that s/he understands the purpose of and procedures required for the study and is willing to participate in the study.

Exclusion criteria

• Gross total excision of the primary and nodal disease.
• Prior treatment with IV or oral rigosertib.
• Prior chemotherapy for the study HNSCC cancer.
• Prior radiotherapy to the region of the study HNSCC cancer or adjacent anatomical sites, or to > 25% of marrow-bearing area.
• Synchronous malignancies.
• Prior invasive malignancy unless the patient is disease-free for a minimum of 3 years; however, patients with prior non-melanoma skin cancer, cervical intraepithelial neoplasia (CIN), or prostate cancer with undetectable prostate-specific antigen (PSA) may be enrolled.
• Severe, active comorbidity.
• Known infection with human immunodeficiency virus (HIV).
• Any uncontrolled condition that, in the opinion of the Investigator, could affect the subject's participation in the study.
• Major surgery within 3 weeks of enrollment or major surgery without full recovery.
• Ascites requiring active medical management, including paracentesis.
• Hyponatremia (defined as serum sodium < 130 milliequivalent mEq/L) or conditions that may predispose patients to hyponatremia.
• Uncontrolled hypertension, defined as systolic blood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 110 mmHg, despite treatment with 2 antihypertensive agents.
• New onset of seizures within 3 months prior to enrollment, or poorly controlled seizures.
• Female patients who are pregnant or lactating.
• Female patients of childbearing potential and male patients with partners of childbearing potential who are unwilling to follow strict contraception requirements.
• Female patients of childbearing potential who do not have a negative blood or urine pregnancy test at Screening.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to rigosertib.
• Prior therapy with a phosphatidyl-inositol 3 kinase (PI3K), Akt or mammalian target of rapamycin (mTOR) inhibitor.
• Any other investigational agent or chemotherapy, radiotherapy, or immunotherapy within 4 weeks of enrollment.
• Psychiatric illness/social situations that would limit the patient's ability to tolerate and/or comply with study requirements, or inability to comply with study and/or follow-up procedures.