Oral Rigosertib for Squamous Cell Carcinoma

Inclusion Criteria: 1. Histologically confirmed SCC; only patients with HNSCC, non-small cell lung SCC, skin SCC, cervical SCC, penile SCC, anal SCC, or esophageal SCC; 2. For patients with HNSCC only, HPV status must be assessed by in situ hybridization (ISH) and/or p16 immunohistochemistry (IHC) according to local standards; 3. For patients with HNSCC only, HPV status must be assessed by in situ hybridization (ISH) and/or p16 immunohistochemistry (IHC) according to local standards. For all other patients with SCC originating in tissues other than the head and neck, attempts should be made to obtain HPV status; 4. Incurable, non-resectable, locally-advanced/relapsed and/or distant metastatic disease after no more than 3 prior treatment regimens, one of which must be platinum-based chemotherapy; 5. Eastern Cooperative Oncology Group (ECOG) performance status ≤2; 6. Life expectancy of at least 3 months; 7. Measurable disease according to RECIST version 1.1; 8. Ability to swallow entire capsules; 9. Adequate hematologic function; 10. Adequate hepatic function; 11. Adequate renal function; 12. Adequate contraceptive regimens for female and male patients; 13. Female patients with reproductive potential must have a negative urine or serum pregnancy test; 14. 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; 15. Willingness to adhere to the prohibitions and restrictions specified in this protocol; 16. The patient must sign an informed consent form (ICF). Exclusion Criteria: 1. Chemotherapy or any potentially myelosuppressive treatment within 3 weeks prior to enrollment (6 weeks are required for nitrosoureas or mitomycin C); 2. Radiotherapy to \>25% of the hematopoietic active bone marrow within 4 weeks prior to enrollment; 3. Systemic administration of corticosteroids within the past 4 weeks prior to enrollment; 4. Prior therapy with a phosphatidylinositol 3-kinase (PI3K), Akt or mammalian target of rapamycin (mTOR) inhibitor; 5. Any other investigational agent or chemotherapy, radiotherapy, or immunotherapy within 4 weeks of enrollment; 6. Major surgery within 3 weeks of enrollment or major surgery without full recovery; 7. Residual clinical signs and symptoms which have not recovered to Common Terminology Criteria for Adverse Events (CTCAE) version 4 Grade 1 severity level or below before enrollment, except for alopecia, stable residual neuropathy, and residual hand/foot syndrome; 8. Known brain metastases, except for those that have been removed or irradiated and have no current clinical impact at the time of enrollment; a computed tomography (CT) scan or magnetic resonance imaging (MRI) of the brain should be obtained in patients with symptoms suggestive of brain metastases; 9. Ascites requiring active medical management, including paracentesis; 10. Serum sodium less than 130 mEq/L or conditions that may predispose patients to hyponatremia (eg, previous syndrome of inappropriate antidiuretic hormone hypersecretion \[syndrome of inappropriate antidiuretic hormone secretion (SIADH)\], chronic diuretic use, etc.); 11. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, bleeding, symptomatic congestive heart failure, unstable angina pectoris, and cardiac arrhythmia; 12. Uncontrolled hypertension, defined as systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥110 mmHg; 13. New onset of seizures within 3 months prior to enrollment, or poorly controlled seizures; 14. Psychiatric illness/social situations that would limit the patient's ability to tolerate and/or comply with study requirements; 15. History of allergic reactions attributed to compounds of similar chemical or biologic composition to rigosertib; 16. Female patients who are pregnant or lactating.