Oral Rigosertib for Squamous Cell Carcinoma

The primary objective of this study is to determine if tumors in patients with papillomavirus (HPV) positive or negative squamous cell carcinoma (SCC) that no longer responds to standard therapy will decrease in size following treatment with the investigational drug, rigosertib sodium (ON 01910.Na). A secondary objective is to determine if treatment with rigosertib causes any side effects.

Rigosertib is an investigational drug, which means that it has not been approved by the U.S. Food and Drug Administration (FDA) to treat any diseases. We are studying rigosertib as a new anticancer drug. Tests that we have done in the laboratory suggest that rigosertib works by blocking cell division in cancer cells and causing them to die.

This will be a multicenter, Phase II study to evaluate the safety and efficacy of oral rigosertib in patients with relapsed or metastatic squamous cell carinoma (SCC) who previously received platinum-based chemotherapy and/or chemo-radiation therapy.

Only patients with head and neck squamous cell carinoma (HNSCC), non-small cell lung SCC, skin SCC, cervical SCC, penile SCC, anal SCC or esophageal SCC will be enrolled in the study.

Patients will be administered rigosertib capsules at a dose of 560 mg BID on days 1 to 14 of a 21-day cycle. Patients will be enrolled in 2 cohorts based on HPV test results:

* Cohort 1 will include up to 40 patients with human papillomavirus (HPV)-positive SCC, of which approximately 30 patients will have HNSCC, and approximately 10 patients with SCC of another origin (eg, cervix, anal, penile);
* Cohort 2 will include up to 40 patients with HPV-negative SCC, of which approximately 30 patients will have HNSCC, and approximately 10 patients with SCC of another origin (eg, lung, skin, esophageal).

Patients will be evaluated for progression after completing 3 cycles of therapy and every 3 cycles thereafter. Patients with stable disease (SD) or better, based on revised Response Criteria in Solid Tumors (mRECIST) 1.1, will receive repeated cycles of treatment on a 21-day cycle schedule until disease progression, development of unacceptable toxicity, or withdrawal of consent. Patients with progressive disease (PD) but who, in the opinion of the Investigator, appear to be deriving clinical benefit, may continue on study with a planned disease reassessment after one further cycle of therapy. Should the patient have SD or PR at this reassessment, s/he may continue on study, with subsequent reassessments every 3 cycles.

Following discontinuation of rigosertib treatment, patients' mortality status will be assessed every 3 months.

Eligibility Criteria:
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.