Oral Rigosertib for Squamous Cell Carcinoma

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.

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.