rigosertib

Bone marrow blast response is defined as bone marrow (BM) complete response, ≥ 50% BM blast decrease from pretreatment value, or stable BM response (no progression) according to the International Working Group (IWG) 2006 criteria and overall survival. Overall survival is defined as the time from first study treatment to death from any cause. All patients will be followed until death and/or progression, even if they have discontinued treatment for whatever cause. Survival time of patients lost to follow-up will be censored at the time they were last known to be alive.

The number of patients who achieve hematologic improvement will be documented. Hematologic improvement is defined by the 2006 International Working Group (IWG) response criteria for the erythroid, platelet and neutrophil lineages.

Outcome is defined as the number of patients with Complete Response (CR) or Partial Response (PR) per revised Response Evaluation Criteria In Solid Tumors (RECIST 1.1). Complete response (CR) is defined as disappearance of all target lesions. Partial Response (PR) is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

Number of units of red blood cell transfusions will be compared with the pretreatment transfusion number in the previous 8 weeks.

MTD is defined as the highest dose for which at most 1 patient out of 6 experiences a dose-limiting toxicity (DLT)

ORR is defined as achieving an objective response of either complete response or partial response

Urine sample collection for radio analysis will be over the intervals of 24-30 hours (hr), 30-36 hr, 36-42 hr, 42-48 hr, 48-72 hr, 72-96 hr, 96-120 hr, and if necessary based on discharge criteria, at 120-144 hr, 144-168 hr, 168-192 hr, and 192-216 hr after the infusion start. Fecal sample collection for radio analysis will be over the intervals of 24-30 hr, 30-36 hr, 36-42 hr, 42-48 hr, 48-72 hr, 72-96 hr, 96-120 hr, and if necessary based on discharge criteria, at 120-144 hr, 144-168 hr, 168-192 hr, and 192-216 hr after the infusion start.

Concentration of rigosertib in plasma will be measured by a validated high performance liquid chromatography (HPLC) method. Plasma samples will be collected at 24 hours (hr) (immediately before the end of the infusion), 24.25 hr, 24.5 hr, 25 hr, 26 hr, 28 hr, 30 hr, 36 hr, 48 hr, 72 hr, and 96 hr after the infusion start, and, if the subject has not been discharged by then, at 144 hr, 192 hr, and 216 hr after the infusion start. Concentration values will be used to derive the following pharmacokinetic parameters: Cmax; tmax; AUC0-t; AUC0-∞; λZ; t1/2; CL; Vz; Vss.

Blood samples for radio analysis will be collected at 24 hours (hr) (immediately before the end of the infusion), 24.25 hr, 24.5 hr, 25 hr, 26 hr, 28 hr, 30 hr, 36 hr, 48 hr, 72 hr, and 96 hr after the infusion start, and, if the subject has not been discharged by then, at 144 hr, 192 hr, and 216 hr after the infusion start.

Plasma samples for radio analysis will be collected at 24 hours (hr) (immediately before the end of the infusion), 24.25 hr, 24.5 hr, 25 hr, 26 hr, 28 hr, 30 hr, 36 hr, 48 hr, 72 hr, and 96 hr after the infusion start, and, if the subject has not been discharged by then, at 144 hr, 192 hr, and 216 hr after the infusion start.

The primary objective of the study is to determine the maximum tolerated dose (MTD) of oral rigosertib when administered with platinum-based chemoradiotherapy to patients with intermediate- and high-risk Head and Neck Squamous Cell Carcinoma. The MTD is defined as the dose level immediately below that at which 2 or more patients experience a dose limiting toxicity (DLT).

Dose Limiting Toxicity is defined as Grade 3 or greater non-hematological toxicity or stomatitis and/or esophagitis/dysphagitis lasting longer than 3 days.

Adverse events will be coded using the most recent version of the Medical Dictionary for Regulatory Activities (MedDRA) and summarized by system organ class (SOC), preferred term (PT), and worst Common Terminology Criteria for Adverse Events (CTCAE) Version 4 grade per patient.

Adverse events will be coded using the most recent version of the Medical Dictionary for Regulatory Activities (MedDRA) and summarized by system organ class (SOC), preferred term (PT), and worst Common Terminology Criteria for Adverse Events (CTCAE) Version 4 grade per patient.

The following time points will be used to collect samples to determine the AUC on Day 1 and 15: Pre-dose the first dose of the day and at 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, and 8.0 hour post dose the first dose of the day.

The following time points will be used to collect samples to determine the Cmax on Day 1 and 15: Pre-dose the first dose of the day and at 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, and 8.0 hour post dose the first dose of the day.

DLT: adverse event possibly related that is: * Grade ≥ 3 non-hematological toxicity other than nausea, vomiting, diarrhea, fever, esophagitis/dysphagia * Grade ≥ 3 nausea and vomiting uncontrolled by antiemetics; grade ≥ 3 diarrhea uncontrolled by antidiarrheal agents; grade ≥ 3 drug-induced fever uncontrolled by antipyretics; grade ≥3 metabolic abnormalities that are not controlled by optimal supportive care measures * Grade ≥ 3 stomatitis and/or esophagitis/dysphagia lasting \> 3 days * Marrow cellularity \<5% on day 42 or later (6 weeks) from start of therapy without evidence of leukemia

Determine the clinical response rate (complete or partial remission) according to response criteria in patients with relapsed/refractory acute myeloid or lymphocytic leukemia (1 Cheson BD, Bennett JM, Kopecky KJ, et al. Revised Recommendations of the International Working Group for Diagnosis, Standardization or Response Criteria, Treatment Outcomes and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. JCO 21:4642, 2003).

Adverse events (AEs) will be regarded as treatment emergent signs and symptoms (TESS) if they started on or after the date and time of administration of the first dose of study drug, or if they were present prior to the administration of the first dose of study drug and increased in severity during the study. Adverse events include clinical laboratory parameters (e.g., Hematology Panel and Serum Chemistry Panel). Other safety parameters include vital signs, physical examination findings, concomitant medications, and drug exposure.

DLTs are defined as: * Grade 3 non-hematological toxicity other than nausea, vomiting, diarrhea, fever, stomatitis, esophagitis/dysphagia. * Grade 3 nausea and vomiting uncontrolled by antiemetics; Grade 3 diarrhea uncontrolled by antidiarrheal agents; Grade 3 drug-induced fever uncontrolled by antipyretics. * Grade 3 stomatitis and/or esophagitis/dysphagia lasting \>3 days. * Grade 4 neutropenia or thrombocytopenia lasting \>5 days. * Episode of neutropenic fever, as defined in Protocol. * Failure to recover neutrophils (\>1,500 per microliter) or platelets (\>75,000 per microliter) by day 28.

Safety assessments will be based on medical review of adverse event reports and the results of vital sign measurements, physical examinations, and clinical laboratory tests. Results will be reported as an aggregate of the adverse events using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0 terminology and grading.