Antineoplastic Agents

All Drugs and Chemicals

ON 01910

Protein Kinase Inhibitors

Enzyme Inhibitors

Patients will receive escalating doses of ON 01910.Na (250 mg/m2 to 4450 mg/m2) intravenously by 24 hour continuous infusion once every week (3 weeks per cycle), until evidence of disease progression, intolerable adverse events, or withdrawal of patient consent.

rigosertib sodium

Sridhar Mani, MD

The primary purpose of this study is to determine the highest dose of ON 01910.Na that can be safely given as an intravenous infusion over 24 hours once a week in a 3-week cycle to patients with advanced solid tumors.

This is an open-label, dose-escalating Phase I study of ON 01910.Na in patients with advanced cancers, who have satisfied the inclusion/exclusion criteria enumerated in this protocol. Patients will receive ON 01910.Na intravenously by 24 hour continuous infusion once every week (3 weeks per cycle), until evidence of disease progression, intolerable adverse events, or withdrawal of patient consent. Safety monitoring will be done for at least 3 weeks before escalation to the next dose level. As of Amendment 7, up to 6 patients with gynecological malignancies will be enrolled at the 2400 mg/m2 dose level to determine the appropriateness of this dose as the Recommended Phase Two Dose (RPTD).

Safety of 24-Hour Infusion of ON 01910.Na in Patients With Advanced Cancer

Phase I Dose Escalation Study of ON 01910.Na by 24 Hour Continuous Infusion Per Week in Patients With Advanced Cancer

DLTs are defined as:

* Grade 3 non-hematological toxicity other than nausea, vomiting, diarrhea, fever, stomatitis, esophagitis/dysphagia.
* Recurrent grade 3 toxicity uncontrolled by optimal therapy or Grade 4 nausea, vomiting, diarrhea and fever.
* Grade 3 stomatitis and/or esophagitis/dysphagia for \> 5 days.
* Grade 4 neutropenia or thrombocytopenia for \> 5 days measured at least 2X 2-3 days apart.
* Neutropenic fever, as defined in Protocol.
* Failure to recover neutrophils (\> 1,500 per microliter) or platelets (\>75,000 per microliter) before the next weekly dose.

All AEs (except Grade 1 and 2 laboratories abnormalities that do not require an intervention) are recorded in Case Report Forms and source documentation.

Severity of AEs are determined according to Common Terminology Criteria for Adverse Events (Version 3.0)

Relationship assessed as Not related, Unlikely, Possibly, Probably, or, Definitely according to Guidance in Appendix II of Protocol.

Blood samples will be collected at following time points: Pre-dose; 1 h after start of infusion; 3 h; 6 h; 12 h; 18 h; 24 h; 10 min after end of infusion; 20 min; 30 min; 1 h; 2 h; 4 h; 8 h; 24 h; and, 48 h. Plasma will be prepared from these samples. Concentration of ON 01910.Na will be determined by validated method.

The same method of assessment for each identified and recorded lesion will be used at baseline and each follow-up.

Traws Pharma, Inc.

Symptoms and General Pathology

All Conditions

Neoplasms

Blood and Lymph Conditions

Rare Diseases

Syndrome

Preleukemia

Myelodysplastic Syndromes

Trisomy

Bone Marrow Diseases

Hematologic Diseases

Precancerous Conditions

Aneuploidy

Chromosome Aberrations

Chromosomal Triplication

560 mg oral rigosertib in the morning and 280 mg rigosertib in the afternoon on days 1 to 21 of 21-day cycle

Rigosertib sodium will be available as soft gel capsules in strengths of 280 mg and 70 mg. Rigosertib will be administered on an outpatient basis.

Patients will take a 560 mg dose (e.g., 2 x 280 mg capsules) of oral rigosertib in the morning and 280 mg dose (e.g., 1 x 280 mg capsules) of oral rigosertib every day of 21-day cycles. Rigosertib should be taken in a fasting state (defined by at least 30 minutes before next meal) BID at 12 hr intervals (with a window of 2 hr). Any vomited dose will be reported as a missed dose.

The patient will fill a diary indicating the day and time of drug intake.

rigosertib

Steven M. Fruchtman, MD

The primary objectives of this study are to determine if rigosertib sodium, given orally in the form of soft gel capsules, is safe and is associated with a reduction in the number of blood transfusion units that are needed in patients with myelodysplastic syndrome (MDS) classified as Low or Intermediate-1 (Int-1) (any cytogenetics) or trisomy 8 Intermediate 2 (Int-2) in the International Prognostic Scoring System (IPSS) who are transfusion-dependent. Rigosertib will be taken on days 1 to 21 of a 21-day cycle.

This will be a Phase II open-label, multicenter (up to 5 centers), single-arm study. Sixty transfusion-dependent patients with MDS classified as Low or Int-1 risk (any cytogenetics) or trisomy 8 Int-2 by International Prognostic Scoring System (IPSS) will be enrolled to receive rigosertib BID for 21 consecutive days of a 21-day cycle.

Patients will be stratified on prior treatment with azacitidine and/or decitabine and/or lenalidomide and/or erythropoietin.

Patients will remain treated on study until 2006 Internation Working Group (IWG) progression criteria are met or until death from any cause.

All study participants will be allowed, as medically justified, access to RBC and platelet transfusions, and to filgrastim \[G-CSF\]. Erythropoiesis-stimulating agents (ESAs) will not be allowed during the initial 3 cycles. Rigosertib dosing adjustment policies are described in Protocol.

Efficacy and Safety of Oral Rigosertib in Transfusion-dependent, Low or Int-1 or Trisomy 8 Int-2 Myelodysplastic Syndrome

A Phase II, Multicenter, Single-arm Study to Assess the Efficacy and Safety of Oral Rigosertib in Transfusion-dependent Low or Intermediate-1 (Any Cytogenetics) or Trisomy 8 Intermediate-2 Myelodysplastic Syndrome Patients Based on IPSS Classification

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

AEs reported by the patient or observed by the Investigator or study site personnel Safety assessments will be counted and documented on Case Report Forms and source documents. All AEs from signature of the ICF through 30 days after a patient discontinues from the study will be included.

Change in number of bone marrow blasts will be compared to pretreatment.

Digestive System Diseases

Gland and Hormone Related Diseases

Adenocarcinoma

Pancreatic Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Endocrine Gland Neoplasms

Gastrointestinal Diseases

Pancreatic Diseases

Endocrine System Diseases

Pancreatic Cancer

Gemcitabine

Antimetabolites

Arm A: Gemcitabine, 1000 mg/m2 weekly for 3 weeks of a 4 week cycle, + ON 01910.Na, 1800 mg/m2 via 2 hr CIV infusions administered twice weekly for 3 weeks of a 4 week cycle.

Arm B: Gemcitabine only, 1000 mg/m2 weekly for 3 weeks of a 4 week cycle.

ON 01910.Na, 1800 mg/m2 via 2 hr CIV infusions administered twice weekly for 3 weeks of a 4 week cycle.

ON 01910.Na

Gemcitabine 1000 mg/m2 weekly for 3 weeks of a 4 week cycle.

Gemcitabine, 1000 mg/m2 weekly for 3 weeks of a 4 week cycle.

Wells Messersmith, MD

Lawrence P. Leichman, MD

Antonio Jimeno, MD, PhD

The question being asked in this study is: Will patients with advanced pancreatic cancer live significantly longer if they are treated with a combination of Gemcitabine and ON 01910.Na than if they are treated with Gemcitabine alone? There are two parts to this study. In the first part of the study, patients with metastatic pancreatic cancer who have received no prior chemotherapy for this disease will be assigned by chance either to the group that will be treated with both Gemcitabine and ON 01910.Na (about 100 patients will be in this group) or, to the group that will be treated with Gemcitabine only (about 50 patients will be in this group). How long patients survive in the 2 groups will be compared. If it looks like there is no difference between the groups, the study will stop. If it looks like patients in the group that were treated with both Gemcitabine and ON 01910.Na survive longer, the study will continue into a second part where more patients will be treated in order to confirm and better understand the findings of the first part of the study.

This will be a Phase III study with sample size recalculation after 100 events have occurred. The study will be open-label, randomized, controlled, multi-center and will be conducted at approximately 200 to 300 study sites (60 to 80 study sites in the first portion of the trial).

In the first portion of the study, a total of 150 patients with metastatic pancreatic cancer who have received no prior chemotherapy for this disease will be randomized in a 2:1 fashion to 1 of the 2 following treatment regimens:

* Arm A: Gemcitabine 1000 mg/m2 weekly for 3 weeks of a 4 week cycle + ON 01910.Na 1800 mg/m2 via 2 hr continuous intravenous infusion (CIV) infusions administered twice weekly for 3 weeks of a 4 week cycle (approximately 100 patients)
* Arm B: Gemcitabine only, 1000 mg/m2 weekly for 3 weeks of a 4 week cycle (approximately 50 patients).

Patients will be stratified at entry using the Eastern Cooperative Oncology Group (ECOG) performance status (ECOG scores of 0 1 vs. ECOG scores of 2; patients with higher scores will not be enrolled).

Patients will remain on study until disease progression or death from any cause, whichever comes first. Moreover, after treatment discontinuation for any cause, all patients will be followed until death.

After 150 patients have been enrolled, accrual will pause and patients will be followed until 100 deaths have occurred. At that time, the Data Safety Monitoring Committee (DSMC) will oversee a formal interim analysis to compare overall survival (OS) between the 2 groups and may recommend early stopping for futility. If the study continues after interim analysis, then the randomization scheme will continue up to 364 patients or the newly-calculated sample size. The maximum number of enrolled patients will be 650. The number of clinical sites may be expanded up to approximately 200 to 300 centers.

Patients in the gemcitabine-only arm (Arm B) will not be allowed to cross over to the combined treatment arm (Arm A). In addition, no palliative radiotherapy will be allowed during the trial.

The primary analysis will compare OS in the ON 01910.Na + gemcitabine arm (Arm A) vs. gemcitabine-only arm (Arm B) once an appropriate number of events has been reached. There are 2 secondary efficacy outcomes: progression-free survival (PFS) and objective response.

Toxicity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v4.03. Grade 3 and 4 hematologic toxicities and \> Grade 2 non-hematologic toxicities will be monitored.

Gemcitabine and ON 01910.Na in Previously Untreated Metastatic Pancreatic Cancer

A Phase III, Multi-center, Randomized, Controlled Study to Compare the Efficacy and Safety of Gemcitabine Alone vs. ON 01910.Na Combined With Gemcitabine in Patients With Previously Untreated Metastatic Pancreatic Cancer

This study's primary outcome is overall survival, defined as the time from randomization to death from any cause. All patients will be followed until death. Patients lost to follow-up will be censored at the time last known alive.

Progression-free survival is defined as the time from the randomization to documented disease progression or death. Patients who are alive and do not have disease progression by the clinical cutoff will be censored at the dates of their last tumor evaluation. Kaplan-Meier curves for PFS will be compared using a stratified log-rank test (stratified by ECOG status: 0-1 vs. 2). Hazard ratios and 95% confidence intervals will be estimated using stratified Cox proportional hazards models.

Objective tumor response rates using Response Evaluation Criteria In Solid Tumors (RECIST).

Toxicity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03

Quality of life (QOL) questionnaire, using the European Organisation for Research and Treatment of Cancer(EORTC) QLQ-C30 version 3.

In this study, archival tissue will be collected and analyzed in order to identify molecular characteristics of pancreas tumors, which may confer susceptibility or resistance to gemcitabine alone or in combination with ON 01910.Na.

Measurement of ON 01910.Na in plasma of all patients in Arm A 1 hour after starting ON 01910.Na infusion at Day 1 and Day 15 in Cycle 1 only.

At a limited number of sites, blood samples for measurement of ON 01910.Na and gemcitabine will be obtained at Cycle 1 Day 1 only, in a subset of 10 patients in Arm A, at the following 12 time-points: predose; 15 min after starting gemcitabine infusion; 30 min, immediately before ending gemcitabine infusion; 15 min after starting ON 01910.Na infusion; 30 min after ON 01910.Na infusion start; immediately before ending ON 01910.Na infusion; and, 15 min, 30 min, 1 hr, 2 hr, 4 hr and 8 hr after ending ON 01910.Na infusion.

Academic GI Cancer Consortium (AGICC)

Leukemia

Leukemia, Myelomonocytic, Chronic

Leukemia, Myelomonocytic, Juvenile

Cytopenia

Anemia

Anemia, Refractory, with Excess of Blasts

Anemia, Refractory

Leukemia, Myeloid

Neoplasms by Histologic Type

Myeloproliferative Disorders

Myelodysplastic-Myeloproliferative Diseases

Chronic Disease

Disease Attributes

Chronic Myelomonocytic Leukemia

Juvenile Myelomonocytic Leukemia

Chronic Graft Versus Host Disease

Myelodysplastic Syndrome With Excess Blasts

Chronic Myeloproliferative Disorders

Myelodysplastic/myeloproliferative Disease

Azacitidine

Decitabine

Rigosertib sodium will be administered as a 72-hr continuous intravenous infusion consisting of 3 consecutive doses of 1800 mg over 24 hours on Days 1, 2, and 3 of a 14-day cycle for the first 8 cycles and then on Days 1, 2, and 3 of a 28-day cycle for the following cycles.

This study will examine the effect intravenously administered rigosertib has on the relationship between bone marrow blasts response and overall survival in myelodysplastic syndromes (MDS) patients who have 5-30% bone marrow blasts and who progressed on or after treatment with azacitidine or decitabine.

Efficacy and Safety of IV Rigosertib in MDS Patients With Excess Blasts Progressing After Azacitidine or Decitabine

Phase IIIB, Open-label, Multi-Center Study of the Efficacy and Safety of Rigosertib Administered as 72-hour Continuous Intravenous Infusions in Patients With Myelodysplastic Syndrome With Excess Blasts Progressing On or After Azacitidine or Decitabine

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.

Overall hematologic response (complete remission \[CR\], partial remission \[PR\], bone marrow complete response \[BMCR\], and stable disease \[SD\]) is defined according to 2006 International Working Group (IWG) response criteria.

Hematological improvement (erythroid response, platelet response and neutrophil response) is defined according to 2006 International Working Group (IWG) response criteria.

Cytogenetic response is defined according to 2006 International Working Group (IWG) response criteria.

Progression-free survival is defined as time from date of first dose until date when progression is documented. Progression is defined according to 2006 International Working Group (IWG) response criteria.

Participants who progress to Acute Myeloid Leukemia (AML) during the study. AML is defined as an increase of at least 50% bone marrow blasts, and more than 20% bone marrow blasts for Refractory Anemia with Excess Blasts types 1 and 2 (RAEB-1 and RAEB-2) and Chronic Myelomonocytic Leukemia (CMML) patients and as an increase of at least 50% bone marrow blasts for Refractory Anemia with Excess Blasts in Transformation (RAEB-t) patients.

Change from baseline in responses in the European Organization for Research and Treatment of Cancer \[EORTC\] Quality of Life Questionnaire \[QLQ\]-C30 version 3. Questionnaire will be administered at baseline and at 4 week intervals.

Incidence of infections requiring treatment with intravenous antimicrobials and of bleeding episodes.

Concentration of rigosertib in plasma will be measured by a validated High Performance Liquid Chromatography (HPLC) method.

Counts of patients who have adverse events (AEs). Adverse events will be grouped by system organ class (SOC) and preferred term (PT) using the most recent version of the Medical Dictionary for Regulatory Activities (MedDRA), and will be summarized by worst grade according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0.

Pharmaceutical Solutions

ON 01910.Na will be supplied as a sterile, concentrated solution (75 mg/ml) in labeled, sealed glass vials. ON 01910.Na concentrated solution (75 mg/ml) must be diluted before intravenous administration. The starting dose will be 50 mg/m2 over 24 hour infusion daily for 3 days. A fresh infusion must be prepared for each day of the 3-day continuous infusion. This 3-day continuous treatment followed by 11 days without administration of study drug will constitute 1 Cycle. Cycles can be repeated every 2 weeks. The dosing of ON 01910.Na will be based on body surface area (BSA). In the absence of toxicity that would cause accelerated dose escalation to cease, drug doses are planned to escalate every 3 weeks.

Takao Ohnuma, MD

The primary objective of this study is to determine the largest dose of ON 01910.Na (rigosertib sodium) that can be given safely as a 3-day continuous infusion once every 2 weeks (2-week cycle) in patients with advanced cancer.

This was an open-label, single-center, dose-escalating Phase I study to determine the Dose-Limiting Toxicities (DLTs) and Recommended Phase 2 Dose (RPTD) of ON 01910.Na (rigosertib sodium) administered as a 3 day continuous intravenous (CIV) infusion every 2 weeks (2-week cycles) to up to 28 patients with advanced cancer (12 to 16 in the dose escalation phase and up to 12 additional patients in the dose confirmation phase). The dosing of rigosertib was based on body surface area (BSA), with a starting dose of 50 mg/m2/24 hour for 3 consecutive days.

In the absence of toxicity after at least a 3-week observation period, rigosertib doses were escalated following a Fibonacci scheme with an initial accelerated dose-escalation phase in which 1-patient cohorts received rigosertib for 3 weeks until drug-related Grade 2 toxicity (according to Common Toxicity Criteria for Adverse Events \[CTCAE\] v.3), excluding alopecia, occurred, at which time 2 additional patients were added to subsequent cohorts. If none of the 3 patients in the cohort experienced DLTs, the dose was escalated by a half-Fibonacci step. If a DLT was seen in the first patient of a cohort, dosing went back a half-step. The next dose level occurred if no DLT was reported in the 3 patients or if no more than 1 DLT occurred in an expanded cohort of 6 patients. If a DLT was seen in 1 of the 3 patients, 3 additional patients were enrolled in the cohort. If DLTs were seen in 2 of 6 patients in a cohort, dose escalation was stopped.

Once the maximum administered dose (MAD) was attained and the RPTD was determined, the dose escalation phase was considered complete. Up to 12 additional patients with histologically confirmed malignant tumors were tested at the RPTD dose to confirm its appropriateness.

Secondary objectives were to determine the qualitative and quantitative toxicity and reversibility of toxicity of rigosertib administered in this fashion; to investigate the clinical pharmacology of rigosertib when administered in this fashion, including plasma pharmacokinetics at each dose level; to confirm the appropriateness of the RPTD; to document any observed antitumor activity of rigosertib; and, to evaluate the biological effect of rigosertib in biomarkers in serum and/or peripheral blood mononuclear cells.

Safety of ON 01910.Na as a 3-day Infusion in Patients With Advanced Cancer

Phase I Dose Escalation Study of ON 01910.Na by 3-day Continuous Infusion in Patients With Advanced Cancer

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.

All adverse events (except grade 1 and 2 laboratory abnormalities that do not require an intervention), regardless of causal relationship, are recorded in the case report form and source documentation.

Severity of AEs are determined according to the NCI Common Terminology Criteria for Adverse Events, Version 3.0.

Blood samples for subsequent preparation of plasma and determination of concentration of ON 01910.Na will be collected at pre-dose at 1 hr, 3 hr, 6 hr, 24 hr, 48 hr and 72 hr (10 min, prior to completion of infusion). After the completion of the infusion, samples will be collected at 10 min, 20 min, 30 min, 1 hr, 2 hr, 4 hr, 8 hr, 24 hr, 48 hr, and 72 hr.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Safety of 24-Hour Infusion of ON 01910.Na in Patients With Advanced Cancer	NCT01538563	Solid Tumors Advanced Cancer Cancer Neoplasms	rigosertib sodi...	18 Years -	Traws Pharma, Inc.
Efficacy and Safety of Oral Rigosertib in Transfusion-dependent, Low or Int-1 or Trisomy 8 Int-2 Myelodysplastic Syndrome	NCT01584531	Myelodysplastic... MDS Trisomy 8	rigosertib	18 Years -	Traws Pharma, Inc.
Gemcitabine and ON 01910.Na in Previously Untreated Metastatic Pancreatic Cancer	NCT01360853	Metastatic Panc...	ON 01910.Na Gemcitabine Gemcitabine	18 Years -	Traws Pharma, Inc.
Efficacy and Safety of IV Rigosertib in MDS Patients With Excess Blasts Progressing After Azacitidine or Decitabine	NCT01928537	Myelodysplastic... Refractory Anem... Chronic Myelomo... Cytopenia	rigosertib sodi...	18 Years -	Traws Pharma, Inc.
Safety of ON 01910.Na as a 3-day Infusion in Patients With Advanced Cancer	NCT01538537	Advanced Cancer Solid Tumors Cancer Neoplasms	rigosertib sodi...	18 Years -	Traws Pharma, Inc.
Safety of 24-Hour Infusion of ON 01910.Na in Patients With Advanced Cancer	NCT01538563	Solid Tumors Advanced Cancer Cancer Neoplasms	rigosertib sodi...	18 Years -	Traws Pharma, Inc.

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