Symptoms and General Pathology

All Conditions

Blood and Lymph Conditions

Neoplasms

Rare Diseases

Syndrome

Anemia

Preleukemia

Myelodysplastic Syndromes

Anemia, Refractory, with Excess of Blasts

Anemia, Refractory

Bone Marrow Diseases

Hematologic Diseases

Precancerous Conditions

Myelodysplastic Syndrome With Excess Blasts

Antineoplastic Agents

All Drugs and Chemicals

Azacitidine

Decitabine

ON 01910

Protein Kinase Inhibitors

Enzyme Inhibitors

Patients will receive intravenous rigosertib 1800 mg/24 hr for 3 days every 2 weeks for first 8 cycles, then every 4 weeks thereafter + best supportive care (BSC).

rigosertib

Patients will receive Physician's Choice of Treatment or alternative treatment which may include any approved or standard-of-care therapy, based on frequently used treatment for MDS (no experimental therapy) + best supportive care.

Any approved or standard-of-care therapy

Patients will receive best supportive care (BSC): azacitidine (AZA) and/or decitabine (DAC) are permitted.

best supportive care (BSC)

Patients will receive best supportive care (BSC).

Steven M. Fruchtman, MD

The study's primary objective \[in a population of patients with MDS after failure of treatment with azacitidine (AZA) or decitabine (DAC)\], is to compare the overall survival (OS) of patients in the rigosertib group vs the Physician's Choice group, in all patients and in a subgroup of patients with IPSS-R very high risk.

This is a Phase III, open-label, randomized, controlled, international study. Approximately 360 patients \< 82 years of age with MDS classified as RAEB-1, RAEB-2, or RAEB-t who received AZA or DAC for ≤ 9 months and/or ≤ 9 cycles over 12 months and had their last dose of AZA or DAC within 6 months prior to screening will be stratified by:

* Very high risk (VHR) vs non-VHR per IPSS-R, and
* Geographic region (North America vs Europe vs Asia; because approved products and standard of care may vary by region), and randomly assigned in a 2:1 ratio to one of the following 2 treatment groups:
* Rigosertib 1800 mg/24 hr administered as a 72 hr CIV infusion on Days 1, 2, and 3 of a 2 week cycle for the first 8 cycles, and on Days 1, 2, and 3 of a 4-week cycle thereafter (N = approximately 240 patients);
* Physician's Choice of alternative treatment, which may include any approved or standard-of-care therapy that the patient has not shown to be hypersensitive to, based on frequently used treatment for MDS, as per institutional guidelines, after receipt of HMAs (N = approximately 120 patients). The drugs used in the Physician's Choice arm should be used according to the recommendations, if clinically appropriate, provided in the corresponding Summary of Product Characteristics (SmPC) and Prescribing Information of these drugs. Experimental therapies are not allowed on the PC arm.

Patients will be treated until 2006 IWG progression criteria are met (ie, 50% increase of BM blasts or worsening of cytopenias) or until an unacceptable toxicity or intolerance.

For all randomized patients who discontinue study treatment, subsequent therapies with their start and end dates, as well as survival time after treatment discontinuation, will be documented at least monthly until death.

Patients in the PC group who progress will not be allowed to cross over to rigosertib.

All patients in both treatment groups will be allowed, as medically justified, access to RBC and platelet transfusions and to growth factors (granulocyte colony-stimulating factor (G-CSF), erythropoietin, and thrombopoietin).

Controlled Study of Rigosertib Versus Physician's Choice of Treatment in MDS Patients After Failure of an HMA

A Phase III, International, Randomized, Controlled Study of Rigosertib Versus Physician's Choice of Treatment in Patients With Myelodysplastic Syndrome After Failure of a Hypomethylating Agent

Transformation time to AML (defined as a bone marrow or peripheral blood blast percentage \>30%).

Treatment-emergent adverse events (TEAEs) will be graded according to NCI CTCAE version 4, grouped by MedDRA preferred term, and summarized by worst grade of severity per patient by treatment group.

Blood samples for population PK analysis will be taken in rigosertib patients

The overall survival (OS) of all randomized patients (ITT population), and the overall survival of patients scored as IPSS-R very high risk.

Evaluate OS of patients with monosomy 7 chromosomal aberrations in the rigosertib vs PC group. Overall survival is the time (months) from date of randomization to date of death or date last known to be alive at the time of date cut-off.

Evaluate OS of patients with trisomy 8 chromosomal aberrations in the rigosertib vs PC group. Overall survival is the time (months) from date of randomization to date of death or date last known to be alive at the time of date cut-off.

Responses of complete remission (CR), partial remission (PR), mCR, SD, failure, and PD will be determined by 2006 IWG criteria. The number and percent of patients with CR, PR, mCR, SD, Failure, or PD will be summarized by treatment group.

Compare rigosertib vs PC in regard to the the scores of the EuroQol EQ-5D-5L Questionnaire. The EuroQol EQ-5D-5L Questionnaire includes five levels of severity in each of the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression and a visual analogue scale.

Compare rigosertib vs PC in regard to the bone marrow blast responses of marrow complete response (mCR ≥ 50% decrease of BMBL vs pretreatment values to a value ≤ 5%), marrow partial response (mPR, ≥ 50% decrease of BMBL vs pretreatment values to a value \> 5%), stable disease (SD, no mCR or mPR, but no progressive disease (PD), and PD (≥ 50% BMBL increase relative to baseline or nadir) will be assessed. The number and percent of patients with mCR, mPR, SD, or PD will be summarized by treatment group. Responses of complete remission (CR), partial remission (PR), mCR, SD, failure, and PD will be determined by 2006 International Working Group (IWG) criteria.

Compare rigosertib vs PC in regard to the number and percent of patients who meet the 2006 IWG criteria.

Traws Pharma, Inc.

Trisomy

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.

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.

Doses of rigosertib up to 700 mg twice a day or three times a day every day of 21-day cycles.

Doses of rigosertib up to 700 mg twice a day or three times a day for 21 days of 21-day cycles. Treatment may continue until progression.

Antonio Jimeno, MD, PhD

This is a phase 1 study in which 2 to 72 patients with advanced cancer will receive oral doses of rigosertib, a new investigational (unapproved) anti-cancer drug. The objective of the study is to determine the highest dose of drug that can be given safely. The study will start by testing a low dose. If this dose is safe, then, higher and higher doses will be tested as long as the previous lower dose was safe. Safety will be determined by looking for any side effects or unusual laboratory values. It is important to know the highest safe dose so that additional studies can be done. The drug will be given in the form of capsules twice or three times a day for 21 consecutive days of 21-day cycles.

Patients will be initially enrolled in two-patient cohorts starting with a 70 mg bid dosing.

* In the absence of drug-related grade 2 or higher toxicity in the two patients treated for an entire 21-day first cycle, the next two patients will be receiving a dose escalated by 100% from prior dose.
* If drug-related grade 2 or higher toxicity is observed in at least one of the two patients treated for a full 21-day cycle, the cohort will be expanded in order to obtain 3 evaluable (treated for an entire 21-day first cycle) patients.
* If no dose limiting toxicity (DLT) is observed in the first three patients treated for an entire 21-day first cycle, then the next three patients will be enrolled at a dose level increased by approximately 50% from prior dose.
* If one DLT is observed in the first three patients treated for an entire 21-day first cycle, then the three next patients will be enrolled at the same dose level.
* If no more than one DLT is observed in the six patients treated for an entire 21-day cycle, then the next six patients will be administered a dose level increased by approximately 25% from prior dose.
* If two or more patients in any cohort experience DLT, then the maximum tolerated dose (MTD) will have been exceeded and no further dose escalation will occur. The MTD will be established as the immediate prior dosing level
* Identical rules will be applied to all cohorts of patients recruited to the study.
* A total of up to 24 patients may be treated at the MTD dose level in order to obtain data on the onset and severity of dysuria symptoms in approximately 12 patients including about 6 patients who will be treated with oral sodium bicarbonate at the time of treatment initiation (early treatment) and \~6 patients who will be treated with oral sodium bicarbonate at the time of symptom onset (late treatment). Alternating patients on a 1-to-1 basis by enrollment date will receive oral sodium bicarbonate as 650 mg tablets given twice daily with two 8-ounce glasses of water 1 hour after rigosertib administration, either at the time of study initiation (early treatment) or at the time of urinary symptom onset (late treatment).

Three additional cohorts will be treated with multiple escalating doses administered orally three time daily (TID) (140 mg, 280 mg and 420 mg) for 21 consecutive days of a 21-day cycle using identical rules as those described above (ie, starting with 2-patient cohorts at 140 mg dosing and expanding to 3-6 patient cohorts if at least 1 Grade 2 or higher drug-related toxicity is observed in 2-patient cohorts).

Up to 12 patients may be treated at the MTD level identified with TID dosing.

Prior to escalating to the next planned dose level, a designated Cohort Review Committee (CRC) consisting of the Principal Investigators (or their representatives), the Medical Monitor and the Sponsor's Medical Representative will review all available safety data over the 21 day duration of Course 1 for the previous cohort. Additional input may be provided from the study monitors, pharmacokinetic or toxicology specialists as required. The CRC also has to ability to recommend dose de-escalation for ON 01910.Na if warranted by the observed toxicity profile.

Safety, Pharmacokinetics and Clinical Activity of Oral Rigosertib in Solid Tumors

A Phase 1 Study To Assess The Tolerability, Pharmacokinetics and Clinical Activity of Rigosertib Administered Orally as Escalating Multiple Doses Twice or Three Times a Day up to 21 Days of a 21-Day Cycle in Patients With Advanced Cancer

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.

The concentration of ON 01910.Na in plasma at various times after administration will be used to derive the following PK parameters for ON 01910.Na using model-independent analysis as appropriate for the data: Tmax, Cmax, t½, AUC0-t, AUC 0-α, CL, and Vss.

Tumor response rates will be evaluated for each patient using RECIST criteria.

Urine PK samples to determine ON 01910.Na urinary concentrations will be collected on Day 1 and Day 21 of the first cycle, and on Day 15 of the second cycle in all patients and will include the predose void volume and a 24-hr post-dose urine collection over the 0-4 hr, 4-8 hr, and 8-24 hr intervals.

Two 280 mg capsules of rigosertib will be taken in the morning and one 280 mg capsule of rigosertib will be taken in the afternoon.

One 280 mg capsule and two 70 mg capsules of rigosertib will be taken in the morning and one 280 mg capsule and two 70 mg capsules of rigosertib will be taken in the afternoon.

One 280 mg capsule of rigosertib will be taken in the morning, one 280 mg capsule of rigosertib will be taken at mid-day, and one 280 mg capsule of rigosertib will be taken in the afternoon.

Rigosertib will be supplied as soft gel capsules in strengths of 280 mg and 70 mg.

Mark Heaney, MD

This study will compare the dosing regimen of oral rigosertib, which has been used in other studies of lower risk Myelodysplastic Syndrome (MDS), with 2 new dosing regimens to determine if one of the new regimens gives improved results as measured by disease status, side effects, and analyses of blood and urine samples.

This will be a Phase I, randomized, 3-treatment arm, single-center study in transfusion-dependent Myelodysplastic Syndrome (MDS) patients classified as Low- or Intermediate-1 (Int-1) or Intermediate-2 (Int-2) risk by the International Prognostic Scoring System (IPSS). Initially, 18 patients (6 per treatment arm) will be randomized in a 1:1:1 ratio to 1 of 3 oral rigosertib dosing regimens, each of which is a cycle consisting of 14 consecutive days of dosing followed by 7 days off drug.

Treatment with erythropoiesis-stimulating agent (ESA) is prohibited for the first 15 weeks (5 cycles). After 15 weeks of dosing (5 cycles), ESA treatment will be initiated if the patient still needs red blood cell (RBC) transfusions and if the pre-transfusion hemoglobin (Hgb) value is ≤ 9 g/dL, unless the clinical judgment of the Investigator determines ESA administration to a patient with a Hgb level \> 9 g/dL is warranted.

All study participants will be allowed, as medically justified, access to RBC and platelet (PLT) transfusions, and to filgrastim. Rigosertib dosing adjustment policies are described.

After all 18 patients have completed 3 cycles, a risk/benefit analysis will be completed assessing the distribution of adverse events (AEs) and serious adverse events (SAEs) and the number of transfusions among the 3 treatment arms. This analysis will select 1 of the 3 dosing regimens as having the best risk/benefit profile and an additional 12 to 18 patients will be enrolled at this dosing regimen. Eligibility criteria may be modified by protocol amendments to enroll patients with different characteristics. All patients will be treated for 48 weeks or until 2006 International Working Group (IWG) progression criteria are met, unacceptable toxicity is observed, intercurrent illness or a change in the patient's condition prevents further administration of study drug treatment, or until death from any cause occurs, whichever comes first. Patients who have continued hematologic response at 48 weeks may continue to be treated in the study beyond 48 weeks until 2006 IWG progression criteria are met or until death from any cause, whichever comes first.

Three Dosing Schedules of Oral Rigosertib in MDS Patients

A Randomized Phase I Study to Assess the Pharmacokinetics, Tolerability, Efficacy and Pharmacodynamics of Three Dosing Schedules of Oral Rigosertib in Transfusion-dependent, Low, Intermediate 1, or Intermediate-2 Myelodysplastic Syndrome Patients Based on the International Prognostic Scoring System

Concentration of rigosertib in plasma will be determined by validated high performance liquid chromatography (HPLC) method.

Concentration of rigosertib in urine will be determined by a validated high performance liquid chromatography (HPLC) method.

Adverse events will be summarized by worst grade according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0.

All AE presentations will summarize treatment-emergent adverse events (TEAEs), defined as AEs with onset on or after first dose, or onset prior to first dose but with worsening severity after first dose.

HI is defined according to IWG criteria (Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006; 108:419-25.) and include Erythroid response, Neutrophil response and Platelet response.

Biomarkers will be measured by immunoassay.

Immune System Diseases

Leukemia

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Myeloproliferative Disorders

Polycythemia Vera

Polycythemia

Primary Myelofibrosis

Thrombocytosis

Thrombocythemia, Essential

Lymphoma

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Chronic Disease

Disease Attributes

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Chronic Graft Versus Host Disease

Acute Non Lymphoblastic Leukemia

Chronic Myeloid Leukemia

Acute Graft Versus Host Disease

Chronic Myeloproliferative Disorders

Essential Thrombocythemia

Lymphosarcoma

Patients will receive 2400 mg dose of rigosertib as a intravenous continuous infusion over 24 hours for 72 to 120 consecutive hours every 2 weeks for the first 4 weeks then will receive oral rigosertib at a 560 mg twice-daily dose as capsules taken continuously.

The dose of rigosertib will be 2400 mg/24h as an intravenous continuous infusion over 72 or 120 hours every 2 weeks for 2 cycles then as oral capsules administered at a dose of 560 mg twice daily on a continuous basis.

Jorge Cortes, MD

For patients with leukemia who have not responded to or have progressed after an initial response to standard therapy, therapeutic options are limited. Although responses to standard regimens do occur, durable remissions are achieved infrequently and current regimens are not curative in the majority of patients. Identification of active agents in patients with relapsed Acute Myeloid Leukemia (AML) ultimately affords the potential for use upfront as a component of induction regimens that may translate to improved outcome. Therefore, development of new agents is of critical importance. This study will look at a new, investigational agent, ON 01910.Na, to determine if it has the potential to help Patients with AML and Acute Lymphocytic Leukemia (ALL) and transformed Myeloproliferative Neoplasms.

This is a single center, open-label, phase 1/2 study in which 2 to 34 patients with refractory acute myeloid or lymphocytic leukemia or transformed myeloproliferative neoplasms (MPNs)who meet all other inclusion/exclusion criteria will be administered a daily dose of 2400 mg ON 01910.Na dose as a intravenous continuous infusion (IVCI) over 24 hours for 72 to 120 consecutive hours every 2 weeks for the first 4 weeks then will receive oral rigosertib at a 560 mg twice-daily dose as capsules taken continuously.

In the phase 1 component of the trial, a standard dose escalation scheme will be followed with the enrolment of at least three patients treated with a daily dose of 2400 mg ON 01910.Na IVCI over 24 hours for 72 hours. The dose escalation scheme will follow a traditional dose escalation rule, also known as the "3+3" rule:

If none of the initial three patients treated in the 72-hour cohort experience dose-limiting toxicity (DLT), during the first two 2-week cycles, then a new cohort of three patients will be treated at the same 2400 mg/24h daily dose but for an increased 120 hours duration.

DLT is defined as an adverse event possibly related to ON 01910.Na 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

If one of the three patients in the 72-hour cohort experiences a DLT during the first two cycles, then three additional patients will be treated for the same 72 hours duration. Escalation to the 120-hour cohort will proceed only if no more than one of the six patients treated in the 72-hour cohort experiences a DLT.

If two or more patients in the 72-hour cohort experience DLT during the first two cycles, then the maximum tolerated dose (MTD) will have been exceeded, no further dosing extension will occur, and a full safety review will determine if further enrollment of patients will proceed.

If none of the initial three patients in the 120-hour cohort experiences DLT during the first two cycles, this regimen will be confirmed as the Maximum Tolerated Dose (MTD) and no further dose escalation will occur.

If one of the three patients in the 120-hour cohort experiences DLT during the first two cycles, then three additional patients will be treated for the same duration. If no more than one patient experiences a DLT, the 120-hour regimen will be confirmed as the Maximum Tolerated Dose (MTD) and no further dose escalation will occur.

If two or more patients in the 120 hours cohort experience DLT during the first two cycles, then the maximum tolerated dose (MTD) will be determined to be 2400 mg/24h administered for 72 hours every other week.

Once the phase 1 portion of the study is completed, accrual to the phase 2 portion will begin. Patients treated at the MTD during the phase 1 portion will be included in the phase 2 component and will be evaluated for response and secondary end points.

The total study duration is 30 weeks, which includes a 2-week screening phase, a 24-week dosing phase (4-week rigosertib CIV administration, followed by 20 weeks of oral rigosertib administration), and a 4-week follow-up phase that begins after the last dose of rigosertib. Beginning at week 5, patients will be assessed for response every time a complete blood count (CBC) is performed and followed up.

Patients who achieve by week 24 a response or stabilization of their disease are eligible to receive an additional 24 weeks of rigosertib at the same dose and will be followed up.

Safety and Efficacy of 72-hour and 120-hour Infusion of Rigosertib in Acute Myeloid Leukemia (AML) and Acute Lymphoid Leukemia (ALL)

A Phase 1/2, Single Arm Study To Assess the Efficacy and Safety of Rigosertib (ON 01910.Na) Administered as 72-Hour and 120-Hour Continuous Intravenous Infusions Every Other Week for Two Cycles Then as Twice Daily Oral Capsules Given Continuously in Patients With Relapsed/Refractory Acute Myeloid or Lymphocytic Leukemia or Transformed Myeloproliferative Neoplasms

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).

Blood samples to determine concentration of rigosertib in plasma will be collected at 6 hours after the start of the second 24-hour infusion (Day 2) at Weeks 1 and 3.

Digestive System Diseases

Carcinoma

Carcinoma, Squamous Cell

Esophageal Squamous Cell Carcinoma

Head and Neck Neoplasms

Squamous Cell Carcinoma of Head and Neck

Neoplasms, Glandular and Epithelial

Neoplasms, Squamous Cell

Esophageal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Esophageal Diseases

Esophageal Cancer

Oral rigosertib capsules at a dose of 560 mg twice a day for 14 consecutive days of a 21-day cycle (2 weeks on, 1 week off regimen).

Michael Kurman, MD

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.

Oral Rigosertib for Squamous Cell Carcinoma

A Phase II Study of Oral Rigosertib in Patients With Relapsed or Metastatic, Platinum-resistant, Human Papillomavirus Positive or Negative Squamous Cell Carcinoma

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.

At the time of analysis, the outcome measure will be number of days between the date the patient is enrolled in the study and the date the patient dies or date the patient is last known to be alive, up to 2 years following discontinuation of rigosertib treatment.

At the time of analysis, the outcome measure will be number of days between the date the patient is enrolled in the study and the date that progressive disease (PD) is documented per revised Response Evaluation Criteria In Solid Tumors (RECIST 1.1).

The concentration (expressed as microgram rigosertib per mL plasma and/or nanogram rigosertib per mL plasma) of rigosertib in plasma will be determined by a validated high performance liquid chromatography (HPLC) method.

Genetic and protein profiling will be conducted in blood (collected at Baseline before study drug administration) and in core biopsy or fine needle aspirate tumor samples (collected at Baseline before study drug administration and at Cycle 1 Day 14).

All Adverse Events reported by the patient or observed by the Investigator or study site personnel will be recorded. An adverse event is defined as any unfavorable or unintended sign, symptom, or disease that appears or worsens in a patient during the period of observation in a clinical study.

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.

rigosertib sodium

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.

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

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.

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

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Controlled Study of Rigosertib Versus Physician's Choice of Treatment in MDS Patients After Failure of an HMA	NCT02562443	Myelodysplastic... MDS Refractory Anem... RAEB	rigosertib Any approved or... best supportive... best supportive...	18 Years - 81 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.
Safety, Pharmacokinetics and Clinical Activity of Oral Rigosertib in Solid Tumors	NCT01168011	Solid Tumor	rigosertib	18 Years -	Traws Pharma, Inc.
Controlled Study of Rigosertib Versus Physician's Choice of Treatment in MDS Patients After Failure of an HMA	NCT02562443	Myelodysplastic... MDS Refractory Anem... RAEB	rigosertib Any approved or... best supportive... best supportive...	18 Years - 81 Years	Traws Pharma, Inc.
Three Dosing Schedules of Oral Rigosertib in MDS Patients	NCT02075034	Myelodysplastic...	rigosertib	18 Years -	Traws Pharma, Inc.
Safety and Efficacy of 72-hour and 120-hour Infusion of Rigosertib in Acute Myeloid Leukemia (AML) and Acute Lymphoid Leukemia (ALL)	NCT01167166	Acute Myelocyti... Acute Lymphocyt... Myeloproliferat... Chronic Myeloid...	rigosertib	18 Years -	Traws Pharma, Inc.
Oral Rigosertib for Squamous Cell Carcinoma	NCT01807546	Head and Neck S... Anal Squamous C... Lung Squamous C... Cervical Squamo... Esophageal Squa... Skin Squamous C... Penile Squamous...	rigosertib	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.
Oral Rigosertib for Squamous Cell Carcinoma	NCT01807546	Head and Neck S... Anal Squamous C... Lung Squamous C... Cervical Squamo... Esophageal Squa... Skin Squamous C... Penile Squamous...	rigosertib	18 Years -	Traws Pharma, Inc.

Spots Global Cancer Trial Database for rigosertib

Every month we try and update this database with for rigosertib cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for rigosertib

Every month we try and update this database with for rigosertib cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for rigosertib cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.