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All Drugs and Chemicals

Darbepoetin alfa

Participants received darbepoetin alfa 500 µg every three weeks (Q3W) for 24 weeks in the double-blind treatment period, and continued to receive darbepoetin alfa 500 µg Q3W during the active treatment period for an additional 48 weeks.

Participants received placebo subcutaneous injection every 3 weeks (Q3W) for 24 weeks during the double-blind treatment period. From week 25 participants received darbepoetin alfa 500 µg Q3W during the active treatment period for 48 weeks.

Administered by subcutaneous injection every 3 weeks

Placebo

The primary objective was to assess the superiority of darbepoetin alfa versus placebo on the incidence of red blood cell transfusions during the 24-week double-blind treatment period in anemic patients with low or intermediate-1 risk MDS.

This study consists of a 3-week screening period, a 24-week double-blind treatment period, and a 48-week active treatment period and the long-term follow-up period.

An end of treatment period (EOTP) visit occurs at week 25, or 3 weeks after last dose of investigational product (IP) for participants who withdraw from the study. After entering the active treatment period, an end of active treatment period (EOATP) visit occurs at week 72 / 73, or 3 weeks after the last dose of darbepoetin alfa.

Long-term follow-up (LTFU) will occur every 26 weeks (± 4 weeks) from the EOATP visit (or EOTP visit if the participant does not enter the active treatment period) and will continue for a minimum of 3 years from the first dose of IP. Follow-up may occur through clinic visit or telephone contacts. Information on the participant's survival and progression to AML status will be collected during LTFU.

Darbepoetin Alfa in Patients With Anemic Low or Intermediate-1 Risk Myelodysplastic Syndrome (MDS)

A Multicenter, Randomised, Double-blind, Placebo-controlled Study of Darbepoetin Alfa for the Treatment of Anaemic Subjects With Low or Intermediate-1 Risk Myelodysplastic Syndrome (MDS)

International Working Group 2006 erythroid response was defined as achieving an initial ≥ 1.5 g/dL increase in hemoglobin from baseline and sustaining an average rise of ≥ 1.5 g/dL in a rolling 56-consecutive day period in the absence of RBC transfusion.

Participants with no hemoglobin collected to the minimum time required to observe an IWG erythroid response (Week 13) were considered non-responders.

The severity of each adverse event was graded using the the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 grading scale, where grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life-threatening and grade 5 = death.

Prespecified adverse events of interest for darbepoetin alfa, based on clinical data in anemic patients with cancer, included the following categories: hypersensitivity, cardiac failure, hypertension, malignancies, embolic and thrombolic events, venous thromboembolic events (VTEs), central nervous system vascular disorders, and ischemic heart disease.

Transformation to AML was assessed according to WHO guidelines in the absence of IP and any haematopoietic growth factors (2 weeks off dosing). Bone marrow and/or cytogenetic report confirmation of AML was required (marrow or peripheral blast cells ≥ 20%, presence of pathognomic AML cytogenetic change, or evidence of marrow blast criteria for erythroleukemia). A pathology report confirming other leukemias such as chloroma (granulocytic sarcoma, myeloid sarcoma) or leukemia cutis also constituted transformation to AML.

Two validated assays were used to detect the presence of anti-darbepoetin alfa antibodies.

Samples were first tested in an immunoassay to detect antibodies capable of binding to darbepoetin alfa. Samples confirmed to be positive for binding antibodies were subsequently tested in a cell-based assay to determine neutralizing activity against darbepoetin alfa. If a sample was positive for binding antibodies and demonstrated neutralizing activity at the same time point, the sample was defined as positive for neutralizing antibodies.

The number of participants who developed antibodies to darbepoetin alfa is defined as participants who were neutralizing antibody positive post-baseline with a negative or no result at baseline.

The FACIT-Fatigue scale was a 13-item self-administered questionnaire that assesses both the physical and functional consequences of fatigue. Each question is answered on a 5-point scale, where 0 means "not at all," and 4 means "very much." The FACIT-Fatigue scale score ranges from 0 to 52, with higher scores denoting lower levels of fatigue.

A positive change from baseline score indicates an improvement. End of treatment period (EOTP) analysis includes last available values.

The EQ-5D visual analog scale (VAS) is a global evaluation of overall health state with scores ranging from 0 (worse health state a participant can imagine) to 100 (best health state a participant can imagine).

End of treatment period (EOTP) analysis includes last available values.

The FACIT-Fatigue scale was a 13-item self-administered questionnaire that assesses both the physical and functional consequences of fatigue. Each question is answered on a 5-point scale, where 0 means "not at all," and 4 means "very much." The FACIT-Fatigue scale score ranges from 0 to 52, with higher scores denoting lower levels of fatigue.

Clinically meaningful improvement in fatigue is defined as an increase of ≥ 3 points in the FACIT-Fatigue subscale score, from baseline to EOTP.

Amgen

One participant randomized to the Placebo arm inadvertently received one 200 µg dose of darbepoetin alfa and is reported in the Darbepoetin alfa group for adverse events.

Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.

Participants received placebo subcutaneous injection every 3 weeks (Q3W) for 24 weeks.

Participants received darbepoetin alfa 500 µg Q3W for 24 weeks.

Darbepoetin Alfa

Total

Age, Continuous

Sex: Female, Male

French clinical sites, per regulation, did not complete the ethnicity question.

Ethnicity (NIH/OMB)

White

Race/Ethnicity, Customized

Intermediate-1

The Myelodysplastic Syndrome (MDS) IPSS score assesses the severity of MDS based on 3 prognostic factors each assigned a score: the percentage of bone marrow blasts, chromosome changes in the marrow cells (karyotype) and the presence of one or more low blood cell counts (cytopenias). The IPSS score is the sum of the bone marrow blast + karyotype + cytopenia score and ranges from 0 (low risk) to 3.5 (high risk). Prognosis is categorized as Low risk (score = 0), Intermediate-1 (score 0.5 to 1.0), Intermediate-2 (score 1.5 to 2.0) or High risk (score ≥ 2.5).

IPSS Risk Category

Refractory anemia (RA)

RA with ringed sideroblasts (RARS)

Refractory cytopenia multilineage dysplasia (RCMD)

MDS, unclassified (MDS-U)

MDS associated with isolated del(5q)

Refractory anemia with excess blasts-1 (RAEB-1)

Refractory anemia with excess blasts-2 (RAEB-2)

Unknown

The World Health Organization (WHO) classification recognizes eight subtypes of MDS that are distinguished by the percentage of myeloblasts, presence or absence of ringed sideroblasts (i.e., erythroid precursors with iron deposits surrounding the nucleus), presence of a monocytosis or a deletion 5q.

World Health Organization (WHO) Classification of MDS

Data available for 43 and 88 participants in each treatment group respectively

Time since MDS Diagnosis

Data available for 35 and 75 participants in each treatment group respectively

Hemoglobin

Primary Analysis Set includes all randomized and consented participants who received at least 1 dose of investigational product.

Study Director

The primary hypothesis to be tested was that the percentage of participants with at least

1 RBC transfusion from week 5 to the EOTP was lower in the darbepoetin alfa group than in the placebo group. This hypothesis was confirmed if the incidence of RBC transfusion in the darbepoetin alfa group was lower and had a p-value \< 0.05 from a 2-sided Chi-square test.

Transfusion Primary Analysis Set which includes all randomized and consented participants who received at least 1 dose of study drug and who had an end of treatment period (EOTP) visit ≥ day 29 (ie, start of week 5).

Percentage of Participants With at Least One Red Blood Cell (RBC) Transfusion During the Double-blind Treatment Period

If the primary hypothesis was confirmed, the secondary hypothesis to be tested was that the percentage of participants achieving an IWG erythroid response during the 24-week double-blind treatment period was greater in the darbepoetin alfa group than in the placebo group. This hypothesis was confirmed if erythroid response was higher in the darbepoetin alfa group and the p-value was \< 0.05 from a 2-sided Cochran-Mantel-Haenszel test using the IPSS as a stratification factor.

Primary analysis set participants with a central laboratory baseline hemoglobin value

Percentage of Participants Who Achieved an Erythroid Response Based on International Working Group (IWG) 2006 Criteria in the Double-blind Treatment Period

Any adverse event (AE)

AE Grade ≥ 2

AE Grade ≥ 3

AE Grade ≥ 4

Serious adverse events (SAE)

AE leading to discontinuation of study drug

Fatal adverse events

Adverse events of special interest

Treatment-related adverse events (TRAE)

Treatment-related serious adverse events

TRAE leading to discontinuation of study drug

Treatment-related fatal adverse events

Safety Analysis Set, including all participants who received at least 1 dose of study drug. One participant in the placebo arm inadvertently received a dose of darbepoetin alfa and is counted in the darbepoetin alfa group for safety analyses.

Number of Participants With Adverse Events

Number of Participants With Disease Progression to Acute Myeloid Leukemia (AML)

Number of Participants With Malignancies Other Than AML, Basal Cell Carcinoma, or Squamous Cell Carcinoma of the Skin

Safety analysis set participants with post-baseline antibody results

Number of Participants Who Developed Neutralizing Antibodies to Darbepoetin Alfa

Baseline (N = 42, 90)

Change from Baseline to Week 13 (n = 41, 85)

Change from Baseline to Week 25 (n = 39, 85)

Change from Baseline to EOTP (n = 42, 90)

FACIT-Fatigue Analysis Set, includes all participants in the primary analysis set who completed or partially completed both the baseline and at least 1 subsequent FACIT-F questionnaire.

Change From Baseline in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F)

Change from Baseline to Week 13 (n = 41, 83)

Change from Baseline to Week 25 (n = 39, 81)

Change from Baseline to EOTP (n = 42, 89)

The EQ-5D visual analog analysis set includes all participants in the primary analysis set who completed both the baseline and at least 1 subsequent visual analog scale.

Change From Baseline in EuroQol-5D (EQ-5D) Visual Analog Scale (VAS)

Percentage of Participants With a Clinically Meaningful Improvement in Fatigue

Overall Study

Antineoplastic Agents

ON 01910

Protein Kinase Inhibitors

Enzyme Inhibitors

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.

rigosertib

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.

Traws Pharma, Inc.

Patients will take 560 mg oral rigosertib (two 280 mg capsules) in the morning and 280 mg (one 280 mg capsule) in the afternoon, in fasting conditions, for 21 consecutive days of 21-day cycle (continuous regimen).

Dose of 560 mg consists of two (2) 280 mg soft gel capsules of rigosertib.

Oral rigosertib

Steven M. Fruchtman, MD

The study will enroll low risk MDS patients who need red blood cell transfusions and who are refractory to or are not using erythropoiesis-stimulating agents. The purpose of the study is to determine whether oral rigosertib treatment results in hematological improvements according to the 2006 International Working Group criteria in these patients. The study will also record any side effects that may occur during the study.

This will be a Phase II, single-arm, multicenter study (approximately 15 centers). Approximately 40 transfusion-dependent patients with Low- or Int-1 risk Myelodysplastic Syndrome (MDS) by International Prognostic Scoring System (IPSS) will be enrolled and treated with oral rigosertib administered twice daily for 21 consecutive days of a 21-day cycle (continuous regimen) in order to obtain at least 35 evaluable patients treated for at least 8 weeks. Patients will take 560 mg rigosertib (two 280 mg capsules) in the morning and 280 mg (one 280 mg capsule) in the afternoon, in fasting conditions. All patients on intermittent regimen at the time of Amendment 2 of the Protocol will be switched to the continuous regimen, including patients on reduced doses.

Oral Rigosertib in Low Risk MDS Patients Refractory to ESAs

A Single-arm Study to Assess the Efficacy and Safety of Oral Rigosertib in Transfusion-dependent, Low or Intermediate-1, Myelodysplastic Syndrome Patients Based on the International Prognostic Scoring System

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.

The number of patients with a complete remission or a partial remission will be documented. Complete remission and partial remission are defined according to 2006 IWG response criteria for MDS. Overall response = complete remission + partial remission.

The number of weeks a complete remission or a partial remission is observed in a patient will be documented.

Specific safety parameters and procedures will include recording of medical history, medication history, physical examination, measurement of vital signs (blood pressure, temperature, respiration rate, and pulse), weight, laboratory evaluations, and toxicity and AE assessments.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Darbepoetin Alfa in Patients With Anemic Low or Intermediate-1 Risk Myelodysplastic Syndrome (MDS)	NCT01362140	MDS	Darbepoetin alf... Placebo	18 Years -	Amgen
Three Dosing Schedules of Oral Rigosertib in MDS Patients	NCT02075034	Myelodysplastic...	rigosertib	18 Years -	Traws Pharma, Inc.
Darbepoetin Alfa in Patients With Anemic Low or Intermediate-1 Risk Myelodysplastic Syndrome (MDS)	NCT01362140	MDS	Darbepoetin alf... Placebo	18 Years -	Amgen
Oral Rigosertib in Low Risk MDS Patients Refractory to ESAs	NCT01904682	Myelodysplastic...	Oral rigosertib	18 Years -	Traws Pharma, Inc.
Darbepoetin Alfa in Patients With Anemic Low or Intermediate-1 Risk Myelodysplastic Syndrome (MDS)	NCT01362140	MDS	Darbepoetin alf... Placebo	18 Years -	Amgen

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