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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT01928537




Registration number
NCT01928537
Ethics application status
Date submitted
21/08/2013
Date registered
26/08/2013
Date last updated
30/06/2020

Titles & IDs
Public title
Efficacy and Safety of IV Rigosertib in MDS Patients With Excess Blasts Progressing After Azacitidine or Decitabine
Scientific title
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
Secondary ID [1] 0 0
2013-001124-19
Secondary ID [2] 0 0
Onconova 04-24
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Myelodysplastic Syndromes 0 0
Refractory Anemia With Excess Blasts 0 0
Chronic Myelomonocytic Leukemia 0 0
Cytopenia 0 0
Condition category
Condition code
Blood 0 0 0 0
Haematological diseases
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia
Cancer 0 0 0 0
Children's - Leukaemia & Lymphoma
Blood 0 0 0 0
Other blood disorders
Blood 0 0 0 0
Anaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - rigosertib sodium

Experimental: rigosertib sodium - 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.


Treatment: Drugs: rigosertib sodium


Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Relationship of bone marrow blast response and overall survival. - 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.
Timepoint [1] 0 0
Up to 2 years.
Secondary outcome [1] 0 0
Number of patients with overall hematologic response. - 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.
Timepoint [1] 0 0
Up to 2 years after study enrollment.
Secondary outcome [2] 0 0
Number of patients with hematological improvement. - Hematological improvement (erythroid response, platelet response and neutrophil response) is defined according to 2006 International Working Group (IWG) response criteria.
Timepoint [2] 0 0
Up to 2 years after study enrollment.
Secondary outcome [3] 0 0
Number of patients with cytogenetic response. - Cytogenetic response is defined according to 2006 International Working Group (IWG) response criteria.
Timepoint [3] 0 0
Up to 2 years after study enrollment.
Secondary outcome [4] 0 0
Progression-free survival. - 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.
Timepoint [4] 0 0
Up to 2 years after study enrollment.
Secondary outcome [5] 0 0
Number of patients who transition to Acute Myeloid Leukemia (AML) - 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.
Timepoint [5] 0 0
Up to 2 years after study enrollment.
Secondary outcome [6] 0 0
Quality of Life Questionnaire - 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.
Timepoint [6] 0 0
Up to 2 years after study enrollment.
Secondary outcome [7] 0 0
Infections. - Incidence of infections requiring treatment with intravenous antimicrobials and of bleeding episodes.
Timepoint [7] 0 0
Up to 2 years after study enrollment.
Secondary outcome [8] 0 0
Concentration of rigosertib in plasma. - Concentration of rigosertib in plasma will be measured by a validated High Performance Liquid Chromatography (HPLC) method.
Timepoint [8] 0 0
Week 1 and week 3.
Secondary outcome [9] 0 0
Safety. - 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.
Timepoint [9] 0 0
Study enrollment until 30 days after patient's last dose of rigosertib up to 2 years.

Eligibility
Key inclusion criteria
- Diagnosis of MDS confirmed within 6 weeks prior to Screening according to WHO criteria
or French-American-British (FAB) classification.

- MDS classified as follows, according to WHO criteria and FAB classification:

- RAEB-1 (5% to 9% BM blasts)

- RAEB-2 (10% to 19% BM blasts)

- CMML (10% to 20% BM blasts) and white blood cells (WBC) < 13,000/µL

- RAEB-t (20% to 30% BM blasts), meeting the following criteria: WBC < 25,000/µL at
study entry; or, Stable White Blood Cell (WBC) at least 4 weeks prior to
Screening and not requiring intervention for WBC control with hydroxyurea,
chemotherapy, or leukopheresis.

- At least one cytopenia (Absolute Neutrophil Count (ANC) < 1800/µL or Platelet (PLT)
count < 100,000/µL or hemoglobin (Hgb) < 10 g/dL).

- Progression (according to 2006 IWG criteria) at any time after initiation of
subcutaneous or intravenous azacitidine or decitabine treatment per labeling during
the past 2 years, defined as follows:

- For patients with ? 5% BMBL, = 50% increase in BMBL to ? 5% BMBL

- For patients with 5-10% BMBL, = 50% increase in BMBL to ? 10% BMBL

- For patients with 10-20% BMBL, = 50% increase in BMBL to ? 20% BMBL

- For patients with 20-30% BMBL, = 50% increase in BMBL to ? 30% BMBL

- Any of the following: = 50% decrease from maximum remission/response levels in
granulocytes or PLT; Decrease in Hgb concentration by = 2 g/dL; or, Transfusion
dependence, defined as administration of at least 4 RBC units in the past 8 weeks
before Screening (patients must have Hgb values ? 9 g/dL prior to transfusion to
be considered), in the absence of another explanation.

- Has failed to respond to, relapsed following, not eligible, or opted not to
participate in bone marrow transplantation.

- Off all other treatments for MDS for at least 4 weeks, except for azacitidine or
decitabine. Filgrastim (G-CSF) and erythropoietin are allowed before and during the
study as clinically indicated.

- No medical need for induction chemotherapy.

- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.

- Willing to adhere to the prohibitions and restrictions specified in this protocol.

- Patient must signed an informed consent form.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Previous participation in a clinical study of IV or oral rigosertib.

- Anemia due to factors other than MDS (including hemolysis or gastrointestinal [GI]
bleeding) unless stabilized for 1 week after RBC transfusion.

- Any active malignancy within the past year, except basal cell or squamous cell skin
cancer or carcinoma in situ of the cervix or breast.

- Uncontrolled intercurrent illness including.

- Active infection not adequately responding to appropriate therapy.

- Total bilirubin = 1.5 mg/dL not related to hemolysis or Gilbert's disease.

- ALT/AST = 2.5 x upper limit of normal (ULN).

- Serum creatinine = 2.0 mg/dL.

- Ascites requiring active medical management including paracentesis, or hyponatremia
(defined as serum sodium value of <130 mEq/L).

- Female patients who are pregnant or lactating.

- Patients who are unwilling to follow strict contraception requirements.

- Female patients with reproductive potential who do not have a negative urine
beta-human chorionic gonadotropin (ßHCG) pregnancy test at Screening.

- Major surgery without full recovery or major surgery within 3 weeks of Baseline/Cycle
1 Day 1 visit.

- Uncontrolled hypertension (defined as a systolic pressure =160 mmHg and/or a diastolic
pressure = 110 mmHg).

- New onset seizures (within 3 months prior to Baseline) or poorly controlled seizures.

- Any other concurrent investigational agent or chemotherapy, radiotherapy, or
immunotherapy.

- Prior treatment with low-dose cytarabine during the past 2 years.

- Investigational therapy within 4 weeks of Baseline/Day 1 visit.

- Psychiatric illness or social situation that would limit the patient's ability to
tolerate and/or comply with study requirements.

Study design
Purpose of the study
Treatment
Allocation to intervention
N/A
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA,VIC
Recruitment hospital [1] 0 0
Royal Adelaide Hospital - Adelaide
Recruitment hospital [2] 0 0
Monash Health, Monash Medical Centre - Clayton
Recruitment hospital [3] 0 0
Peter MacCallum Cancer Center - East Melbourne
Recruitment hospital [4] 0 0
Royal Melbourne Hospital - Parkville
Recruitment postcode(s) [1] 0 0
5000 - Adelaide
Recruitment postcode(s) [2] 0 0
3168 - Clayton
Recruitment postcode(s) [3] 0 0
3002 - East Melbourne
Recruitment postcode(s) [4] 0 0
3050 - Parkville
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Illinois
Country [3] 0 0
United States of America
State/province [3] 0 0
Kansas
Country [4] 0 0
United States of America
State/province [4] 0 0
Maryland
Country [5] 0 0
United States of America
State/province [5] 0 0
Massachusetts
Country [6] 0 0
United States of America
State/province [6] 0 0
Minnesota
Country [7] 0 0
United States of America
State/province [7] 0 0
New York
Country [8] 0 0
United States of America
State/province [8] 0 0
Texas
Country [9] 0 0
Denmark
State/province [9] 0 0
Hovedstaden
Country [10] 0 0
Denmark
State/province [10] 0 0
Jylland
Country [11] 0 0
France
State/province [11] 0 0
IDF
Country [12] 0 0
France
State/province [12] 0 0
Marseille
Country [13] 0 0
Germany
State/province [13] 0 0
Hessen
Country [14] 0 0
Germany
State/province [14] 0 0
Dresden
Country [15] 0 0
Germany
State/province [15] 0 0
Düsseldorf
Country [16] 0 0
Germany
State/province [16] 0 0
Göttingen
Country [17] 0 0
Germany
State/province [17] 0 0
Köln
Country [18] 0 0
Germany
State/province [18] 0 0
München
Country [19] 0 0
Italy
State/province [19] 0 0
Firenze
Country [20] 0 0
Italy
State/province [20] 0 0
Novara
Country [21] 0 0
Italy
State/province [21] 0 0
Rome
Country [22] 0 0
Spain
State/province [22] 0 0
Salamanca
Country [23] 0 0
Sweden
State/province [23] 0 0
Skåne
Country [24] 0 0
Sweden
State/province [24] 0 0
Västra Götalandsregionen
Country [25] 0 0
Sweden
State/province [25] 0 0
Stockholm

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Onconova Therapeutics, Inc.
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
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.
Trial website
https://clinicaltrials.gov/show/NCT01928537
Trial related presentations / publications
Olnes MJ, Shenoy A, Weinstein B, Pfannes L, Loeliger K, Tucker Z, Tian X, Kwak M, Wilhelm F, Yong AS, Maric I, Maniar M, Scheinberg P, Groopman J, Young NS, Sloand EM. Directed therapy for patients with myelodysplastic syndromes (MDS) by suppression of cyclin D1 with ON 01910.Na. Leuk Res. 2012 Aug;36(8):982-9. doi: 10.1016/j.leukres.2012.04.002. Epub 2012 Apr 21.
Seetharam M, Fan AC, Tran M, Xu L, Renschler JP, Felsher DW, Sridhar K, Wilhelm F, Greenberg PL. Treatment of higher risk myelodysplastic syndrome patients unresponsive to hypomethylating agents with ON 01910.Na. Leuk Res. 2012 Jan;36(1):98-103. doi: 10.1016/j.leukres.2011.08.022. Epub 2011 Sep 14.
Silverman LR, Greenberg P, Raza A, Olnes MJ, Holland JF, Reddy P, Maniar M, Wilhelm F. Clinical activity and safety of the dual pathway inhibitor rigosertib for higher risk myelodysplastic syndromes following DNA methyltransferase inhibitor therapy. Hematol Oncol. 2015 Jun;33(2):57-66. doi: 10.1002/hon.2137. Epub 2014 Apr 29.
Public notes

Contacts
Principal investigator
Name 0 0
Steven M. Fruchtman, MD
Address 0 0
Onconova Therapeutics, Inc.
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications