Controlled Study of Rigosertib Versus Physician's Choice of Treatment in MDS Patients After Failure of an HMA (INSPIRE)
|Myelodysplastic Syndrome MDS Refractory Anemia With Excess Blasts RAEB||Drug: rigosertib Drug: Any approved or standard-of-care therapy Drug: best supportive care (BSC)||Phase 3|
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Official Title:||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|
- Overall survival of all randomized patients and overall survival of patients scored as IPSS-R very high risk. [ Time Frame: Up to 30 Months ]The overall survival (OS) of all randomized patients (ITT population), and the overall survival of patients scored as IPSS-R very high risk.
- Overall survival of patients with monosomy 7 chromosomal aberrations. [ Time Frame: Up to 30 Months ]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.
- Overall survival of patients with trisomy 8 chromosomal aberrations. [ Time Frame: Up to 30 Months ]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.
- Percent of patients with response according to 2006 IWG criteria. [ Time Frame: Up to 30 Months ]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.
- Scores of Quality of Life Questionnaire. [ Time Frame: At Baseline, at Week 4, Every 4 Weeks thereafter, and at the End-of-treatment. ]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.
- Percent of patients with bone marrow blast response rate according to 2006 IWG criteria. [ Time Frame: Up to 30 Months ]Compare rigosertib vs PC in regard to the bone marrow blast responses of marrow complete response (mCR, BMBL ≤ 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 progression), and progressive disease (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.
- Percent of patients with hematologic improvement (HI) (erythroid, platelet and neutrophil responses) according to 2006 IWG criteria. [ Time Frame: Up to 30 Months ]Compare rigosertib vs PC in regard to the number and percent of patients who meet the 2006 IWG criteria.
- Exploratory Objective: Bone Marrow Genomic Mutational Status [ Time Frame: At screening, every 8 week during study treatment, and at the end of study treatment ]Bone marrow genomic mutational status.
- Exploratory Objective: Transition to Acute Myelogenous Leukemia (AML) [ Time Frame: Through study completion, an average of 8 months ]Transformation time to AML (defined as a bone marrow or peripheral blood blast percentage >30%).
- Safety Objective: Number of Patients with AEs. [ Time Frame: Monthly, through study completion ]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.
- Safety Objective: Plasma concentration of rigosertib. [ Time Frame: At Day 1, Day 2, Day 15 and Day 16. ]The concentration of rigosertib in the plasma of patients in the rigosertib arm will be measured by a validated method.
|Study Start Date:||October 2015|
|Estimated Study Completion Date:||September 2018|
|Estimated Primary Completion Date:||June 2018 (Final data collection date for primary outcome measure)|
|Experimental: rigosertib + best supportive care (BSC)||
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).
Other Name: ON 01910.NaDrug: best supportive care (BSC)
Patients will receive best supportive care (BSC).
|Active Comparator: Physician's Choice (PC) + best supportive care (BSC)||
Drug: Any approved or standard-of-care therapy
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.Drug: best supportive care (BSC)
Patients will receive best supportive care (BSC): azacitidine (AZA) and/or decitabine (DAC) are permitted.
This is a Phase III, open-label, randomized, controlled, international study. Approximately 225 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 150 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 75 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).
Please refer to this study by its ClinicalTrials.gov identifier: NCT02562443
|Contact: Joseph Morgan, MD||(267) email@example.com|
|Contact: Steven M Fruchtman, MD||(267) firstname.lastname@example.org|
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|Study Chair:||Steven M. Fruchtman, MD||Onconova Therapeutics, Inc.|