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

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

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

Brief Summary: 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.

Detailed Summary:

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 wi
Sponsor: Onconova Therapeutics, Inc.

Current Primary Outcome: Overall survival of all randomized patients and overall survival of patients scored as IPSS-R very high risk. [ Time Frame: Up to 30 Months ]

Original Primary Outcome:

• Overall survival of all randomized patients. [ Time Frame: Up to 30 Months ]
  Compare the overall survival (OS) of patients receiving IV rigosertib to the OS of patients receiving PC Overall survival is the median 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 scored as IPSS-R very high risk. [ Time Frame: Up to 30 Months ]
  Evaluate OS of patients with very high risk (VHR) per the Revised International Prognostic Scoring System (IPSS-R) in the rigosertib vs PC group. Overall survival is the median time (months) from date of randomization to date of death or date last known to be alive at the time of date cut-off.
• Number of Patients with AEs. [ Time Frame: Throughout the study and up to 30 days after the last dose ]
  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.

Current Secondary Outcome:

• 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.

Original Secondary Outcome:

• 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 median 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 median 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.
• 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.

Dates:
Date Received: September 25, 2015
Date Started: October 2015
Date Completion: September 2018
Last Updated: May 22, 2017
Last Verified: May 2017