Clinical Trials /

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

NCT02562443

Description:

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.

Related Conditions:
  • Refractory Anemia with Excess Blasts
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: Onconova 04-30
  • SECONDARY ID: 2015-001476-22
  • NCT ID: NCT02562443

Conditions

  • Myelodysplastic Syndrome
  • MDS
  • Refractory Anemia With Excess Blasts
  • RAEB

Interventions

DrugSynonymsArms
rigosertibON 01910.Narigosertib + best supportive care (BSC)
Any approved or standard-of-care therapyPhysician's Choice (PC) + best supportive care (BSC)
best supportive care (BSC)Physician's Choice (PC) + best supportive care (BSC)
best supportive care (BSC)rigosertib + best supportive care (BSC)

Purpose

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 Description

      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).
    

Trial Arms

NameTypeDescriptionInterventions
rigosertib + best supportive care (BSC)Experimental
  • rigosertib
  • best supportive care (BSC)
Physician's Choice (PC) + best supportive care (BSC)Active Comparator
  • Any approved or standard-of-care therapy
  • best supportive care (BSC)

Eligibility Criteria

        Inclusion Criteria:

          -  MDS classified as follows:

               -  RAEB-1 per World Health Organization (WHO) MDS criteria (5% to <10% BM blasts)

               -  RAEB-2 per WHO MDS criteria (10% to <20% BM blasts)

               -  RAEB-t per French-American-British (FAB) classification (20% to 30% BM blasts)

          -  At least one cytopenia (ANC < 1800/µL or platelet count < 100,000/µL or hemoglobin
             [Hgb] < 10 g/dL)

          -  Progression (according to 2006 IWG criteria) at any time after initiation of AZA or
             DAC treatment or Failure to achieve complete or partial response or hematological
             improvement (HI) (according to 2006 IWG) after at least six 4-week cycles of AZA or
             either four 4-week or four 6-week cycles of DAC administered or Relapse after initial
             complete or partial response or HI (according to 2006 IWG criteria)

          -  Duration of prior HMA therapy ≤ 9 months and/or total ≤ 9 cycles of prior HMA therapy
             in ≤ 12 months

          -  Last dose of AZA or DAC within 6 months before the planned date of randomization;
             however, must be off these treatments for ≥ 4 weeks before randomization

          -  Has failed to respond to, relapsed following, not eligible for, or opted not to
             participate in allogeneic stem cell transplantation

          -  Off all treatments for MDS (including AZA and DAC) for ≥ 4 weeks before randomization;
             growth factors (G-CSF, erythropoietin and thrombopoietin) and transfusions are allowed
             before and during the study as clinically indicated

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

          -  Willing to adhere to protocol prohibitions and restrictions

          -  Patient must sign informed consent form to indicate patient's understanding study's
             purpose and procedures and willingness to participate. Should patient be incapable of
             giving consent, the patient's legally authorized representative (as defined by local
             regulation) must give consent. However, should patient, in any manner, choose not to
             participate this takes precedence and will be respected.

          -  Patients with 5q- syndrome should have failed to respond to or progressed on treatment
             with lenalidomide, where available and indicated

        Exclusion Criteria:

          -  Previous participation in a clinical study of IV or oral rigosertib; patients who
             failed screening for other rigosertib studies may be screened for participation

          -  Eligible to receive induction chemotherapy, such as 7-10 days of cytosine arabinoside
             plus 2-3 days of an anthracycline, or high-dose cytarabine

          -  Suitable candidate to receive allogeneic stem cell transplantation; patient is
             eligible for study if a suitable candidate refuses to undergo an allogeneic stem cell
             transplant or a suitable donor cannot be found

          -  Any active malignancy within the past year, except basal cell or squamous cell skin
             cancer or carcinoma in situ that is unlikely to progress in two years

          -  Uncontrolled intercurrent illness including, but not limited to, symptomatic
             congestive heart failure or unstable angina pectoris

          -  Active infection not adequately responding to appropriate therapy

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

          -  Alanine transaminase (ALT)/aspartate transaminase (AST) ≥2.5 x upper limit of normal
             (ULN)

          -  Serum creatinine ≥2.0 mg/dL or eGFR (estimated Glomerular Filtration Rate) < 40
             mL/min.

          -  Known active HIV, hepatitis B or hepatitis C, where active is defined as follows:

               -  HIV or hepatitis C - presence of viral load

               -  Hepatitis B - antigen positive

          -  Uncorrected hyponatremia (defined as serum sodium value of <130 mEq/L)

          -  Female patients of child-bearing potential and male patients with sexual partners of
             child-bearing potential who are unwilling to follow strict contraception requirements
             before entry and throughout the study, up to and including the 30-day non-treatment
             follow-up period. Examples of acceptable contraception methods include:

               -  estrogen-gestagen based contraceptives associated with inhibition of ovulation
                  (oral, intravaginal, transdermal),

               -  gestagen-only based contraceptives associated with inhibition of ovulation (oral,
                  injectable, implantable),

               -  intra-uterine devices (IUDs),

               -  intra-uterine hormone-releasing systems (IUSs),

               -  bilateral tubal occlusion

               -  vasectomized partner

               -  sexual abstinence in accordance with an individual's lifestyle

          -  Female patients of child-bearing potential (pre-menopausal and not surgically
             sterilized) who are breast-feeding or have a positive blood beta-human chorionic
             gonadotropin pregnancy test at Screening

          -  Major surgery without full recovery or within 3 weeks before planned randomization;

          -  Uncontrolled hypertension

          -  New onset seizures (within 3 months before planned randomization) or poorly controlled
             seizures

          -  Any other concurrent investigational agent or chemotherapy, radiotherapy,
             immunotherapy, or corticosteroids (prednisone up to 20 mg/day or its equivalent is
             permitted for chronic conditions)

          -  Treatment with cytarabine at any dose, lenalidomide, or any other therapy targeted to
             the treatment of MDS (other than growth factors and other supportive care measures)
             within 4 weeks of planned randomization

          -  Investigational therapy within 4 weeks of planned randomization

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

          -  Patient previously diagnosed with AML (defined as a bone marrow or peripheral blood
             blast percentage of >30%).
      
Maximum Eligible Age:81 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall survival of all randomized patients and overall survival of patients scored as IPSS-R very high risk.
Time Frame:Up to 30 Months
Safety Issue:
Description:The overall survival (OS) of all randomized patients (ITT population), and the overall survival of patients scored as IPSS-R very high risk.

Secondary Outcome Measures

Measure:Overall survival of patients with monosomy 7 chromosomal aberrations.
Time Frame:Up to 30 Months
Safety Issue:
Description: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.
Measure:Overall survival of patients with trisomy 8 chromosomal aberrations.
Time Frame:Up to 30 Months
Safety Issue:
Description: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.
Measure:Percent of patients with response according to 2006 IWG criteria.
Time Frame:Up to 30 Months
Safety Issue:
Description: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.
Measure:Scores of Quality of Life Questionnaire.
Time Frame:At Baseline, at Week 4, Every 4 Weeks thereafter, and at the End-of-treatment.
Safety Issue:
Description: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.
Measure:Percent of patients with bone marrow blast response rate according to 2006 IWG criteria.
Time Frame:Up to 30 Months
Safety Issue:
Description: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.
Measure:Percent of patients with hematologic improvement (HI) (erythroid, platelet and neutrophil responses) according to 2006 IWG criteria.
Time Frame:Up to 30 Months
Safety Issue:
Description:Compare rigosertib vs PC in regard to the number and percent of patients who meet the 2006 IWG criteria.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Onconova Therapeutics, Inc.

Trial Keywords

  • Myelodysplastic Syndrome
  • MDS

Last Updated

October 11, 2018