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

• ClinicalTrials.gov Identifier: NCT02562443
• Recruitment Status: Active, not recruiting
• First Posted: September 29, 2015
• Last Update Posted: June 23, 2020
• Sponsor: Onconova Therapeutics, Inc.
• Information provided by (Responsible Party): Onconova Therapeutics, Inc.

Tracking Information

• First Submitted Date: September 25, 2015
• First Posted Date: September 29, 2015
• Last Update Posted Date: June 23, 2020
• Actual Study Start Date: December 2, 2015
• Estimated Primary Completion Date: December 31, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 9, 2016)

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.

Original Primary Outcome Measures (submitted: September 25, 2015)

• 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 Measures (submitted: December 6, 2017)

• 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 ≥ 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.
• 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 Measures (submitted: September 25, 2015)

• 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.

Current Other Pre-specified Outcome Measures (submitted: December 6, 2017)

• 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: Rigosertib population pharmacokinetics (PK). [ Time Frame: At Cycle 1 (Week 1) and Cycle 2 (Week 3), on Day 1 of the infusion, 1 hr after its start and on Day 2 of the infusion, 6 hr after its start ]
  Blood samples for population PK analysis will be taken in rigosertib patients

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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
• 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 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).

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

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

Intervention

• Drug: rigosertib
  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.Na
• 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.
• Drug: best supportive care (BSC)
  Patients will receive best supportive care (BSC).

Study Arms

• Experimental: rigosertib + best supportive care (BSC)
  Interventions:

  • Drug: rigosertib
  • Drug: best supportive care (BSC)
• Active Comparator: Physician's Choice (PC) + best supportive care (BSC)
  Interventions:

  • Drug: Any approved or standard-of-care therapy
  • Drug: best supportive care (BSC)

Publications *

• Garcia-Manero G, Fenaux P, Al-Kali A, Baer MR, Sekeres MA, Roboz GJ, Gaidano G, Scott BL, Greenberg P, Platzbecker U, Steensma DP, Kambhampati S, Kreuzer KA, Godley LA, Atallah E, Collins R Jr, Kantarjian H, Jabbour E, Wilhelm FE, Azarnia N, Silverman LR; ONTIME study investigators. Rigosertib versus best supportive care for patients with high-risk myelodysplastic syndromes after failure of hypomethylating drugs (ONTIME): a randomised, controlled, phase 3 trial. Lancet Oncol. 2016 Apr;17(4):496-508. doi: 10.1016/S1470-2045(16)00009-7. Epub 2016 Mar 9.
• Athuluri-Divakar SK, Vasquez-Del Carpio R, Dutta K, Baker SJ, Cosenza SC, Basu I, Gupta YK, Reddy MV, Ueno L, Hart JR, Vogt PK, Mulholland D, Guha C, Aggarwal AK, Reddy EP. A Small Molecule RAS-Mimetic Disrupts RAS Association with Effector Proteins to Block Signaling. Cell. 2016 Apr 21;165(3):643-55. doi: 10.1016/j.cell.2016.03.045.
• Navada SC, Silverman LR. The safety and efficacy of rigosertib in the treatment of myelodysplastic syndromes. Expert Rev Anticancer Ther. 2016 Aug;16(8):805-10. doi: 10.1080/14737140.2016.1209413. Epub 2016 Jul 15. Review.
• Garcia-Manero G, Fenaux P. Comprehensive Analysis of Safety: Rigosertib in 557 Patients with Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML). Blood Dec 2016, 128 (22) 2011; ASH 2016.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: January 19, 2018): 360
• Original Estimated Enrollment (submitted: September 25, 2015): 225
• Estimated Study Completion Date: December 31, 2021
• Estimated Primary Completion Date: December 31, 2020 (Final data collection date for primary outcome measure)

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%).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 81 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Austria, Belgium, Canada, Croatia, Czechia, Estonia, France, Germany, Hungary, India, Ireland, Israel, Italy, Japan, Poland, Russian Federation, Spain, Sweden, Switzerland, United Kingdom, United States
• Removed Location Countries: Czech Republic, Netherlands

Administrative Information

• NCT Number: NCT02562443
• Other Study ID Numbers: Onconova 04-30; 2015-001476-22 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Onconova Therapeutics, Inc.
• Study Sponsor: Onconova Therapeutics, Inc.
• Collaborators: Not Provided

Investigators

• Study Chair: Steven M. Fruchtman, MD; Onconova Therapeutics, Inc.

• PRS Account: Onconova Therapeutics, Inc.
• Verification Date: June 2020