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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT02562443




Registration number
NCT02562443
Ethics application status
Date submitted
25/09/2015
Date registered
29/09/2015
Date last updated
23/06/2020

Titles & IDs
Public title
Controlled Study of Rigosertib Versus Physician's Choice of Treatment in MDS Patients After Failure of an HMA
Scientific 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
Secondary ID [1] 0 0
2015-001476-22
Secondary ID [2] 0 0
Onconova 04-30
Universal Trial Number (UTN)
Trial acronym
INSPIRE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Myelodysplastic Syndrome 0 0
MDS 0 0
Refractory Anemia With Excess Blasts 0 0
RAEB 0 0
Condition category
Condition code
Blood 0 0 0 0
Haematological diseases
Blood 0 0 0 0
Other blood disorders
Blood 0 0 0 0
Anaemia
Other 0 0 0 0
Research that is not of generic health relevance and not applicable to specific health categories listed above

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - rigosertib
Treatment: Drugs - Any approved or standard-of-care therapy
Treatment: Drugs - best supportive care (BSC)
Treatment: Drugs - best supportive care (BSC)

Experimental: rigosertib + best supportive care (BSC) -

Active Comparator: Physician's Choice (PC) + best supportive care (BSC) -


Treatment: Drugs: 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).

Treatment: Drugs: 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.

Treatment: Drugs: best supportive care (BSC)
Patients will receive best supportive care (BSC): azacitidine (AZA) and/or decitabine (DAC) are permitted.

Treatment: Drugs: best supportive care (BSC)
Patients will receive best supportive care (BSC).

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

Outcomes
Primary outcome [1] 0 0
Overall survival of all randomized patients and overall survival of patients scored as IPSS-R very high risk. - The overall survival (OS) of all randomized patients (ITT population), and the overall survival of patients scored as IPSS-R very high risk.
Timepoint [1] 0 0
Up to 30 Months
Secondary outcome [1] 0 0
Overall survival of patients with monosomy 7 chromosomal aberrations. - 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.
Timepoint [1] 0 0
Up to 30 Months
Secondary outcome [2] 0 0
Overall survival of patients with trisomy 8 chromosomal aberrations. - 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.
Timepoint [2] 0 0
Up to 30 Months
Secondary outcome [3] 0 0
Percent of patients with response according to 2006 IWG criteria. - 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.
Timepoint [3] 0 0
Up to 30 Months
Secondary outcome [4] 0 0
Scores of Quality of Life Questionnaire. - 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.
Timepoint [4] 0 0
At Baseline, at Week 4, Every 4 Weeks thereafter, and at the End-of-treatment.
Secondary outcome [5] 0 0
Percent of patients with bone marrow blast response rate according to 2006 IWG criteria. - 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.
Timepoint [5] 0 0
Up to 30 Months
Secondary outcome [6] 0 0
Percent of patients with hematologic improvement (HI) (erythroid, platelet and neutrophil responses) according to 2006 IWG criteria. - Compare rigosertib vs PC in regard to the number and percent of patients who meet the 2006 IWG criteria.
Timepoint [6] 0 0
Up to 30 Months

Eligibility
Key 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
Minimum age
18 Years
Maximum age
81 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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%).

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
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
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
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)
QLD,TAS,VIC
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Icon Cancer Care Icon South Brisbane - South Brisbane
Recruitment hospital [2] 0 0
Royal Hobart Hospital - Hobart
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Monash Health, Monash Medical Centre - Melbourne
Recruitment postcode(s) [1] 0 0
4101 - South Brisbane
Recruitment postcode(s) [2] 0 0
7000 - Hobart
Recruitment postcode(s) [3] 0 0
3168 - Melbourne
Recruitment outside Australia
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Liverpool
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London

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

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/show/NCT02562443
Trial related presentations / 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.
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