Trial document




drksid header

  DRKS00011259

Trial Description

start of 1:1-Block title

Title

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

end of 1:1-Block title
start of 1:1-Block acronym

Trial Acronym

04-30 (INSPIRE)

end of 1:1-Block acronym
start of 1:1-Block url

URL of the Trial

http://www.onconova.com/clinical-trials/inspire.php

end of 1:1-Block url
start of 1:1-Block public summary

Brief Summary in Lay Language

Objective:
• 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

end of 1:1-Block public summary
start of 1:1-Block scientific synopsis

Brief Summary in Scientific Language

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 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).

end of 1:1-Block scientific synopsis
start of 1:1-Block organizational data

Organizational Data

  •   DRKS00011259
  •   2016/11/03
  •   2015/09/25
  •   no
  •   Approved
  •   EK 528122015, Ethikkommission der Medizinischen Fakultät der Technischen Universität Dresden
end of 1:1-Block organizational data
start of 1:n-Block secondary IDs

Secondary IDs

  •   2015-001476-22 
  •   NCT02562443  (ClinicalTrials.gov)
end of 1:n-Block secondary IDs
start of 1:N-Block indications

Health Condition or Problem studied

  •   D46 -  Myelodysplastic syndromes
end of 1:N-Block indications
start of 1:N-Block interventions

Interventions/Observational 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.
    Regarding overall-survival, all patients are followed-up until death.
  •   Physician's Choice of 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
end of 1:N-Block interventions
start of 1:1-Block design

Characteristics

  •   Interventional
  •   [---]*
  •   Randomized controlled trial
  •   Open (masking not used)
  •   [---]*
  •   Active control (effective treament of control group)
  •   Treatment
  •   Parallel
  •   III
  •   No
end of 1:1-Block design
start of 1:1-Block primary endpoint

Primary Outcome

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. Post-treatment Follow-up: All patients will have monthly follow-up for transformation to AML or survival until death.

end of 1:1-Block primary endpoint
start of 1:1-Block secondary endpoint

Secondary Outcome

To compare rigosertib to Physician’s Choice with regard to the following:
o Overall survival of patients with monosomy 7 chromosomal aberrations
o Overall survival of patients with trisomy 8 chromosomal aberrations
o Overall response according to 2006 International Working Group (IWG) criteria
o Quality-of-life (QoL) scores using the EuroQol EQ-5D Questionnaire (timepoints: Baseline, Q4W (+/- 2 days), End-of-treatment)
o Overall bone marrow blast response according to 2006 IWG criteria
o Hematologic improvement (HI) (erythroid, platelet or neutrophil response) according
to 2006 IWG criteria
Post-treatment Follow-up: All patients will have monthly follow-up for transformation to AML or survival until death.

end of 1:1-Block secondary endpoint
start of 1:n-Block recruitment countries

Countries of Recruitment

  •   Germany
  •   Switzerland
  •   Austria
  •   Belgium
  •   Croatia
  •   Czech Republic
  •   France
  •   Ireland
  •   Italy
  •   Portugal
  •   Netherlands
  •   Poland
  •   Spain
  •   Australia
  •   Canada
  •   Israel
  •   Japan
end of 1:n-Block recruitment countries
start of 1:n-Block recruitment locations

Locations of Recruitment

  • University Medical Center 
  • Medical Center 
  • Medical Center 
  • Medical Center 
  • Medical Center 
  • Medical Center 
  • Medical Center 
  • Medical Center 
end of 1:n-Block recruitment locations
start of 1:1-Block recruitment

Recruitment

  •   Actual
  •   2015/12/03
  •   225
  •   Multicenter trial
  •   International
end of 1:1-Block recruitment
start of 1:1-Block inclusion criteria

Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   81   Years
end of 1:1-Block inclusion criteria
start of 1:1-Block inclusion criteria add

Additional Inclusion Criteria

a. 18-81 years of age;
b. Disease classification and cytogenetics confirmed within 8 weeks prior to or during screening
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 modified French-American-British (FAB) classification (20% to 30% BM
blasts)
c. At least one cytopenia (ANC < 1800/μL or platelet count < 100,000/μL or hemoglobin [Hgb] < 10 g/dL)
d. 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)
or
Intolerance to AZA or DAC
e. Total duration of prior HMA therapy ≤ 9 months
f. 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
g. Has failed to respond to, relapsed following, not eligible for, or opted not to participate in
allogeneic stem cell transplantation
h. Off all treatments for MDS (including AZA and DAC) for ≥ 4 weeks before randomization;
growth factors (G-CSF, erythropoietin and TPO) and transfusions are allowed before and
during the study as clinically indicated
i. Patients with 5q- syndrome should have failed to respond to or progressed on treatment with
lenalidomide
j. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
k. Willing to adhere to the prohibitions and restrictions specified in this protocol
l. Patient (or patient’s legally authorized representative) must have signed an informed consent
document indicating that the patient understands the purpose of and procedures required for the
study and is willing to participate in the study.

end of 1:1-Block inclusion criteria add
start of 1:1-Block exclusion criteria

Exclusion Criteria

a. Previous participation in a clinical study of IV or oral rigosertib; patients who failed screening
for other rigosertib studies may be screened for participation in this study
b. Eligible to receive induction chemotherapy, such as 7-10 days of cytosine arabinoside plus 2-3
days of an anthracycline, or high-dose cytarabine (HDAC)
c. Patient previously diagnosed with AML (defined as a bone marrow blast percentage of
>30%)
d. 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.
e. Any active malignancy within the past year, except basal cell or squamous cell skin cancer or
carcinoma in situ of the cervix or breast
f. Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart
failure or unstable angina pectoris
g. Active infection not adequately responding to appropriate therapy
h. Total bilirubin ≥1.5 mg/dL not related to hemolysis or Gilbert’s disease
i. Alanine transaminase (ALT)/aspartate transaminase (AST) ≥2.5 x upper limit of normal (ULN)
j. Serum creatinine ≥2.0 mg/dL
k. Known HIV, hepatitis B or hepatitis C
l. Uncorrected hyponatremia (defined as serum sodium value of <130 mEq/L)
m. 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 (βHCG)
pregnancy test at Screening
n. Female patients of child-bearing potential and male patients with 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
o. Major surgery without full recovery or major surgery within 3 weeks before planned
randomization
p. Uncontrolled hypertension
q. New onset seizures (within 3 months before planned randomization) or poorly controlled
seizures
r. 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)
s. 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
t. Investigational therapy within 4 weeks of planned randomization
u. Psychiatric illness or social situation that would limit the patient’s ability to tolerate and/or
comply with study requirements.

end of 1:1-Block exclusion criteria
start of 1:n-Block addresses

Addresses

  • start of 1:1-Block address primary-sponsor
    • Onconova Therapeutics, Inc.
    • Mr.  Dr.  Ramesh  Kumar 
    • 375 Pheasant Run
    • PA 18940  Newtown
    • United States
    end of 1:1-Block address primary-sponsor
    start of 1:1-Block address contact primary-sponsor
    end of 1:1-Block address contact primary-sponsor
  • start of 1:1-Block address scientific-contact
    • Universitätsklinikum Carl Gustav CarusMedizinische Klinik und Poliklinik I
    • Mr.  Professor  Uwe  Platzbecker 
    • Fetscherstraße 74
    • 01307  Dresden
    • Germany
    end of 1:1-Block address scientific-contact
    start of 1:1-Block address contact scientific-contact
    end of 1:1-Block address contact scientific-contact
  • start of 1:1-Block address public-contact
    • Universitätsklinikum Carl Gustav CarusMedizinische Klinik und Poliklinik I
    • Mr.  Professor  Uwe  Platzbecker 
    • Fetscherstraße 74
    • 01307  Dresden
    • Germany
    end of 1:1-Block address public-contact
    start of 1:1-Block address contact public-contact
    end of 1:1-Block address contact public-contact
end of 1:n-Block addresses
start of 1:n-Block material support

Sources of Monetary or Material Support

  • start of 1:1-Block address materialSupport
    • Onconova Therapeutics
    • Inc. 375 Pheasant Run Newtown
    • PA 18940 
    • United States
    end of 1:1-Block address materialSupport
    start of 1:1-Block address contact materialSupport
    •   [---]*
    •   [---]*
    •   [---]*
    •   [---]*
    end of 1:1-Block address contact materialSupport
end of 1:n-Block material support
start of 1:1-Block state

Status

  •   Recruiting ongoing
  •   [---]*
end of 1:1-Block state
start of 1:n-Block publications

Trial Publications, Results and other Documents

  •   Athuluri-Divakar et al., 2016, Cell 165, 643–655
end of 1:n-Block publications
* This entry means the parameter is not applicable or has not been set.