E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Myelodysplastic syndrome (MDS) is a group of disorders in which the red blood cells, white blood cells and platelets produced by the bone marrow do not grow and mature normally |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10028533 |
E.1.2 | Term | Myelodysplastic syndrome |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objectives of this clinical trial are
• to compare the overall survival (OS) of patients receiving IV rigosertib to the OS of patients receiving the physician’s choice of treatment (PC) in a population of patients with myelodysplastic syndromes (MDS) after failure of treatment with azacitidine (AZA) or decitabine (DEC)
• to evaluate OS of patients with very high risk (VHR) per the Revised International Prognostic Scoring System (IPSS-R) in the rigosertib group vs the PC group
• to evaluate the safety and tolerability of rigosertib administered as 72-hour CIV infusions in the rigosertib group vs the PC group. |
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E.2.2 | Secondary objectives of the trial |
• To compare rigosertib to PC 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
o Bone marrow blast response according to 2006 IWG criteria
o Hematologic improvement (HI) (erythroid, platelet or neutrophil response) according
to 2006 IWG criteria
• Rigosertib population pharmacokinetics (PK) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
a. 18-79 years of age;
b. Disease classified as follows:
• RAEB-1 per World Health Organization (WHO) MDS criteria (5% to 9% BM blasts)
• RAEB-2 per WHO MDS criteria (10% to 19% BM blasts)
• RAEB-t per modified French-American-British (FAB) classification (20% to 30% BM blasts)
c. Diagnosis of MDS confirmed within 8 weeks prior to the Screening Visit
d. At least one cytopenia (ANC < 1800/μL or platelet count < 100,000/μL or hemoglobin [Hgb] < 10 g/dL)
e. Progression (according to 2006 IWG criteria) at any time after initiation of AZA or DEC 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 DEC administered
or
Relapse after initial complete or partial response or HI (according to 2006 IWG criteria)
or
Intolerance to AZA or DEC
f. Duration of prior HMA therapy ≤ 9 months
g. Last dose of AZA or DEC within 6 months before the planned date of randomization; however, must be off these treatments for ≥ 4 weeks before randomization
h. Has failed to respond to, relapsed following, not eligible for, or opted not to participate in allogeneic stem cell transplantation
i. Off all treatments for MDS (including AZA and DEC) for ≥ 4 weeks before randomization; growth factors (G-CSF, erythropoietin and thrombopoietin) and transfusions are allowed before and during the study as clinically indicated
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. |
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E.4 | Principal 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. Eligible to receive allogeneic stem cell transplantation
d. Any active malignancy within the past year, except basal cell or squamous cell skin cancer or carcinoma in situ of the cervix or breast
e. Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure or unstable angina pectoris
f. Active infection not adequately responding to appropriate therapy
g. Total bilirubin ≥1.5 mg/dL not related to hemolysis or Gilbert’s disease
h. Alanine transaminase (ALT)/aspartate transaminase (AST) ≥2.5 x upper limit of normal (ULN)
i. Serum creatinine ≥2.0 mg/dL
j. Known HIV, hepatitis B or hepatitis C
k. Uncorrected hyponatremia (defined as serum sodium value of <130 mEq/L)
l. 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
m. Female patients of child-bearing potential who are breast-feeding or have a positive blood betahuman chorionic gonadotropin (βHCG) pregnancy test at Screening
n. Major surgery without full recovery or major surgery within 3 weeks before planned randomization
o. Uncontrolled hypertension
p. New onset seizures (within 3 months before planned randomization) or poorly controlled seizures
q. 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)
r. 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
s. Investigational therapy within 4 weeks of planned randomization
t. Psychiatric illness or social situation that would limit the patient’s ability to tolerate and/or comply with study requirements. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoints are overall survival of all randomized patients (ITT population), and overall survival of patients scored as IPSS-R very high risk. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
at each individual patient's death |
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E.5.2 | Secondary end point(s) |
• Overall survival of patients with monosomy 7 chromosomal aberrations
• Overall survival of patients with trisomy 8 chromosomal aberrations
• Overall response rate according to 2006 IWG criteria
• Quality-of-life scores using the EuroQol EQ-5D Questionnaire
• Bone marrow blast response rate according to 2006 IWG criteria
• Hematologic improvement (erythroid, platelet, or neutrophil response) according to 2006 IWG criteria.
• Worst-grade adverse events (AEs)
• Deaths, other serious AEs, and other AEs leading to discontinuation of study treatment
• Worst-grade laboratory abnormalities |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Physician’s Choice of Treatment |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 46 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Austria |
Canada |
Croatia |
France |
Germany |
Ireland |
Israel |
Italy |
Spain |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Patients will be treated until until 2006 IWG progression criteria are met (ie, 50% increase of BM blasts or worsening of cytopenias).
The end of the trial is given by the last patient's death. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 15 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |