E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Myelodysplastic syndrome with excess blasts |
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E.1.1.1 | Medical condition in easily understood language |
Disease of the blood and bone marrow |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.1 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10028536 |
E.1.2 | Term | Myelodysplastic syndromes |
E.1.2 | System Organ Class | 100000004851 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of the study is to compare overall survival (OS) in patients receiving 1800 mg/24 hr of ON 01910.Na via 72-hour continuous intravenous infusion administered every other week + best supportive care (BSC) to OS of patients receiving BSC in a population of patients with myelodysplastic syndrome with excess blasts (5% to 30% bone marrow blasts) having failed, being intolerant, or progressing after azacitidine or decitabine treatment. |
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E.2.2 | Secondary objectives of the trial |
Compare the BSC + ON 01910.Na group to the BSC group with respect to:
• Overall survival in each of the subsets of patients as defined in the
protocol
•Overall response (complete + partial remission) according to 2006 IWG criteria
• Complete bone marrow response according to 2006 IWG criteria
• Hematological improvements in ANC, platelet count, and erythroid responses according to 2006 IWG criteria
• Improvements of cytogenetics as evaluated by the change in aneuploidy in bone marrow according to 2006 IWG criteria
•Relationship between best BM blast response and OS
• Transition time to AML:
-Defined for RAEB-1 and RAEB-2 MDS and chronic myelomonocytic leukemia (CMML) patients (with BM blasts from 10% to 20% for CMML) by an increase of at least 50% BM blasts and more than 20% BM blasts
-Defined for RAEB-t by an increase of at least 50% BM blasts
• Quality-of-life (QOL) scores (using the EORTC Quality of Life Questionnaire [QLQ]-C30 version 3
• Incidence of infections |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Male and female patients who meet all of the following criteria are eligible for enrollment in the trial:
a. ≥18 years of age;
b. Diagnosis of MDS confirmed within 6 weeks prior to study entry according to WHO criteria or FAB classification;
c. MDS classified as follows, according to WHO criteria and FAB classification:
• RAEB-1 (5% to 9% BM blasts)
• RAEB-2 (10% to 19% BM blasts)
• CMML (10% to 20% BM blasts) and WBC < 13,000/μL
• RAEB-t (20% to 30% BM blasts), meeting the following criteria:
o WBC < 25 x 109/L at study entry
o Stable WBC at least 4 weeks prior to study entry and not requiring intervention for WBC control with hydroxyurea, chemotherapy, or leukophoresis;
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 azacitidine or decitabine treatment during the past 2 years;
or
Failure to achieve complete or partial response or hematological improvement (according to 2006 IWG) after at least six 4-week cycles of azacitidine or either four 4-week or four 6-week cycles of decitabine administered during the past 2 years;
or
Relapse after initial complete or partial response or hematological improvement (according to 2006 IWG criteria) observed after at least six 4-week cycles of azacitidine or either four 4-week or four 6-week cycles of decitabine administered during the past 2 years;
or
Intolerance to azacitidine or decitabine defined by drug-related ≥Grade 3 liver or renal toxicity leading to treatment discontinuation during the past 2 years;
f. Has failed to respond to, relapsed following, not eligible, or opted not to participate in bone marrow transplantation;
g. Off all other treatments for MDS for at least 4 weeks. Filgrastim (G-CSF) and erythropoietin are allowed before and during the study as clinically indicated;
h. No medical need for induction chemotherapy;
i. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2;
j. Willing to adhere to the prohibitions and restrictions specified in this protocol;
k. Patient (or patient’s legally authorized representative) must 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 |
Patients with any of the following will not be enrolled in the study:
a. Anemia due to factors other than MDS (including hemolysis or gastrointestinal [GI] bleeding) unless stabilized for 1 week after RBC transfusion;
b. Any active malignancy within the past year, except basal cell or squamous cell skin cancer or carcinoma in situ of the cervix or breast;
c. Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia;
d. Active infection not adequately responding to appropriate therapy;
e. Total bilirubin ≥1.5 mg/dL not related to hemolysis or Gilbert’s disease;
f. Alanine transaminase (ALT)/aspartate transaminase (AST) ≥2.5 x upper limit of normal (ULN);
g. Serum creatinine ≥2.0 mg/dL;
h. Ascites requiring active medical
management including paracentesis, or hyponatremia (defined as serum sodium value of <130 mEq/L);
i. Female patients who are pregnant or lactating;
j. Patients who are unwilling to follow strict contraception requirements (including condom use for males with sexual partners, and for females: prescription oral contraceptives [birth control pills], contraceptive injections, intrauterine device, double-barrier method [spermicidal jelly or foam with condoms or diaphragm], contraceptive patch, or surgical sterilization) before entry and throughout the study;
k. Female patients with reproductive potential who do not have a negative urine beta-human chorionic gonadotropin (βHCG) pregnancy test at screening;
l. Major surgery without full recovery or major surgery within 3 weeks of ON 01910.Na treatment start;
m. Uncontrolled hypertension (defined as a systolic pressure ≥160 mmHg and/or a diastolic pressure ≥110 mmHg);
n. New onset seizures (within 3 months prior to the first dose of ON 01910.Na) or poorly controlled seizures;
o. Any other concurrent investigational agent or chemotherapy, radiotherapy, or immunotherapy;
p. Prior treatment with low-dose cytarabine during the past 2 years;
q. Investigational therapy within 4 weeks of starting ON 01910.Na;
r. 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) |
3.4.2. Efficacy Assessments
The following outcomes will be assessed:
• Overall survival
• Blastic response in BM
• Progression to AML defined as:
o ≥50% BM blasts increase and >20% BM blasts for RAEB-1, RAEB-2, and CMML patients
o ≥50% BM blasts increase for RAEB-t patients
• Change in BM cytogenetics
• Changes in ANC
• Changes in platelet count and platelet transfusions requirements
• Changes in Hgb and RBC transfusion requirements
• QOL questionnaire using EORTC QLQ-C30 version 3
• Incidence of infections (treated with intravenous antimicrobials) and bleeding episodes (and their severity) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
During and at the end of study |
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E.5.2 | Secondary end point(s) |
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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 | No |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 40 |
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 |
Belgium |
France |
Germany |
Spain |
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
|
Last patient last visit. Patients will be treated until progression or until death from any cause, whichever comes first. |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 7 |
E.8.9.2 | In all countries concerned by the trial days | 0 |