A study in patients with Myelodysplastic Syndromes

• Register: EUCTR
• Last refreshed on: 8 January 2018
• Main ID: EUCTR2013-003235-30-DE
• Date of registration: 08/11/2013
• Prospective Registration: Yes
• Primary sponsor: Eli Lilly and Company
• Public title: A study in patients with Myelodysplastic Syndromes
• Scientific title: Phase 2/3 Study of Monotherapy LY2157299 Monohydrate in Very Low-, Low-, and Intermediate-Risk Patients with Myelodysplastic Syndromes
• Date of first enrolment: 21/02/2014
• Target sample size: 140
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2013-003235-30
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: no Cross over: no Other: yes Other trial design description: Phase 2 single arm unblinded; phase 3 2-arm, randomized, placebo controlled If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Canada, Germany, Israel, Italy, Japan, Spain, United States

Contacts

• Name: Clinical Trial Information
• Affiliation: Eli Lilly and Company

• Name: Clinical Trial Information
• Affiliation: Eli Lilly and Company

Key inclusion & exclusion criteria

Inclusion criteria:
[1] have a confirmed diagnosis of MDS based on the WHO criteria. Patients with 5q deletions are allowed only if they have failed or are intolerant to lenalidomide treatment. Patients with WHO diagnosis of nonproliferative MDS/myeloproliferative neoplasms are also included.
[2] have IPSS-R category of very low-, low-, or intermediate-risk disease as confirmed by
• bone marrow examination during screening period (will be used also for the correlative/exploratory studies)
•=10% marrow blasts
•appropriate calculation of their IPSS-R score that is not influenced by rise of haematology scores by prior infusions (eg, by reviewing the transfusion history and associated Hb levels prior to each transfusion during the 8 weeks prior to the screening period)
[3] meet the following haematologic criteria 8 weeks prior to registration (according to the IWG criteria):
• Phase 2: anaemia with Hb =10.0 g/dL (based on the average of 2 baseline measurements and untransfused for at least 1 week) with or without RBC transfusion dependence confirmed for a minimum of 8 weeks before enrolment (eg, transfusion dependency defined by at least 4 units of RBC administered within 8 weeks before baseline).
•Phase 3: anaemia with RBC transfusion dependence confirmed within 8 weeks before enrolment (eg, transfusion dependency defined by at least 4 units of RBC administered within 8 weeks before date of enrolment).
[4] have a performance status of =2 on the Eastern Cooperative Oncology Group (ECOG) scale.
[5] have discontinued all disease-modifying therapy for MDS, including investigational treatments, for 28 days prior to initiation of study treatment, with the exception of transfusions and the following supportive care:
• Patients may receive prophylactic steroids (such as prednisolone, methylprednisolone, or dexamethasone) to prevent transfusion reactions.
• Iron chelation therapy is allowed if started prior to enrolment and patients have been stable for at least 3 months.
• Granulocyte colony stimulating factor (G-CSF) or granulocyte macrophage colony stimulating factor (GM-CSF) is allowed in the presence of neutropaenic fever or documented neutropaenic infection.
• Patients may have been treated with danazol or prior hypomethylating agents
[6] have adequate hepatic function, defined as bilirubin =1.5 x the upper limit of normal (ULN) and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels =2.5 x ULN
[7] have adequate renal function, defined as serum creatinine levels =2.0 x ULN
[8] are at least 18 years old at the time of screening
[9] use an approved contraceptive method (for example, intrauterine device, birth control pills, or barrier device), if appropriate (male and female patients with reproductive potential) during and for 6 months after discontinuation of study treatment
• Women of childbearing potential must have a negative beta-human chorionic gonadotropin pregnancy test documented within 7 days prior to treatment. If condoms are used as a barrier contraceptive, a spermicidal agent should be added to ensure that pregnancy does not occur. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
[10] have given written informed consent/assent prior to any study-specific procedures
[11] are able to swallow tablets
[12] are willing and able to comply with protocol procedures (including completion of diaries
Exclusion criteria:
[14] have moderate or severe cardiovascular disease:
• have the presence of cardiac disease, including a myocardial infarction within 6 months prior to study entry, unstable angina pectoris, New York Heart Association Class III/IV congestive heart failure, or uncontrolled hypertension.
• have documented major ECG abnormalities (not responding to medical treatments).
• have major abnormalities documented by ECHO with Doppler (for example, moderate or severe heart valve function defect and/or left ventricular [LV] ejection fraction <50%, evaluation based on the institutional lower limit of normal). For additional details, refer to the attached ECHO protocol (Attachment 9).
• have predisposing conditions that are consistent with development of aneurysms of the ascending aeorta or aeortic stress (for example, family history of aneurysms, Marfan-Syndrome, bicuspid aeortic valve, evidence of damage to the large vessels of the heart documented by CT scan/MRI with contrast)
[15] have previous history of AML
[16] are women who are pregnant or lactating
[17] have a serious concomitant systemic disorder including active infection with hepatitis B virus (positive hepatitis B surface antigen [+HBsAg]), hepatitis C virus (HCV), and human immunodeficiency virus (HIV)
[18] have a second primary malignancy that, in the judgment of the investigator and Lilly, may affect the interpretation of results
[19] have prior malignancies. Patients with carcinoma in situ of any origin and patients with prior malignancies who are in remission and whose likelihood of recurrence is very low (such as basal cell carcinoma), as judged by the Lilly clinical research physician (CRP), are eligible for this study. The Lilly CRP will approve enrolment of patients with prior malignancies in remission before these patients are enrolled.
[20] are unwilling or unable to participate in, or do not have tissue adequate for participation in, the translational research portion of the study. Patients with inadequate tissue are ineligible for this study.
[21] are currently enrolled in a clinical trial involving an investigational product or nonapproved use of a drug or device (other than the study drug/device used in this study) or are concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study
[22] have untreated hypothyroidism as determined by the investigator
[23] have received ESAs within 28 days prior to enrolment
[24] are receiving immunosuppressive agents (eg, cyclosporine) except for corticosteroids for transfusions



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Cancer [C04]

Myelodysplastic Syndromes
MedDRA version: 17.1 Level: HLT Classification code 10028536 Term: Myelodysplastic syndromes System Organ Class: 100000004851

Intervention(s)

Product Name: LY2157299 monohydrate
Product Code: LY2157299 monohydrate
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: LY2157299
CAS Number: 924898-09-9
Current Sponsor code: LY2157299
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 80-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Product Name: LY2157299 monohydrate
Product Code: LY2157299 monohydrate
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: LY2157299
CAS Number: 924898-09-9
Current Sponsor code: LY2157299
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 150-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Primary end point(s): Phase 2 portion
Distribution of best Haematological Improvement (HI) based on IWG 2006 criteria

Phase 3 portion
Compare % patients who are transfusion free or have Hb increase =1.5 g/dL maintained for at least 8 weeks in first 24 weeks

Main Objective: Phase 2 portion
To estimate the distribution of best HI, based on IWG 2006 criteria in patients with very low-, low-, and intermediate-risk MDS by IPSS-R treated with LY2157299 plus best supportive care. This includes a broad range of responses (see secondary objectives).

Phase 3 portion
To compare the percentage of patients with very low-, low-, and intermediate-risk MDS by IPSS-R when treated with LY2157299 versus placebo, in combination with best supportive care, who are transfusion-free or have a rise of =1.5 g/dL Hb maintained for at least 8 weeks within the first 24 weeks of treatment.

Timepoint(s) of evaluation of this end point: Phase 2 portion
Distribution of best Haematological Improvement (HI) based on IWG 2006 criteria - Timepoint: date of start of treatment to study discontinuation any cause

Phase 3 portion
Compare % patients who are transfusion free or have Hb increase =1.5 g/dL maintained for at least 8 weeks in first 24 weeks - Timepoint: date of randomization to 24 weeks of treatment

Secondary Objective: Secondary objectives of both Phase 2 and Phase 3:
•to evaluate the safety and tolerability
•to characterise the PK profile
•to estimate within-treatment response (Phase 2) and between-treatment differences (Phase 3) using haematological HI parameters according to IWG criteria, such as
- freq. of responses or progression for each of the 3 haematopoietic lineages
- time to best HI
- duration of best HI
- change in transfusion requirement for platelets and red cells
- change in blood counts
- change in bone marrow fibrosis
- frequency of bone marrow response (CR + PR) and cytogenetic response
- duration of HI following discontinuation of LY2157299
- rate of HI at 3&6 cycles
•to evaluate PROs to assess fatigue and health status as assessed by the Brief Fatigue Inventory (Phases 2&3) and the EuroQol 5-Dimension 5-Level questionnaire (Phase 3 only)
•to assess resource utilisation including hospitalisations and emergency room visits
•to determine PFS and OS at 6&12 months

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Phase 2 and 3 portions:
Timepoint – HI-Baseline to disease progression, Safety, PRO – Start of treatment until study discontinuation, PK Cycle 1 to end of treatment, PFS - start of treatment until documented disease progression or death from any cause

Secondary end point(s): Phase 2 and 3 portions:
Estimate within-treatment response (Phase 2) and between-treatment differences (Phase 3) using haematological HI parameters : frequency of responses or progression for each of the 3 haematopoietic lineages; time to and duration of best HI, change in transfusion requirements & blood counts, change in bone marrow fibrosis,frequency of bone marrow and cytogenetic response, rate of HI at 3 & 6 months. Evaluate Safety & PK, Changes in patient-reported outcomess. Progression-free & Overall survival at 6 months, 12 months.

Secondary ID(s)

H9H-MC-JBAV