E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Anemia in Patients with Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes (MDS). |
|
E.1.1.1 | Medical condition in easily understood language |
Myelodysplastic syndromes (MDS) are conditions that are observed when the blood-forming cells in the bone marrow become abnormal. |
|
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 | 27.0 |
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) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10002272 |
E.1.2 | Term | Anemia |
E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
|
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 |
Part 1: Dose Escalation • To evaluate the safety and tolerability of ascending doses of KER-050 in participants with very low, low, or intermediate risk MDS in order to determine the dose(s) that will be evaluated in Part 2 of the study. Part 2: Dose Confirmation • To confirm the safety and tolerability of the dose(s) selected in Part 1. Long-Term Extension •To evaluate the long-term safety and tolerability of KER-050 in participants with very low, low, or intermediate risk MDS in the Long-term Extension (LTE).
|
|
E.2.2 | Secondary objectives of the trial |
Secondary Objectives (All Parts): Safety Objective: •To evaluate the progression to higher risk MDS or acute myeloid leukemia (AML)
Efficacy Objective: •To evaluate the efficacy of KER-050 on anemia in participants with very low, low, orintermediate risk MDS, separately for ring sideroblast (RS)-positive and non-RS populations
Pharmacodynamic Objective: •To evaluate the pharmacodynamic (PD) effects of KER-050 on erythropoiesis in participantswith very low, low, or intermediate risk MDS, separately for RS-positive and non-RSpopulations |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Diagnosis of MDS (Parts 1 and 2) according to WHO classification that meets International Prognostic Scoring System-Revised (IPSS-R) classification of very low, low, or intermediate risk disease. 2. < 5% blasts in bone marrow during the Pretreatment Period. 3. Peripheral blood white blood cell (WBC) count < 13,000/µL during the Pretreatment Period. 4. Anemia defined as: a. In LTB participants, having received 1 to 3 units of RBCs for Hgb ≤ 9.0 g/dL within 8 weeks of the Pretreatment Period OR b. In HTB participants (defined as requiring > or = 4 units of RBCs for hemoglobin < or = 9.0 g/dL within 8 weeks) 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 (if related to anemia). 6. Females of child-bearing potential and sexually active males must agree to use effective methods of contraception.
|
|
E.4 | Principal exclusion criteria |
1. Active infection requiring parenteral antibiotic therapy within 28 days prior to C1D1 or oral antibiotics within 14 days of C1D1. Prophylactic antibiotics and/or antifungals for neutropenia are allowed. 2. Diagnosis of secondary MDS (ie, MDS that is known to have arisen as the result of chemical injury or treatment with chemotherapy and/or radiation for other diseases). 3. Vitamin B12 deficiency. 4. Prior treatment with azacitidine, decitabine, lenalidomide, luspatercept, or sotatercept. 5. Treatment with ESA within 56 days prior to C5D1. 6. Prior or concurrent chronic treatment with G-CSF or GM-CSF. 7. Iron chelation therapy if initiated within 8 weeks prior to Cycle 1 Day 1. 8. Vitamin B12 therapy within 8 weeks prior to Cycle 1 Day 1. 9. Treatment with another investigational drug or device or approved therapy for investigational use < or = 28 days prior to Cycle 1 Day 1, or if the half-life of the previous product is known, within 5 times the half-life prior to Cycle 1 Day 1, whichever is longer. 10. Platelet count > 450 x 10*9/L or < 30 x 10*9/L. 11. Transferrin saturation < 15%. 12. Ferritin < 50 µg/L. 13. Folate < 4.5 nmol/L (< 2.0 ng/mL). 14. Vitamin B12 < 148 pmol/L (< 200 pg/mL). 15. Estimated glomerular filtration rate (GFR) < 40 mL/min/1.73 m2 (as determined by the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]. 16. Pregnant or lactating females.
Medical History •Diagnosis of MDS with deletion of chromosome 5q (Del5q). •Presence of uncontrolled heart disease or New York Heart Association Class III or IV heart failure. •Presence of uncontrolled hypertension (Grade ≥ 2 high blood pressure). •History of stroke, deep venous thrombosis, or arterial embolism within 6 months prior to C1D1(or C5D1 for the Part 1 Extension). •Any malignancy other than MDS that has not been in remission and/or has required systemictherapy 1 year prior to C1D1 (or C5D1 for the Part 1 Extension). •Diagnosis of secondary MDS. •History of solid organ or hematological transplantation •Body mass index ≥ 40 kg/m2.
Treatment History •Prior treatment with azacitidine, decitabine, lenalidomide, luspatercept, or sotatercept. •Treatment with ESA within 8 weeks prior to C1D1 (or C5D1 for the Part 1 Extension). •Prior or concurrent chronic treatment with granulocyte colony-stimulating factor (G-CSF) orgranulocyte-macrophage colony-stimulating factor (GM-CSF), for reasons other than thetreatment of MDS.
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
Part 1 and Part 2: •Safety and tolerability as determined by the incidence of treatment-emergent adverse events(TEAEs) and serious adverse events (SAEs).
Long-term Extension: •Safety and tolerability as determined by the incidence of TEAEs and SAEs over time |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
105 Weeks unless participants elect to continue in the Long-term Extension (LTE) |
|
E.5.2 | Secondary end point(s) |
1. Incidence of progression to higher risk MDS or AML per World Health Organization (WHO) 2016 criteria. 2. Proportion of low transfusion burden (LTB) and high transfusion burden (HTB) participants who achieve red blood cell (RBC) transfusion independence (TI) ≥ 8 weeks, overall and by RS status. 3. Proportion of participants who achieve modified 2006 International Working Group (IWG) Hematologic Improvement-Erythroid (HI E) response overall and by RS status, where: - In LTB participants and participants with non-transfused anemia, response is defined as a mean hemoglobin (Hgb) increase of ≥ 1.5 g/dL from Baseline during any 8 week period during the treatment period. - In HTB participants, response is defined as a reduction by ≥ 4 units of RBCs transfused during any 8-week period on study compared with the 8-week period prior to study Cycle 1 Day 1 (C1D1). 4. Proportion of participants who achieve overall erythroid response, defined as either HI-E or TI over any 8-week period, overall and by RS status. 5. Proportion of participants who achieve erythropoietic improvement overall and by RS status, where: - In low-transfusion burden (LTB) participants and participants with non-transfused anemia, improvement is defined as a mean hemoglobin (Hgb) increase of ≥ 1.5 g/dL from Baseline for ≥ 14 days (in the absence of red blood cell [RBC] transfusions). - In high transfusion burden (HTB) participants, improvement is defined as a reduction of ≥ 50% or ≥ 4 RBC units transfused compared to pretreatment over an 8-week period. 6. Mean change from baseline in hemoglobin [Time Frame: Measured over the course of study, up to approximately 25 weeks from study day 1 unless participants elect to continue on in the LTE]. 7. Time to HI-E response [Time Frame: From treatment initiation to End of Study visit (approximately 25 weeks unless participants elect to continue on in the LTE)]. 8. Duration of HI-E response [Time Frame: From treatment initiation to End of Study visit (approximately 25 weeks unless participants elect to continue on in the LTE)]. 9. Time to TI response. 10. Duration of TI response. 11. Proportion of LTB and HTB participants who achieve TI ≥ 12 weeks, 16 weeks, 24 weeks, 48 weeks. 12. Change from baseline of red cell parameters, including reticulocyte count, mean corpuscular volume, mean corpuscular hemoglobin, and reticulocyte count, mean corpuscular volume, mean corpuscular volume, mean corpuscular hemoglobin and reticulocyte cell Hgb by visit. [Time Frame: From treatment initiation to End of Study visit (approximately 25 weeks unless participants elect to continue on in the LTE)].
Safety Endpoint: •Incidence of progression to higher risk MDS or AML per World Health Organization (WHO)2016 criteria
Efficacy Endpoints: •Proportion of low transfusion burden (LTB) and high transfusion burden (HTB) participants who achieve red blood cell (RBC) transfusion independence (TI) ≥ 8 weeks, overall and by RSstatus •Proportion of participants who achieve modified 2006 International Working Group (IWG)Hematologic Improvement-Erythroid (HI-E) response overall and by RS status, where:−In LTB participants and participants with non-transfused anemia, response is definedas a mean hemoglobin (Hgb) increase of ≥ 1.5 g/dL from Baseline during any 8-weekperiod during the treatment period −In HTB participants, response is defined as a reduction by ≥ 4 units of RBCstransfused during any 8-week period on study compared with the 8-week period priorto study Cycle 1 Day 1 (C1D1)
•Proportion of participants who achieve overall erythroid response, defined as either HI-E or TIover any 8-week period, overall and by RS status •Proportion of participants who achieve erythropoietic improvement overall and by RS status,where: −In LTB participants and participants with non-transfused anemia, improvement isdefined as a mean Hgb increase of ≥ 1.5 g/dL from Baseline for ≥ 14 days (in theabsence of RBC transfusions) −In HTB participants, improvement is defined as a reduction of ≥ 50% or ≥ 4 RBC unitstransfused compared with pretreatment over an 8-week period •Mean change from Baseline in Hgb by visit •Time to HI-E response •Duration of HI-E response •Time to TI response •Duration of TI response •Proportion of LTB and HTB participants who achieve TI ≥ 12 weeks, 16 weeks, 24 weeks, 48weeks
Pharmacodynamic Endpoint: •Change from Baseline of red cell parameters, including reticulocyte count, mean corpuscularvolume, mean corpuscular hemoglobin, and reticulocyte cell Hgb by visit.
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Timepoints indicated above. |
|
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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
|
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
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 | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
2-part Ascending Dose and Long-term Extension |
|
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 | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 23 |
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 |
New Zealand |
Australia |
Israel |
United States |
|
E.8.7 | Trial has a data monitoring committee | No |
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
|
The End of Trial is defined as when all of the participants have completed the treatment period in Part 1, Part 2, or the LTE. Participants will continue to be followed in the Survival Follow-up Period until all participants have withdrawn consent, are declared lost to follow-up, have died, or until study closure, whichever is earliest. |
|
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 | 9 |
E.8.9.1 | In the Member State concerned days | 12 |
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 | 9 |
E.8.9.2 | In all countries concerned by the trial days | 12 |