| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with higher risk myelodysplastic syndrome (MDS) who have not yet been treated for their disease |
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| E.1.1.1 | Medical condition in easily understood language |
| Myelodysplastic syndrome is a type of cancer where the blood-forming cells in the bone marrow are abnormal |
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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 | 21.1 |
| 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 |
| To assess the effect of ALX148 administered at the RP2D determined in Phase 1 in combination with AZA versus AZA alone on the investigator-assessed complete response rate (CRR) per IWG 2006 criteria in adult patients with previously-untreated higher risk MDS (IPSS-R score >3.5) |
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| E.2.2 | Secondary objectives of the trial |
• To assess the effect of ALX148 administered at the RP2D determined in Phase 1 in combination with AZA versus AZA alone on the complete response rate (CRR) per IWG 2006 criteria as determined by independent central review in adult patients with previously-untreated higher risk MDS (IPSS-R score >3.5)
• To assess secondary measures of efficacy for ALX148 administered in combination with AZA versus AZA alone
• To assess the safety and tolerability of ALX148 administered in combination with AZA versus AZA alone
• To assess if ALX148 in combination with AZA improves global health status/quality of life (GHS/QoL) versus AZA alone based on patient reported outcome (PRO) assessment |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Adult patients with documented diagnosis of higher risk MDS (IPSS-R score >3.5) who have had no prior exposure to hypomethylating agents or cytotoxic chemotherapy (prior use of single agent lenalidomide for low or intermediate-1 risk MDS with deletion 5q abnormality is allowed) for the treatment of MDS, and are considered appropriate candidates for single-agent AZA.
2. Bone marrow with >5% to <20% myeloblasts.
3. Adequate Renal Function with estimated creatinine clearance ≥30 mL/min as calculated using the method standard for the institution.
4. Adequate Liver Function, including:
a. Total serum bilirubin ≤1.5 x ULN (≤3.0 x ULN if the patient has documented Gilbert syndrome);
b. Aspartate and alanine transaminase (AST and ALT) ≤3.0 x ULN; ≤5.0 x ULN if due to leukemic organ involvement;
c. Alkaline phosphatase ≤2.5 x ULN; (≤5.0 x ULN if bone or liver metastasis).
5. WBC < 20,000/μL. Administration of hydroxyurea for WBC control is permitted during the screening period up to and including treatment day -1 of the study (ie, one day prior to starting study treatment).
6. QTcF interval of ≤480 msec (Based upon mean value from triplicate ECGs).
7. Age ≥18 years because MDS is extremely rare in the pediatric (<18 yrs) population.
8. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) must be 0, 1 or 2.
9. For Phase 1 only: resolved acute effects of any prior therapy to baseline severity or Grade ≤1 NCI CTCAE v.5.0 except for AEs not constituting a safety risk by Investigator judgment.
10. Serum pregnancy test (for females of childbearing potential) negative at screening.
11. Male and female patients of childbearing potential must agree to use a highly effective method of contraception throughout the study and for at least 120 days after the last dose of assigned treatment. A patient is of childbearing potential if, in the opinion of the Investigator, he/she is biologically capable of having children and is sexually active.
12. Evidence of a personally signed and dated informed consent document indicating that the patient (or legal representative) has been informed of all pertinent aspects of the study before any study-specific activity is performed.
13. Patients who are willing and able to comply with scheduled visits, treatment plans, laboratory, tests and other procedures. |
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| E.4 | Principal exclusion criteria |
1. Patients with a history of autoimmune hemolytic anemia, autoimmune thrombocytopenia, or hemolytic transfusion reaction secondary to an acquired allo-antibody.
2. Previous allogeneic hematopoietic stem cell transplant (allo-HSCT) for MDS or AML. If allo-HSCT was performed for another disease, patient must be at least a year post-HSCT, off all treatment for graft-versus-host disease (GVHD), and without any active GVHD.
3. Prior treatment with any anti-CD47 or anti-SIRPα agent.
4. Prior treatment with any hypomethylating agents or cytotoxic chemotherapy for MDS (except hydroxyurea up to day -1 of study and lenalidomide for low or intermediate-1 risk MDS with deletion 5q abnormality).
5. Patients with MPN/MDS overlap syndromes, including CMML.
6. Prior treatment with myeloid growth factors and erythropoiesis stimulating agents (ESAs) must be discontinued a minimum of 4-5 half-lives prior to initiation of study treatment.
7. Patients with intolerance to or who have had a severe allergic or anaphylactic reaction to antibodies or infused therapeutic proteins or patients who have had a severe allergic or anaphylactic reaction to any of the substances included in the study drug (including excipients).
8. Any experimental antibodies or live vaccines in the last 28 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
9. Known active viral infections, including hepatitis B (HBV), hepatitis C (HCV), human immunodeficiency virus (HIV), acquired immunodeficiency syndrome (AIDS) related illness, or known active infection with SARS-CoV-2 (testing to be performed per local criteria).
10. Any of the following in the previous 6 months: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, NYHA Class II or greater congestive heart failure, uncontrolled hypertension, cerebrovascular accident, transient ischemic attack, deep venous thrombosis (except for thrombi considered device-associated and not clinically significant), arterial thrombosis, symptomatic pulmonary embolism, or any other significant thromboembolism. Any major surgery, within 28 days prior to enrollment.
11. Current active treatment in another interventional therapeutic clinical study.
12. Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, prostate/breast/other cancer under control with hormone therapy alone, or other cancer from which the subject has been disease free for at least 2 years and felt to be at low risk for recurrence by the treating physician.
13. Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
14. Other severe acute or chronic medical or psychiatric condition, including uncontrolled systemic infection, recent (within the past year) or active suicidal ideation or behavior, or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this study.
15. Males and females of childbearing potential not using highly effective contraception or not agreeing to continue highly effective contraception for at least 120 days after last dose of investigational product.
16. Patients who are pregnant or breastfeeding. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of the Phase 2 part of the study is complete response rate (CRR), assessed by investigator using IWG 2006 response criteria for MDS, defined as a best response of CR, with the final analysis to be performed after the last patient has completed 6 cycles of treatment or is considered evaluable for response. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| In Phase 2, the final analysis to be performed after the last patient has completed 6 cycles of treatment or is considered evaluable for response. |
|
| E.5.2 | Secondary end point(s) |
• Incidence of marrow CR, objective response rate (ORR), hematologic improvement (HI) in erythrocytes (E), platelets (P), and neutrophils (N), red blood cell (RBC) and platelet (PLT) transfusion independence, frequency and level of measurable residual disease (MRD)
• Duration of response (DOR), event-free survival (EFS), progression-free survival (PFS), overall survival (OS), time to progression (TTP).
• Percentage of patients able to proceed to allogeneic hematopoietic stem cell transplant (allo-HSCT).
• Changes in global health status/quality of life (GHS/QoL) status based on patient reported outcome (PRO) assessment (Phase 2 only).
• Adverse Events as characterized by type, frequency, severity (as graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v. 5.0), timing, seriousness, and relationship to study therapy;
• Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE v. 5.0) and timing;
• Pharmacokinetic parameters of ALX148 such as Cmax, Tmax, AUC, CL, and t1/2 as data permit;
• Immunogenicity; Human serum ADA (anti-ALX148 antibody) samples will be analyzed for the presence or absence of anti-ALX148 antibodies. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Duration of response (DOR) is measured from the time measurement criteria are first met for CR, PR, mCR, CyR, or HI, until the first date that progressive disease (PD) is documented. Duration of CR is also measured from the time measurement criteria are first met for CR only, until the first date that progressive disease (PD) is documented. Patients who do not have any documentation of progression will be censored at their last tumor assessment. DOR will be evaluated in the responders population.
Time to progression (TTP) is measured from start of treatment until progressive disease (PD) is documented. Patients who do not have any documentation of progression will be censored at their last tumor assessment.
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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 | 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 |
| Tolerability; Immunogenicity; Pharmacodynamic for CD47 occupancy |
|
| 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 | 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 | No |
| 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 | 6 |
| 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 |
| Korea, Republic of |
| United States |
| Belgium |
| France |
| Germany |
| Italy |
| Spain |
| United Kingdom |
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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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| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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