| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
-Myelodysplastic Syndrome
-Chronic Myelomonocytic Leukemia
-Acute Myeloid Leukemia |
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| E.1.1.1 | Medical condition in easily understood language |
| Advanced haematological malignancies |
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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 | 20.0 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10005329 |
| E.1.2 | Term | Blood and lymphatic system disorders |
| E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
|
| 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 |
| •To determine the safety and tolerability of bexmarilimab in combination with azacitidine in participants with MDS, CMML and relapsed AML and in combination with azacitidine/venetoclax in newly diagnosed AML patients non-fit for conventional induction therapy and to determine a recommended dose for Part II of the study. |
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| E.2.2 | Secondary objectives of the trial |
•To assess preliminary efficacy of bexmarilimab in combination with azacitidine in participants with MDS, CMML and relapsed AML or in combination with azacitidine/venetoclax in newly diagnosed AML patients non-fit for conventional induction therapy
•To assess the PK profile of bexmarilimab during repeated dosing
•To assess the host immune response to bexmarilimab (immunogenicity)
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Written informed consent
2.Patients who present with one of the following conditions: Morphologically confirmed diagnosis of MDS based on 2016 WHO classification with indication for azacitidine treatment based on local standard medical practice with one of the following risk categories based on the revised International Prognostic Scoring System (IPSS-R):
i.Very high (> 6 points)
ii.High (> 4.5 - ≤ 6 points)
iii.Intermediate (> 3 - ≤ 4.5 points)
b.Morphologically confirmed diagnosis of CMML based on WHO2016 classification with 10-19 percent marrow blasts without myeloproliferative disorder with indication for azacitidine treatment based on local standard medical practice
c.CMML (without myeloproliferative phenotype) and MDS patients who presents with failure to achieve response to therapy with hypomethylating agent or therapy regimen including hypomethylating agent. Failure is considered if the patient has not achieved response after 4 cycles of therapy or the disease is progressing during hypomethylating agent.
d.Morphologically confirmed diagnosis of relapsed or refractory AML (except acute promyelocytic leukemia) following at least 1 line of prior therapies with indication for azacitidine treatment based on local standard medical practice.
e.Morphologically confirmed diagnosis of acute myeloid leukemia in patients unfit for induction therapy with indication for azacitidine-venetoclax treatment based on local standard medical practice. Specific criteria for non-eligibility for induction chemotherapy:
Participant must be:
≥ 75 years of age;
OR
≥ 18 to 74 years of age and ineligible for intensive chemotherapy meeting at least one of the criteria following:
Clinically significant comorbidities, as reflected by at least 1 of:
•Left ventricular ejection fraction (LVEF) < 50%.
•Lung diffusion capacity for carbon monoxide (DLCO) ≤ 65% of expected.
•Forced expiratory volume in 1 second (FEV1) ≤ 65% of expected.
•Chronic stable angina or congestive heart failure controlled with medication.
Other contraindication(s) to anthracycline therapy (must be documented)
Adverse risk genetics associated with poor outcome with standard chemotherapy
Antecedent MDS treated previously with standard chemotherapy and/or allogeneic transplantation.
3.Leukocyte count < 25 x109/l. Hydroxycarbamide use is permitted to meet this criterion in MDS and AML but not in CMML.
4.Subject must have adequate renal function as demonstrated by a calculated creatinine clearance ≥ 30 mL/min; determined by the Cockcroft Gault formula.
5.Subject must have adequate liver function as demonstrated by
a.alanine aminotransferase (ALT) ≤ 3.0 × ULN
b.bilirubin ≤ 1.5 × ULN.
|
|
| E.4 | Principal exclusion criteria |
1.Subject has acute promyelocytic leukemia (APL)
2.Myeloproliferative CMML as defined by leukocyte count > 13 x109/l. Of note, the use hydroxycarbamide is not allowed to meet this criterion in subjects with CMML.
3.ECOG >2
4.Subject has known CNS involvement with myeloid malignancy (note: CSF or radiological investigations are not required without clinical suspicion)
5.Subject with HIV infection or active hepatitis B virus (HBV), or hepatitis C virus (HCV) infection
6.Subject has cardiovascular disability status of New York Heart Association Class ≥ 2. Class 2 is defined as cardiac disease in which subjects are comfortable at rest but ordinary physical activity results in palpitations, fatigue, dyspnea, or anginal pain.
7.Subject has a chronic respiratory disease that requires continuous oxygen use; evidence of other clinically significant condition(s) that in the opinion of the investigator would adversely affect his/her participation in this study; systemic infection requiring therapy (viral, bacterial or fungal); or graft versus host disease requiring treatment
8.Allogeneic transplantation less than 6 months prior screening.
9.Subject has a history of other malignancies prior to study entry, with the exception of previous malignancy confined and surgically resected (or treated with other modalities) with curative intent and have not recurred within 2 years prior to study treatment.
10.Subject with active auto-immune disorder (except type I diabetes, celiac disease, hypothyroidism requiring only hormone replacement, vitiligo, psoriasis, or alopecia)
11.The subject requires systemic corticosteroid (≥10 mg/day prednisone or equivalent) or other immunosuppressive treatment. Topical, nasal, inhaled and ophthalmic steroids are allowed.
12.Use of live (attenuated) vaccines for 30 days prior to the start of study treatment, during treatment, and until last visit
13.Less than 21 days since the last dose of intravenous anticancer chemotherapy or less than five half-lives from a small molecule targeted therapy or oral anticancer chemotherapy before the first IMP administration
14.Major surgery within 2 weeks of the first dose of study treatment (procedures like insertion of a central venous access device are not considered as major surgery)
15.Any immunotherapy or investigational therapy within preceding 4 weeks from the first IMP administration
16.Pregnant or lactating women
17.Women of child-bearing potential, unless they are using highly effective methods of contraception for at least 1 month prior to first dose and agreement to use such a method during study participation and for an additional 12 weeks after stopping study medication.
18.Men of reproductive potential: use of condoms, vasectomy, or other method to ensure effective contraception with partner during study participation and for an additional 12 weeks after stopping study medication.
19. History of chronic ulcers or clinically relevant liver disease leading to Child Pugh Score C or higher. If the history of abnormal liver function is related to previous hematologic malignancy or it’s treatment, the patient may be enrolled after discussing with the sponsor.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
•Incidence of adverse events and serious adverse events and laboratory values will be collected until 90 days after the end of treatment visit
•The incidence of dose limiting toxicities during the first two cycles
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
-90 days
-First two cycles
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|
| E.5.2 | Secondary end point(s) |
•Overall response rate (ORR), MRD negativity rates
•CR rates, CR+CRi rates, CR+CRh rates, 4- and 8-week mortality, progression free survival (PFS), duration of response (DOR), and overall survival (OS)
•PK parameters (e.g., AUC, Cmax, Tmax, half-life)
•Anti-bexmarilimab antibodies (immunogenicity)
|
|
| 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 | 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 | Yes |
| 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) | 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 |
|
| 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 | 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 5 |
| 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 |
|
| 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
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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 | 3 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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