| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10000886 |
| E.1.2 | Term | Acute myeloid leukemia |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 efficacy of cusatuzumab in combination with azacitidine in patients with previously untreated acute myeloid leukemia (AML) who are not eligible for intensive chemotherapy |
|
| E.2.2 | Secondary objectives of the trial |
1) To determine the below responses
a) Complete response (CR)
b) CR with incomplete recovery (CRi)
c) CR with partial hematological revovery (CRh)
d) CR without MRD (CRMRD-)
e) Morphologic leukemia-free state (MLFS)
f) Partial response (PR)
g) Stable disease
h) Relapse after CR, CRi, CRh
i) Progressive Disease
2) To assess time to response and duration of response
3) To assess the safety profile of cusatuzumab in combination with azacitidine
4) To assess the pharmacokinetics of cusatuzumab alone and in combination with azacitidine
5) To assess the immunogenicity of cusatuzumab alone and in combination with azacitidine |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
1. ≥18 years of age
2. AML according to WHO 2016 criteria and fulfilling all of the following criteria that defines “not candidates for intensive chemotherapy”:
● ≥75 years of age or
● Comorbidity of at least one of the following:
o Eastern Cooperative Oncology Group (ECOG) Performance Status of 2
o Severe cardiac comorbidity defined as congestive heart failure or ejection fraction ≤50%
o Severe pulmonary comorbidity defined as documented pulmonary disease with lung diffusing capacity for carbon monoxide (DLCO) ≤65% of expected, or forced expiratory volume in 1 second (FEV1) ≤65% of expected or dyspnea at rest requiring oxygen
o Moderate hepatic impairment defined according to National Cancer Institute (NCI) organ dysfunction classification criteria (total bilirubin ≥1.5 up to 3 times upper lmit of normal [ULN])
o Creatinine clearance <45 mL/ min/1.73 m² (by MDRD formula)
o Comorbidity that, in the Investigator’s opinion, makes the patient unsuitable for intensive chemotherapy and must be documented and approved by the Sponsor before randomization
● De novo or secondary AML;
● Previously untreated AML (except: emergency leukapheresis, 1 low dose of cytarabine and/or hydroxyurea during the screening phase to control hyperleukocytosis but must be discontinued at least one day prior to start of azacitidine). All trans retinoic acid (ATRA) treatment for presumed acute promyelocytic leukemia is permitted but must be discontinued at least 1 day prior to the start of azacitidine;
● Not eligible for an allogeneic hematopoietic stem cell transplantation.
3. ECOG Performance Status score of 0, 1 or 2.
4. The following clinical laboratory values at screening:
● Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) <3 times ULN; for participants with leukemic infiltration of the liver (documented by biopsy or imaging), AST and ALT <5 times ULN is permitted
● Total bilirubin ≤ 3 times ULN unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin or in case of liver infiltration by AML (documented by biopsy or imaging) serum total bilirubin <5 times ULN
● Creatinine Clearance >30 mL/min (by MDRD formula)
5. A woman must be either:
● Not of childbearing potential: postmenopausal (>45 years of age with amenorrhea for at least 12 months);
● Of childbearing potential and practicing a highly effective method of birth control consistent with local regulations regarding the use of birth control methods for participants participating in clinical studies for at least 3 months: eg, established use of oral, injected or implanted hormonal methods of contraception; placement of an intrauterine device (IUD) or intrauterine system (IUS); barrier methods: condom with spermicidal foam/gel/film/cream/suppository or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository; male partner sterilization (the vasectomized partner should be the sole partner for that participant); true abstinence (when this is in line with the preferred and usual lifestyle of the participant).
A woman of childbearing potential must have a negative highly-sensitive serum (β-human chorionic gonadotropin [β-hCG]) or urine pregnancy test at screening.
Note: If the childbearing potential changes after start of the study (eg, woman who is not heterosexually active becomes active, premenarchal woman experiences menarche) a woman must begin a highly effective method of birth control, as described above.
6. A man who is sexually active with a woman of childbearing potential and has not had a vasectomy must agree to use a barrier method of birth control eg, either condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository for at least 3 months after last study treatment.
7. Must sign an informed consent form (ICF) indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study. |
|
| E.4 | Principal exclusion criteria |
Any potential participant who meets any of the following criteria will be excluded from participating in the study:
1. Acute promyelocytic leukemia with t (15;17), or its molecular equivalent (PML-RARα).
2. Leukemic involvement or clinical symptoms of leukemic involvement of the central nervous system.
3. Use of immune suppressive agents for the past 4 weeks before the first administration of cusatuzumab on Cycle 1 Day 1. For regular use of systemic corticosteroids, participants may only be included if free of systemic corticosteroids for a minimum of 5 days before the first administration of cusatuzumab.
4. Prior treatment with a hypomethylating agent for treatment of AML or MDS
5. A diagnosis of other malignancy that requires concurrent non surgical treatment
6. Any active untreated systemic infection
7. A history of human immunodeficiency virus (HIV) antibody positive or tests positive for HIV if tested at screening
8. Active systemic hepatitis infection requiring treatment or other clinically active liver disease
9. New York Heart Association Class IV heart failure or ongoing unstable angina
10. Known allergies, hypersensitivity, or intolerance to cusatuzumab or azacitidine or its excipients (ie, mannitol, an excipient of azacitidine).
11. Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, compromise the well-being) or physical limitations that could prevent, limit, or confound the protocol-specified assessments.
12. Major surgery, (eg, requiring general anesthesia) within 4 weeks before screening, or will not have fully recovered from surgery, or has surgery planned during the time the participant is expected to participate in the study.
Note: participants with planned surgical procedures to be conducted under local
anesthesia may participate. In such cases, the investigator must notify the Sponsor before randomization. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Complete response (CR) rate per ELN 2017 (Dohner 2017) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Every 2 cycles (approximately every 2 months) |
|
| E.5.2 | Secondary end point(s) |
1. Rate of CRh
2. Rate of CR + CRh
3. Rate of CRi
4. Overall response rate (ORR) = Rate of CR+ CRh+ CRi
5. Rate of CR without MRD
6. Rate of MRD negativity among participants achieving CR, CRh, CRi, or MLFS ; defined as less than 1 blast or leukemic stem cell in 1,000 leukocytes (MRD level <10^-3)
7. Time to response, defined as time from randomization to achieving the best response; duration of response, defined as time from achieving best response to disease relapse
8. Safety profile of Adverse Events (AE) and Serious Adverse Events (SAE)
9. Pharmacokinetics
10. Immunogenicity / anti-drug antibody testing |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1 to 7. Every 2 cycles (approximately every 2 months)
8. Throughout the study
9. Cycle (C) 1 Day (D) 1, C1D3, C1D4, C1D7, C1D10, C1D17, Cycle ≥2 D3, Cycle ≥2 D17, C3D21 to C4D1, C5D21 to C6D1, and EOT (end of treatment)
10. C1D3, C1D17, Cycle ≥2 D3, and EOT |
|
| 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 and Biomarker evaluations |
|
| 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 | 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) | 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 28 |
| 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 |
| Australia |
| Brazil |
| France |
| Israel |
| Italy |
| Russian Federation |
| Spain |
| Switzerland |
| Turkey |
| 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 study (study completion) is defined as the time at which 50% of participants have died. |
|
| 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 | 10 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 10 |
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