E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML) |
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E.1.1.1 | Medical condition in easily understood language |
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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.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10054350 |
E.1.2 | Term | Chronic myelomonocytic leukemia |
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 | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To compare overall response rate (ORR) between treatment groups in subjects with higher-risk myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) who are not eligible for hematopoietic stem cell transplantation (HSCT) |
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E.2.2 | Secondary objectives of the trial |
1. To compare the following between treatment groups: • Proportion of subjects achieving complete remission (CR)+partial remission (PR) • Proportion of subjects achieving CR • Time to response • Duration of response • Transfusion (red blood cell [RBC] or platelets) independence • Transformation to acute myeloid leukemia (AML) according to World Health Organization (WHO) criteria • Progression-free survival (PFS) • Overall survival (OS) • Hematologic improvement 2. To assess the safety profile of cusatuzumab in combination with azacitidine 3. To assess changes in physical function/symptoms 4. To assess the pharmacokinetics (PK) of cusatuzumab in combination with azacitidine 5. To assess the immunogenicity of cusatuzumab |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Each potential subject must satisfy all of the following criteria to be randomized in the study: 1. Age ≥18 years. 2. Diagnosis of de novo or secondary higher-risk MDS or CMML per WHO 2016 criteria. 3. At study entry, higher-risk MDS (intermediate, high, and very high risk MDS per IPSS-R) OR higher-risk CMML (intermediate-2 or high risk CMML per CPSS-Mol). Appendix 5 of the protocol presents the relevant prognostic tools. Subjects with previous lower-risk MDS or CMML that has evolved to higher-risk MDS or CMML are eligible. 4. At study entry, not a candidate for HSCT. 5. Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2 6. Adequate liver and renal function defined as follows: • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) <3× upper limit of normal (ULN) • Total bilirubin ≤1.5×ULN, unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin • Creatinine clearance (CrCl) >30 mL/min/1.73 m² (by Modification of Diet in Renal Disease formula). 7. A woman of childbearing potential must have a negative highly-sensitive serum (β-human chorionic gonadotropin [β-hCG]) or urine pregnancy test at screening. 8. Women of childbearing potential (defined as: fertile, following menarche and until becoming postmenopausal unless permanently sterile): a. Must be practicing a highly-effective method of birth control (failure rate of <1% per year when used consistently and correctly) during treatment and for 3 months after the last dose of study drug. Examples of highly effective methods of contraception are located in Appendix 6 of the protocol. b. Must agree to not donate eggs (ova, oocytes) for the purposes of assisted reproduction during treatment and for 3 months after the last dose of study drug. c. Must not be breastfeeding and not planning to become pregnant during treatment and for 3 months after the last dose of study drug. 9. Men who are sexually active with women of childbearing potential and have not had a vasectomy, must: a. 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) during treatment and for 3 months after the last dose of study drug b. Agree to not donate sperm during treatment and for 3 months after the last dose of study drug c. Not plan to father a child during treatment or within 3 months after the last dose of study drug 10. The potential subject or a legally authorized representative 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.
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E.4 | Principal exclusion criteria |
Any potential subject who meets any of the following criteria will be excluded from participating in the study: 1. Received prior HSCT or any prior treatment, including HMAs, for higher-risk MDS or CMML. Prior supportive therapies including transfusion and growth factors are acceptable. 2. Received prior treatment with cusatuzumab. 3. Presence of any of the following genetic abnormalities regardless of blast count: a. t(8;21)(q22;q22); RUNX1-RUNX1T1 (previously AML1-ETO) b. inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 c. t(15;17)(q22;q21.1); PML-RARA 4. Presence of the bcr-abl rearrangement (ie, Philadelphia chromosome). 5. Received a live, attenuated vaccine within 4 weeks prior to initiation of study drug. 6. Active malignancies (ie, progressing or requiring treatment change in the last 24 months) other than the disease being treated under study. The only allowed exceptions are: a. Non-muscle invasive bladder cancer b. Skin cancer (non-melanoma or melanoma) treated within the last 24 months that is considered completely cured c. Non-invasive cervical cancer treated within the last 24 months that is considered completely cured. d. Localized prostate cancer (N0M0): • With a Gleason score of 6, treated within the last 24 months or untreated and under surveillance • With a Gleason score of 3+4 that has been treated more than 6 months prior to full study screening and considered to have a very low risk of recurrence • Or history of localized prostate cancer (N0M0) and receiving androgen deprivation therapy and considered to have a very low risk of recurrence e. Breast cancer: • Adequately treated lobular carcinoma in situ or ductal carcinoma in situ • Or history of localized breast cancer and receiving antihormonal agents and considered to have a very low risk of recurrence f. Malignancy that is considered cured with minimal risk of recurrence. 7. Any active systemic infection. 8. History of human immunodeficiency virus (HIV) antibody positive or tests positive for HIV at screening. 9. Known hepatitis C infection or positive serologic testing for hepatitis C (anti-hepatitis C virus antibody). 10. Seropositive for hepatitis B, defined by a positive test for hepatitis B surface antigen [HBsAg]. Subjects with resolved infection (ie, subjects who are HBsAg negative with antibodies to total hepatitis B core antigen [anti-HBc] with or without the presence of hepatitis B surface antibody [anti-HBs]) must be screened using real-time polymerase chain reaction (RT-PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are RT-PCR positive will be excluded. Subjects with serologic findings suggestive of HBV vaccination (ie, anti-HBs positivity as the only serologic marker) and a known history of prior HBV vaccination do not need to be tested for HBV DNA by RT-PCR. 11. New York Heart Association Class 4 heart failure or ongoing unstable angina. 12. Known allergies, hypersensitivity, or intolerance to cusatuzumab, azacitidine, or their excipients (eg, mannitol, an excipient of azacitidine). 13. Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (eg, compromise the well-being) or physical limitations that could prevent, limit, or confound the protocol-specified assessments. 14. Major surgery (eg, requiring general anesthesia) within 4 weeks prior to initiation of study treatment. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Overall response rate (ORR) (rate of Complete remission [CR] + partial remission [PR] + marrow complete remission [mCR]), per modified International Working Group (IWG) criteria |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Within 14 days of Cycle (C)1 Day (D)1; Cycles 4, 8, and 12, then every 6 cycles until disease relapse from CR, PR, or mCR; progression; or transformation to AML or death, End of treatment |
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E.5.2 | Secondary end point(s) |
1. a) CR + PR rate, per modified IWG criteria b) CR rate, per modified IWG criteria c) Time to response for subjects who achieved such responses, defined as time from randomization to achieving the first response of CR, PR, or mCR, per modified IWG criteria d) Time from achieving the first response of CR, PR, or mCR to relapse or death from any cause for those subjects who responded e) Transfusion independence, defined as a period of ≥56 consecutive days with no transfusion occurring between the first and last dose of study drug +30 days f) Transformation to AML, defined as ≥20% bone marrow blasts g) Progression-free survival (PFS), defined as the time from randomization to disease progression; relapse from CR, PR, or mCR; or death from any cause h) OS, defined as the time from randomization to death i) Hematologic improvement rate, per modified IWG criteria 2. Safety parameters, including AEs and laboratory tests 3. Proportion of subjects achieving a clinically meaningful improvement in Functional Assessment of Cancer Therapy-Anemia -Trial Outcome Index (FACT-An TOI) 4. Serum concentration-time profile and PK parameters for cusatuzumab 5. Characterization and quantification of anti-drug antibodies (ADAs) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Within 14 days of Cycle (C)1 Day (D)1; Cycles 4, 8, and 12, then every 6 cycles until relapse or disease progression; or transformation to AML or death, End of treatment 2. Screening Day 1 of each 28 day cycle until 30 days after end of treatment or death 3. C1D1; Cycles 4, 8 and 12, then every 6 cycles until relapse or disease progression, transformation to AML or death; End of treatment 4. Screening, Cycle 1: Day 3, Day 4 and Day 17, C2D3, C3D3, C4D3, C4D21 to Cycle 5 Day 1 at disease evaluation, C8D3, C11D3, and End of treatment 5. C1D3, C1D17, C2D3, C3D3, C4D3, C8D3, C11D3, and End of treatment |
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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 | 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 |
Immunogenicity, Biomarker Evaluation, Patient-Reported Outcomes (PRO) Evaluation, Medical Resource Utilization Evaluation and Receptor Occupancy |
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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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 40 |
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 |
Czech Republic |
France |
Germany |
Italy |
Japan |
Russian Federation |
Saudi Arabia |
Spain |
Switzerland |
Turkey |
United Kingdom |
United States |
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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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The end of study (study completion) is defined as the time at which 50% of subjects have died or when the Sponsor decides to stop the study, whichever occurs first. The Sponsor will ensure that subjects benefiting from study treatment will be able to continue receiving study therapy. |
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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 | 0 |
E.8.9.1 | In the Member State concerned days | 13 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 13 |