An Investigator-Initiated, Phase II, Multicenter, Open-Label, Single-Arm, Prospective Clinical Trial to Evaluate the Efficacy and Safety of Alternating Bortezomib-Based Regimens in Combination with DaratUMumab followed by Maintenance with Daratumumab in the Frontline Setting of Primary Plasma CEll LEukemIA: A Trial of the Greek Myeloma Study Group. The “EUMELEIA” Study

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Hellenic Society Of Hematology

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

23 Nov 2021 → ongoing

Decision date (initial)

2024-12-09

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Janssen Cilag

External identifiers

EU CT number

2024-518263-35-00

EudraCT number

2021-001990-22

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Therapy

The primary objective of this study is to evaluate the efficacy of the alternating D-PAD/D-CVD induction regimen followed by D-CVD consolidation regimen and maintenance with daratumumab monotherapy, in terms of PFS, in the first-line setting of pPCL.

Secondary objectives 14

1. To evaluate the ORR post-induction, post-ASCT, post- consolidation, and post-maintenance treatment
2. To evaluate the rates of VGPR post-induction, post-ASCT, postconsolidation, and post-maintenance treatment
3. To evaluate the rates of complete response (CR) or better postinduction, post-ASCT, post-consolidation, and post-maintenance treatment
4. To evaluate time to response (PR or better)
5. To evaluate time to VGPR or better
6. To evaluate time to CR or better
7. To evaluate duration of response (PR or better)
8. To evaluate duration of CR or better
9. To estimate the PFS rate at 12 and 24 months post-induction treatment initiation
10. To evaluate time to disease progression (TTP)
11. To evaluate time to next treatment (TTNT)
12. To evaluate the post-induction, post-consolidation and overall MRD negativity rate
13. To evaluate the OS as well as the OS rates at 12 and 24 months postinduction treatment initiation
14. To assess the safety and tolerability of the study treatment

Conditions and MedDRA coding

Primary plasma cell leukemia

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Female or male patients of any race or ethnicity, aged between 18 and 80 years (inclusive) at the time of signing the ICF.
2. Patients newly diagnosed with documented pPCL as defined by the current IMWG criteria for PCL and MM [5,34]: 2.1 Documented presence of ≥5% PBPCs and/or absolute number ≥ 0.5 × 103/μL (by flow cytometry) 2.2 Clonal BMPCs ≥10% or biopsy-proven bony or extramedullary plasmacytoma (EMP) 2.3 At least one of the following myeloma defining events (CRAB or malignancy biomarkers criteria - Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically (one or more of the following): a) Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of normal (ULN) or >2.75 mmol/L (>11 mg/dL) b) Renal insufficiency: Creatinine clearance (CrCl) <40 mL/min (measured or estimated by validated equations) or serum creatinine >177 μmol/L (>2 mg/dL) c) Anemia: hemoglobin value of >20 g/L below the lower limit of normal (LLN), or a hemoglobin value <100 g/L d) Bone lesions: One or more osteolytic lesions on skeletal radiography, computed tomography (CT), or positron emission tomography (PET)-CT. - Any one or more of the following biomarkers of malignancy: a) Clonal bone marrow plasma cell percentage ≥60% b) Involved:Uninvolved serum free light chain (sFLC) ratio ≥100 c) >1 focal lesions on MRI studies (each focal lesion must be 5 mm or more in size).
3. Measurable disease by protein electrophoresis as defined by any of the following: 3.1 Serum M-protein level: - For IgG MM: ≥1.0 g/dL or urine M-protein level ≥200 mg/24 hours - For IgA, IgE and IgM MM: ≥0.5 g/dL or urine M-protein level ≥ 200 mg/24 hours - For IgD MM: ≥0.05 g/dL or urine M-protein level ≥200 mg/24 hours 3.2 Light chain MM without measurable disease in the serum or the urine: sFLC ≥10 mg/dL (involved light chain) and abnormal sFLC κ/λ ratio.
4. Patients for whom high-dose therapy, with or without stem cell transplantation, is part of the intended treatment plan.
5. Patient not currently or previously treated with any systemic therapy or stem cell transplant for any plasma cell dyscrasia, apart from a short course of corticosteroid therapy (equivalent of dexamethasone 40 mg/day for up to 4 days).
6. Adequate bone marrow function as determined by the following: 6.1 Hemoglobin ≥7.0 g/dL [≥4.34 mmol/L; prior red blood cell (RBC) transfusion or recombinant human erythropoietin use is permitted] 6.2 Absolute neutrophil count (ANC) ≥1.0 x 109/L 6.3 Platelet count ≥50 x 109/L if disease involvement in bone marrow is >50%; otherwise ≥75% x 109/L.
7. Adequate liver function as determined by the following: 7.1 Serum Aspartate Transaminase (AST) ≤2.5 x ULN 7.2 Serum Alanine Aminotransferase (ALT) ≤2.5 x ULN 7.3 Total bilirubin ≤1.5 x ULN
8. Adequate renal function as determined by estimated CrCl ≥20 mL/min
9. Performance status (PS) according to (ECOG) 0-3
10. If females of childbearing potential (FCBP)*, the following apply: 10.1 Willingness to use an acceptable form of birth control 10.2 They must agree not to donate eggs 10.3 They must have 2 negative serum or urine pregnancy tests
11. If male subjects of reproductive potential who are sexually active with FCBPs the following apply. 11.1 Must always use a latex or synthetic condom during the study and for 3 months (90 days) after discontinuing study treatment (even if they have undergone a successful vasectomy). 11.2 They must not donate sperm during the study or for 3 months after the last dose of study treatment.
12. Patients who are able to comprehend and willing to follow the requirements of the study (including adherence to the study-specific prohibitions and restrictions and availability on scheduled visit dates).
13. Patients (or patients' legally acceptable representative as applicable) who are able to understand and willing to provide voluntary written informed consent before any clinical trial-related procedure is performed.

Exclusion criteria 22

1. Patients with secondary PCL.
2. Prior or concurrent invasive malignancy (other than PCL) within 5 years of date of study treatment initiation except for the following: 2.1 Malignancy treated with curative intent and with no known active disease present for ≥3 years before study treatment initiation. 2.2 Adequately treated non-melanoma skin cancer, carcinoma in situ of the cervix or breast, incidental histologic finding of prostate cancer (T1a or T1b) or other non-invasive lesion that, as per Investigator's judgement, is considered cured with minimal risk of recurrence over the next 3 years.
3. Radiation therapy within 14 days before study treatment initiation.
4. Plasmapheresis within 28 days before study treatment initiation.
5. Exhibiting clinical signs of meningeal or central nervous system involvement by PCL.
6. Patients with peripheral neuropathy or neuropathic pain Grade 2 or higher
7. Concurrent systemic amyloidosis, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and/or skin changes), active systemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease, and any other medical condition/disease that is likely to interfere with the study procedures or results, or that in the opinion of the Investigator, places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study
8. Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second [FEV1] <50% of predicted normal
9. Known moderate or severe persistent asthma within the past 2 years (refer to Appendix 2), or the patient currently has uncontrolled asthma of any classification
10. Any of the following: 10.1 Known seropositivity for human immunodeficiency virus (HIV) 10.2 Seropositivity for hepatitis B virus (HBV) 10.3 Known seropositivity for hepatitis C virus (HCV)
11. Clinically significant cardiac disease including: 11.1 Myocardial infarction within 6 months before study treatment initiation (C1D1) 11.2 Unstable or uncontrolled disease/condition related to or affecting cardiac function (e.g., unstable angina, congestive heart failure, New York Heart Association [NYHA] Class III-IV) 11.3 Pericardial disease 11.4 Cardiac amyloidosis 11.5 Uncontrolled cardiac arrhythmia (NCI CTCAE v5 Grade 2 or higher) or clinically significant electrocardiogram (ECG) abnormalities 11.6 Screening 12-lead ECG showing a baseline QT interval >470 msec (except for subjects with pacemaker) 11.7 Screening transthoracic echocardiogram (TTE) showing left ventricular ejection fraction (LVEF) <40% (screening TTE is required only for subjects aged ≥ 65 years)
12. Receipt of a strong CYP3A4 inducer (e.g., rifampicin, carbamazepine, phenytoin, phenobarbital and St. John's Wort) within 5 half-lives prior to study treatment initiation
13. Known allergies, hypersensitivity, or intolerance to boron or mannitol, corticosteroids, monoclonal antibodies or human proteins, or their excipients (refer to respective SmPCs and Investigator's Brochure [IB]), or known sensitivity to mammalian-derived products
14. Gastrointestinal disease that may significantly affect the absorption of oral drugs as per Investigator's discretion
15. Vaccination with live attenuated vaccines within 4 weeks of study treatment initiation
16. Major surgery within 2 weeks before study treatment initiation or will not have fully recovered from surgery, or has surgery planned during the time the subject is expected to start the study treatment
17. Concurrent use of other anti-cancer agents/treatments
18. Subject is known or suspected of not being able to comply with the study protocol (e.g., because of alcoholism, drug dependency, or psychological disorder). Subject has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments
19. Females who are pregnant, breast feeding, or planning to become pregnant while enrolled in this study or within 3 months following the last dose of any component of the study treatment
20. Males who plan to father a child while enrolled in this study or within 3 months following the last dose of any component of the study treatment.
21. Patients who currently receive treatment with any investigational drug/vaccine/device/intervention or who have received any investigational product within 30 days or 5 half-lives of the investigational agent (whichever is longer) before the screening
22. Contraindications to the use of any components of the study treatment (daratumumab, bortezomib, dexamethasone, cyclophosphamide, doxorubicin) per local prescribing information (SmPCs)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. PFS: Duration from the date of induction treatment initiation to the date of first documented evidence of progressive disease (PD) (assessed by the IMWG criteria or death, whichever occurs earlier.

Secondary endpoints 1

1. Proportions of patients achieving PR or better, VGPR or better, and sCR or CR (as determined by the IMWG criteria)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 6

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Hellenic Society Of Hematology

Sponsor organisation

Hellenic Society Of Hematology

Address

Kifissias Leoforos 27

City

Athens

Postcode

115 23

Country

Greece

Scientific contact point

Organisation

Hellenic Society Of Hematology

Contact name

Eirini Katodritou

Public contact point

Organisation

Hellenic Society Of Hematology

Contact name

Eirini Katodritou

Third parties 3

Locations

1 EU/EEA country · 7 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 11 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications