| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Primary plasma cell leukemia |
| Πρωτοπαθή Πλασματοκυτταρική Λευχαιμία |
|
| E.1.1.1 | Medical condition in easily understood language |
| Primary plasma cell leukemia |
|
| 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 | LLT |
| E.1.2 | Classification code | 10035223 |
| E.1.2 | Term | Plasma cell 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 |
| 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. |
|
| E.2.2 | Secondary objectives of the trial |
•To evaluate the ORR post-induction, post-ASCT, post- consolidation, and post-maintenance treatment
•To evaluate the rates of VGPR post-induction, post-ASCT, post-consolidation, and post-maintenance treatment
•To evaluate the rates of complete response (CR) or better post-induction, post-ASCT, post-consolidation, and post-maintenance treatment
•To evaluate time to response (PR or better)
•To evaluate time to VGPR or better
•To evaluate time to CR or better
•To evaluate duration of response (PR or better)
•To evaluate duration of CR or better
•To estimate the PFS rate at 12 and 24 months post-induction treatment initiation
•To evaluate time to disease progression (TTP)
•To evaluate time to next treatment (TTNT)
•To evaluate the post-induction, post-consolidation and overall MRD negativity rate
•To evaluate the OS as well as the OS rates at 12 and 24 months post-induction treatment initiation
•To assess the safety and tolerability of the study treatment. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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 (ova, oocytes)
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.
|
|
| E.4 | Principal exclusion criteria |
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).
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 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. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| PFS: Duration from the date of induction treatment initiation to the date of first documented evidence of PD (assessed by the IMWG criteria) or death, whichever occurs earlier |
|
| E.5.2 | Secondary end point(s) |
Proportions of patients achieving PR or better, VGPR or better, and sCR or CR (as determined by the IMWG criteria)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- After 6 cycles of induction treatment (and before ASCT for the transplant-eligible patients)
- Following ASCT and before consolidation initiation (applicable for transplant-eligible patients)
- At the end of consolidation treatment (Cycle 8)
- At the end of the maintenance treatment
|
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| 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 | 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 | 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.8.3 |
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 | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
Print
