Evaluation of Bortezomib and Daratumumab-Based Regimens in Primary Plasma Cell Leukemia: A Phase II Multicenter Study
- Trial ID
- 2024-518263-35-00
- Protocol
- 54767414LEU2002
Trial statistics
Diseases & Conditions
Objectives
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 **progression-free survival (PFS)**, in the first-line setting of primary plasma cell leukemia (pPCL). This is clinically relevant as PFS is a critical endpoint in assessing the effectiveness of treatment regimens in prolonging the time patients remain free from disease progression, which is particularly important in aggressive conditions like pPCL.
Secondary objectives include:
- Evaluating the overall response rate (ORR) post-induction, post-autologous stem cell transplantation (ASCT), post-consolidation, and post-maintenance treatment.
- Assessing the rates of very good partial response (VGPR) and complete response (CR) or better at various treatment stages.
- Determining the time to response, VGPR, and CR or better.
- Evaluating the duration of response and CR or better.
- Estimating the PFS rate at 12 and 24 months post-induction treatment initiation.
- Evaluating time to disease progression (TTP) and time to next treatment (TTNT).
- Assessing the post-induction, post-consolidation, and overall minimal residual disease (MRD) negativity rate.
- Evaluating overall survival (OS) and OS rates at 12 and 24 months post-induction treatment initiation.
- Assessing the safety and tolerability of the study treatment.
Participants
The clinical trial involves participants diagnosed with **primary plasma cell leukemia** (pPCL). The study population includes both male and female subjects, aged between 18 and 80 years, who are newly diagnosed with documented pPCL. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Participants were selected based on their ability to comprehend and adhere to the study requirements, as well as their willingness to provide informed consent. The trial includes individuals with adequate bone marrow, liver, and renal function, and a performance status according to the Eastern Cooperative Oncology Group (ECOG) of 0-3. The study population is characterized by a diverse range of races and ethnicities, and includes individuals who are part of a vulnerable population. Lifestyle considerations such as diet, physical activity, or habits were not specified in the available data.
Plans and Procedures
The clinical trial is designed as a **Phase II**, multicenter, open-label, single-arm, prospective study 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. The trial aims to assess the progression-free survival (PFS) as the primary endpoint, with secondary endpoints including the proportion of patients achieving partial response (PR) or better, very good partial response (VGPR) or better, and stringent complete response (sCR) or complete response (CR) as determined by the International Myeloma Working Group (IMWG) criteria. The trial is expected to run from September 2021 to October 2028, with an estimated participant involvement duration of up to 30 months, depending on individual response and treatment tolerance.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, disease status, and organ function. Following successful screening, participants will enter the induction phase, receiving alternating D-PAD/D-CVD regimens. Subsequent visits will occur at regular intervals to monitor treatment response, manage any adverse events, and adjust dosages as necessary. The consolidation phase will follow, with continued monitoring and assessments. The end-of-study visit will conclude the trial, where final evaluations will be conducted to assess the overall treatment efficacy and safety.
Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they choose to withdraw consent. Additionally, any significant protocol deviations or non-compliance with study requirements may also result in early termination. The trial is conducted under strict adherence to ethical guidelines and regulatory requirements, ensuring the safety and well-being of all participants throughout the study duration.
Treatment
**Bortezomib**, marketed as VELCADE, is utilized in this clinical trial as a **powder for solution for injection**. The pharmaceutical form is a solution for injection, and it is administered via **subcutaneous use**. The maximum daily dose is 1.3 mg, with a total treatment period of 24 weeks. Bortezomib is of chemical origin and is subject to labeling and repackaging modifications for the trial.
**Daratumumab**, known commercially as DARZALEX, is provided as an **1800 mg solution for injection**. This recombinant medicinal product is administered subcutaneously. The maximum daily dose is 1800 mg, with a treatment duration of up to 30 weeks. Daratumumab is designated as an orphan drug and is also subject to labeling and repackaging changes.
**Doxorubicin Hydrochloride** is included in the trial as a **concentrate for solution for infusion**. It is administered intravenously, with a maximum daily dose of 30 mg/m². The treatment period is limited to 3 weeks. This chemical-origin product undergoes relabeling for the study.
**Dexamethasone Sodium Phosphate** is administered as an **oral solution**. The maximum daily dose is 40 mg, with a treatment period of 24 weeks. This chemical-origin product is also relabeled for the trial.
**Cyclophosphamide** is provided in **tablet form** and is administered orally. The maximum daily dose is 300 mg/m², with a treatment period of 15 weeks. This chemical-origin product is relabeled for the study.
All medications are monitored for participant compliance, and any deviations from the dosing schedule are documented. The trial does not include a placebo or comparator treatment, as it is a single-arm study focusing on the efficacy and safety of the experimental regimens.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the measurement of **Progression-Free Survival (PFS)**. PFS is defined as the duration from the date of induction treatment initiation to the date of first documented evidence of progressive disease (PD) or death, whichever occurs earlier. This will be evaluated using the International Myeloma Working Group (IMWG) criteria. Secondary efficacy endpoints include the proportions of patients achieving Partial Response (PR) or better, Very Good Partial Response (VGPR) or better, and stringent Complete Response (sCR) or Complete Response (CR), as determined by the IMWG criteria. These efficacy parameters will be collected and analyzed at specified intervals throughout the trial to ensure comprehensive assessment of the treatment's impact on patients with primary plasma cell leukemia (pPCL).
Inclusion and Exclusion Criteria
Inclusion Criteria
- Female or male patients of any race or ethnicity, aged between 18 and 80 years (inclusive) at the time of signing the ICF.
- 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).
- 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.
- Patients for whom high-dose therapy, with or without stem cell transplantation, is part of the intended treatment plan.
- 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).
- 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.
- 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
- Adequate renal function as determined by estimated CrCl ≥20 mL/min
- Performance status (PS) according to (ECOG) 0-3
- 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
- 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.
- 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).
- 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
- Patients with secondary PCL.
- 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.
- Radiation therapy within 14 days before study treatment initiation.
- Plasmapheresis within 28 days before study treatment initiation.
- Exhibiting clinical signs of meningeal or central nervous system involvement by PCL.
- Patients with peripheral neuropathy or neuropathic pain Grade 2 or higher
- 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
- Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second [FEV1] <50% of predicted normal
- 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
- 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)
- 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)
- 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
- 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
- Gastrointestinal disease that may significantly affect the absorption of oral drugs as per Investigator's discretion
- Vaccination with live attenuated vaccines within 4 weeks of study treatment initiation
- 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
- Concurrent use of other anti-cancer agents/treatments
- 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
- 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
- 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.
- 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
- Contraindications to the use of any components of the study treatment (daratumumab, bortezomib, dexamethasone, cyclophosphamide, doxorubicin) per local prescribing information (SmPCs)
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Greece | Recruiting | 30 Sept 2021 | 43 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
DARZALEX 1800 mg solution for injection | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS USE | 1800 | 30 | PRD8157846 |
VELCADE 3.5 mg powder for solution for injection | Test | POWDER FOR SOLUTION FOR INJECTION | SUBCUTANEOUS USE | 1.3 | 24 | PRD3353088 |
DOXORUBICIN HYDROCHLORIDE | Test | — | INTRAVENOUS USE | 30 | 3 | SUB01827MIG |
DEXAMETHASONE SODIUM PHOSPHATE | Test | — | ORAL USE | 40 | 24 | SUB01615MIG |
DOXORUBICIN HYDROCHLORIDE | Test | — | INTRAVENOUS USE | 30 | 3 | SUB01827MIG |
CYCLOPHOSPHAMIDE | Test | — | ORAL USE | 300 | 15 | SUB06859MIG |