Evaluation of Daratumumab, Bortezomib, and Dexamethasone in Relapsed/Refractory Plasmablastic Lymphoma Patients Ineligible for Transplantation
- Trial ID
- 2024-511635-94-00
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **activity** of daratumumab, both as a single agent and in combination with bortezomib/dexamethasone, in patients with relapsed or refractory Plasmablastic lymphoma (PBL). This is particularly relevant for patients who are not eligible for autologous or allogeneic transplantation or have experienced relapse following a prior autologous stem cell transplantation. Understanding the activity of these treatments can provide critical insights into potential therapeutic options for this challenging patient population.
Secondary objectives include:
- Evaluating the efficacy in terms of **Progression-free survival (PFS)**, **Overall survival (OS)**, and **Duration of response (DOR)**.
- Assessing the safety of daratumumab as a single agent and in combination with bortezomib/dexamethasone.
- Investigating the role of daratumumab maintenance therapy.
- Evaluating the association between the intensity of **CD38 expression** and treatment response.
- Exploring the biological effects of daratumumab/bortezomib on CD4 and CD8 T cell homeostasis, regulatory cells (MDSC and Treg) homeostasis, and inflammatory cytokines profile.
- Assessing the impact of daratumumab/bortezomib treatment on the functional properties of HIV-specific, EBV-specific, and CMV-specific T cells.
- Analyzing the microenvironment of the peripheral blood lymphocytes (PBL).
Participants
The clinical trial involves participants diagnosed with **relapsed or refractory plasmablastic lymphoma**. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a histologically confirmed diagnosis of plasmablastic lymphoma, with CD38-positive status confirmed by immunohistochemistry. The trial does not involve a vulnerable population. Participants must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 3 or less, and both HIV-negative and HIV-positive individuals are eligible, provided the latter have an HIV infection responsive to ongoing combination antiretroviral therapy (cART). The trial does not specify the total number of participants, as this information was not provided by the sponsor. Participants must have at least one measurable disease lesion identifiable by imaging. Lifestyle considerations include the requirement for women of childbearing potential and men to use effective contraception if sexually active, with specific guidelines on contraception duration relative to the administration of study drugs. The selection criteria ensure that participants can adhere to the study visit schedule and other protocol requirements, and all subjects must provide informed consent approved by the National Ethics Committee before any study-specific procedures are initiated.
Plans and Procedures
The clinical trial is designed to evaluate the activity and safety of **daratumumab** in combination with **bortezomib** and **dexamethasone** in patients with relapsed or refractory plasmablastic lymphoma. This is an open-label, Phase 2 study, which involves a non-randomized, controlled trial design. The trial is expected to run from July 2022 to January 2025, with the primary objective of assessing the overall response rate (ORR) after various induction and maintenance cycles, as defined by the Lugano 2014 criteria. Secondary endpoints include progression-free survival, overall survival, and duration of response, among others.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed plasmablastic lymphoma, CD38-positive status, and an ECOG performance status of ≤ 3. The study will include multiple follow-up visits to monitor treatment response and safety, with assessments occurring after induction cycles 1, 3, 6, and 9, and maintenance cycles 12 and 15. The end-of-study visit will mark the conclusion of the participant's involvement, which is anticipated to last up to 51 weeks, depending on individual response and treatment tolerance.
Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they are unable to adhere to the study protocol. The trial will also explore the biological impact of the treatment regimen on immune activation and cytokine levels, providing a comprehensive evaluation of the therapeutic potential of the drug combination in this patient population.
Treatment
The clinical trial involves the administration of **daratumumab**, a monoclonal antibody targeting CD38, used in the treatment of relapsed or refractory Plasmablastic lymphoma. Daratumumab is administered in a **subcutaneous** pharmaceutical form, with a maximum daily dose of 1800 mg and a total maximum dose of 37800 mg over a treatment period of up to 51 weeks. The administration schedule and participant compliance are monitored to ensure adherence to the dosing regimen.
**Dexamethasone sodium phosphate**, a synthetic glucocorticoid, is used as a non-experimental treatment in this study. It is administered **orally** with a maximum daily dose of 20 mg and a total maximum dose of 920 mg over a treatment period of up to 24 weeks. Dexamethasone serves as a standard-of-care therapy in combination with other investigational drugs, and its administration is closely monitored to ensure participant compliance.
**Bortezomib**, an antineoplastic agent, is also included in the treatment regimen. It is administered in a **subcutaneous** form with a dosing unit of mg/m², having a maximum daily dose of 1.3 mg/m² and a total maximum dose of 41.6 mg/m² over a treatment period of up to 24 weeks. The administration of bortezomib is carefully scheduled and monitored to maintain the integrity of the trial and ensure participant adherence to the treatment protocol.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is the **Overall Response Rate (ORR)**, which includes complete response (CR) and partial response (PR) after various induction and maintenance cycles. Specifically, ORR will be evaluated after induction cycle 1 with daratumumab alone, after induction cycles 3, 6, and 9 (end of induction), and after maintenance cycles 12 and 15 (end of treatment). The response will be defined according to the Lugano 2014 criteria, and the best response achieved per patient will be considered for analysis.
Secondary endpoints include **Progression-Free Survival (PFS)**, defined as the time from treatment start to progression, relapse, or death from any cause, and **Overall Survival (OS)**, defined as the time from treatment start to death from any cause. Additionally, the **Duration of Response (DOR)** will be measured for all patients who achieve a response, from the date when criteria for response are met until the date of progression or relapse. The trial will also assess the role of daratumumab maintenance in terms of conversion rates from stable disease (SD) to PR or from SD/PR to CR, and the association between the intensity of CD38 expression and response. The extent of CD38 expression will be evaluated by immunochemistry and correlated with response at various timepoints according to the Lugano 2014 criteria.
Furthermore, the trial includes endpoints of a biological study to evaluate the impact of daratumumab/bortezomib treatment on immune activation, T cell differentiation, and myeloid-derived suppressor cells (MDSC) using multiparametric flow cytometry. The study will also assess the impact on pro- and anti-inflammatory cytokine levels using Luminex technology and analyze the tumor microenvironment through immunohistochemistry (ICH) or alternative methods.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Histologically confirmed plasmablastic lymphoma according to WHO 2017, CD38-positive by immunohistochemistry (≥5% of positive cells) Local diagnosis of PBL and local CD38 assessment ≥5% will suffice for enrollment and start of treatment.
- Patients with plasmablastic lymphoma relapsed or refractory: - after at least one line of conventional-dose chemotherapy followed or not by autologous stem cell transplantation; - after at least one line of conventional-dose chemotherapy and not eligible for salvage autologous or allogeneic transplantation;
- ECOG Performance Status ≤ 3;
- Age ≥ 18 years;
- Both HIV-negative and HIV-positive patients are eligible;
- HIV infection responsive to ongoing cART (combination antiretroviral therapy);
- At least one measurable disease lesion identifiable by imaging: - A nodal lesion must be at least 11 mm x 11 mm OR ≥ 16 mm in the greatest transverse diameter (regardless of short axis measurement). - An extranodal lesion must be at least 10 mm x 10 mm.
- Women of childbearing potential (WOCBP) and men must agree to use effective contraception if sexually active. This applies for the time period between signing of the informed consent form and 7 months (for women) o 4 months (for men) after last administration of bortezomib or 6 months after last daratumumab dose, regardless of sex. A woman is considered of childbearing potential, i.e., fertile, following menarche and until becoming postmenopausal unless permanently sterile. Permanent sterilization methods include but are not limited to hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for continuous 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. The investigator or a designated associate is requested to advise the patient how to achieve highly effective birth control method (failure rate of less than 1%) e.g., intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner, and sexual abstinence. The use of condoms by male patients is required unless the female partner is permanently sterile. WOCBP must have two negative pregnancy tests as verified by the study doctor prior to starting study therapy and must agree to undergo monthly pregnancy testing during the course of the study and after end of study therapy if clinically indicated. This applies even if the subject practices complete abstinence from heterosexual contact.
- Subject understands and voluntarily signs and dates an informed consent form approved by the National Ethics Committee (NEC), prior to the initiation of any screening or study-specific procedures
- Subject must be able to adhere to the study visit schedule and other protocol requirements
Exclusion Criteria
- Histologic diagnosis different from confirmed plasmablastic lymphoma according to WHO 2017 and/or CD38 expression < 5% of positive cells
- CNS involvement
- Patients with known hypersensitivity to the investigational drug or to product components or severe allergic or anaphylactic reactions to humanized products
- Subject has received any anti-cancer therapy including chemotherapy, immunotherapy, radiotherapy, investigational therapy including targeted small molecule agents within 14 days prior to the first dose of study drug
- Concomitant Kaposi sarcoma; however, patients with only skin involvement of KS can be included.
- Subject is: - Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]. Subjects with resolved infection (i.e., subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [HBcAb] ± antibodies to hepatitis B surface antigen [HBsAb]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (HBsAb positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR - Known to be seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy)
- Any history of another cancer during the last 5 years with the exception of non-melanoma skin tumors, in situ cervical carcinoma, or in situ breast cancer treated with curative intent with no history of metastatic disease.
- Chronic or ongoing active infectious disease requiring systemic treatment such as, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis or tuberculosis. Drugs for HIV treatment are allowed, as per local investigator prescription.
- Active ongoing infection from SARS-CoV-2.
- Screening laboratory values (due to causes different than lymphoma): - Absolute neutrophil count (ANC) <1.0 x 109/L (unless secondary to documented marrow involvement by lymphoma) - Platelet count <75 x 109/L - Hemoglobin < 7.5 g/dL - Alanine aminotransferase (ALT) and/or Aspartate aminotransferase (AST) > 3.5 times the upper limit of normal (ULN) - Alkaline phosphatase > 3.5 times ULN - Bilirubin > 2 times x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin) - Serum Creatinine Clearance < 20 ml/min
- Subject has clinically significant cardiac disease, including: - Myocardial infarction within 6 months before date of registration, or unstable or uncontrolled disease/condition related to or affecting cardiac function (e.g., unstable angina, congestive heart failure, New York Heart Association Class III-IV) - Cardiac arrhythmia (Common Terminology Criteria for Adverse Events [CTCAE] current version Grade 2 or higher) or clinically significant ECG abnormalities. Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia’s formula (QTcF) > 470 msec
- Evidence of any other clinically significant uncontrolled condition(s)
- Significant history of neurologic, psychiatric, endocrinological, metabolic, immunologic, or hepatic disease that would preclude participation in the study or compromise ability to give informed consent
- Breastfeeding women or women with a positive pregnancy test at screening
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Recruiting | 11 Jul 2022 | 28 |
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 |
|---|---|---|---|---|---|---|
DARATUMUMAB | Test | PHF00231MIG | SUBCUTANEOUS | 1800 | 51 | SCP12565263 |
BORTEZOMIB | Test | PHF00231MIG | SUBCUTANEOUS | 1.3 | 24 | SCP109528812 |
DEXAMETHASONE | Test | PHF00169MIG | ORAL | 20 | 24 | SCP10332310 |