Efficacy of Loncastuximab Tesirine in Relapsed/Refractory Diffuse Large B-Cell Lymphoma and High-Grade B-Cell Lymphoma Post-CAR T-Cell Therapy
- Trial ID
- 2024-516929-31-00
- Protocol
- LORELY
- Sponsor
- Humanitas Mirasole S.p.A.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to **assess the efficacy** of **loncastuximab tesirine** by measuring the overall response rate (ORR) in patients with relapsed or refractory **Diffuse Large B-Cell Lymphoma (DLBCL)** and **High Grade B-Cell Lymphoma (HGBCL)** who have experienced disease progression following CAR T-cell therapy. This evaluation is clinically relevant as it aims to determine the potential of loncastuximab tesirine as a therapeutic option for patients who have limited treatment alternatives after failing CAR T-cell therapy.
Secondary objectives include:
- Evaluating survival outcomes following treatment with loncastuximab tesirine.
- Assessing the safety profile of loncastuximab tesirine.
- Exploratory objectives involve assessing changes in blood serum markers of disease and inflammation during the study and exploring the correlation between clinical activity and changes in plasma circulating tumor DNA (ctDNA) throughout the study course.
Participants
The clinical trial involves **patients** diagnosed with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) or high-grade B-cell lymphoma (HGBCL) who have not responded to CAR T-cell therapy. The study population includes both male and female participants aged 18 years and older. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, indicating they are fully active or capable of self-care. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Participants must have measurable disease as per the 2014 Lugano Classification and meet specific health criteria, including adequate renal, hepatic, pulmonary, and cardiac function. Lifestyle considerations such as diet and physical activity are not detailed, but participants must agree to use effective contraception methods if of childbearing potential. The trial population was selected based on their medical condition and previous treatment history, with a focus on those who have failed CAR T-cell therapy. The study includes a vulnerable population, emphasizing the need for careful monitoring and ethical considerations.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **loncastuximab tesirine** in patients with relapsed or refractory **Diffuse Large B-Cell Lymphoma (DLBCL)** or High-Grade B-Cell Lymphoma (HGBCL) who have shown progressive disease following CAR T-cell therapy. This is a phase II, randomized, double-blind, controlled study. The trial aims to measure the overall response rate (ORR) as the primary endpoint, with secondary endpoints including progression-free survival (PFS), overall survival (OS), duration of response (DOR), and the frequency and severity of adverse events (AEs) and serious adverse events (SAEs). The study is expected to last approximately two years, with an estimated end date in January 2025.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, and previous treatment history. The trial will include follow-up visits to monitor the efficacy and safety of the treatment, with assessments conducted through imaging techniques like PET-CT or MRI. The end-of-study visit will conclude the participant's involvement, assessing the final treatment outcomes and any long-term effects. The expected length of participant involvement is up to six months, corresponding to the maximum treatment period with the investigational drug.
Participants may be subject to early termination from the study if they experience unacceptable toxicity, withdraw consent, or if the investigator deems it in the participant's best interest. The trial will adhere to rigorous ethical standards, ensuring that all participants provide informed consent and that their health and safety are prioritized throughout the study duration.
Treatment
The clinical trial involves the administration of **Zynlonta**, a pharmaceutical product containing the active substance **loncastuximab tesirine**. This medication is provided in the form of a **powder for concentrate for solution for infusion**. The pharmaceutical form is specifically designed for **intravenous infusion**. The maximum daily dose is set at 150 µg/kg, with the same limit applied to the total dose. The treatment period is capped at six cycles. The product is not formulated for pediatric use and is not classified as an orphan drug. The active substance, **loncastuximab tesirine**, is a protein-based compound, categorized under the ATC code L01FX22. The product is manufactured by Swedish Orphan Biovitrum AB (Publ) and holds the marketing authorization number EU/1/22/1695/001.
In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on assessing the efficacy of **loncastuximab tesirine** in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) or high-grade B-cell lymphoma (HGBCL) who have shown disease progression following CAR T-cell therapy. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimen.
Efficacy
The efficacy of **loncastuximab tesirine** in the clinical trial will be assessed primarily through the measurement of the overall response rate (ORR) in patients with relapsed or refractory Diffuse Large B-Cell Lymphoma (DLBCL) or High Grade B-Cell Lymphoma (HGBCL) who have experienced progressive disease following CAR T-cell therapy. The ORR is defined as the proportion of patients achieving a best overall response of complete response (CR) or partial response (PR) to the study treatment, as per the 2014 Lugano Classification.
Secondary efficacy endpoints include progression-free survival (PFS), overall survival (OS), and duration of response (DOR). PFS is defined as the time from the first dose administration to the first documentation of recurrence or progression, or death, as determined by independent central review. OS is measured as the time from the first dose administration to death from any cause. DOR is defined as the time from the first documentation of response to recurrence or progression, or death, also assessed by independent central review.
Exploratory endpoints will examine the relationship between blood serum markers of disease and inflammation, such as LDH, CRP, and ferritin, and selected efficacy endpoints. Additionally, the relationship between changes in plasma circulating tumor DNA (ctDNA) and selected efficacy endpoints will be explored. The frequency and severity of adverse events (AEs) and serious adverse events (SAEs) will also be monitored as part of the trial's safety assessments.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male or female, aged ≥18 years. 2. Willing and able to give written, informed consent. 3. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2. 4. Histologically confirmed DLBCL or large B cell lymphoma (at last relapse) as defined by the 2016 WHO classification, including one of the following: • DLBCL, Not Otherwise Specified (NOS) • Transformed DLBCL from indolent lymphoma • HGBCL with MYC and BCL2 and/or BCL6 rearrangements (double/triple hit) 5. Patients failing CAR T-cell therapy, defined as: a. Progressive disease (PD) at any time b. Partial Remission (PR) or stable disease (SD) at 3 months after CAR T-cell infusion. 6. Measurable disease as defined by the 2014 Lugano Classification as assessed by positron-emission tomography (PET)- computed tomography (CT) or by CT or MRI if tumour is not FDG-avid on screening PET-CT. 7. Previous treatment with loncastuximab tesirine is allowed, provided that the patient was in CR or PR at the time of drug withdrawal. 8. Negative beta-human chorionic gonadotropin (β-HCG) pregnancy test within 7 days prior to start of study drug (C1D1) for women of childbearing potential. 9. Women of childbearing potential must agree to use a highly effective method of contraception from the time of giving informed consent until at least 9 months after the last dose of loncastuximab tesirine. Men with female partners who are of childbearing potential must agree that they will use a highly effective method of contraception from the time of giving informed consent until at least 6 months after the patient receives his last dose of loncastuximab tesirine. 10. Adequate renal, hepatic, pulmonary, and cardiac function defined as: • Creatinine clearance ≥40 ml/min. • Serum alanine aminotransferase / aspartate aminotransferase ≤2.5 x ULN. • Total bilirubin ≤1.5 x ULN, except in subjects with Gilbert's syndrome. • Known history of LVEF ≥50% unless the institutional lower limit of normal is lower. • Baseline oxygen saturation >92% on room air and ≤Grade 1 dyspnoea. 11. Adequate Bone Marrow (BM) function without requiring ongoing blood product or granulocyte-colony stimulating factor support (GCSF) and meeting the following criteria: • Absolute neutrophil count ≥1.0 × 10^6/dL. • Haemoglobin ≥9.0 g/dL • Platelets ≥50 × 10^6/dL
Exclusion Criteria
- Known history of hypersensitivity to or positive serum human antidrug antibody (ADA) to a CD19 antibody. 2. Females who are pregnant or lactating.3. Active second primary malignancy other than non-melanoma skin cancers, non-metastatic prostate cancer, in situ cervical cancer, ductal or lobular carcinoma in situ of the breast, or other malignancy that the Sponsor's medical monitor and Investigator agree and document should not be exclusionary. 4. Lymphoma with active CNS involvement at the time of screening, including leptomeningeal disease. 5. Bulky disease, defined as largest tumour diameter >10 cm. 6. Known seropositive and requiring anti-viral therapy for human immunodeficiency (HIV) virus, hepatitis B virus (HBV), or hepatitis C virus (HCV). 7. Clinically significant third space fluid accumulation (i.e., ascites requiring drainage or pleural effusion that is either requiring drainage or associated with shortness of breath) 8. Significant medical comorbidities, including but not limited to, uncontrolled hypertension (blood pressure ≥160/100 mm Hg repeatedly), unstable angina, congestive heart failure (greater than New York Heart Association class II), electrocardiographic evidence of acute ischemia, coronary angioplasty or myocardial infarction within 6 months prior to screening, uncontrolled atrial or ventricular cardiac arrhythmia, poorly controlled diabetes, or severe chronic pulmonary disease. 9. Active autoimmune disease, motor neuropathy considered of autoimmune origin, and other central nervous system (CNS) autoimmune disease. 10. History of Steven's Johnson's syndrome or toxic epidermal necrolysis syndrome. 11. Major surgery, radiotherapy, chemotherapy or other antineoplastic therapy within 14 days prior to start of study drug (C1D1), except shorter if approved by the Sponsor. 12. Planned live vaccine administration after starting study drug (C1D1). 13. Use of any other experimental medication within 14 days prior to start of study drug (C1D1). 14. Failure to recover to Grade ≤1 (Common Terminology Criteria for Adverse Events version 5.0 [CTCAE v5.0]) from acute nonhematologic toxicity (Grade ≤2 neuropathy or alopecia) due to previous therapy prior to screening. 15. Any other significant medical illness, abnormality, or condition that would, in the Investigator’s judgment, make the patient inappropriate for study participation or put the patient at risk.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Not Recruiting | 13 Jan 2023 | 50 |
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 |
|---|---|---|---|---|---|---|
Zynlonta 10 mg powder for concentrate for solution for infusion | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 150 | 6 | PRD10278221 |