A Phase 2 Open-label Study of Loncastuximab Tesirine in Combination with Rituximab (Lonca-R) in Previously Untreated Unfit/Frail Patients with Diffuse Large B-cell Lymphoma (DLBCL) (LOTIS-9)
- Trial ID
- 2022-501601-12-00
- Protocol
- ADCT-402-203
- Sponsor
- ADC Therapeutics SA
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 2 open-label study is to assess the **efficacy** of a response-adapted treatment regimen of Loncastuximab Tesirine in combination with Rituximab (Lonca-R) in patients with previously untreated Diffuse Large B-cell Lymphoma (DLBCL), High-Grade B-cell Lymphoma (HGBCL), or Grade 3b Follicular Lymphoma (FL). Specifically, the study aims to evaluate this treatment in two cohorts: Cohort A focuses on unfit patients, while Cohort B targets frail patients or those with cardiac comorbidities who are ineligible for standard R-mini-CHOP therapy. The clinical relevance of this objective lies in providing an alternative therapeutic option for patients who are unable to undergo conventional treatment due to their health status.
The secondary objectives include further evaluation of the efficacy of Lonca-R, characterization of its safety profile, and assessment of the pharmacokinetic (PK) profile of Loncastuximab Tesirine when administered with Rituximab. Additionally, the study aims to evaluate the immunogenicity of Loncastuximab Tesirine in combination with Rituximab and to assess the impact of Lonca-R treatment on treatment-related and disease-related symptoms, patient-reported functions, and overall health status.
Participants
The clinical trial involves a total of **65 participants** diagnosed with **Diffuse large B-cell Lymphoma** (DLBCL), high-grade B cell lymphoma (HGBCL), or Grade 3b follicular lymphoma (FL). The study population includes both male and female subjects, with an age range primarily focusing on individuals aged 65 years and older. Participants are characterized by their vulnerability, as the trial specifically targets unfit and frail patients, including those with cardiac comorbidities. The selection criteria ensure that participants have a pathologic diagnosis of DLBCL, HGBCL, or Grade 3b FL, with measurable disease as per the 2014 Lugano Classification, and are in stages I-IV. The trial population was selected based on their **ECOG performance status** and adequate organ function, as defined by specific laboratory values. Lifestyle considerations such as diet and physical activity are not explicitly mentioned, but participants must adhere to contraception guidelines if applicable. The trial does not provide additional information on lifestyle habits or other demographic details.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and tolerability of **Loncastuximab Tesirine** in combination with **Rituximab** for patients with previously untreated **Diffuse Large B-cell Lymphoma** (DLBCL). This is a Phase 2, open-label study involving two cohorts: Cohort A focuses on unfit patients, while Cohort B includes frail patients or those with cardiac comorbidities. The trial employs a response-adapted treatment approach, with the primary objective of assessing the complete response (CR) rate according to the 2014 Lugano Classification criteria. Secondary endpoints include overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and the frequency and severity of adverse events.
The trial is expected to last until February 2030, with participant involvement spanning up to 18 months. The study begins with a screening visit to confirm eligibility based on criteria such as age, disease stage, and organ function. Participants will undergo regular follow-up visits to monitor treatment response and safety, with assessments including laboratory tests, physical examinations, and imaging studies. The end-of-study visit will evaluate the overall treatment outcomes and any long-term effects. Participants may be withdrawn from the study early due to adverse events, disease progression, or withdrawal of consent.
Inclusion criteria require participants to have a pathologic diagnosis of DLBCL, measurable disease, and adequate organ function. Specific criteria for Cohort A include being aged 80 years or older with certain functional scores, while Cohort B includes frail individuals or those aged 65-79 with cardiac comorbidities. The study excludes individuals who do not meet these criteria or have conditions that could interfere with the trial's objectives. The trial's design ensures a rigorous evaluation of the investigational treatment's efficacy and safety in a specific patient population, contributing valuable data to the field of oncology.
Treatment
The clinical trial involves the administration of **Loncastuximab Tesirine**, a humanized monoclonal antibody, as an experimental treatment. This medication is provided in the form of a **solution for infusion** and is administered intravenously. The dosing regimen for Loncastuximab Tesirine is set at a maximum daily dose of 150 µg/kg, with a total maximum dose of 600 µg/kg over the treatment period. The treatment duration is capped at 18 cycles, with each cycle lasting approximately one month. Participant compliance with the dosing schedule is monitored through regular assessments and documentation of infusion sessions.
In addition to the experimental treatment, the study includes the administration of **Truxima**, a biosimilar of **Rituximab**, which is used as a comparator treatment. Truxima is available in two formulations: a 500 mg concentrate and a 100 mg concentrate, both intended for solution for infusion. The active substance, Rituximab, is classified as an antineoplastic agent and monoclonal antibody. The administration route is intravenous, with a maximum daily dose of 375 mg/m² and a total maximum dose of 2250 mg/m² over the treatment period. The treatment period for Truxima is also set at 18 cycles, aligning with the experimental treatment schedule. Compliance with the administration of Truxima is similarly monitored to ensure adherence to the protocol.
Efficacy
The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints for Cohort A and Cohort B include the **Complete Response (CR) rate**, defined as the proportion of patients achieving a Best Overall Response (BOR) of CR according to the 2014 Lugano Classification criteria. Additionally, for Cohort B, tolerability will be evaluated by the percentage of patients completing a total of four cycles of therapy.
Secondary endpoints encompass a range of measures, including the **Overall Response Rate (ORR)**, which is the proportion of patients with a BOR of CR or Partial Response (PR) according to the 2014 Lugano Classification. Other secondary endpoints include the 2-year Progression-Free Survival (PFS) rate, 3-year Overall Survival (OS) rate, and Duration of Response (DoR). The trial will also monitor the frequency and severity of adverse events (AEs) and serious adverse events (SAEs), as well as changes from baseline in safety laboratory variables, vital signs, and Eastern Cooperative Oncology Group scale of performance status (ECOG PS).
Pharmacokinetic (PK) parameters will be assessed, including concentrations of loncastuximab tesirine pyrrolobenzodiazepine (PBD)-conjugated antibody, total antibody, and SG3199 unconjugated warhead. The frequency of confirmed positive anti-drug antibody (ADA) responses and their associated titers will also be evaluated. Patient-reported outcomes, such as symptoms, functions, and overall health status, will be measured using the Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) to assess changes from baseline.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male or female
- Pathologic diagnosis of DLBCL, as defined by the 2016 World Health Organization (WHO) classification (including patients with DLBCL transformed from indolent lymphoma), or high-grade B cell lymphoma (HGBCL), or Grade 3b follicular lymphoma (FL).
- Measurable disease as defined by the 2014 Lugano Classification
- Stages I-IV
- ECOG PS 0-2; ECOG PS 3 allowed if decline in status is deemed related to lymphoma & felt to be potentially reversible by the treating physician
- Adequate organ function as defined by screening laboratory values within the following parameters: a. Absolute neutrophil count (ANC) ≥ 1.0 × 10^3/µL (off growth factors at least 72 hours) b. Platelet count ≥ 75 × 10^3/µL without transfusion in the past 7 days c. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma glutamyl transferase (GGT) ≤ 2.5 × the upper limit of normal (ULN) d. Total bilirubin ≤ 1.5 × ULN (patients with known Gilbert’s syndrome may have a total bilirubin up to ≤ 3 × ULN) e. Calculated creatinine clearance > 30 mL/min by the Cockcroft and Gault equation
- Women of childbearing potential (WOCBP) must agree to use a highly effective method of contraception from the time of giving informed consent until at least 12 months after the last dose of study treatment. Men with female partners who are of childbearing potential must agree to use a condom when sexually active or practice total abstinence from the time of the first dose until at least 7 months after the patient receives her/his last dose of study treatment
- Inclusion Criteria specific for Cohort A: Unfit as defined by the sGA (includes all of the following): a. Aged ≥ 80 years b. ADL score of 6 c. IADL score of 8 d. CIRS-G: no score of 3-4 and < 5 scores of 2
- Inclusion Criteria specific for Cohort B: Frail as defined by the sGA: a. Aged ≥ 80 years b. ADL score of < 6 and/or c. IADL score of < 8 and/or d. CIRS-G ≥ 1 score of 3-4 and/or ≥ 5 scores of 2 OR Aged ≥ 65 - <80 with at least one of the following cardiac comorbidities that make anthracycline-containing regimens inadvisable as determined by the investigator. a. Left ventricular ejection fraction (LVEF) ≥ 30 to < 50% b. History of myocardial infarction within 6 months prior to screening c. Ischemic heart disease d. History of stroke within 12 months prior to screening
Exclusion Criteria
- Known history of hypersensitivity to or positive serum human anti-drug antibody to a CD19 antibody
- Previous therapy for DLBCL, HGBCL, Grade 3b FL (with exception of corticosteroid course for symptom management of less than 14 days)
- Previous therapy with loncastuximab tesirine and rituximab for any indication
- Known history of hypersensitivity to any component of study treatment (loncastuximab tesirine and rituximab)
- Human immunodeficiency virus (HIV) seropositive with any of the following: a. CD4+ T-cell (CD4+) counts < 350 cells/µL b. Acquired immunodeficiency syndrome (AIDS) – defining opportunistic infection within 12 months prior to screening c. Not on anti-retroviral therapy, or on anti-retroviral therapy for < 4 weeks at the time of screening d. HIV viral load ≥ 400 copies/mL
- Serologic evidence of chronic hepatitis B virus (HBV) infection and unable or unwilling to receive standard prophylactic antiviral therapy or with detectable HBV viral load
- Serologic evidence of hepatitis C virus (HCV) infection without completion of curative treatment or with detectable HCV viral load
- History of Stevens-Johnson syndrome or toxic epidermal necrolysis
- Lymphoma with active central nervous system involvement at the time of screening, including leptomeningeal disease
- 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)
- Major surgery, radiotherapy, chemotherapy, or other anti-neoplastic therapy within 14 days prior to start of study drug (Cycle 1 Day 1 [C1D1]), except shorter if approved by the Sponsor
- Use of any other experimental medication within 14 days prior to start of study drug (C1D1)
- Received live vaccine within 4 weeks of C1D1
- Congenital long QT syndrome or a corrected QTcF interval of > 480 ms at screening (unless secondary to pacemaker or bundle branch block)
- 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
- 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 | 25 Mar 2023 | 17 |
 Spain | Not Recruiting | 25 Mar 2023 | 11 |
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 |
|---|---|---|---|---|---|---|
Loncastuximab Tesirine | Test | SOLUTION FOR INFUSION | INTRAVENOUS USE | 150 | 18 | PRD3805524 |
Truxima 500 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 375 | 18 | PRD4797328 |
Truxima 100 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 375 | 18 | PRD5065907 |