Loncastuximab Tesirine and Rituximab for the Treatment of Patients with Post-Transplant Lymphoproliferative Disorder, PLUTO Trial
This phase I/II trial tests the safety, side effects, best dose and how well loncastuximab tesirine and rituximab works for the treatment of post-transplant lymphoproliferative disorders. Loncastuximab tesirine is a monoclonal antibody, called loncastuximab, linked to a cytotoxic drug, called pyrrolobenzodiazepine. Loncastuximab is a form of targeted therapy because it attaches to specific molecules (receptors) on the surface of cancer cells, known as CD19 receptors, and delivers pyrrolobenzodiazepine to kill them. Rituximab is a monoclonal antibody. It binds to a protein called CD20, which is found on B cells (a type of white blood cell) and some types of cancer cells. This may help the immune system kill cancer cells. Giving loncastuximab tesirine and rituximab may be safe, tolerable and/or effective in treating patients with post-transplant lymphoproliferative disorders.
Inclusion Criteria
- Subject aged ≥ 18 years
- Histologically confirmed B-cell PTLD (monomorphic and polymorphic) following solid organ transplantation; with or without Epstein-Barr virus (EBV) association. * Note: Subjects with classic Hodgkin-like PTLD are excluded
- Measurable disease as defined by the 2014 Lugano Classification as assessed by positron-emission tomography (PET)- computed tomography (CT) or by CT or magnetic resonance imaging (MRI) if the tumor is not fluorodeoxyglucose (FDG)-avid on screening
- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
- Absolute neutrophil count (ANC) ≥ 1000/mm3
- Platelet count ≥ 75,000/mm3
- Hemoglobin ≥ 8 g/dL
- Bilirubin ≤1.5 x upper limit of normal (ULN) or ≤ 3 x ULN with document liver involvement and/ or Gilbert’s disease
- Transaminases (aspartate aminotransferase [AST] or alanine aminotransferase [ALT]) ≤ 3 x ULN or ≤ 5 x ULN with documented liver involvement
- Estimated creatinine clearance ≥ 60 mL/min by Cockcroft-Gault formula
- For female subjects: Negative pregnancy test or evidence of post-menopausal status. The post-menopausal status will be defined as having been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply: * Women < 50 years of age: ** Amenorrheic for ≥ 12 months following cessation of exogenous hormonal treatments; and ** Luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution; or ** Underwent surgical sterilization (bilateral oophorectomy or hysterectomy). * Women ≥ 50 years of age: ** Amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments; or ** Had radiation-induced menopause with last menses > 1 year ago; or ** Had chemotherapy-induced menopause with last menses > 1 year ago; or ** Underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy)
- Female subjects of childbearing potential and male subjects with a sexual partner of childbearing potential must agree to use a highly effective method of contraception and the lactation requirements
- Subjects or their legal representatives must be able to read, understand, and provide informed consent to participate in the trial
- Willing and capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol
Exclusion Criteria
- PTLD following liquid transplantation
- Central nervous system (CNS) involvement
- Prior treatment for PTLD with the exception of radiation, antivirals, steroids and reduced immunosuppression
- Human immunodeficiency virus (HIV) infection
- Major surgery within 4 weeks prior to enrolment
- History of bleeding diathesis (e.g., von Willebrand's disease), hemophilia, or active bleeding
- Subjects with chronic liver disease with hepatic impairment Child-Pugh class C
- Pregnant or lactating or intending to become pregnant during the study
- Active autoimmune disease which, in the opinion of the investigator, may negatively impact subject safety or interfere with study participation
- The diagnosis of another malignancy which, in the opinion of the investigator, is likely to negatively impact subject safety or interfere with study participation
- Significant medical diseases or conditions including those requiring substantial changes in concomitant medications, as assessed by the investigator, that would substantially increase the risk-to-benefit ratio of participating in the study. This includes, but is not limited to the following conditions: * Cardiovascular disorders: ** Congestive heart failure New York Heart Association class III or IV, unstable angina pectoris, serious cardiac arrhythmias. ** Myocardial infarction (MI) within 6 months before the first dose. ** QTc prolongation defined as a Fridericia's corrected QT interval (QTcF) > 480 ms. ** Congenital long QT syndrome or a corrected QT measure (QTc) interval of > 480 ms at screening (unless secondary to pacemaker or bundle branch block). ** Grade 2 or higher edema (peripheral, pleural or ascites) ** Grade 1 or higher pericardial effusion * Severe pulmonary disease * Uncontrolled diabetes mellitus * Severely immunocompromised state * Any other condition that would, in the Investigator’s judgment, contraindicate the subject’s participation in the clinical study due to safety concerns or compliance with clinical study procedures
- Active systemic bacterial, viral, fungal, or other infection requiring systemic treatment at time of screening
- Subjects with evidence of active hepatitis B infection, based on positive surface antigen or hepatitis B deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) are excluded. Subjects who are hepatitis B core antibody positive must take prophylaxis with entecavir or equivalent and be willing to undergo monthly hepatitis B DNA PCR testing
- Active hepatitis C infection
- Grade 2 or higher rash
- Clinically significant fluid accumulation in the third space
- Subjects taking prohibited medications. A washout period of prohibited medications for a period of at least five half-lives or as clinically indicated should occur before the start of treatment
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT07573436.
Locations matching your search criteria
United States
Utah
Salt Lake City
PRIMARY OBJECTIVES:
I. To assess the Recommended Phase 2 Dose (RP2D) of loncastuximab tesirine and rituximab in participants with post-transplant lymphoproliferative disorders (PTLD). (Phase I)
II. To assess the efficacy of the combination of loncastuximab tesirine and rituximab (lonca-R) based on complete response (CR) rate after 4 cycles. (Phase II)
SECONDARY OBJECTIVES:
I. To assess the safety and tolerability of lonca-R in subjects with B-cell post transplant lymphoproliferative disorders (PTLD).
II. To determine overall response rate (ORR) after 4 cycles of lonca-R in subjects with B-cell PTLD.
III. To determine the best CR rate in subjects with B-cell PTLD.
IV. To assess progression-free survival (PFS).
V. To assess overall survival (OS).
EXPLORATORY OBJECTIVES:
I. To describe the baseline CD19 and CD20 expression on malignant lymphocytes by flow cytometry in subjects with PTLD.
II. To describe the relationship of tumor microenvironment characteristics using ribonucleic acid (RNA) sequencing (seq) with clinical response to lonca-R in subjects with B-cell PTLD.
III. To determine the rate of undetectable minimal residual disease (uMRD) following Cycle 2 (at Cycle 3pre-dose), Cycle 4 (to coincide with timing of imaging or on consolidation Cycle 1 pre-dose) and after completion of consolidation treatment (4-6 weeks to coincide with the timing of imaging).
IV. To describe the type of immunosuppression and amount reduced in subjects with B-cell PTLD.
OUTLINE: This is a phase I, dose-escalation study of loncastuximab tesirine followed by a phase II study.
Patients receive loncastuximab tesirine intravenously (IV), over at least 30 minutes, and rituximab IV on day 1 of each cycle. Cycles repeat every 21 days for 4 cycles. Patient undergo disease assessment at 6 weeks from the last treatment. Patients with progressive or stable disease are removed from the study. Patients with complete response receive 4 additional cycles of consolidation rituximab as described above. Patients with partial response receive either 4 additional cycles of consolidation rituximab as described above or rituximab, cyclophosphamide, doxorubicin, prednisone, and vincristine (R-CHOP) every 3 weeks for 4 cycles, per the investigators discretion. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo positron emission tomography (PET)/ computed tomography (CT) scan and blood sample collection throughout the study. Patients may also undergo biopsy during screening.
After completion of study treatment, patients are followed up at 60 days and every 3 months for 2 years.
Trial PhasePhase I/II
Trial Typetreatment
Lead OrganizationHuntsman Cancer Institute/University of Utah
Principal InvestigatorNarendranath Epperla
- Primary IDHCI198713
- Secondary IDsNCI-2026-04502, PLUTO
- ClinicalTrials.gov IDNCT07573436