Loncastuximab Tesirine and Rituximab as First-line Therapy in Patients With Post-transplant Lymphoproliferative Disorder (PLUTO) (PLUTO)

A Phase 1/2 Study of Loncastuximab Tesirine and Rituximab as First-line Therapy in Patients With Post-transplant Lymphoproliferative Disorder (PLUTO)

The purpose of phase I of this clinical trial is to learn the recommended dose of the drugs loncastuximab tesirine and rituximab in participants with post-transplant lymphoproliferative disorders (PTLD).

The purpose of phase II of this clinical trial is to learn if the drugs loncastuximab tesirine and rituximab are effective in participants with post-transplant lymphoproliferative disorders (PTLD).

Study Overview

• Status: Not yet recruiting
• Conditions: Post-transplant Lymphoproliferative Disorder
• Intervention / Treatment: Drug: Loncastuximab tesirine; Drug: Rituximab or rituximab biosimilar

• Study Type: Interventional
• Enrollment (Estimated): 23
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Rachel Kingsford; Phone Number: 801-585-0115; Email: Rachel.Kingsford@hci.utah.edu
• Study Contact Backup: Name: Narendranath Epperla, MD; Phone Number: 801-585-0255; Email: naren.epperla@hci.utah.edu

Study Locations

• United States
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute at University of Utah
      • Contact: Rachel Kingsford; Phone Number: 801-585-0115; Email: Rachel.Kingsford@hci.utah.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Subject aged ≥ 18 years.

• Histologically confirmed B-cell PTLD (monomorphic and polymorphic) following solid organ transplantation; with or without 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
• ECOG Performance Status ≤ 2.

• Adequate organ function as defined as:

  • Hematologic:

    • Absolute neutrophil count (ANC) ≥ 1000/mm3
    • Platelet count ≥ 75,000/mm3
    • Hemoglobin ≥ 8 g/dL

  • Hepatic:

    • Bilirubin ≤1.5 x upper limit of normal (ULN) or ≤3 x ULN with document liver involvement and/ or Gilbert's disease
    • Transaminases (AST or ALT) ≤ 3 x ULN or ≤ 5 x ULN with documented liver involvement

  • Renal:

    • 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 as described in Sections 5.4.1 and 5.4.2.
• 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
• 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 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 DNA 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 as described in Section 6.8.1. 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose Level 1 (starting dose): SD or PD; Dose Level 1: Loncastuximab tesirine: 0.075 mg/kg IV every 3 weeks; Rituximab: 375 mg/m2 IV This arm included participants who had SD (Stable Disease) or PD (Progressive Disease) after the first 6 weeks of treatment. Lonca-R will be administered for 4 cycles with response assessment at 6 weeks (+/- 1 week) following the last Lonca-R treatment. If they do not achieve a response, they will come off the study but will be monitored for survival.	Drug: Loncastuximab tesirine; Lonca will be administered by IV at 75µg/kg every 3 weeks (DL1).; Drug: Rituximab or rituximab biosimilar; Rituximab or rituximab biosimilar will be administered by IV at 375 mg/m2 on Day 1 of every cycle. Lonca will be administered first, followed by rituximab (with a 30 min wait time between the two agents); Other Names: Riabni; Ruxience; Truxima; RITUXAN
Experimental: Dose Level 1 (starting dose): PR; Dose Level 1: Loncastuximab tesirine: 0.075 mg/kg IV every 3 weeks; Rituximab: 375 mg/m2 IV This arm included participants who had a Partial Response (PR) after the first 6 weeks of treatment. Lonca-R will be administered for 4 cycles with response assessment at 6 weeks (+/- 1 week) following the last Lonca-R treatment. If they achieve PR, they will have the option to receive either rituximab consolidation or R-CHOP (at the physician's discretion).	Drug: Loncastuximab tesirine; Lonca will be administered by IV at 75µg/kg every 3 weeks (DL1).; Drug: Rituximab or rituximab biosimilar; Rituximab or rituximab biosimilar will be administered by IV at 375 mg/m2 on Day 1 of every cycle. Lonca will be administered first, followed by rituximab (with a 30 min wait time between the two agents); Other Names: Riabni; Ruxience; Truxima; RITUXAN
Experimental: Dose Level 1 (starting dose): CR; Dose Level 1: Loncastuximab tesirine: 0.075 mg/kg IV every 3 weeks; Rituximab: 375 mg/m2 IV This arm included participants who had a Complete Response (CR) after the first 6 weeks of treatment. Lonca-R will be administered for 4 cycles with response assessment at 6 weeks (+/- 1 week) following the last Lonca-R treatment. If they achieve a CR after 4 cycles of Lonca-R, they will receive rituximab consolidation (SOC).	Drug: Loncastuximab tesirine; Lonca will be administered by IV at 75µg/kg every 3 weeks (DL1).; Drug: Rituximab or rituximab biosimilar; Rituximab or rituximab biosimilar will be administered by IV at 375 mg/m2 on Day 1 of every cycle. Lonca will be administered first, followed by rituximab (with a 30 min wait time between the two agents); Other Names: Riabni; Ruxience; Truxima; RITUXAN
Experimental: Dose Level 2: SD or PD; Dose Level 2: Loncastuximab tesirine: 0.15 mg/kg IV every 3 weeks for the first 2 cycles, then 0.075 mg/kg starting C3; Rituximab: 375 mg/m2 IV This arm included participants who had SD (Stable Disease) or PD (Progressive Disease) after the first 6 weeks of treatment. Lonca-R will be administered for 4 cycles with response assessment at 6 weeks (+/- 1 week) following the last Lonca-R treatment. If they do not achieve a response, they will come off the study but will be monitored for survival.	Drug: Loncastuximab tesirine; Lonca will be administered by IV at 75µg/kg every 3 weeks (DL1).; Drug: Rituximab or rituximab biosimilar; Rituximab or rituximab biosimilar will be administered by IV at 375 mg/m2 on Day 1 of every cycle. Lonca will be administered first, followed by rituximab (with a 30 min wait time between the two agents); Other Names: Riabni; Ruxience; Truxima; RITUXAN
Experimental: Dose Level 2: PR; Dose Level 2: Loncastuximab tesirine: 0.15 mg/kg IV every 3 weeks for the first 2 cycles, then 0.075 mg/kg starting C3; Rituximab: 375 mg/m2 IV This arm included participants who had a Partial Response (PR) after the first 6 weeks of treatment. Lonca-R will be administered for 4 cycles with response assessment at 6 weeks (+/- 1 week) following the last Lonca-R treatment. If they achieve PR, they will have the option to receive either rituximab consolidation or R-CHOP (at the physician's discretion).	Drug: Loncastuximab tesirine; Lonca will be administered by IV at 75µg/kg every 3 weeks (DL1).; Drug: Rituximab or rituximab biosimilar; Rituximab or rituximab biosimilar will be administered by IV at 375 mg/m2 on Day 1 of every cycle. Lonca will be administered first, followed by rituximab (with a 30 min wait time between the two agents); Other Names: Riabni; Ruxience; Truxima; RITUXAN
Experimental: Dose Level 2: CR; Dose Level 2: Loncastuximab tesirine: 0.15 mg/kg IV every 3 weeks for the first 2 cycles, then 0.075 mg/kg starting C3; Rituximab: 375 mg/m2 IV This arm included participants who had a Complete Response (CR) after the first 6 weeks of treatment. Lonca-R will be administered for 4 cycles with response assessment at 6 weeks (+/- 1 week) following the last Lonca-R treatment. If they achieve a CR after 4 cycles of Lonca-R, they will receive rituximab consolidation (SOC).	Drug: Loncastuximab tesirine; Lonca will be administered by IV at 75µg/kg every 3 weeks (DL1).; Drug: Rituximab or rituximab biosimilar; Rituximab or rituximab biosimilar will be administered by IV at 375 mg/m2 on Day 1 of every cycle. Lonca will be administered first, followed by rituximab (with a 30 min wait time between the two agents); Other Names: Riabni; Ruxience; Truxima; RITUXAN

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase I: Define Maximum Tolerated Dose (MTD) based on the rate of dose-limiting toxicities (DLTs) during the DLT evaluation period.	To assess the Recommended Phase 2 Dose (RP2D) of loncastuximab tesirine and rituximab in participants with post-transplant lymphoproliferative disorders (PTLD).	4 years
Phase II: The complete response (CR) rate after 4 cycles of lonca-R per Lugano 2014 criteria1.	To assess the efficacy of the combination of lonca-R based on CR rate after 4 cycles.	4 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The frequency of adverse events (AEs) and serious adverse events (SAEs) characterized by type, severity (as defined by the NIH CTCAE, version 6.0), seriousness, duration, and relationship to study treatment.	To assess the safety and tolerability of lonca-R in subjects with B-cell PTLD.	4 years
The overall response rate (ORR) after 4 cycles of lonca-R.	To determine ORR after 4 cycles of lonca-R in subjects with B-cell PTLD.	4 years
The best complete response (CR) rate is defined as CR at the completion of 4 cycles of lonca-R or 4 cycles of lonca-R and 4 cycles of consolidation of rituximab monotherapy (every 3 weeks) in subjects with B-cell PTLD.	To determine the best CR rate in subjects with B-cell PTLD.	4 years
Median and two year progression-free survival (PFS). PFS will be as defined as the time from study drug initiation to the time of documented disease progression (as assessed by Lugano Criteria), or death from any cause.	To assess PFS.	4 years
Median and two year overall survival (OS). OS is defined as the time from initiation of treatment until death from any cause.	To assess OS.	4 years

Collaborators and Investigators

• Sponsor: University of Utah
• Collaborators: ADC Therapeutics S.A.
• Investigators: Principal Investigator: Narendranath Epperla, MD, Huntsman Cancer Institute

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): June 1, 2030
• Study Completion (Estimated): June 1, 2031

Study Registration Dates

• First Submitted: April 30, 2026
• First Submitted That Met QC Criteria: April 30, 2026
• First Posted (Actual): May 7, 2026

Study Record Updates

• Last Update Posted (Actual): May 7, 2026
• Last Update Submitted That Met QC Criteria: April 30, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Amino Acids, Peptides, and Proteins; Proteins; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Antibodies, Monoclonal, Murine-Derived; Rituximab; loncastuximab tesirine
• Other Study ID Numbers: HCI198713

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No