Loncastuximab Tesirine in Combination With DA-EPOCH-R in Patients With Previously Untreated Aggressive B-cell Lymphoid Malignancies

NCT05270057 | Active Not Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: PRO43132
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 3

Brief Summary

The overarching hypothesis for this study is that a safe and tolerable dose (i.e., the maximum tolerated dose) will be identified for loncastuximab tesirine in combination with dose-adjusted etoposide phosphate, prednisone, vincristine sulfate (Oncovin), cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), and rituximab (DA-EPOCH-R) for patients with previously untreated aggressive B-cell lymphoid malignancies.

Conditions

B-cell Lymphoma; Burkitt Lymphoma

Outcome Measures

Primary Outcomes (2)

• The maximum tolerated dose (MTD).

  MTD is defined as the highest dose level where zero of the first three patients treated or ≤1 of the first six patients treated had a dose-limiting toxicity (DLT) during cycle 1 of phase 1a.

  Up to 21 days (one cycle) for each dosing cohort.

• The number of dose-limiting toxicities (dose-escalation phase only).

  A dose-limiting toxicity is defined as any of the following within 21 days after administration of the first dose of loncastuximab tesirine in phase 1a part 1a only (except any toxicity clearly due to disease or other causes): adverse events and lab data, using Common Terminology Criteria for Adverse Events (CTCAE) v.5.0.

  Up to 21 days (one cycle).

Study Arms (5)

Loncastuximab Tesirine Dose Escalation 0.075 mg/kg by IV.

EXPERIMENTAL

The study uses a classic 3+3 dose-escalation design. Three patients will be enrolled into a cohort receiving 0.075 mg/kg by IV. If there is no dose-limiting toxicity (DLT) seen in any of these participants, the trial will enroll additional participants into the next higher dose cohort, which is 0.12 mg/kg by IV. If one patient experiences a DLT at a specific dose, an additional three individuals will be accrued into that same dose cohort. The third dose level is 0.15 mg/kg by IV. DLTs in two or more at a specific dose level indicates that the MTD has been exceeded; dose escalation will not be pursued, and the prior dose level will be expanded to six patients; if there is no more than one patient who experiences a DLT among those six patients, that dose level is considered the MTD.

Drug: Etoposide; Drug: Doxorubicin; Drug: Cyclophosphamide; Drug: Rituximab; Drug: Vincristine; Drug: Prednisone; Drug: Loncastuximab Tesirine 0.075 mg/kg by IV

Loncastuximab Tesirine Dose Escalation 0.12 mg/kg by IV.

EXPERIMENTAL

The study uses a classic 3+3 dose-escalation design. Three patients will be enrolled into a cohort receiving 0.075 mg/kg by IV. If there is no dose-limiting toxicity (DLT) seen in any of these participants, the trial will enroll additional participants into the next higher dose cohort, which is 0.12 mg/kg by IV. If one patient experiences a DLT at a specific dose, an additional three individuals will be accrued into that same dose cohort. The third dose level is 0.15 mg/kg by IV. DLTs in two or more at a specific dose level indicates that the MTD has been exceeded; dose escalation will not be pursued, and the prior dose level will be expanded to six patients; if there is no more than one patient who experiences a DLT among those six patients, that dose level is considered the MTD.

Drug: Etoposide; Drug: Doxorubicin; Drug: Cyclophosphamide; Drug: Rituximab; Drug: Vincristine; Drug: Prednisone; Drug: Loncastuximab tesirine 0.12 mg/kg by IV

Loncastuximab Tesirine Dose Escalation 0.15 mg/kg by IV.

EXPERIMENTAL

The study uses a classic 3+3 dose-escalation design. Three patients will be enrolled into a cohort receiving 0.075 mg/kg by IV. If there is no dose-limiting toxicity (DLT) seen in any of these participants, the trial will enroll additional participants into the next higher dose cohort, which is 0.12 mg/kg by IV. If one patient experiences a DLT at a specific dose, an additional three individuals will be accrued into that same dose cohort. The third dose level is 0.15 mg/kg by IV. DLTs in two or more at a specific dose level indicates that the MTD has been exceeded; dose escalation will not be pursued, and the prior dose level will be expanded to six patients; if there is no more than one patient who experiences a DLT among those six patients, that dose level is considered the MTD.

Drug: Etoposide; Drug: Doxorubicin; Drug: Cyclophosphamide; Drug: Rituximab; Drug: Vincristine; Drug: Prednisone; Drug: Loncastuximab tesirine 0.15 mg/kg by IV

Loncastuximab Tesirine Dose Escalation Maximum Tolerated Dose

EXPERIMENTAL

The study uses a classic 3+3 dose-escalation design. Three patients will be enrolled into a cohort receiving 0.075 mg/kg by IV. If there is no dose-limiting toxicity (DLT) seen in any of these participants, the trial will enroll additional participants into the next higher dose cohort, which is 0.12 mg/kg by IV. If one patient experiences a DLT at a specific dose, an additional three individuals will be accrued into that same dose cohort. The third dose level is 0.15 mg/kg by IV. DLTs in two or more at a specific dose level indicates that the MTD has been exceeded; dose escalation will not be pursued, and the prior dose level will be expanded to six patients; if there is no more than one patient who experiences a DLT among those six patients, that dose level is considered the MTD. This dose will be added to this record when it is determined.

Drug: Etoposide; Drug: Doxorubicin; Drug: Cyclophosphamide; Drug: Rituximab; Drug: Vincristine; Drug: Prednisone; Drug: Loncastuximab Tesirine 0.075 mg/kg by IV; Drug: Loncastuximab tesirine 0.12 mg/kg by IV; Drug: Loncastuximab tesirine 0.15 mg/kg by IV

Dose Expansion Phase

EXPERIMENTAL

Subjects will receive the recommended phase 2 dose (RP2D) identified from dose-escalation phase. This dose will be added to this record when it is determined.

Drug: Etoposide; Drug: Doxorubicin; Drug: Cyclophosphamide; Drug: Rituximab; Drug: Vincristine; Drug: Prednisone; Drug: Loncastuximab Tesirine 0.075 mg/kg by IV; Drug: Loncastuximab tesirine 0.12 mg/kg by IV; Drug: Loncastuximab tesirine 0.15 mg/kg by IV

Interventions

Etoposide DRUG

Dose level -2=50 mg/m\^2; dose level -1=50 mg/m\^2; dose level 1=50 mg/m\^2; dose level 2=60 mg/m\^2; dose level 3=72 mg/m\^2; dose level 4=86.4 mg/m\^2; dose level 5=103.7 mg/m\^2; dose level 6=124.4 mg/m\^2; dose level 7=149.3 mg/m\^2

Also known as: Etopophos, Toposar, Vepesid

Dose Expansion Phase; Loncastuximab Tesirine Dose Escalation 0.075 mg/kg by IV.; Loncastuximab Tesirine Dose Escalation 0.12 mg/kg by IV.; Loncastuximab Tesirine Dose Escalation 0.15 mg/kg by IV.; Loncastuximab Tesirine Dose Escalation Maximum Tolerated Dose

Doxorubicin DRUG

Dose level -2=10 mg/m\^2; dose level -1; dose level -1=10 mg/m\^2; dose level 1=10 mg/m\^2; dose level 2=12 mg/m\^2; dose level 3=14.4 mg/m\^17.3 mg/m\^2; dose level 4=17.3 mg/m\^2; dose level 5=20.7 mg/m\^2; dose level 6=24.8 mg/m\^2; dose level 7=29.8 mg/m\^2.

Also known as: Lipodox, Lipodox 50, Doxil, Adriamycin, Rubex

Dose Expansion Phase; Loncastuximab Tesirine Dose Escalation 0.075 mg/kg by IV.; Loncastuximab Tesirine Dose Escalation 0.12 mg/kg by IV.; Loncastuximab Tesirine Dose Escalation 0.15 mg/kg by IV.; Loncastuximab Tesirine Dose Escalation Maximum Tolerated Dose

Cyclophosphamide DRUG

Dose level -2=480 mg/m\^2; dose -1=600 mg/m\^2; dose level 1=750 mg/m\^2; level 2=900 mg/m\^2; level 3=1080 mg/m\^2; level 4=1296 mg/m\^2; level 5=1555 mg/m\^2; level 6=1866 mg/m\^2; level 7=2239 mg/m\^2.

Also known as: Cytoxan, Neosar, Endoxan, Procytox, Revimmune

Dose Expansion Phase; Loncastuximab Tesirine Dose Escalation 0.075 mg/kg by IV.; Loncastuximab Tesirine Dose Escalation 0.12 mg/kg by IV.; Loncastuximab Tesirine Dose Escalation 0.15 mg/kg by IV.; Loncastuximab Tesirine Dose Escalation Maximum Tolerated Dose

Rituximab DRUG

Level -2 through level 7: 375 mg/m\^2

Also known as: Rituxan, MabThera

Dose Expansion Phase; Loncastuximab Tesirine Dose Escalation 0.075 mg/kg by IV.; Loncastuximab Tesirine Dose Escalation 0.12 mg/kg by IV.; Loncastuximab Tesirine Dose Escalation 0.15 mg/kg by IV.; Loncastuximab Tesirine Dose Escalation Maximum Tolerated Dose

Vincristine DRUG

Level -2 through level 7: 0.4 mg/m\^2/day

Also known as: Oncovin, Vincasar, Marqibo, Leurocristine

Dose Expansion Phase; Loncastuximab Tesirine Dose Escalation 0.075 mg/kg by IV.; Loncastuximab Tesirine Dose Escalation 0.12 mg/kg by IV.; Loncastuximab Tesirine Dose Escalation 0.15 mg/kg by IV.; Loncastuximab Tesirine Dose Escalation Maximum Tolerated Dose

Prednisone DRUG

Level -2 through level 7: 60 mg/m\^2/twice daily (BID)

Also known as: Deltasone, Orasone, Meticorten, Liquid Pred

Dose Expansion Phase; Loncastuximab Tesirine Dose Escalation 0.075 mg/kg by IV.; Loncastuximab Tesirine Dose Escalation 0.12 mg/kg by IV.; Loncastuximab Tesirine Dose Escalation 0.15 mg/kg by IV.; Loncastuximab Tesirine Dose Escalation Maximum Tolerated Dose

Loncastuximab Tesirine 0.075 mg/kg by IV DRUG

Cohort 1: 0.075 mg/kg by IV. The dose-expansion phase will use the maximum-tolerated dose.

Also known as: Zynlonta, ADCT-402, loncastuximab tesirine-lpyl

Dose Expansion Phase; Loncastuximab Tesirine Dose Escalation 0.075 mg/kg by IV.; Loncastuximab Tesirine Dose Escalation Maximum Tolerated Dose

Loncastuximab tesirine 0.12 mg/kg by IV DRUG

Cohort 2: 0.12 mg/kg by IV. The dose-expansion phase will use the maximum-tolerated dose.

Also known as: Zynlonta, ADCT-402, loncastuximab tesirine-lpyl

Dose Expansion Phase; Loncastuximab Tesirine Dose Escalation 0.12 mg/kg by IV.; Loncastuximab Tesirine Dose Escalation Maximum Tolerated Dose

Loncastuximab tesirine 0.15 mg/kg by IV DRUG

Cohort 3: 0.15 mg/kg by IV The dose-expansion phase will use the maximum-tolerated dose.

Also known as: Zynlonta, ADCT-402, loncastuximab tesirine-lpyl

Dose Expansion Phase; Loncastuximab Tesirine Dose Escalation 0.15 mg/kg by IV.; Loncastuximab Tesirine Dose Escalation Maximum Tolerated Dose

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥ 18 years.
• Adult patients with B-cell lymphoma, specifically one of the following: high-grade B-cell lymphoma with MYC and B-cell lymphoma 2 (BCL2) and/or B cell lymphoma 6 (BCL6) rearrangements; high-grade B-cell lymphoma, not otherwise specified, primary mediastinal diffuse large B-cell lymphoma; Burkitt lymphoma; diffuse large B-cell lymphoma with MYC rearrangement; or Cluster of Differentiation 19 (CD19) -positive plasmablastic lymphoma.
• Patients must not have received prior multiagent chemotherapy for their lymphoma. Limited palliative radiation is allowed. Corticosteroid therapy in symptomatic patients will be permitted and does not require a washout period. Prephase treatment with cyclophosphamide and corticosteroids or vincristine and corticosteroids is allowed in symptomatic patients.
• Eastern Cooperative Oncology Group (ECOG) Performance Status criteria of 0-3.
• Adequate hematological function, defined as absolute neutrophil count (ANC) ≥1 × 103/μL and platelet count ≥50 x 10\^3/μL.
• \- These requirements do not apply to patients with bone marrow involvement of lymphoma.
• Adequate hepatic function: aspartate aminotransferase (AST) / alanine aminotransferase (ALT) / gamma-glutamyl transferase (GGT) ≤ 3 x institutional upper limit of normal (ULN) and bilirubin \< 1.5 x ULN, unless due to hepatic involvement with lymphoma or Gilbert's syndrome.
• \- Exceptions can be granted from principal investigator for primarily indirect bilirubinemia if due to recent transfusion and/or hemolysis.
• Creatinine clearance ≥ 30 ml/min calculated using the Cockroft-Gault formula.
• Left ventricular ejection fraction (LVEF) of ≥50%, assessed by echocardiography or cardiac multi-gated acquisition (MUGA) scan.
• Patients with marrow-only disease will be eligible.
• Patients rendered no evidence of disease via surgery will be eligible.
• Central nervous system (CNS) involvement is not considered contraindication for patients with Burkitt lymphoma.
• Known HIV-positive patients compliant with antiretroviral therapy and with undetectable viral loads will be permitted.
• Pregnancy It is not known what effects this treatment has on human pregnancy or development of the embryo or fetus. Therefore, female patients participating in this study should avoid becoming pregnant, and male patients should avoid impregnating a female partner. Non-sterilized female patients of reproductive age and male patients should use effective methods of contraception through defined periods during and after study treatment as specified below.

You may not qualify if:

• Presence of clinically significant pericardial or pleural effusions, or third space fluid accumulations (i.e., ascites requiring drainage or pleural effusion that is either requiring drainage or associated with shortness of breath).
• Known history of hypersensitivity to CD19 antibody, components of study medication, or DA-EPOCH-R.
• Serologic evidence of chronic hepatitis B virus (HBV) infection and unable or unwilling to receive standard prophylactic antiviral therapy. These subjects MUST HAVE undetectable HBV viral load to be considered for this protocol.
• Serologic evidence of hepatitis C virus (HCV) infection without completion of curative treatment or with detectable HCV viral load.
• Breastfeeding or pregnant.
• Active systemic bacterial, viral, fungal, or other infection requiring systemic treatment at time of screening.
• Congenital long QT syndrome or a corrected QT measure (QTc) interval of \>480 ms at screening (unless secondary to pacemaker or bundle branch block).
• Significant medical comorbidities such as New York Heart Association class ≥III heart failure, unstable angina, uncontrolled arrhythmias, or severe chronic pulmonary disease.
• Lymphoma with active CNS involvement at time of screening unless the patient has Burkitt lymphoma.
• Patient with known intraparenchymal CNS involvement (including those with Burkitt lymphoma).
• Patients with known Child Pugh Class C hepatic impairment.

Sponsors & Collaborators

• Medical College of Wisconsin: lead

Study Sites (3)

University of Texas Southwestern

Dallas, Texas, 75390, United States

Location

University of Wisconsin School of Medicine and Public Health

Madison, Wisconsin, 53705, United States

Location

Froedtert Hospital & the Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

MeSH Terms

Conditions

Lymphoma, B-Cell; Burkitt Lymphoma

Interventions

Etoposide; etoposide phosphate; Doxorubicin; liposomal doxorubicin; Cyclophosphamide; Rituximab; Vincristine; Prednisone; loncastuximab tesirine

Condition Hierarchy (Ancestors)

Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Epstein-Barr Virus Infections; Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Infections; Tumor Virus Infections

Intervention Hierarchy (Ancestors)

Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Glucosides; Glycosides; Carbohydrates; Daunorubicin; Anthracyclines; Naphthacenes; Aminoglycosides; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds

Study Officials

• Mehdi Hamadani, MD

  Medical College of Wisconsin

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: Phase 1a will involve a standard 3+3 dose escalation design to find the maximal tolerated dose (MTD) and/or recommended dose for expansion.

Study Record Dates

• First Submitted: February 24, 2022
• First Posted: March 8, 2022
• Study Start: January 26, 2023
• Primary Completion: May 28, 2025
• Study Completion (Estimated): October 11, 2027
• Last Updated: October 9, 2025

Record last verified: 2025-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)