Title
A Multicenter Phase 1, Open-Label Trial of Loncastuximab Tesirine in Combination with DA-EPOCH-R in Patients with Previously Untreated Aggressive B-cell Lymphoid Malignancies

Description
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.

Objective
Primary Objectives:
-Evaluate the safety and tolerability of loncastuximab tesirine in combination with DA-EPOCH-R.
-Define the maximum tolerated dose (MTD) and the recommended dose for expansion cohort

Secondary Objectives:
-Evaluate the end-of-treatment overall, complete, and partial response rates using the Lugano 2014 criteria (of total study population and phase 1b subset). Assessments will be completed after cycles 2 and 6, then at the discretion of the treating investigator. Anti-tumor activity will be defined as the detect of PR or CR by PET/CT or CT.
-Determine the duration of response (DOR) defined as the time from the first documentation of tumor response to disease progression or death.
-Determine one-year and two-year event-free survival (of total study population and phase 1b subset) [defined from C1D1 to date of therapy failure, discontinuation or death].
-Determine one-year and two-year OS (of total study population and phase 1b subset) [overall survival defined from time C1D1 to date of death].
-Characterize the pharmacokinetic (PK) profile and immunogenicity of loncastuximab tesirine in combination with DA-EPOCH-R (in collaboration with ADC Therapeutics).
-To evaluate the immunogenic response of loncastuximab tesirine in combination with DA-EPOCH-R.

Treatment This is a multicenter phase 1, open-label trial that will evaluate the safety and tolerability of loncastuximab tesirine in combination with DA-EPOCH-R.

Phase 1a will involve a standard 3+3 dose escalation design to find the maximum tolerated dose (MTD) and/or recommended dose for expansion. The MTD will be determined based on the results of the safety evaluation. No intra-patient dose escalation is allowed.

Phase 1b will involve a cohort expansion at the dose level determined to be the recommended phase 2 dose.

Key Eligibility Inclusion Criteria:

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) - 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.



Female patients of childbearing potential must use a highly effective method of contraception during the entire study treatment period and through nine months after the last dose of loncastuximab tesirine.

Male patients, even if surgically sterilized (i.e., status postvasectomy), with female partners who are of childbearing potential should use a condom when sexually active during the entire study treatment period and through six months after the last dose of loncastuximab tesirine.



Ability to understand a written informed consent document, and the willingness to sign it.

Applicable Disease Sites
Lymphoma

Participating Institutions
UW Health Eastpark Medical Center; UW Health University Hospital