Study of ADCT-402 in Patients With Relapsed or Refractory B-cell Lineage Non Hodgkin Lymphoma (B-NHL)

ADC Therapeutics

Status and phase: Completed; Phase 1

Conditions: Waldenstrom Macroglobulinemia; Lymphoma, Marginal Zone; Lymphoma, Mantle-Cell; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Chronic Lymphocytic Leukemia; Primary Mediastinal B-cell Lymphoma; Burkitt's Lymphoma; Non-Hodgkin Lymphoma

Treatments: Drug: ADCT-402

Study type: Interventional

Funder types: Industry

Identifiers

NCT02669017

2016-000952-92 (EudraCT Number)

ADCT-402-101

Details and patient eligibility

About

This study evaluates ADCT-402 in participants with Relapsed or Refractory B-cell Lineage Non Hodgkin Lymphoma (B-NHL). Participants will participate in a dose escalation phase (Part 1) and dose expansion (Part 2). In Part 2, participants will receive the dose level identified in Part 1.

Full description

Study ADCT-402-101 is the first clinical study with ADCT-402 in participants with B-cell Non Hodgkin Lymphoma (NHL).

ADCT-402 is an antibody drug conjugate (ADC) composed of a humanized antibody directed against human cluster of differentiation 19 (CD19), stochastically conjugated via a valine-alanine cleavable, maleimide linker to a pyrrolobenzodiazepine (PBD) dimer cytotoxin.

The study will be conducted in 2 parts. In Part 1 (dose escalation) participants will receive infusions of ADCT-402, at escalating doses. Part 1 will continue until the maximum tolerated dose is determined. In Part 2 (expansion), participants will be assigned to the recommended dose level(s) and schedule(s) of ADCT-402 identified in Part 1 by the Dose Escalation Steering Committee.

For each participant, the study will include a screening period (up to 28 days), a treatment period (until withdrawal), and a follow-up period to assess disease progression and survival for up to 12 months after the last dose of study drug. The total study duration will be dependent on overall participant tolerability to the study drug and response to treatment. It is anticipated that the duration of the entire study (Parts 1 and 2) could be approximately 3 years from first participant treated to last participant completed.

Enrollment: 183 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Male or female participants, ages 18 years or older with pathologically confirmed relapsed or refractory B-cell lineage NHL who have failed or are intolerant to established therapy, or for whom no other treatment options are available.
• Refractory or relapsed B-cell NHL (per World health Organization [WHO] Classification system).
• Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue block.
• Measurable disease, as defined by the 2014 Lugano Classification.
• Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2.
• Absolute neutrophil count (ANC) ≥1000/μL.
• Platelet count of ≥75000/μL.
• Hemoglobin ≥9.0 g/dL without transfusion within the 2 weeks prior to Day 1.
• Serum/plasma creatinine ≤1.5 mg/dL.
• Serum/plasma alkaline phosphatase, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤2 times the upper limit of normal (ULN); ≤ 5 times ULN if there is liver or bone involvement.
• Total serum/plasma bilirubin ≤1.5 times ULN.
• Negative blood or urine beta-human chorionic gonadotropin (β-HCG) pregnancy test within 7 days prior to Day 1 for women of childbearing potential.
• Males, and female participants who are biologically capable of having children, must agree to use a medically acceptable method of birth control.

Exclusion criteria

• Participants who have any option for other treatment for B-cell NHL at the current state of disease.
• Active graft-versus-host disease.
• Autologous or allogenic transplant within the 60 days prior to the Screening visit.
• Known history of immunogenicity or hypersensitivity to a CD19 antibody.
• Evidence of myelodysplasia or myeloid leukemia by morphology, immunostains, flow cytometry, or cytogenetics on a bone marrow aspirate or biopsy.
• Known history of positive serum human ADA.
• Active autoimmune disease, motor neuropathy considered of autoimmune origin, and other central nervous system (CNS) autoimmune disease.
• Known seropositive for human immunodeficiency (HIV) virus, hepatitis B surface antigen (HbsAg), or antibody to hepatitis C virus (anti-HCV).
• History of Steven's Johnson's syndrome or toxic epidermal necrolysis syndrome.
• Pregnant or breastfeeding women.
• Significant medical comorbidities, including uncontrolled hypertension (diastolic blood pressure greater than 115 mm Hg), unstable angina, congestive heart failure (greater than New York Heart Association class II), severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia, poorly controlled diabetes, severe chronic pulmonary disease, coronary angioplasty, or myocardial infarction within 6 months prior to screening, or uncontrolled atrial or ventricular cardiac arrhythmias.
• Use of any other experimental medication(s) within 14 days or 5 half-lives but in no case less than 14 days prior to start of study treatment on Cycle 1, Day 1, except if approved by Sponsor.
• Steroid use equivalent to greater than 20 mg of prednisone within 4 weeks (28 days) prior to Day 1.
• Major surgery, chemotherapy, systemic therapy (excluding steroids hydroxyurea steroids, and any targeted small molecules or biologics), or radiotherapy, within 14 days or 5 half-lives (whichever is shorter) prior to Cycle 1, Day 1 treatment, except if approved by the Sponsor.
• Failure to recover (to Common Terminology Criteria for Adverse Events [CTCAE] Grade 0 or Grade 1) from acute non hematologic toxicity (except all grades alopecia or Grade 2 or lower neuropathy), due to previous therapy, prior to Screening.
• Congenital long QT syndrome or a corrected QTc interval ≥450 ms at the Screening visit.
• 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 determined not be exclusionary.
• Any other significant medical illness, abnormality, or condition that would make the participant inappropriate for study participation or put the participant at risk.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Single Group Assignment

Masking: None (Open label)

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183 participants in 2 patient groups

Part 1: ADCT-402 dose escalation

Experimental group

Description:

In Part 1 (dose escalation) participants will receive intravenous (IV) infusions of ADCT-402 at escalating doses, according to a 3+3 study design. Doses will be escalated from 15 µg/kg to 200 µg/kg on Day 1 of each cycle, with cycle lengths of 3 or 6 weeks.

Treatment:

Drug: ADCT-402

Part 2: ADCT-402 dose expansion

Experimental group

Description:

In Part 2 (expansion), participants will be assigned to the recommended dose level(s) and schedule(s) of ADCT-402 identified in Part 1 by the Dose Escalation Steering Committee. Participants will receive intravenous (IV) infusions of ADCT-402 at either 120 μg/kg or 150 μg/kg on Day 1 of each 3 week cycle (Q3W).

Treatment:

Drug: ADCT-402