Clinical trial NCT02669017: Study of ADCT-402 in Patients With Relapsed or Refractory B-cell Lineage Non Hodgkin Lymphoma (B-NHL)
Official title: A Phase 1 Dose-escalation Study to Evaluate the Tolerability, Safety, Pharmacokinetics, and Antitumor Activity of ADCT-402 in Patients With Relapsed or Refractory B-cell Lineage Non Hodgkin Lymphoma (B-NHL)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Non-Hodgkin Lymphoma
Burkitt's Lymphoma
Chronic Lymphocytic Leukemia
Lymphoma, Large B-Cell, Diffuse
Lymphoma, Follicular
Lymphoma, Mantle-Cell
Lymphoma, Marginal Zone
Waldenstrom Macroglobulinemia
Primary Mediastinal B-cell Lymphoma
Keywords: Loncastuximab tesirine
Lead sponsor: ADC Therapeutics S.A.
Sponsor class: INDUSTRY
First posted: 2016-01-29
Enrollment: 183
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs)
timeFrame: Q3W schedule: Day 1 to End of Cycle 1 (3 weeks); Q6W schedule: Day 1 to End of Cycle 1 (6 weeks)
measure: Recommended Dose of ADCT-402 for Part 2
timeFrame: Q3W schedule: Day 1 to End of Cycle 1 (3 weeks); Q6W schedule: Day 1 to End of Cycle 1 (6 weeks)
measure: Number of Participants Reporting at Least One Treatment Emergent Adverse Event (TEAE)
timeFrame: Day 1 to End of Study (a maximum of 18 months)
measure: Number of Participants Reporting at Least One Treatment Emergent Serious Adverse Event (SAE)
timeFrame: Day 1 to End of Study (a maximum of 18 months)
Secondary outcomes:
measure: Overall Response Rate (ORR)
timeFrame: Baseline to End of Study (a maximum of 18 months)
measure: Duration of Response (DoR)
timeFrame: Baseline to End of Study (a maximum of 18 months)
measure: Overall Survival (OS)
timeFrame: Baseline to End of Study (a maximum of 18 months)
measure: Progression-free Survival (PFS)
timeFrame: Baseline to End of Study (a maximum of 18 months)
measure: Maximum Observed Serum Concentration (Cmax) for ADCT-402
timeFrame: Q3W schedule: Day 1 (pre-dose and 1 to 6 hours post-dose), and days 2, 3, 5, 8, 15 and 21 of Cycles 1 and 2 (3 weeks cycle); Q6W schedule: Day 1 (pre-dose and 1 to 6 hours post-dose), and days 2, 3, 5, 8, 15 and 21 of Cycles 1 and 2 (6 week cycle)
measure: Time to Reach the Maximum Serum Concentration (Tmax) for ADCT-402
timeFrame: Q3W schedule: Day 1 (pre-dose and 1 to 6 hours post-dose), and days 2, 3, 5, 8, 15 and 21 of Cycles 1 and 2 (3 weeks cycle); Q6W schedule: Day 1 (pre-dose and 1 to 6 hours post-dose), and days 2, 3, 5, 8, 15 and 21 of Cycles 1 and 2 (6 week cycle)
measure: Area Under the Serum Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) for ADCT-402
timeFrame: Q3W schedule: Day 1 (pre-dose and 1 to 6 hours post-dose), and days 2, 3, 5, 8, 15 and 21 of Cycles 1 and 2 (3 weeks cycle); Q6W schedule: Day 1 (pre-dose and 1 to 6 hours post-dose), and days 2, 3, 5, 8, 15 and 21 of Cycles 1 and 2 (6 week cycle)
measure: Area Under the Serum Concentration-Time Curve From Time 0 to the End of the Dosing Interval (AUCtau) for ADCT-402
timeFrame: Q3W schedule: Day 1 (pre-dose and 1 to 6 hours post-dose), and days 2, 3, 5, 8, 15 and 21 of Cycles 1 and 2 (3 weeks cycle); Q6W schedule: Day 1 (pre-dose and 1 to 6 hours post-dose), and days 2, 3, 5, 8, 15 and 21 of Cycles 1 and 2 (6 week cycle)
measure: Area Under the Serum Concentration-time Curve From Time 0 to Infinity (AUCinf) for ADCT-402
timeFrame: Q3W schedule: Day 1 (pre-dose and 1 to 6 hours post-dose), and days 2, 3, 5, 8, 15 and 21 of Cycles 1 and 2 (3 weeks cycle); Q6W schedule: Day 1 (pre-dose and 1 to 6 hours post-dose), and days 2, 3, 5, 8, 15 and 21 of Cycles 1 and 2 (6 week cycle)
measure: Terminal Half-life (Thalf) of ADCT-402
timeFrame: Q3W schedule: Day 1 (pre-dose and 1 to 6 hours post-dose), and days 2, 3, 5, 8, 15 and 21 of Cycles 1 and 2 (3 weeks cycle); Q6W schedule: Day 1 (pre-dose and 1 to 6 hours post-dose), and days 2, 3, 5, 8, 15 and 21 of Cycles 1 and 2 (6 week cycle)
measure: Apparent Clearance (CL) at Steady State for ADCT-402
timeFrame: Q3W schedule: Day 1 (pre-dose and 1 to 6 hours post-dose), and days 2, 3, 5, 8, 15 and 21 of Cycles 1 and 2 (3 weeks cycle); Q6W schedule: Day 1 (pre-dose and 1 to 6 hours post-dose), and days 2, 3, 5, 8, 15 and 21 of Cycles 1 and 2 (6 week cycle)
measure: Volume of Distribution at Steady State (Vss) for ADCT-402
timeFrame: Q3W schedule: Day 1 (pre-dose and 1 to 6 hours post-dose), and days 2, 3, 5, 8, 15 and 21 of Cycles 1 and 2 (3 weeks cycle); Q6W schedule: Day 1 (pre-dose and 1 to 6 hours post-dose), and days 2, 3, 5, 8, 15 and 21 of Cycles 1 and 2 (6 week cycle)
measure: Accumulation Index (AI) for ADCT-402
timeFrame: Q3W schedule: Day 1 (pre-dose and 1 to 6 hours post-dose), and days 2, 3, 5, 8, 15 and 21 of Cycles 1 and 2 (3 weeks cycle); Q6W schedule: Day 1 (pre-dose and 1 to 6 hours post-dose), and days 2, 3, 5, 8, 15 and 21 of Cycles 1 and 2 (6 week cycle)
measure: Number of Participants With Anti-drug Antibody Response (ADA) Against ADCT-402
timeFrame: Q3W schedule: Day 1 to End of Cycle 1 (3 weeks); Q6W schedule: Day 1 to End of Cycle 1 (6 weeks)
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: UC San Diego Moores Cancer Center
state: California
city: Atlanta
country: United States
facility: Winship Cancer Institute of Emory University
state: Georgia
city: Atlanta
country: United States
facility: Blood and Marrow Transplant Group of Georgia
state: Georgia
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: New York
country: United States
facility: Columbia University Medical Center Herbert Irving Pavilion
state: New York
city: Cleveland
country: United States
facility: University Hospitals of Cleveland
state: Ohio
city: Greenville
country: United States
facility: Greenville Health System, Institute for Translational Oncology Research, Clinical Research Unit
state: South Carolina
city: Milwaukee
country: United States
facility: Froedtert Hospital & the Medical College of Wisconsin
state: Wisconsin
city: Milano
country: Italy
facility: U.O Oncologia e Ematologia - Istituto Clinico Humanitas
city: London
country: United Kingdom
facility: University College London Hospitals
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
Study officials:
References:
citation: Hess B, Townsend W, Ai W, Stathis A, Solh M, Alderuccio JP, Ungar D, Liao S, Liao L, Khouri L, Zhang X, Boni J. Efficacy and Safety Exposure-Response Analysis of Loncastuximab Tesirine in Patients with B cell non-Hodgkin Lymphoma. AAPS J. 2021 Dec 10;24(1):11. doi: 10.1208/s12248-021-00660-3.
citation: Hamadani M, Radford J, Carlo-Stella C, Caimi PF, Reid E, O'Connor OA, Feingold JM, Ardeshna KM, Townsend W, Solh M, Heffner LT, Ungar D, Wang L, Boni J, Havenith K, Qin Y, Kahl BS. Final results of a phase 1 study of loncastuximab tesirine in relapsed/refractory B-cell non-Hodgkin lymphoma. Blood. 2021 May 13;137(19):2634-2645. doi: 10.1182/blood.2020007512.
citation: Kahl BS, Hamadani M, Radford J, Carlo-Stella C, Caimi P, Reid E, Feingold JM, Ardeshna KM, Solh M, Heffner LT, Ungar D, He S, Boni J, Havenith K, O'Connor OA. A Phase I Study of ADCT-402 (Loncastuximab Tesirine), a Novel Pyrrolobenzodiazepine-Based Antibody-Drug Conjugate, in Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma. Clin Cancer Res. 2019 Dec 1;25(23):6986-6994. doi: 10.1158/1078-0432.CCR-19-0711. Epub 2019 Nov 4.