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

• ClinicalTrials.gov Identifier: NCT02669017
• Recruitment Status: Completed
• First Posted: January 29, 2016
• Results First Posted: April 13, 2020
• Last Update Posted: May 19, 2021
• Sponsor: ADC Therapeutics S.A.
• Information provided by (Responsible Party): ADC Therapeutics S.A.

Study Description

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.

Condition or disease	Intervention/treatment	Phase
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	Drug: ADCT-402	Phase 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 183 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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 Start Date: March 2016
• Actual Primary Completion Date: February 21, 2019
• Actual Study Completion Date: February 21, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Part 1: ADCT-402 dose escalation; 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.	Drug: ADCT-402; intravenous infusion; Other Names: Loncastuximab tesirine; Zynlonta
Experimental: Part 2: ADCT-402 dose expansion; 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).	Drug: ADCT-402; intravenous infusion; Other Names: Loncastuximab tesirine; Zynlonta

Outcome Measures

Primary Outcome Measures :

1. Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs) [ Time Frame: Q3W schedule: Day 1 to End of Cycle 1 (3 weeks); Q6W schedule: Day 1 to End of Cycle 1 (6 weeks) ]

   A DLT is defined as any of the following events, except those that are clearly due to underlying disease or extraneous causes:

   A hematologic DLT is defined as:

   • CTCAE Grade 3 or 4 febrile neutropenia or neutropenic infection.
   • CTCAE Grade 4 neutropenia lasting >7 days.
   • CTCAE Grade 4 thrombocytopenia.
   • CTCAE Grade 3 thrombocytopenia with clinically significant bleeding, or Grade 3 thrombocytopenia requiring a platelet transfusion.
   • CTCAE Grade 4 anemia.

   A non-hematologic DLT is defined as:

   • CTCAE Grade 4 tumor lysis syndrome (TLS). Grade 3 TLS will not constitute DLT unless it leads to irreversible end-organ damage.
   • CTCAE Grade 3 or higher AE (including nausea, vomiting, diarrhea, and electrolyte imbalances lasting more than 48 hours despite optimal therapy; excluding all grades of alopecia).
   • CTCAE Grade 3 or higher hypersensitivity reaction (regardless of premedication).
   • CTCAE Grade 2 or higher skin ulceration.
2. Recommended Dose of ADCT-402 for Part 2 [ Time Frame: Q3W schedule: Day 1 to End of Cycle 1 (3 weeks); Q6W schedule: Day 1 to End of Cycle 1 (6 weeks) ]
   The recommended dose was established by the dose escalation steering committee and based on safety findings during Part 1 of the study.
3. Number of Participants Reporting at Least One Treatment Emergent Adverse Event (TEAE) [ Time Frame: Day 1 to End of Study (a maximum of 18 months) ]
   An adverse event (AE) is defined as any untoward medical occurrence in a participants enrolled into this study regardless of its causal relationship to study drug. A TEAE is defined as any event not present before exposure to study drug or any event already present that worsens in either intensity or frequency after exposure to study drug.
4. Number of Participants Reporting at Least One Treatment Emergent Serious Adverse Event (SAE) [ Time Frame: Day 1 to End of Study (a maximum of 18 months) ]
   An adverse event (AE) is defined as any untoward medical occurrence in a participant enrolled into this study regardless of its causal relationship to study drug. A treatment emergent AE (TEAE) is defined as any event not present before exposure to study drug or any event already present that worsens in either intensity or frequency after exposure to study drug. An SAE is defined as any event that results in death, is immediately life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.

Secondary Outcome Measures :

1. Overall Response Rate (ORR) [ Time Frame: Baseline to End of Study (a maximum of 18 months) ]

   ORR was defined as the number of participants with a best overall response of complete response (CR) or partial response (PR) at the time each participant discontinued treatment with ADCT-402, before the start of subsequent anticancer therapy or procedure. Tumor response was assessed using the 2014 Lugano Classification for response.

   CR is defined as achieving either of the following:

   • Complete metabolic response.
   • Complete radiologic response (target node regress to <1.5 cm, no nonmeasured lesions, no organ enlargement, no new lesions and normal bone marrow morphology).

   PR is defined as achieving either of the following:

   • Partial metabolic response (findings indicate residual disease).
   • Partial remission (>50% decrease in target measurable nodes, regression/ absence/ no increase of nonmeasured lesions, spleen regressed by >50% in length and no new lesions).
2. Duration of Response (DoR) [ Time Frame: Baseline to End of Study (a maximum of 18 months) ]

   DoR is defined among responders (complete response [CR] and partial response [PR]) as the time from the earliest date of first response until the first date of either disease progression or death due to any cause. Tumor response was assessed using the 2014 Lugano Classification for response.

   Disease progression is defined as progressive metabolic disease or one of the follow:

   • Target node progression.
   • An individual extranodal lesion must be abnormal with length >1.5cm and/or increase of length >50%.
   • New or clear progression of nonmeasured lesions.
   • Regrowth of previously resolved lesions or new nodes >1.5 cm in length.
   • New or recurrent bone marrow involvement.

   DoR is presented overall for all participants who received ADCT-402, as specified in protocol section 7.4.

3. Overall Survival (OS) [ Time Frame: Baseline to End of Study (a maximum of 18 months) ]

   OS is defined as the time from the first dose of study drug treatment until the date of death due to any cause.

   OS is presented overall for all participants who received ADCT-402, as specified in protocol section 7.4.

4. Progression-free Survival (PFS) [ Time Frame: Baseline to End of Study (a maximum of 18 months) ]

   PFS is defined among the efficacy population as the time from first dose of study drug until either disease progression or death due to any cause. Tumor response was assessed using the 2014 Lugano Classification for response.

   Disease progression is defined as progressive metabolic disease or one of the follow:

   • Target node progression.
   • An individual extranodal lesion must be abnormal with length >1.5cm and/or increase of length >50%.
   • New or clear progression of nonmeasured lesions.
   • Regrowth of previously resolved lesions or new nodes >1.5 cm in length.
   • New or recurrent bone marrow involvement.

   PFS is presented overall for all participants who received ADCT-402, as specified in protocol section 7.4.

5. Maximum Observed Serum Concentration (Cmax) for ADCT-402 [ Time Frame: 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) ]

   Cmax for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199).

   Results for Part 1 and Part 2 have been pooled for the same dosage and schedule, as specified in the protocol.

6. Time to Reach the Maximum Serum Concentration (Tmax) for ADCT-402 [ Time Frame: 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) ]

   Tmax for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199).

   Results for Part 1 and Part 2 have been pooled for the same dosage and schedule, as specified in the protocol.

7. Area Under the Serum Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) for ADCT-402 [ Time Frame: 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) ]

   AUClast for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199).

   Results for Part 1 and Part 2 have been pooled for the same dosage and schedule, as specified in the protocol.

8. Area Under the Serum Concentration-Time Curve From Time 0 to the End of the Dosing Interval (AUCtau) for ADCT-402 [ Time Frame: 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) ]

   AUCtau for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199).

   Results for Part 1 and Part 2 have been pooled for the same dosage and schedule, as specified in the protocol.

9. Area Under the Serum Concentration-time Curve From Time 0 to Infinity (AUCinf) for ADCT-402 [ Time Frame: 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) ]

   AUCinf for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199).

   Results for Part 1 and Part 2 have been pooled for the same dosage and schedule, as specified in the protocol.

10. Terminal Half-life (Thalf) of ADCT-402 [ Time Frame: 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) ]

    Thalf of Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199).

    Results for Part 1 and Part 2 have been pooled for the same dosage and schedule, as specified in the protocol.

11. Apparent Clearance (CL) at Steady State for ADCT-402 [ Time Frame: 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) ]

    CL of Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199).

    Results for Part 1 and Part 2 have been pooled for the same dosage and schedule, as specified in the protocol.

12. Volume of Distribution at Steady State (Vss) for ADCT-402 [ Time Frame: 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) ]

    Vss for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199).

    Results for Part 1 and Part 2 have been pooled for the same dosage and schedule, as specified in the protocol.

13. Accumulation Index (AI) for ADCT-402 [ Time Frame: 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) ]

    AI for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199). AI is the ratio of area under the serum concentration-time curve (AUC) from 0 to 21 days for Cycle 2 divided by AUC from 0 to 21 days for Cycle 1 (Q3W schedule: 3 week cycle length; Q6W schedule: 6 week cycle length). It is the increase in drug plasma concentration after multiple dosing until a steady state is reached.

    Results for Part 1 and Part 2 have been pooled for the same dosage and schedule, as specified in the protocol.

14. Number of Participants With Anti-drug Antibody Response (ADA) Against ADCT-402 [ Time Frame: Q3W schedule: Day 1 to End of Cycle 1 (3 weeks); Q6W schedule: Day 1 to End of Cycle 1 (6 weeks) ]

    Blood serum samples were collected and analysed to determine the presence or absence of ADA.

    ADA is presented overall for all participants who received ADCT-402, as specified in protocol section 7.4.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, California

UC San Diego Moores Cancer Center

La Jolla, California, United States, 92093

United States, Georgia

Winship Cancer Institute of Emory University

Atlanta, Georgia, United States, 30322

Blood and Marrow Transplant Group of Georgia

Atlanta, Georgia, United States, 30342

United States, Missouri

Washington University School of Medicine

Saint Louis, Missouri, United States, 63110

United States, New York

Columbia University Medical Center Herbert Irving Pavilion

New York, New York, United States, 10032

United States, Ohio

University Hospitals of Cleveland

Cleveland, Ohio, United States, 44106

United States, South Carolina

Greenville Health System, Institute for Translational Oncology Research, Clinical Research Unit

Greenville, South Carolina, United States, 29605

United States, Wisconsin

Froedtert Hospital & the Medical College of Wisconsin

Milwaukee, Wisconsin, United States, 53226

Italy

U.O Oncologia e Ematologia - Istituto Clinico Humanitas

Milano, Italy

United Kingdom

University College London Hospitals

London, United Kingdom, NW1 2BU

The Christie NHS Foundation Trust

Manchester, United Kingdom, M20 4BX

Sponsors and Collaborators

ADC Therapeutics S.A.

  Study Documents (Full-Text)

Documents provided by ADC Therapeutics S.A.:

Study Protocol  [PDF] October 16, 2017

Statistical Analysis Plan  [PDF] June 10, 2019

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

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.

• Responsible Party: ADC Therapeutics S.A.
• ClinicalTrials.gov Identifier: NCT02669017
• Other Study ID Numbers: ADCT-402-101; 2016-000952-92 ( EudraCT Number )
• First Posted: January 29, 2016
• Results First Posted: April 13, 2020
• Last Update Posted: May 19, 2021
• Last Verified: April 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by ADC Therapeutics S.A.:

Loncastuximab tesirine

Additional relevant MeSH terms:

Burkitt Lymphoma; Lymphoma; Lymphoma, Non-Hodgkin; Leukemia, Lymphocytic, Chronic, B-Cell; Waldenstrom Macroglobulinemia; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Follicular; Lymphoma, Mantle-Cell; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, Lymphoid; Leukemia; Lymphoma, B-Cell; Leukemia, B-Cell; Epstein-Barr Virus Infections; Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Infections; Tumor Virus Infections; Neoplasms, Plasma Cell; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders