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Study to Evaluate the Efficacy and Safety of Loncastuximab Tesirine in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma (LOTIS-2)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03589469
Recruitment Status : Active, not recruiting
First Posted : July 18, 2018
Results First Posted : July 29, 2021
Last Update Posted : July 29, 2021
Sponsor:
Information provided by (Responsible Party):
ADC Therapeutics S.A.

Tracking Information
First Submitted Date  ICMJE May 4, 2018
First Posted Date  ICMJE July 18, 2018
Results First Submitted Date  ICMJE May 20, 2021
Results First Posted Date  ICMJE July 29, 2021
Last Update Posted Date July 29, 2021
Actual Study Start Date  ICMJE August 1, 2018
Actual Primary Completion Date May 24, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 9, 2021)
Overall Response Rate (ORR) [ Time Frame: Up to 21.5 months ]
ORR, as determined by central review according to the 2014 Lugano classification, defined as the percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR).
Original Primary Outcome Measures  ICMJE
 (submitted: July 5, 2018)
Overall Response Rate (ORR) [ Time Frame: Up to 3 years ]
ORR, as determined by central review according to the 2014 Lugano classification, defined as the proportion of patients with a best overall response (BOR) of complete response (CR) or partial response (PR)
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 9, 2021)
  • Duration of Response (DOR) [ Time Frame: Up to 21.5 months ]
    DOR defined as the time from the first documentation of tumor response to disease progression or death.
  • Complete Response (CR) Rate [ Time Frame: Up to 21.5 months ]
    CR rate defined as the percentage of treated participants with a best overall response (BOR) of CR.
  • Relapse-free Survival (RFS) [ Time Frame: Up to 21.5 months ]
    RFS was defined as the time from the documentation of complete response (CR) to disease progression or death.
  • Progression-free Survival (PFS) [ Time Frame: Up to 21.5 months ]
    PFS was defined as the time between start of treatment and the first documentation of recurrence, progression, or death.
  • Overall Survival (OS) [ Time Frame: Up to 21.5 months ]
    OS was defined as the time between the start of treatment and death from any cause.
  • Number of Participants Who Experience Treatment-emergent Adverse Events (TEAEs) [ Time Frame: Up to 21.5 months ]
    An adverse event (AE) was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product that did not necessarily have to have a causal relationship with treatment. A TEAE was an adverse event with an onset that began or worsened on or after the first dose date and until 30 days after the last dose date, or start of a new anticancer therapy/procedure, whichever came earlier. TEAE assessments also included those per the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 Grade ≥3 AEs and serious TEAEs. AEs were graded using CTCAE version 4 and according to the following: Grade 1 = mild AE, Grade 2 = Moderate AE, Grade 3 = a severe AE, Grade 4 = life-threatening AE, and Grade 5 = death due to AE. For events not listed in the CTCAE criteria, the same grading was used.
  • Number of Participants With Clinically Significant Changes From Baseline in Clinical Laboratory Tests [ Time Frame: Baseline to end of treatment (up to 30 days after the last dose) or data cut off: Maximum treatment duration time at date of primary analysis was 351 days. ]
    Clinical laboratory tests included hematology and chemistry. Clinically significant changes were determined by the Investigator.
  • Number of Participants With Clinically Significant Change From Baseline in Vital Signs [ Time Frame: Baseline to end of treatment (up to 30 days after the last dose) or data cut off. Maximum treatment duration time at date of primary analysis was 351 days. ]
    Vital sign measurements included arterial blood pressure, heart rate, respiratory rate, and body temperature. Clinical significance was determined by the investigator.
  • Eastern Cooperative Oncology Group (ECOG) Performance Status at Baseline and End of Treatment [ Time Frame: Baseline to end of treatment (up to 30 days after the last dose) or data cut off. Maximum treatment duration time at date of primary analysis was 351 days. ]
    ECOG (Eastern Cooperative Oncology Group) Performance Status is scored on a 6-point scale where higher scores indicate a worse outcome. ECOG scores include the following:
    • 0 = fully active, able to carry on all pre-disease performance without restriction
    • 1 = restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work
    • 2 = ambulatory and capable of all self-care but unable to carry out any work activities; up and about more than 50% of waking hours
    • 3 = capable of only limited self-care; confined to bed or chair more than 50% of waking hours
    • 4 = completely disabled; cannot carry on any self-care; totally confined to bed or chair
    • 5 = dead
  • Number of Participants With Clinically Significant Change From Baseline in 12-lead Electrocardiograms (ECGs) [ Time Frame: Baseline to end of treatment (up to 30 days after the last dose) or data cut off. Maximum treatment duration time at date of primary analysis was 351 days. ]
    Clinically significant changes from baseline for 12-lead ECGs were measured as abnormal QT interval corrected by Fridericia formula (QTcF) and QT interval corrected by Bazett formula (QTcB) values.
  • Maximum Concentration (Cmax) of Loncastuximab Tesirine Conjugated Antibody, Total Antibody and Warhead SG3199 [ Time Frame: Cycles 1 and 2: Day 1 pre-dose, and at 0, 4, 168 and 336 hours post-dose; Cycle 3: Day 1 pre-dose and end of infusion. ]
  • Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUC0-last) of Loncastuximab Tesirine Conjugated Antibody, Total Antibody and Warhead SG3199 [ Time Frame: Cycles 1 and 2: Day 1 pre-dose, and at 0, 4, 168 and 336 hours post-dose; Cycle 3: Day 1 pre-dose. ]
  • Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-∞) of Loncastuximab Tesirine Conjugated Antibody, Total Antibody and Warhead SG3199 [ Time Frame: Cycles 1 and 2: Day 1 pre-dose, and at 0, 4, 168 and 336 hours post-dose; Cycle 3: Day 1 pre-dose. ]
  • Apparent Terminal Half-life (Thalf) of Loncastuximab Tesirine Conjugated Antibody, Total Antibody and Warhead SG3199 [ Time Frame: Cycles 1 and 2: Day 1 pre-dose, and at 0, 4, 168 and 336 hours post-dose; Cycle 3: Day 1 pre-dose. ]
    Noncompartmental analysis of the area under the concentration-time curve from time zero to the end of the dosing interval (AUC0-τ)
  • Apparent Clearance (CL) of Loncastuximab Tesirine Conjugated Antibody, Total Antibody and Warhead SG3199 [ Time Frame: Cycles 1 and 2: Day 1 pre-dose, and at 0, 4, 168 and 336 hours post-dose; Cycle 3: Day 1 pre-dose. ]
  • Apparent Volume of Distribution at Steady State (Vss) of Loncastuximab Tesirine Conjugated Antibody, Total Antibody and Warhead SG3199 [ Time Frame: Cycles 1 and 2: Day 1 pre-dose, and at 0, 4, 168 and 336 hours post-dose; Cycle 3: Day 1 pre-dose. ]
  • Accumulation Index (AI) of Loncastuximab Tesirine Conjugated Antibody, Total Antibody and Warhead SG3199 [ Time Frame: Cycles 1 and 2: Day 1 pre-dose, and at 0, 4, 168 and 336 hours post-dose; Cycle 3: Day 1 pre-dose. ]
  • Number of Participants With an Anti-drug Antibody (ADA) Response to Loncastuximab Tesirine [ Time Frame: Cycle 1 Day 1 to end of treatment or data cut off. Maximum treatment duration time at date of primary analysis was 351 days. ]
  • Change From Baseline Score in the EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS) [ Time Frame: Baseline to end of treatment (up to 30 days after the last dose) or data cut off. Maximum treatment duration time at date of primary analysis was 351 days. ]
    EQ-5D-5L is designed as an international, standardized, instrument for describing and evaluating quality of life (QoL). In the EQ-5D-5L VAS participants are asked to indicate their health state today on a VAS with the endpoints labeled 'the best health you can imagine' (score 100) and 'the worst health you can imagine' (score 0). A higher score on the VAS indicates better health related QoL. A positive change from baseline indicates an improvement in health related QoL
  • Change From Baseline Score in the Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) - Lymphoma Subscale (LymS) [ Time Frame: Baseline to end of treatment (up to 30 days after the last dose) or data cut off. Maximum treatment duration time at date of primary analysis was 351 days. ]
    Composed of the Functional Assessment of Cancer Therapy - General (FACT-G) plus the 15-item LymS. The FACT-G questionnaire contains 27 items covering 4 core health related quality of life (QoL) subscales: Physical Wellbeing (7 items), Social/Family Wellbeing (7), Emotional Wellbeing (6), and Functional Wellbeing (7). The LymS addresses issues including pain, itching, night sweats, trouble sleeping, fatigue and trouble concentrating. Score range for the LymS was 0 - 60, where a higher score indicate less symptoms. The LymS score is reported. A positive change from baseline indicates an improvement in health related QoL.
Original Secondary Outcome Measures  ICMJE
 (submitted: July 5, 2018)
  • Duration of Response (DOR) [ Time Frame: Up to 3 years ]
    DOR defined as the time from the first documentation of tumor response to disease progression or death
  • CR rate [ Time Frame: Up to 3 years ]
    CR rate defined as the percentage of treated patients with a BOR of CR
  • Relapse-free Survival (RFS) [ Time Frame: Up to 3 years ]
    RFS defined as the time from the documentation of CR to disease progression or death
  • Progression-free Survival (PFS) [ Time Frame: Up to 3 years ]
    PFS defined as the time between start of treatment and the first documentation of recurrence, progression, or death
  • Overall Survival (OS) [ Time Frame: Up to 3 years ]
    OS defined as the time between the start of treatment and death from any cause
  • Frequency and severity of adverse events (AEs) and serious AEs (SAEs) [ Time Frame: Up to 3 years ]
  • Maximum concentration (Cmax) of Loncastuximab Tesirine , pyrrolobenzodiazepine (PBD) conjugated and warhead SG3199 [ Time Frame: Blood sample collection within cycles 1 and 2 and every other cycle starting with cycle 3, until disease progression/discontinuation within 30 days of last dose (each cycle is 3 weeks) ]
    Noncompartmental analysis of the maximum concentration (Cmax)
  • Time to maximum concentration (Tmax) of Loncastuximab Tesirine, pyrrolobenzodiazepine (PBD) conjugated and warhead SG3199 [ Time Frame: Blood sample collection within cycles 1 and 2 and every other cycle starting with cycle 3, until disease progression/discontinuation within 30 days of last dose (each cycle is 3 weeks) ]
    Noncompartmental analysis of the time to maximum concentration (Tmax)
  • Area under the curve (AUC0-last) of Loncastuximab Tesirine, pyrrolobenzodiazepine (PBD) conjugated and warhead SG3199 [ Time Frame: Blood sample collection within cycles 1 and 2 and every other cycle starting with cycle 3, until disease progression/discontinuation within 30 days of last dose (each cycle is 3 weeks) ]
    Noncompartmental analysis of the area under the concentration-time curve from time zero to the last quantifiable concentration (AUC0-last)
  • Area under the curve (AUC0-τ) of Loncastuximab Tesirine, pyrrolobenzodiazepine (PBD) conjugated and warhead SG3199 [ Time Frame: Blood sample collection within cycles 1 and 2 and every other cycle starting with cycle 3, until disease progression/discontinuation within 30 days of last dose (each cycle is 3 weeks) ]
    Noncompartmental analysis of the area under the concentration-time curve from time zero to the end of the dosing interval (AUC0-τ)
  • Area under the curve (AUC0-∞) of Loncastuximab Tesirine, pyrrolobenzodiazepine (PBD) conjugated and warhead SG3199 [ Time Frame: Blood sample collection within cycles 1 and 2 and every other cycle starting with cycle 3, until disease progression/discontinuation within 30 days of last dose (each cycle is 3 weeks) ]
    Noncompartmental analysis of the area under the concentration-time curve from time zero to infinity (AUC0-∞)
  • Accumulation index (AI) of Loncastuximab Tesirine, pyrrolobenzodiazepine (PBD) conjugated and warhead SG3199 [ Time Frame: Blood sample collection within cycles 1 and 2 and every other cycle starting with cycle 3, until disease progression/discontinuation within 30 days of last dose (each cycle is 3 weeks) ]
    Noncompartmental analysis of the accumulation index (AI)
  • Clearance (CL) of Loncastuximab Tesirine, pyrrolobenzodiazepine (PBD) conjugated and warhead SG3199 [ Time Frame: Blood sample collection within cycles 1 and 2 and every other cycle starting with cycle 3, until disease progression/discontinuation within 30 days of last dose (each cycle is 3 weeks) ]
    Noncompartmental analysis of Clearance (CL)
  • Measurement of Anti-drug antibodies to Loncastuximab Tesirine [ Time Frame: Blood sample collection within cycles 1 and 2 and every other cycle starting with cycle 3, until disease progression/discontinuation within 30 days of last dose (each cycle is 3 weeks) ]
    Measurement of Anti-drug antibodies to ADCT-301 before, during and after treatment with Loncastuximab Tesirine
  • Change from baseline in HRQoL as measured by EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) [ Time Frame: Day 1 of each cycle until up to 30 days after last dose (each cycle is 3 weeks) ]
    EQ-5D-5L is designed as an international, standardized, instrument for describing and evaluating QoL. The EQ-5D-5L consists of two parts:
    • The descriptive system: QoL is classified according to five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension comprises five levels of perceived problems (e.g., none, slight, moderate, severe, extreme).
    • The visual analog scale (VAS): patients are asked to indicate their health state today on a VAS with the endpoints labeled 'the best health you can imagine' (score 100) and 'the worst health you can imagine' (score 0).Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym)(EQ-5D-5L)
  • Change from baseline in Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) [ Time Frame: Day 1 of each cycle until up to 30 days after last dose (each cycle is 3 weeks) ]
    FACT-Lym is a lymphoma-specific subscale for the Functional Assessment of Cancer Therapy (FACT) questionnaire. It consists of 15 specific items that are used together with the core 27-item questionnaire FACT-G (General). The patient is asked to respond to each item with a score of 0-4, where 0 = not at all, 1 = a little bit, 2 = somewhat, 3 = quite a bit, 4 = very much. A higher score equals a worse level of QoL.
  • Changes from baseline of ECOG performance status [ Time Frame: Up to 3 years ]
    ECOG (Eastern Cooperative Oncology Group) Performance Status is a 5-point scale, from 0 (fully active) to 5 (dead). Characterize the safety profile of loncastuximab tesirine.
  • Changes from baseline of 12-lead electrocardiograms (ECGs) [ Time Frame: Up to 3 years ]
    Characterize the safety profile of loncastuximab tesirine
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study to Evaluate the Efficacy and Safety of Loncastuximab Tesirine in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma
Official Title  ICMJE A Phase 2 Open-Label Single-Arm Study to Evaluate the Efficacy and Safety of Loncastuximab Tesirine in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL) (LOTIS-2)
Brief Summary The purpose of this Phase 2 study is to evaluate the clinical efficacy and safety of Loncastuximab Tesirine (ADCT-402) in patients with relapsed or refractory Diffuse Large B-Cell Lymphoma.
Detailed Description

This is a Phase 2, multi-center, open-label, single-arm study of the efficacy and safety of loncastuximab tesirine used as monotherapy in patients with relapsed or refractory DLBCL. The study will enroll approximately 140 patients

Loncastuximab Tesirine is an antibody drug conjugate (ADC) composed of a humanized antibody directed against human cluster of differentiation 19 (CD19), stochastically conjugated through a cathepsin-cleavable linker to SG3199, a pyrrolobenzodiazepine (PBD) dimer cytotoxin. Loncastuximab tesirine has been designed to target and kill CD19-expressing malignant B-cells.

A 2-stage design will be used in this clinical study, with an interim analysis for futility on the first 52 patients. If ≥10 patients respond (CR+PR), the study will proceed to complete full enrollment. Enrollment will continue during the interim analysis; however, further enrollment will be halted if futility is confirmed.

For each patient, the study will include a Screening Period (of up to 28 days), a Treatment Period (cycles of 3 weeks), and a Follow-up Period (approximately every 12 week visits for up to 3 years after treatment discontinuation).

Patients may continue treatment until disease progression, unacceptable toxicity, or other discontinuation criteria, whichever occurs first.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Diffuse Large B-Cell Lymphoma Refractory
  • Diffuse Large B-cell Lymphoma Recurrent
Intervention  ICMJE Drug: Loncastuximab tesirine
intravenous infusion
Other Names:
  • Zynlonta
  • ADCT-402
Study Arms  ICMJE Experimental: Loncastuximab tesirine
Participants will receive loncastuximab tesirine as an IV infusion over 30 minutes on Day 1 of each cycle (every 3 weeks) at a dose of 150 μg/kg Q3W for 2 cycles, then 75 μg/kg Q3W for subsequent cycles for up to one year or until disease progression, unacceptable toxicity, or other discontinuation criteria, whichever occurs first.
Intervention: Drug: Loncastuximab tesirine
Publications * Caimi PF, Ai W, Alderuccio JP, Ardeshna KM, Hamadani M, Hess B, Kahl BS, Radford J, Solh M, Stathis A, Zinzani PL, Havenith K, Feingold J, He S, Qin Y, Ungar D, Zhang X, Carlo-Stella C. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2021 Jun;22(6):790-800. doi: 10.1016/S1470-2045(21)00139-X. Epub 2021 May 11.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: October 22, 2019)
145
Original Estimated Enrollment  ICMJE
 (submitted: July 5, 2018)
140
Estimated Study Completion Date  ICMJE January 27, 2023
Actual Primary Completion Date May 24, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Male or female patient aged 18 years or older.
  • Pathologic diagnosis of DLBCL, as defined by the 2016 WHO classification, to include: DLBCL not otherwise specified; primary mediastinal large B-cell lymphoma; and high-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements
  • Relapsed or refractory disease following two or more multi-agent systemic treatment regimens
  • Patients who have received previous CD19-directed therapy must have a biopsy that shows CD19 protein expression after completion of the CD19-directed therapy.
  • Measurable disease as defined by the 2014 Lugano Classification
  • Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue block or minimum 10 freshly cut unstained slides if block is not available
  • ECOG performance status 0-2
  • Adequate organ function
  • Negative beta-human chorionic gonadotropin (β-HCG) pregnancy test within 7 days prior to start of study drug (C1D1) for women of childbearing potential
  • Women of childbearing potential must agree to use a highly effective method of contraception from the time of giving informed consent until at least 16 weeks after the last dose of loncastuximab tesirine. Men with female partners who are of childbearing potential must agree that they will use a highly effective method of contraception from the time of giving informed consent until at least 16 weeks after the patient receives his last dose of loncastuximab tesirine.

Exclusion Criteria:

  • Previous treatment with loncastuximab tesirine
  • Known history of hypersensitivity to or positive serum human ADA to a CD19 antibody
  • Pathologic diagnosis of Burkitt lymphoma
  • 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 that the Sponsor's medical monitor and Investigator agree and document should not be exclusionary
  • Autologous stem cell transplant (ASCT) within 30 days prior to start of study drug (C1D1)
  • Allogeneic stem cell transplant (AlloSCT) within 60 days prior to start of study drug (C1D1)
  • Active graft-versus-host disease
  • Post-transplant lymphoproliferative disorders
  • Active autoimmune disease, including motor neuropathy considered of autoimmune origin and other central nervous system (CNS) autoimmune disease
  • Known seropositive and requiring anti-viral therapy for human immunodeficiency (HIV) virus, hepatitis B virus (HBV), or hepatitis C virus (HCV).
  • History of Stevens-Johnson syndrome or toxic epidermal necrolysis
  • Lymphoma with active CNS involvement at the time of screening, including leptomeningeal disease
  • Clinically significant third space fluid accumulation (i.e., ascites requiring drainage or pleural effusion that is either requiring drainage or associated with shortness of breath)
  • Breastfeeding or pregnant
  • Significant medical comorbidities
  • Major surgery, radiotherapy, chemotherapy or other anti-neoplastic therapy within 14 days prior to start of study drug (C1D1), except shorter if approved by the Sponsor
  • Use of any other experimental medication within 14 days prior to start of study drug (C1D1)
  • Planned live vaccine administration after starting study drug (C1D1)
  • Failure to recover to Grade ≤1 (Common Terminology Criteria for Adverse Events version 4.0 [CTCAE v4.0]) from acute non-hematologic toxicity (Grade ≤2 neuropathy or alopecia) due to previous therapy prior to screening
  • Congenital long QT syndrome or a corrected QTcF interval of >480 ms at screening (unless secondary to pacemaker or bundle branch block)
  • Any other significant medical illness, abnormality, or condition that would, in the Investigator's judgment, make the patient inappropriate for study participation or put the patient at risk
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Italy,   Switzerland,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03589469
Other Study ID Numbers  ICMJE ADCT-402-201
2017-004288-11 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party ADC Therapeutics S.A.
Study Sponsor  ICMJE ADC Therapeutics S.A.
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account ADC Therapeutics S.A.
Verification Date July 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP