Diffuse Large B-Cell LymphomaPhase 1/2NCT03684694
Safety and Efficacy Study of Loncastuximab Tesirine + Ibrutinib in Diffuse Large B-Cell or Mantle Cell Lymphoma
A Phase 1/2 study testing Loncastuximab Tesirine and Ibrutinib in people with Diffuse Large B-Cell Lymphoma and Mantle Cell Lymphoma, run by ADC Therapeutics S.A. at 35 sites in 6 countries.
Trial summary
The purpose of this Phase 1/2 study is to evaluate the safety and efficacy of Loncastuximab Tesirine (ADCT-402) in combination with Ibrutinib in participants with Advanced Diffuse Large B-Cell Lymphoma or Mantle Cell Lymphoma. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Diffuse Large B-Cell Lymphoma, Mantle Cell Lymphoma
- What is being tested?
- Loncastuximab Tesirine and Ibrutinib
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 136 participants
- Where
- 35 sitesin 6 countries
- Study dates
- 1 Dec 2018to 8 Nov 2022
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Male or female participant aged 18 years or older
- Pathologic diagnosis of DLBCL or MCL (For Italy Sites Only: MCL patients are excluded.)
- Participants with DLBCL must have relapsed or refractory disease and have failed or been intolerant to available standard therapy
- Participants with MCL must have relapsed or refractory disease and have received at least one prior line of therapy (For Italy Sites Only: This exclusion criterion is not applicable)
- Participants who have received previous CD19-directed therapy must have a biopsy which shows CD19 expression after completion of the CD19-directed therapy
- Measurable disease as defined by the 2014 Lugano Classification
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- 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 to 2
- Screening laboratory values within the following parameters:
- Absolute neutrophil count (ANC) ≥1.0 × 103/µL (off growth factors at least 72 hours)
- Platelet count ≥75 × 103/µL without transfusion in the past 7 days
- Hemoglobin ≥8 g/dL (4.96 mmol/L), transfusion allowed
- Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma glutamyl transferase (GGT) ≤2.5 × the ULN
- Total bilirubin ≤1.5 × ULN (participants with known Gilbert's syndrome may have a total bilirubin up to ≤3 × ULN)
- Blood creatinine ≤1.5 × ULN or calculated creatinine clearance ≥60 mL/min by the Cockcroft and Gault equation
- Negative beta-human chorionic gonadotropin (β-HCG) pregnancy test within 7 days prior to start of study drugs on 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 9 months after the last dose of loncastuximab tesirine or 1 month after last dose of ibrutinib, whichever comes last. 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 6 months after the participant receives his last dose of loncastuximab tesirine or 3 months after last dose of ibrutinib, whichever comes last
Who cannot join
- Known history of hypersensitivity to or positive serum human anti-drug antibody (ADA) to a CD19 antibody
- Known history of hypersensitivity to ibrutinib
- Previous therapy with ibrutinib or other BTK inhibitors
- Previous therapy with loncastuximab tesirine
- Requires treatment or prophylaxis with a moderate or strong cytochrome P450 (CYP) 3A inhibitor
- Allogenic or autologous transplant within 60 days prior to start of study drugs (C1D1)
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- Active graft-versus-host disease
- Post-transplantation lymphoproliferative disorder
- 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, including but not limited to, uncontrolled hypertension (blood pressure [BP] ≥160/100 millimeters of mercury (mmHg) repeatedly), unstable angina, congestive heart failure (greater than New York Heart Association class II), electrocardiographic evidence of acute ischemia, coronary angioplasty or myocardial infarction within 6 months prior to screening, uncontrolled atrial or ventricular cardiac arrhythmia, poorly controlled diabetes mellitus, or severe chronic pulmonary disease, or tuberculosis infection (tuberculosis screening based on local standards).
- Major surgery, radiotherapy, chemotherapy, or other anti-neoplastic therapy within 14 days prior to start of study drugs (C1D1), except shorter if approved by the Sponsor
- Use of any other experimental medication within 14 days prior to start of study drugs (C1D1)
- Planned live vaccine administration after starting study drugs (C1D1)
- Any condition that could interfere with the absorption or metabolism of ibrutinib including malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel
- Inherited or acquired bleeding disorders
- Ongoing anticoagulation treatment, except for low-dose heparinisation or equivalent
- Failure to recover to Grade ≤1 (Common Terminology Criteria for Adverse Events [CTCAE] version 4.0) 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)
- 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
- Any other significant medical illness, abnormality, or condition that would, in the Investigator's judgement, make the participant inappropriate for study participation or put the participant at risk
Trial locations and contacts
35 sites in 6 countries.
35 sites in 6 countries
United States12 sites
University of Michigan Comprehensive Cancer Center
Ann Arbor, Michigan, 48109
The Blood and Marrow Transplant Group of Georgia
Atlanta, Georgia, 30342
Georgia Cancer Center at Augusta University
Augusta, Georgia, 30912
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, Maryland, 21287
Saint Vincent Healthcare
Billings, Montana, 59101
Case Western Reserve University
Cleveland, Ohio, 44106
Norton Cancer Institute, St. Matthews Campus
Louisville, Kentucky, 40207
University of Miami
Miami, Florida, 33136
Miami Cancer Institute
Miami, Florida, 33176
University of Minnesota
Minneapolis, Minnesota, 55455
University of California Irvine Health Chao Family Comprehensive Cancer Center
Orange, California, 92868
Redlands Community Hospital
Redlands, California, 92373
Italy7 sites
Azienda Ospedaliera Pap Giovanni XXIII
Bergamo, 24127
Policlinico Sant'Orsola Malpighi
Bologna, 40138
Azienda Socio Sanitaria Territoriale Degli Spedali Civili Di Brescia
Brescia, 25123
Istituto Scientifico Rmagnolo per lo Studio e la Cura dei Tumori
Meldola FC, 47014
Istituto Europeo di Oncologia
Milan, 20141
Azienda Unita Sanitaria Locale de Ravenna
Ravenna, 48100
IRCCS istituto Clinico Humanitas U.O. di Oncologia ed Ematologia
Via Manzoni, Rozzano, 20089
France6 sites
Centre Hospitalier Universitaire de Rennes Hôpital Pontchailou
Bretagne, 35033
Hôpital Hôtel-Dieu
Loiré, 44093
Hôpital Saint-Eloi
Montpellier, 34295
Hôpital Saint-Louis
Paris, 75475
Centre Hospitalier Lyon Sud
Pierre-Bénite, 69495
Centre Hospitalier Universitaire De Poitier - Hopital De La Miletrie - Hopital Jean Bernard
Poitiers, 86021
Spain6 sites
Hospital Universitario Vall d'Hebrón
Barcelona, 08035
Hospital Duran I Reynals
Barcelona, 08908
Hospital General Universitario Gregorio Marañón
Madrid, 28007
Hospital Universitario Fundación Jiménez Díaz
Madrid, 28040
Hospital Universitario Marqués de Valdecilla
Santander, 39008
Hospital Universitario Virgen del Rocio
Seville, 41013
Belgium2 sites
GasthuisZusters Antwerpen Sint-Augustinus
Wilrijk, 2610
CHU UCL Namur (Site Godinne)
Yvoir, 5530
United Kingdom2 sites
The Christie NHS Foundation Trust
Manchester, M20 4BX
Abertawe Bro Morgannwg University Health Board
Swansea, SA2 8QA
About this study
Official title: A Phase 1/2 Open-Label Study to Evaluate the Safety and Efficacy of Loncastuximab Tesirine and Ibrutinib in Patients With Advanced Diffuse Large B-Cell Lymphoma or Mantle Cell Lymphoma (LOTIS-3)
The purpose of this Phase 1/2 study is to evaluate the safety and efficacy of Loncastuximab Tesirine (ADCT-402) in combination with Ibrutinib in participants with Advanced Diffuse Large B-Cell Lymphoma or Mantle Cell Lymphoma.
Read the detailed description
The Phase 1 portion of the study will cover the dose escalation portion of the study. This will then be followed by the Phase 2 portion of the study, which will treat participants with the dose of loncastuximab tesirine determined in the Phase 1 portion of the study. The ibrutinib dose of 560 mg daily, will remain the same throughout both phases of the study.
A standard 3+3 dose escalation design will be used for the Phase 1 portion of the study. The dose-limiting toxicity (DLT) period will be the 21 days following the first dose of ibrutinib. The dose escalation cohort will receive loncastuximab tesirine for 2 cycles with concurrent ibrutinib (concomitant therapy) and may then continue ibrutinib therapy up to one year.
The Phase 2 portion of the study will involve 3 cohorts:
- Non-germinal center B-cell diffuse large B-cell lymphoma (Non-GCB DLBCL) cohort
- Germinal center B-cell diffuse large B-cell lymphoma (GCB DLBCL) cohort
- Mantle cell lymphoma (MCL) cohort
Each of the cohorts will be treated with the recommended dose of loncastuximab tesirine determined in the Phase 1 portion of the study.
The study will include a Screening Period (of up to 28 days), a Treatment Period (cycles of 3 to 4 weeks), and a Follow-up Period (approximately every 12 week visits for up to 2 years after treatment discontinuation).
- Being tested
- Loncastuximab Tesirine, Ibrutinib
- Keywords
- Loncastuximab Tesirine in Combination with Ibrutinib
- Medical subject headings
- Lymphoma, Large B-Cell, Diffuse, Lymphoma, Mantle-Cell
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Loncastuximab TesirineDrug
Also called Zynlonta, ADCT-402
Intravenous (IV) infusion.
IbrutinibDrug
Oral capsule.
| Study group | Role | What they receive |
|---|---|---|
| Phase 1: Dose-Escalation of ADCT-402 | Experimental | A standard 3+3 dose escalation design will be used. The dose-limiting toxicity (DLT) period will be the 21 days following the first dose of ibrutinib. The dose escalation cohort will receive loncastuximab tesirine for Cycle 1 and 2 (3 weeks each) with concurrent ibrutinib (concomitant therapy) daily. Participants may continue to receive ibrutinib therapy up to 1 year after Cycle 1 Day 1 (once every 4 weeks from Cycle 3 onwards). Loncastuximab tesirine will be administered intravenously (IV). Receives: Drug: Loncastuximab Tesirine; Drug: Ibrutinib |
| Phase 2: MTD or RP2D of ADCT-402 in Non-GCB DLBCL | Experimental | Participants with non-germinal center B-cell diffuse large B-cell lymphoma (Non-GCB DLBCL) will receive the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of loncastuximab tesirine, as determined in Phase 1, once every 3 weeks for Cycle 1 and 2 and a daily dose of ibrutinib. Participants can continue treatment up to 1 year (once every 4 weeks from Cycle 3 onwards). Loncastuximab tesirine will be administered IV. Receives: Drug: Loncastuximab Tesirine; Drug: Ibrutinib |
| Phase 2: MTD or RP2D of ADCT-402 in GCB DLBCL | Experimental | Participants with germinal center B-cell diffuse large B-cell lymphoma (GCB DLBCL) will receive the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of loncastuximab tesirine, as determined in Phase 1, once every 3 weeks for Cycle 1 and 2 and a daily dose of ibrutinib. Participants can continue treatment up to 1 year (once every 4 weeks from Cycle 3 onwards). Loncastuximab tesirine will be administered IV. Receives: Drug: Loncastuximab Tesirine; Drug: Ibrutinib |
| Phase 2: MTD or RP2D of ADCT-402 in MCL | Experimental | Participants with mantle cell lymphoma (MCL) will receive the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of loncastuximab tesirine, as determined in Phase 1, once every 3 weeks for Cycle 1 and 2 and a daily dose of ibrutinib. Participants can continue treatment up to 1 year (once every 4 weeks from Cycle 3 onwards). Loncastuximab tesirine will be administered IV. Receives: Drug: Loncastuximab Tesirine; Drug: Ibrutinib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Phase 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs)
A TEAE was defined as an adverse event (AE) that occurred or worsened in the period extending from the first dose of study drug to 30 days after the last dose of study drug in this study or start of a new anticancer therapy, whichever is earlier. Any clinically significant changes form baseline in safety laboratory values, vital signs, Eastern Cooperative Oncology Group (ECOG) performance status, and 12-lead electrocardiograms (ECGs) which occurred after first dose of study drug were recorded as TEAEs.
Measured: Day 1 until 30 days after last dose; max duration of treatment was 686 days for Phase 1 (up to approximately 716 days total)
Phase 1: Number of Participants With Serious TEAEs
A serious TEAE was defined as any AE which occurred after the first dose of study drug that resulted in death, was life threatening, required inpatient hospitalization or prolongation of existing hospitalization (hospitalization for elective procedures or for protocol compliance was not considered a serious adverse event), resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or important medical events that did not meet the preceding criteria but based on appropriate medical judgement may have jeopardized the participant or may have required medical or surgical intervention to prevent any of the outcomes listed above.
Measured: Day 1 until 30 days after last dose; max duration of treatment was 686 days for Phase 1 (up to approximately 716 days total)
Phase 1: Number of Participants With Dose-Limiting Toxicities (DLTs)
A DLT was defined as any of the following events which occur during the DLT Period (first 21 days of ibrutinib treatment), except those that are clearly due to underlying disease or extraneous causes: a hematologic DLT (grade ≥3 anaemia, grade 4/febrile neutropenia, grade ≥3 thrombocytopenia), a non-hematologic DLT (including aspartate aminotransferase [AST] and/or alanine aminotransferase [ALT] >3× upper limit of normal (ULN) and bilirubin >2× ULN), any other non-hematologic toxicities ≥ Grade 3, with exceptions.
Measured: 21 days
Phase 1: Number of Participants With Dose Interruptions
Measured: Up to a maximum of 686 days
Phase 1: Number of Participants With Dose Reductions
Measured: Up to a maximum of 686 days
Phase 2: Complete Response Rate (CRR)
CRR according to the 2014 Lugano classifications determined by Independent Review Committee (IRC). CRR was defined as the percentage of participants with a best overall response (BOR) of complete response (CR).
Measured: Up to approximately 38 months
Secondary outcomes (17)
Phase 1: Overall Response Rate (ORR)
ORR according to the 2014 Lugano classification, defined as the percentage of participants with a BOR of CR or partial response (PR).
Measured: Up to approximately 38 months
Phase 1 and Phase 2: Duration of Response (DOR)
DOR was defined as the time from the first documentation of tumor response to disease progression or death.
Measured: Up to approximately 36 months
Phase 1 and Phase 2: Relapse-Free Survival (RFS)
RFS was defined as the time from the documentation of CR to disease progression or death.
Measured: Up to approximately 36 months
Phase 1 and Phase 2: Progression-Free Survival (PFS)
PFS was defined as the time between start of treatment and the first documentation of progression, or death.
Measured: Up to approximately 37 months
Phase 1 and Phase 2: Overall Survival (OS)
OS was defined as the time between the start of treatment and death from any cause.
Measured: Up to approximately 38 months
Phase 1 and Phase 2: Time to Reach Maximum Concentration (Tmax) of Loncastuximab Tesirine (Total Antibody, PBD-Conjugated Antibody and Unconjugated Cytotoxin SG3199)
Blood samples were collected for analysis of PK data of loncastuximab tesirine (total antibody, PBD-conjugated antibody and unconjugated cytotoxin SG3199)
Measured: C1D1 pre-dose, EOI, 4h PD, C1D8 168h PD, C1D15 336h PD, C2D1 pre-dose, EOI, 4h PD, C2D8 168h PD, C2D15 336h PD (3 week cycles)
Phase 1 and Phase 2: Maximum Observed Concentration (Cmax) of Loncastuximab Tesirine (Total Antibody, PBD-Conjugated Antibody and Unconjugated Cytotoxin SG3199)
Blood samples were collected for analysis of PK data of loncastuximab tesirine (total antibody, PBD-conjugated antibody and unconjugated cytotoxin SG3199)
Measured: C1D1 pre-dose, EOI, 4h PD, C1D8 168h PD, C1D15 336h PD, C2D1 pre-dose, EOI, 4h PD, C2D8 168h PD, C2D15 336h PD (3 week cycles)
Phase 1 and Phase 2: Area Under the Concentration-Time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) of Loncastuximab Tesirine (Total Antibody, PBD-Conjugated Antibody and Unconjugated Cytotoxin SG3199)
Blood samples were collected for analysis of PK data of loncastuximab tesirine (total antibody, PBD-conjugated antibody and unconjugated cytotoxin SG3199)
Measured: C1D1 pre-dose, EOI, 4h PD, C1D8 168h PD, C1D15 336h PD, C2D1 pre-dose, EOI, 4h PD, C2D8 168h PD, C2D15 336h PD (3 week cycles)
Phase 1 and Phase 2: Area Under the Concentration-Time Curve From Time Zero to the End of the Dosing Interval (AUCtau) of Loncastuximab Tesirine (Total Antibody, PBD-Conjugated Antibody and Unconjugated Cytotoxin SG3199)
Blood samples were collected for analysis of PK data of loncastuximab tesirine (total antibody, PBD-conjugated antibody and unconjugated cytotoxin SG3199).
Measured: C1D1 pre-dose, EOI, 4h PD, C1D8 168h PD, C1D15 336h PD, C2D1 pre-dose, EOI, 4h PD, C2D8 168h PD, C2D15 336h PD (3 week cycles)
Phase 1 and Phase 2: Area Under the Concentration-Time Curve From Time Zero to Infinity (AUCinf) of Loncastuximab Tesirine (Total Antibody, PBD-Conjugated Antibody and Unconjugated Cytotoxin SG3199)
Blood samples were collected for analysis of PK data of loncastuximab tesirine (total antibody, PBD-conjugated antibody and unconjugated cytotoxin SG3199).
Measured: C1D1 pre-dose, EOI, 4h PD, C1D8 168h PD, C1D15 336h PD, C2D1 pre-dose, EOI, 4h PD, C2D8 168h PD, C2D15 336h PD (3 week cycles)
Phase 1 and Phase 2: Clearance (CL) of Loncastuximab Tesirine (Total Antibody, PBD-Conjugated Antibody and Unconjugated Cytotoxin SG3199)
Blood samples were collected for analysis of PK data of loncastuximab tesirine (total antibody, PBD-conjugated antibody and unconjugated cytotoxin SG3199).
Measured: C1D1 pre-dose, EOI, 4h PD, C1D8 168h PD, C1D15 336h PD, C2D1 pre-dose, EOI, 4h PD, C2D8 168h PD, C2D15 336h PD (3 week cycles)
Phase 1 and Phase 2: Accumulation Index (AI) Loncastuximab Tesirine (Total Antibody, PBD-Conjugated Antibody and Unconjugated Cytotoxin SG3199)
Blood samples were collected for analysis of PK data of loncastuximab tesirine (total antibody, PBD-conjugated antibody and unconjugated cytotoxin SG3199).
Measured: C1D1 pre-dose, EOI, 4h PD, C1D8 168h PD, C1D15 336h PD, C2D1 pre-dose, EOI, 4h PD, C2D8 168h PD, C2D15 336h PD (3 week cycles)
Phase 1 and Phase 2: Number of Participants With Positive Anti-Drug Antibody (ADA) Titers to Loncastuximab Tesirine at Any Time
Detection of ADAs was performed by using a screening assay for identification of antibody positive samples/participants, a confirmation assay, and titer assessment.
Measured: Up to a maximum of 711 days
Phase 2: ORR
ORR according to the 2014 Lugano classification, defined as the percentage of participants with a BOR of CR or PR.
Measured: Up to approximately 38 months
Phase 2: CRR in Non-GCB DLBCL, GCB DLBCL, All DLBCL and MCL Participants
CRR according to the 2014 Lugano classifications determined by the IRC. CRR was defined as the percentage of participants with a BOR of CR in non-GCB DLBCL, GCB DLBCL, all DLBCL, and MCL participants.
Measured: Up to approximately 38 months
Phase 2: Number of Participants With TEAEs
A TEAE was defined as an adverse event (AE) that occurred or worsened in the period extending from the first dose of study drug to 30 days after the last dose of study drug in this study or start of a new anticancer therapy, whichever is earlier. Any clinically significant changes form baseline in safety laboratory values, vital signs, ECOG performance status, and 12-lead ECGs which occurred after first dose of study drug were recorded as TEAEs.
Measured: Day 1 until 30 days after last dose; max duration of treatment was 711 days for Phase 2 (up to approximately 741 days total)
Phase 2: Number of Participants With Serious TEAEs
A serious TEAE was defined as any AE which occurred after the first dose of study drug that resulted in death, was life threatening, required inpatient hospitalization or prolongation of existing hospitalization (hospitalization for elective procedures or for protocol compliance was not considered a serious adverse event), resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or important medical events that did not meet the preceding criteria but based on appropriate medical judgement may have jeopardized the participant or may have required medical or surgical intervention to prevent any of the outcomes listed above.
Measured: Day 1 until 30 days after last dose; max duration of treatment was 711 days for Phase 2 (up to approximately 741 days total)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Sep 2018
- Study start1 Dec 2018
- Primary completion8 Nov 2022
- Study completion8 Nov 2022
Why it stopped: Administrative decision
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Diffuse Large B-Cell LymphomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 136 participants (actual)
Sponsor and investigators
- Lead sponsor
- ADC Therapeutics S.A.
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03684694
- Sponsor's protocol ID
- ADCT-402-103
- Other IDs
- 2018-002625-38, 2018
- Status last verified
- Jan 2024
- First submitted
- 11 Sep 2018
- Last updated
- 6 Feb 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 6 Feb 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 1/2 Open-Label Study to Evaluate the Safety and Efficacy of Loncastuximab Tesirine and Ibrutinib in Patients With Advanced Diffuse Large B-Cell Lymphoma or Mantle Cell Lymphoma (LOTIS-3)
- ClinicalTrials.gov ID
- NCT03684694
- Acronym / sponsor ID
- ADCT-402-103
- Keywords
- Loncastuximab Tesirine in Combination with Ibrutinib
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Administrative decision
- Enrolment
- 136 participants (actual)
- Lead sponsor
- ADC Therapeutics S.A.Industry (pharma, biotech, devices)
- Study start
- 1 Dec 2018 (actual)
- Primary completion
- 8 Nov 2022 (actual)
- Study completion
- 8 Nov 2022 (actual)
- First posted
- 26 Sep 2018 (actual)
- Results
- Posted 6 Feb 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this Phase 1/2 study is to evaluate the safety and efficacy of Loncastuximab Tesirine (ADCT-402) in combination with Ibrutinib in participants with Advanced Diffuse Large B-Cell Lymphoma or Mantle Cell Lymphoma.
Detailed description
The Phase 1 portion of the study will cover the dose escalation portion of the study. This will then be followed by the Phase 2 portion of the study, which will treat participants with the dose of loncastuximab tesirine determined in the Phase 1 portion of the study. The ibrutinib dose of 560 mg daily, will remain the same throughout both phases of the study.
A standard 3+3 dose escalation design will be used for the Phase 1 portion of the study. The dose-limiting toxicity (DLT) period will be the 21 days following the first dose of ibrutinib. The dose escalation cohort will receive loncastuximab tesirine for 2 cycles with concurrent ibrutinib (concomitant therapy) and may then continue ibrutinib therapy up to one year.
The Phase 2 portion of the study will involve 3 cohorts:
- Non-germinal center B-cell diffuse large B-cell lymphoma (Non-GCB DLBCL) cohort
- Germinal center B-cell diffuse large B-cell lymphoma (GCB DLBCL) cohort
- Mantle cell lymphoma (MCL) cohort
Each of the cohorts will be treated with the recommended dose of loncastuximab tesirine determined in the Phase 1 portion of the study.
The study will include a Screening Period (of up to 28 days), a Treatment Period (cycles of 3 to 4 weeks), and a Follow-up Period (approximately every 12 week visits for up to 2 years after treatment discontinuation).
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Phase 1: Dose-Escalation of ADCT-402 | Experimental | Drug: Loncastuximab Tesirine, Drug: IbrutinibA standard 3+3 dose escalation design will be used. The dose-limiting toxicity (DLT) period will be the 21 days following the first dose of ibrutinib. The dose escalation cohort will receive loncastuximab tesirine for Cycle 1 and 2 (3 weeks each) with concurrent ibrutinib (concomitant therapy) daily. Participants may continue to receive ibrutinib therapy up to 1 year after Cycle 1 Day 1 (once every 4 weeks from Cycle 3 onwards). Loncastuximab tesirine will be administered intravenously (IV). |
| Phase 2: MTD or RP2D of ADCT-402 in Non-GCB DLBCL | Experimental | Drug: Loncastuximab Tesirine, Drug: IbrutinibParticipants with non-germinal center B-cell diffuse large B-cell lymphoma (Non-GCB DLBCL) will receive the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of loncastuximab tesirine, as determined in Phase 1, once every 3 weeks for Cycle 1 and 2 and a daily dose of ibrutinib. Participants can continue treatment up to 1 year (once every 4 weeks from Cycle 3 onwards). Loncastuximab tesirine will be administered IV. |
| Phase 2: MTD or RP2D of ADCT-402 in GCB DLBCL | Experimental | Drug: Loncastuximab Tesirine, Drug: IbrutinibParticipants with germinal center B-cell diffuse large B-cell lymphoma (GCB DLBCL) will receive the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of loncastuximab tesirine, as determined in Phase 1, once every 3 weeks for Cycle 1 and 2 and a daily dose of ibrutinib. Participants can continue treatment up to 1 year (once every 4 weeks from Cycle 3 onwards). Loncastuximab tesirine will be administered IV. |
| Phase 2: MTD or RP2D of ADCT-402 in MCL | Experimental | Drug: Loncastuximab Tesirine, Drug: IbrutinibParticipants with mantle cell lymphoma (MCL) will receive the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of loncastuximab tesirine, as determined in Phase 1, once every 3 weeks for Cycle 1 and 2 and a daily dose of ibrutinib. Participants can continue treatment up to 1 year (once every 4 weeks from Cycle 3 onwards). Loncastuximab tesirine will be administered IV. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (17 listed)
- Male or female participant aged 18 years or older
- Pathologic diagnosis of DLBCL or MCL (For Italy Sites Only: MCL patients are excluded.)
- Participants with DLBCL must have relapsed or refractory disease and have failed or been intolerant to available standard therapy
- Participants with MCL must have relapsed or refractory disease and have received at least one prior line of therapy (For Italy Sites Only: This exclusion criterion is not applicable)
- Participants who have received previous CD19-directed therapy must have a biopsy which shows CD19 expression after completion of the CD19-directed therapy
Key exclusion criteria (25 listed)
- Known history of hypersensitivity to or positive serum human anti-drug antibody (ADA) to a CD19 antibody
- Known history of hypersensitivity to ibrutinib
- Previous therapy with ibrutinib or other BTK inhibitors
- Previous therapy with loncastuximab tesirine
- Requires treatment or prophylaxis with a moderate or strong cytochrome P450 (CYP) 3A inhibitor
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Loncastuximab TesirineAlso: Zynlonta, ADCT-402Intravenous (IV) infusion. | Drug | Phase 1: Dose-Escalation of ADCT-402, Phase 2: MTD or RP2D of ADCT-402 in GCB DLBCL, Phase 2: MTD or RP2D of ADCT-402 in MCL, Phase 2: MTD or RP2D of ADCT-402 in Non-GCB DLBCL |
| IbrutinibOral capsule. | Drug | Phase 1: Dose-Escalation of ADCT-402, Phase 2: MTD or RP2D of ADCT-402 in GCB DLBCL, Phase 2: MTD or RP2D of ADCT-402 in MCL, Phase 2: MTD or RP2D of ADCT-402 in Non-GCB DLBCL |
Primary outcome
Phase 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs)
Time frame: Day 1 until 30 days after last dose; max duration of treatment was 686 days for Phase 1 (up to approximately 716 days total)
A TEAE was defined as an adverse event (AE) that occurred or worsened in the period extending from the first dose of study drug to 30 days after the last dose of study drug in this study or start of a new anticancer therapy, whichever is earlier. Any clinically significant changes form baseline in safety laboratory values, vital signs, Eastern Cooperative Oncology Group (ECOG) performance status, and 12-lead electrocardiograms (ECGs) which occurred after first dose of study drug were recorded as TEAEs.
Phase 1: Number of Participants With Serious TEAEs
Time frame: Day 1 until 30 days after last dose; max duration of treatment was 686 days for Phase 1 (up to approximately 716 days total)
A serious TEAE was defined as any AE which occurred after the first dose of study drug that resulted in death, was life threatening, required inpatient hospitalization or prolongation of existing hospitalization (hospitalization for elective procedures or for protocol compliance was not considered a serious adverse event), resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or important medical events that did not meet the preceding criteria but based on appropriate medical judgement may have jeopardized the participant or may have required medical or surgical intervention to prevent any of the outcomes listed above.
Phase 1: Number of Participants With Dose-Limiting Toxicities (DLTs)
Time frame: 21 days
A DLT was defined as any of the following events which occur during the DLT Period (first 21 days of ibrutinib treatment), except those that are clearly due to underlying disease or extraneous causes: a hematologic DLT (grade ≥3 anaemia, grade 4/febrile neutropenia, grade ≥3 thrombocytopenia), a non-hematologic DLT (including aspartate aminotransferase [AST] and/or alanine aminotransferase [ALT] >3× upper limit of normal (ULN) and bilirubin >2× ULN), any other non-hematologic toxicities ≥ Grade 3, with exceptions.
Phase 1: Number of Participants With Dose Interruptions
Time frame: Up to a maximum of 686 days
Phase 1: Number of Participants With Dose Reductions
Time frame: Up to a maximum of 686 days
Phase 2: Complete Response Rate (CRR)
Time frame: Up to approximately 38 months
CRR according to the 2014 Lugano classifications determined by Independent Review Committee (IRC). CRR was defined as the percentage of participants with a best overall response (BOR) of complete response (CR).
17 secondary outcomes
Phase 1: Overall Response Rate (ORR)
Time frame: Up to approximately 38 months
Phase 1 and Phase 2: Duration of Response (DOR)
Time frame: Up to approximately 36 months
Phase 1 and Phase 2: Relapse-Free Survival (RFS)
Time frame: Up to approximately 36 months
Phase 1 and Phase 2: Progression-Free Survival (PFS)
Time frame: Up to approximately 37 months
Phase 1 and Phase 2: Overall Survival (OS)
Time frame: Up to approximately 38 months
Phase 1 and Phase 2: Time to Reach Maximum Concentration (Tmax) of Loncastuximab Tesirine (Total Antibody, PBD-Conjugated Antibody and Unconjugated Cytotoxin SG3199)
Time frame: C1D1 pre-dose, EOI, 4h PD, C1D8 168h PD, C1D15 336h PD, C2D1 pre-dose, EOI, 4h PD, C2D8 168h PD, C2D15 336h PD (3 week cycles)
Phase 1 and Phase 2: Maximum Observed Concentration (Cmax) of Loncastuximab Tesirine (Total Antibody, PBD-Conjugated Antibody and Unconjugated Cytotoxin SG3199)
Time frame: C1D1 pre-dose, EOI, 4h PD, C1D8 168h PD, C1D15 336h PD, C2D1 pre-dose, EOI, 4h PD, C2D8 168h PD, C2D15 336h PD (3 week cycles)
Phase 1 and Phase 2: Area Under the Concentration-Time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) of Loncastuximab Tesirine (Total Antibody, PBD-Conjugated Antibody and Unconjugated Cytotoxin SG3199)
Time frame: C1D1 pre-dose, EOI, 4h PD, C1D8 168h PD, C1D15 336h PD, C2D1 pre-dose, EOI, 4h PD, C2D8 168h PD, C2D15 336h PD (3 week cycles)
Phase 1 and Phase 2: Area Under the Concentration-Time Curve From Time Zero to the End of the Dosing Interval (AUCtau) of Loncastuximab Tesirine (Total Antibody, PBD-Conjugated Antibody and Unconjugated Cytotoxin SG3199)
Time frame: C1D1 pre-dose, EOI, 4h PD, C1D8 168h PD, C1D15 336h PD, C2D1 pre-dose, EOI, 4h PD, C2D8 168h PD, C2D15 336h PD (3 week cycles)
Phase 1 and Phase 2: Area Under the Concentration-Time Curve From Time Zero to Infinity (AUCinf) of Loncastuximab Tesirine (Total Antibody, PBD-Conjugated Antibody and Unconjugated Cytotoxin SG3199)
Time frame: C1D1 pre-dose, EOI, 4h PD, C1D8 168h PD, C1D15 336h PD, C2D1 pre-dose, EOI, 4h PD, C2D8 168h PD, C2D15 336h PD (3 week cycles)
Phase 1 and Phase 2: Clearance (CL) of Loncastuximab Tesirine (Total Antibody, PBD-Conjugated Antibody and Unconjugated Cytotoxin SG3199)
Time frame: C1D1 pre-dose, EOI, 4h PD, C1D8 168h PD, C1D15 336h PD, C2D1 pre-dose, EOI, 4h PD, C2D8 168h PD, C2D15 336h PD (3 week cycles)
Phase 1 and Phase 2: Accumulation Index (AI) Loncastuximab Tesirine (Total Antibody, PBD-Conjugated Antibody and Unconjugated Cytotoxin SG3199)
Time frame: C1D1 pre-dose, EOI, 4h PD, C1D8 168h PD, C1D15 336h PD, C2D1 pre-dose, EOI, 4h PD, C2D8 168h PD, C2D15 336h PD (3 week cycles)
Phase 1 and Phase 2: Number of Participants With Positive Anti-Drug Antibody (ADA) Titers to Loncastuximab Tesirine at Any Time
Time frame: Up to a maximum of 711 days
Phase 2: ORR
Time frame: Up to approximately 38 months
Phase 2: CRR in Non-GCB DLBCL, GCB DLBCL, All DLBCL and MCL Participants
Time frame: Up to approximately 38 months
Phase 2: Number of Participants With TEAEs
Time frame: Day 1 until 30 days after last dose; max duration of treatment was 711 days for Phase 2 (up to approximately 741 days total)
Phase 2: Number of Participants With Serious TEAEs
Time frame: Day 1 until 30 days after last dose; max duration of treatment was 711 days for Phase 2 (up to approximately 741 days total)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Feb 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
35 sites in 6 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Loncastuximab Tesirine and Ibrutinib in people with Diffuse Large B-Cell Lymphoma and Mantle Cell Lymphoma, run by ADC Therapeutics S.A. at 35 sites in 6 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 17 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 6 Feb 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 35 sites in United States, Italy, France, Spain, Belgium and 1 more country. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 6 Feb 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Phase 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) (time frame: Day 1 until 30 days after last dose; max duration of treatment was 686 days for Phase 1 (up to approximately 716 days total)). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Feb 2024.