Clinical trial NCT03684694: Safety and Efficacy Study of Loncastuximab Tesirine + Ibrutinib in Diffuse Large B-Cell or Mantle Cell Lymphoma
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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Diffuse Large B-Cell Lymphoma
Mantle Cell Lymphoma
Keywords: Loncastuximab Tesirine in Combination with Ibrutinib
Lead sponsor: ADC Therapeutics S.A.
Sponsor class: INDUSTRY
First posted: 2018-09-26
Enrollment: 136
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief 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.

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).

Eligibility criteria: Inclusion Criteria:

1. Male or female participant aged 18 years or older
2. Pathologic diagnosis of DLBCL or MCL (For Italy Sites Only: MCL patients are excluded.)
3. Participants with DLBCL must have relapsed or refractory disease and have failed or been intolerant to available standard therapy
4. 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)
5. Participants who have received previous CD19-directed therapy must have a biopsy which shows CD19 expression after completion of the CD19-directed therapy
6. Measurable disease as defined by the 2014 Lugano Classification
7. Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue block (or minimum 10 freshly cut unstained slides if block is not available)
8. ECOG performance status 0 to 2
9. Screening laboratory values within the following parameters:

   1. Absolute neutrophil count (ANC) ≥1.0 × 103/µL (off growth factors at least 72 hours)
   2. Platelet count ≥75 × 103/µL without transfusion in the past 7 days
   3. Hemoglobin ≥8 g/dL (4.96 mmol/L), transfusion allowed
   4. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma glutamyl transferase (GGT) ≤2.5 × the ULN
   5. Total bilirubin ≤1.5 × ULN (participants with known Gilbert's syndrome may have a total bilirubin up to ≤3 × ULN)
   6. Blood creatinine ≤1.5 × ULN or calculated creatinine clearance ≥60 mL/min by the Cockcroft and Gault equation
10. 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
11. 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

Exclusion Criteria:

1. Known history of hypersensitivity to or positive serum human anti-drug antibody (ADA) to a CD19 antibody
2. Known history of hypersensitivity to ibrutinib
3. Previous therapy with ibrutinib or other BTK inhibitors
4. Previous therapy with loncastuximab tesirine
5. Requires treatment or prophylaxis with a moderate or strong cytochrome P450 (CYP) 3A inhibitor
6. Allogenic or autologous transplant within 60 days prior to start of study drugs (C1D1)
7. Active graft-versus-host disease
8. Post-transplantation lymphoproliferative disorder
9. Active autoimmune disease, including motor neuropathy considered of autoimmune origin and other central nervous system (CNS) autoimmune disease
10. Known seropositive and requiring anti-viral therapy for human immunodeficiency (HIV) virus, hepatitis B virus (HBV), or hepatitis C virus (HCV).
11. History of Stevens-Johnson syndrome or toxic epidermal necrolysis
12. Lymphoma with active CNS involvement at the time of screening, including leptomeningeal disease
13. 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)
14. Breastfeeding or pregnant
15. 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).
16. 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
17. Use of any other experimental medication within 14 days prior to start of study drugs (C1D1)
18. Planned live vaccine administration after starting study drugs (C1D1)
19. 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
20. Inherited or acquired bleeding disorders
21. Ongoing anticoagulation treatment, except for low-dose heparinisation or equivalent
22. 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
23. Congenital long QT syndrome or a corrected QTcF interval of \>480 ms at screening (unless secondary to pacemaker or bundle branch block)
24. 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
25. 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

Primary outcomes:
measure: Phase 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs)
timeFrame: Day 1 until 30 days after last dose; max duration of treatment was 686 days for Phase 1 (up to approximately 716 days total)
measure: Phase 1: Number of Participants With Serious TEAEs
timeFrame: Day 1 until 30 days after last dose; max duration of treatment was 686 days for Phase 1 (up to approximately 716 days total)
measure: Phase 1: Number of Participants With Dose-Limiting Toxicities (DLTs)
timeFrame: 21 days
measure: Phase 1: Number of Participants With Dose Interruptions
timeFrame: Up to a maximum of 686 days
measure: Phase 1: Number of Participants With Dose Reductions
timeFrame: Up to a maximum of 686 days
measure: Phase 2: Complete Response Rate (CRR)
timeFrame: Up to approximately 38 months
Secondary outcomes:
measure: Phase 1: Overall Response Rate (ORR)
timeFrame: Up to approximately 38 months
measure: Phase 1 and Phase 2: Duration of Response (DOR)
timeFrame: Up to approximately 36 months
measure: Phase 1 and Phase 2: Relapse-Free Survival (RFS)
timeFrame: Up to approximately 36 months
measure: Phase 1 and Phase 2: Progression-Free Survival (PFS)
timeFrame: Up to approximately 37 months
measure: Phase 1 and Phase 2: Overall Survival (OS)
timeFrame: Up to approximately 38 months
measure: Phase 1 and Phase 2: Time to Reach Maximum Concentration (Tmax) of Loncastuximab Tesirine (Total Antibody, PBD-Conjugated Antibody and Unconjugated Cytotoxin SG3199)
timeFrame: 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)
measure: Phase 1 and Phase 2: Maximum Observed Concentration (Cmax) of Loncastuximab Tesirine (Total Antibody, PBD-Conjugated Antibody and Unconjugated Cytotoxin SG3199)
timeFrame: 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)
measure: 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)
timeFrame: 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)
measure: 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)
timeFrame: 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)
measure: 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)
timeFrame: 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)
measure: Phase 1 and Phase 2: Clearance (CL) of Loncastuximab Tesirine (Total Antibody, PBD-Conjugated Antibody and Unconjugated Cytotoxin SG3199)
timeFrame: 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)
measure: Phase 1 and Phase 2: Accumulation Index (AI) Loncastuximab Tesirine (Total Antibody, PBD-Conjugated Antibody and Unconjugated Cytotoxin SG3199)
timeFrame: 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)
measure: Phase 1 and Phase 2: Number of Participants With Positive Anti-Drug Antibody (ADA) Titers to Loncastuximab Tesirine at Any Time
timeFrame: Up to a maximum of 711 days
measure: Phase 2: ORR
timeFrame: Up to approximately 38 months
measure: Phase 2: CRR in Non-GCB DLBCL, GCB DLBCL, All DLBCL and MCL Participants
timeFrame: Up to approximately 38 months
measure: Phase 2: Number of Participants With TEAEs
timeFrame: Day 1 until 30 days after last dose; max duration of treatment was 711 days for Phase 2 (up to approximately 741 days total)
measure: Phase 2: Number of Participants With Serious TEAEs
timeFrame: Day 1 until 30 days after last dose; max duration of treatment was 711 days for Phase 2 (up to approximately 741 days total)
Other outcomes:
Locations:
city: Orange
country: United States
facility: University of California Irvine Health Chao Family Comprehensive Cancer Center
state: California
city: Redlands
country: United States
facility: Redlands Community Hospital
state: California
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Miami
country: United States
facility: Miami Cancer Institute
state: Florida
city: Atlanta
country: United States
facility: The Blood and Marrow Transplant Group of Georgia
state: Georgia
city: Augusta
country: United States
facility: Georgia Cancer Center at Augusta University
state: Georgia
city: Louisville
country: United States
facility: Norton Cancer Institute, St. Matthews Campus
state: Kentucky
city: Baltimore
country: United States
facility: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
state: Maryland
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Billings
country: United States
facility: Saint Vincent Healthcare
state: Montana
city: Cleveland
country: United States
facility: Case Western Reserve University
state: Ohio
city: Wilrijk
country: Belgium
facility: GasthuisZusters Antwerpen Sint-Augustinus
city: Yvoir
country: Belgium
facility: CHU UCL Namur (Site Godinne)
city: Bretagne
country: France
facility: Centre Hospitalier Universitaire de Rennes Hôpital Pontchailou
city: Loiré
country: France
facility: Hôpital Hôtel-Dieu
city: Montpellier
country: France
facility: Hôpital Saint-Eloi
city: Paris
country: France
facility: Hôpital Saint-Louis
city: Pierre-Bénite
country: France
facility: Centre Hospitalier Lyon Sud
city: Poitiers
country: France
facility: Centre Hospitalier Universitaire De Poitier - Hopital De La Miletrie - Hopital Jean Bernard
city: Via Manzoni
country: Italy
facility: IRCCS istituto Clinico Humanitas U.O. di Oncologia ed Ematologia
state: Rozzano
city: Bergamo
country: Italy
facility: Azienda Ospedaliera Pap Giovanni XXIII
city: Bologna
country: Italy
facility: Policlinico Sant'Orsola Malpighi
city: Brescia
country: Italy
facility: Azienda Socio Sanitaria Territoriale Degli Spedali Civili Di Brescia
city: Meldola FC
country: Italy
facility: Istituto Scientifico Rmagnolo per lo Studio e la Cura dei Tumori
city: Milano
country: Italy
facility: Istituto Europeo di Oncologia
city: Ravenna
country: Italy
facility: Azienda Unita Sanitaria Locale de Ravenna
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebrón
city: Barcelona
country: Spain
facility: Hospital Duran I Reynals
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañón
city: Madrid
country: Spain
facility: Hospital Universitario Fundación Jiménez Díaz
city: Santander
country: Spain
facility: Hospital Universitario Marqués de Valdecilla
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
city: Swansea
country: United Kingdom
facility: Abertawe Bro Morgannwg University Health Board
Study officials:
References: