Safety and Efficacy Study of Loncastuximab Tesirine + Ibrutinib in Diffuse Large B-Cell or Mantle Cell Lymphoma

NCT03684694 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: ADCT-402-1032018-002625-38
• Study Type: interventional
• Target: 136
• Locations: 6 countries
• Sites: 35

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.

Conditions

Diffuse Large B-Cell Lymphoma; Mantle Cell Lymphoma

Keywords

Loncastuximab Tesirine in Combination with Ibrutinib

Outcome Measures

Primary Outcomes (6)

• 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.

  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.

  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.

  21 days

• Phase 1: Number of Participants With Dose Interruptions

  Up to a maximum of 686 days

• Phase 1: Number of Participants With Dose Reductions

  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).

  Up to approximately 38 months

Secondary Outcomes (17)

• Phase 1: Overall Response Rate (ORR)

  Up to approximately 38 months

• Phase 1 and Phase 2: Duration of Response (DOR)

  Up to approximately 36 months

• Phase 1 and Phase 2: Relapse-Free Survival (RFS)

  Up to approximately 36 months

• Phase 1 and Phase 2: Progression-Free Survival (PFS)

  Up to approximately 37 months

• Phase 1 and Phase 2: Overall Survival (OS)

  Up to approximately 38 months

Study Arms (4)

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).

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.

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.

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.

Drug: Loncastuximab Tesirine; Drug: Ibrutinib

Interventions

Loncastuximab Tesirine DRUG

Intravenous (IV) infusion.

Also known as: Zynlonta, ADCT-402

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

Ibrutinib DRUG

Oral capsule.

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

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 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
• 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

You may not qualify if:

• 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)
• 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).

Sponsors & Collaborators

• ADC Therapeutics S.A.: lead

Study Sites (35)

University of California Irvine Health Chao Family Comprehensive Cancer Center

Orange, California, 92868, United States

Location

Redlands Community Hospital

Redlands, California, 92373, United States

Location

University of Miami

Miami, Florida, 33136, United States

Location

Miami Cancer Institute

Miami, Florida, 33176, United States

Location

The Blood and Marrow Transplant Group of Georgia

Atlanta, Georgia, 30342, United States

Location

Georgia Cancer Center at Augusta University

Augusta, Georgia, 30912, United States

Location

Norton Cancer Institute, St. Matthews Campus

Louisville, Kentucky, 40207, United States

Location

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, 21287, United States

Location

University of Michigan Comprehensive Cancer Center

Ann Arbor, Michigan, 48109, United States

Location

University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

Saint Vincent Healthcare

Billings, Montana, 59101, United States

Location

Case Western Reserve University

Cleveland, Ohio, 44106, United States

Location

GasthuisZusters Antwerpen Sint-Augustinus

Wilrijk, 2610, Belgium

Location

CHU UCL Namur (Site Godinne)

Yvoir, 5530, Belgium

Location

Centre Hospitalier Universitaire de Rennes Hôpital Pontchailou

Bretagne, 35033, France

Location

Hôpital Hôtel-Dieu

Loiré, 44093, France

Location

Hôpital Saint-Eloi

Montpellier, 34295, France

Location

Hôpital Saint-Louis

Paris, 75475, France

Location

Centre Hospitalier Lyon Sud

Pierre-Bénite, 69495, France

Location

Centre Hospitalier Universitaire De Poitier - Hopital De La Miletrie - Hopital Jean Bernard

Poitiers, 86021, France

Location

IRCCS istituto Clinico Humanitas U.O. di Oncologia ed Ematologia

Via Manzoni, Rozzano, 20089, Italy

Location

Azienda Ospedaliera Pap Giovanni XXIII

Bergamo, 24127, Italy

Location

Policlinico Sant'Orsola Malpighi

Bologna, 40138, Italy

Location

Azienda Socio Sanitaria Territoriale Degli Spedali Civili Di Brescia

Brescia, 25123, Italy

Location

Istituto Scientifico Rmagnolo per lo Studio e la Cura dei Tumori

Meldola FC, 47014, Italy

Location

Istituto Europeo di Oncologia

Milan, 20141, Italy

Location

Azienda Unita Sanitaria Locale de Ravenna

Ravenna, 48100, Italy

Location

Hospital Universitario Vall d'Hebrón

Barcelona, 08035, Spain

Location

Hospital Duran I Reynals

Barcelona, 08908, Spain

Location

Hospital General Universitario Gregorio Marañón

Madrid, 28007, Spain

Location

Hospital Universitario Fundación Jiménez Díaz

Madrid, 28040, Spain

Location

Hospital Universitario Marqués de Valdecilla

Santander, 39008, Spain

Location

Hospital Universitario Virgen del Rocio

Seville, 41013, Spain

Location

The Christie NHS Foundation Trust

Manchester, M20 4BX, United Kingdom

Location

Abertawe Bro Morgannwg University Health Board

Swansea, SA2 8QA, United Kingdom

Location

MeSH Terms

Conditions

Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell

Interventions

loncastuximab tesirine; ibrutinib

Condition Hierarchy (Ancestors)

Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Results Point of Contact

• Title: Clinical Trials Information
• Organization: ADC Therapeutics SA

clinical.trials@adctherapeutics.com

954-903-7994

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 11, 2018
• First Posted: September 26, 2018
• Study Start: December 1, 2018
• Primary Completion: November 8, 2022
• Study Completion: November 8, 2022
• Last Updated: February 6, 2024
• Results First Posted: February 6, 2024

Record last verified: 2024-01

Data Sharing

• IPD Sharing: Will not share

Locations

GB (2); BE (2); US (12); FR (6); IT (7); ES (6)