Consolidation with ADCT-402 (loncastuximab tesirine) after a short course of immunochemotherapy: a phase II study in BTKi-treated (or BTKi intolerant) Relapsed/Refractory (R/R) Mantle Cell Lymphoma (MCL) patients

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondazione Italiana Linfomi Ets

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

21 Mar 2022 → ongoing

Decision date (initial)

2024-08-07

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

ADC Therapeutics SA

External identifiers

EU CT number

2024-511633-35-00

EudraCT number

2021-000715-23

ClinicalTrials.gov

NCT05249959

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Therapy

To assess the efficacy of a consolidation with loncastuximab tesirine following salvage immunochemotherapy (2 courses of Rituximab-Bendamustine-Cytarabine, R-BAC) in Bruton Tyrosine Kinase inhibitors (BTKi) treated (or BTKi intolerant) relapsed/refractory (R/R) Mantle Cell Lymphomas (MCL).

Secondary objectives 2

1. To evaluate the safety profile of loncastuximab tesirine consolidation.
2. To assess the rate of Minimal Residual Disease (MRD) negativity after loncastuximab tesirine consolidation.

Conditions and MedDRA coding

Mantle cell lymphoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 15

1. Histologically documented diagnosis of MCL as defined in the 2017 edition of the World Health Organization (WHO) classification;
2. Age ≥ 18 and < 85 years
3. Relapsed/Refractory disease after one, two, three or four lines of treatment;
4. Bendamustine-naive or relapsed after at least one year after the last cycle of a bendamustine-containing regimen
5. Previous treatment with BTKi monotherapy or BTKi containing regimens with R/R disease; and/or patients who discontinued BTKi monotherapy or BTKi containing regimens for adverse events and have active disease necessitating treatment;
6. Previous treatment with any anti-CD19 agents is allowed (included CAR-T treatment) If previous anti-CD19 treatment has occurred, tissue CD19 expression must be assessed by histology or flow cytometry.
7. Venetoclax treated patients are allowed;
8. Stem cell transplant eligible patients are allowed;
9. Measurable nodal or extranodal disease ≥ 1.5 cm in longest diameter, and measurable in 2 perpendicular dimensions. Note: Patients with bone marrow involvement only are eligible. In case of bone marrow infiltration only, bone marrow aspiration and biopsy are mandatory for all staging evaluations;
10. ECOG/WHO performance status ≤ 2 (unless MCL-related);
11. The following laboratory values at screening (unless due to bone marrow involvement by lymphoma): - Absolute neutrophil count (ANC)  1.0×109/L, - Platelets  75.000/mm3, - Creatinine clearance ≥ 40 mL/min (Cockcroft-Gault formula); - Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 x ULN; - Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin);
12. Subject understands and voluntarily signs an informed consent form approved by the National Ethic Committee (NEC), prior to the initiation of any screening or study-specific procedures
13. Subject must be able to adhere to the study visit schedule and other protocol requirements;
14. Life expectancy ≥ 3 months;
15. Women of childbearing potential (WOCBP) must agree to use effective contraception if sexually active. This applies for the time period between signing of the informed consent form and at least 10 months after last loncastuximab tesirine (ADCT-402) dose. Men with female partners who are of childbearing potential must agree to use effective contraception if sexually active. This applies for the time period between signing of the informed consent form and at least 7 months after last loncastuximab tesirine (ADCT-402) dose.

Exclusion criteria 15

1. Subjects who have received a bendamustine containing regimen and relapsed less than one year after the end of treatment
2. Known history of hypersensitivity to human antibodies;
3. Allogenic stem cell transplant within 6 months prior to start of first study drug;
4. Allogenic stem cell transplant with active / uncontrolled graft-versus-host disease;
5. More than four lines of previous treatment (autologous stem cell transplant performed as part of consolidation to a previous line of therapy should not be considered as a line of therapy);
6. Active second malignancy in the last three years other than non-melanoma skin cancers, non-metastatic prostate cancer, in situ cervical cancer, ductal or lobular carcinoma in situ of the breast, or any other tumor that the Sponsor and Coordinating Investigator agree and document should not be considered preclusive to participate in the study;
7. Major surgery or any anticancer therapy including chemotherapy, immunotherapy, radiotherapy, investigational therapy, including targeted small molecule agents within 14 days prior to start of study drug (R-BAC). A shorter interval in special settings must be approved by the Sponsor and/or Investigator;
8. Cardiovascular disease (NYHA class ≥2);
9. Significant history of neurologic, psychiatric, endocrinological, metabolic, immunologic, or hepatic disease that would preclude participation in the study or compromise ability to give informed consent;
10. Evidence of other clinically significant uncontrolled condition(s) including, but not limited to: - Uncontrolled and/or active systemic infection (viral including COVID 19, bacterial or fungal); - Chronic or acute hepatitis B (HBV) or hepatitis C (HCV) requiring treatment. Note: subjects with serologic evidence of prior vaccination to HBV (i.e., HBsAg negative, HBsAb positive and HBcAb negative) or positive HBcAb from previous infection or intravenous immunoglobulins (IVIG) may participate; inactive carriers (HBsAg positive with undetectable HBV DNA) are eligible. Patients with presence of HCV antibody are eligible only if PCR result are negative for HCV RNA;
11. HIV seropositivity;
12. Lymphoma with active CNS involvement at the time of screening, including leptomeningeal disease;
13. Congenital long QT syndrome or a corrected QTcF interval of >480 msec at screening (unless secondary to pacemaker or bundle branch block);
14. 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;
15. If female, the patient is pregnant or breast-feeding.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 12-month Progression-Free Survival (PFS), defined as the time between the date of enrollment and the first documentation of recurrence, progression or death from any cause; responding patients and patients who are lost to follow up will be censored at their last assessment date. PFS will be assessed on an ITT (Intention to Treat) basis.

Secondary endpoints 7

1. Overall survival (OS), defined as the time between the start of treatment until death from any cause; patients who are lost at follow up will be censored at their last assessment date. Analysis will be on an ITT basis.
2. Rate of conversion from partial response to complete response (PR to CR) and from stable disease (SD) to PR/CR rate, assessed by comparing responses prior to and after loncastuximab tesirine.
3. Overall Response Rate (ORR), CR, PR and SD rate, will be defined according to Lugano 2014 criteria. The best overall response will be defined as the best response between the date of beginning of therapy and the last restaging. Patients without response assessment (due to whatever reason) will be considered as non-responders.
4. Duration of Response (DOR), defined as the time from the first documentation of tumor response (CR/PR) to disease progression or death according to Lugano 2014 criteria. Analysis will be on an ITT basis
5. Event-Free Survival (EFS), defined as the time from start of treatment to disease progression, death, or discontinuation of treatment for any reason (e.g. toxicity, patient preference), or initiation of a new treatment without documented progression. Analysis will be on an ITT basis.
6. MRD negativity rate, defined as the rate of MRD (Minimal Residual Disease) negativity after induction treatment (2 x R-BAC), at the end of consolidation with the loncastuximab tesirine and after 6 and 12 months after the end of consolidation.
7. Rate of Adverse Events Any grade III or higher toxicities will be recorded and classified according to the definitions of the current version of the NCI Common Terminology Criteria for Adverse Events (CTCAE). Toxicity events will be determined by the incidence of severe, life-threatening (CTCAE grade 3, 4 and 5) and/or serious adverse events (SAEs) commencing after the first induction dose or at any time during therapy.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fondazione Italiana Linfomi Ets

Sponsor organisation

Fondazione Italiana Linfomi Ets

Address

Piazza Filippo Turati 5

City

Alexandria

Postcode

15121

Country

Italy

Scientific contact point

Organisation

Fondazione Italiana Linfomi Ets

Contact name

Marco Ladetto, MD

Public contact point

Organisation

Fondazione Italiana Linfomi Ets

Contact name

Marco Ladetto, MD

Locations

1 EU/EEA country · 21 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 2 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications