A Phase 2 Open-label Study of Loncastuximab Tesirine in Combination with Rituximab (Lonca-R) in Previously Untreated Unfit/Frail Patients with Diffuse Large B-cell Lymphoma (DLBCL) (LOTIS-9)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

ADC Therapeutics S.A.

Participant type

Patients

Age range

65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

22 May 2023 → 22 Jan 2024

Decision date (initial)

2023-03-01

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

ADC Therapeutics SA

External identifiers

EU CT number

2022-501601-12-00

ClinicalTrials.gov

NCT05144009

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Pharmacodynamic, Efficacy, Pharmacokinetic, Safety

Cohort A
To assess the efficacy of a response-adapted treatment of Lonca-R in unfit patients with previously untreated DLBCL, or HGBCL, or Grade 3b FL
Cohort B
To assess the tolerability and efficacy of a response-adapted treatment of Lonca-R in frail patients or patients with cardiac comorbidities with previously untreated DLBCL, or HGBCL, or Grade 3b FL, who are ineligible for standard R-mini-CHOP

Secondary objectives 1

1. Cohort A and Cohort B • Further evaluate the efficacy of Lonca-R • To characterize the safety profile of Lonca-R • To characterize the PK profile of Lonca when given in combination with rituximab • To evaluate the immunogenicity of Lonca when given in combination with rituximab • To evaluate the impact of Lonca-R treatment on treatment-related and disease-related symptoms, patient-reported functions, and overall health status

Conditions and MedDRA coding

Diffuse large B-cell Lymphoma

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Male or female
2. Pathologic diagnosis of DLBCL, as defined by the 2016 World Health Organization (WHO) classification (including patients with DLBCL transformed from indolent lymphoma), or high-grade B cell lymphoma (HGBCL), or Grade 3b follicular lymphoma (FL).
3. Measurable disease as defined by the 2014 Lugano Classification
4. Stages I-IV
5. ECOG PS 0-2; ECOG PS 3 allowed if decline in status is deemed related to lymphoma & felt to be potentially reversible by the treating physician
6. Adequate organ function as defined by screening laboratory values within the following parameters: a. Absolute neutrophil count (ANC) ≥ 1.0 × 10^3/µL (off growth factors at least 72 hours) b. Platelet count ≥ 75 × 10^3/µL without transfusion in the past 7 days c. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma glutamyl transferase (GGT) ≤ 2.5 × the upper limit of normal (ULN) d. Total bilirubin ≤ 1.5 × ULN (patients with known Gilbert’s syndrome may have a total bilirubin up to ≤ 3 × ULN) e. Calculated creatinine clearance > 30 mL/min by the Cockcroft and Gault equation
7. Women of childbearing potential (WOCBP) must agree to use a highly effective method of contraception from the time of giving informed consent until at least 12 months after the last dose of study treatment. Men with female partners who are of childbearing potential must agree to use a condom when sexually active or practice total abstinence from the time of the first dose until at least 7 months after the patient receives her/his last dose of study treatment
8. Inclusion Criteria specific for Cohort A: Unfit as defined by the sGA (includes all of the following): a. Aged ≥ 80 years b. ADL score of 6 c. IADL score of 8 d. CIRS-G: no score of 3-4 and < 5 scores of 2
9. Inclusion Criteria specific for Cohort B: Frail as defined by the sGA: a. Aged ≥ 80 years b. ADL score of < 6 and/or c. IADL score of < 8 and/or d. CIRS-G ≥ 1 score of 3-4 and/or ≥ 5 scores of 2 OR Aged ≥ 65 - <80 with at least one of the following cardiac comorbidities that make anthracycline-containing regimens inadvisable as determined by the investigator. a. Left ventricular ejection fraction (LVEF) ≥ 30 to < 50% b. History of myocardial infarction within 6 months prior to screening c. Ischemic heart disease d. History of stroke within 12 months prior to screening

Exclusion criteria 16

1. Known history of hypersensitivity to or positive serum human anti-drug antibody to a CD19 antibody
2. Previous therapy for DLBCL, HGBCL, Grade 3b FL (with exception of corticosteroid course for symptom management of less than 14 days)
3. Previous therapy with loncastuximab tesirine and rituximab for any indication
4. Known history of hypersensitivity to any component of study treatment (loncastuximab tesirine and rituximab)
5. Human immunodeficiency virus (HIV) seropositive with any of the following: a. CD4+ T-cell (CD4+) counts < 350 cells/µL b. Acquired immunodeficiency syndrome (AIDS) – defining opportunistic infection within 12 months prior to screening c. Not on anti-retroviral therapy, or on anti-retroviral therapy for < 4 weeks at the time of screening d. HIV viral load ≥ 400 copies/mL
6. Serologic evidence of chronic hepatitis B virus (HBV) infection and unable or unwilling to receive standard prophylactic antiviral therapy or with detectable HBV viral load
7. Serologic evidence of hepatitis C virus (HCV) infection without completion of curative treatment or with detectable HCV viral load
8. History of Stevens-Johnson syndrome or toxic epidermal necrolysis
9. Lymphoma with active central nervous system involvement at the time of screening, including leptomeningeal disease
10. 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)
11. Major surgery, radiotherapy, chemotherapy, or other anti-neoplastic therapy within 14 days prior to start of study drug (Cycle 1 Day 1 [C1D1]), except shorter if approved by the Sponsor
12. Use of any other experimental medication within 14 days prior to start of study drug (C1D1)
13. Received live vaccine within 4 weeks of C1D1
14. Congenital long QT syndrome or a corrected QTcF interval of > 480 ms at screening (unless secondary to pacemaker or bundle branch block)
15. 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
16. 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Cohort A • CR rate defined as proportion of patients with a BOR of CR according to the 2014 Lugano Classification criteria
2. Cohort B • CR rate defined as proportion of patients with a BOR of CR according to the 2014 Lugano Classification criteria
3. Cohort B • Tolerability as defined by the percentage of patients completing a total of 4 cycles of therapy divided by the total number of patients.

Secondary endpoints 9

1. ORR according to the 2014 Lugano Classification defined as the proportion of patients with a BOR of CR or PR.
2. 2 year PFS, defined as the proportion of patients that are PFS event-free at 2 years
3. 3 year overall survival (3-yr OS), defined as the proportion of patients that are OS event-free at 3 years.
4. Duration of response (DoR) defined as the time from the first documentation of tumor response (CR or PR) to disease progression or death
5. Frequency and severity of adverse events (AEs) and serious adverse events (SAEs)
6. Changes from baseline in safety laboratory variables, vital signs, physical examinations, Eastern Cooperative Oncology Group scale of performance status (ECOG PS)
7. Concentrations and PK parameters of loncastuximab tesirine pyrrolobenzodiazepine (PBD)-conjugated antibody, total antibody, and SG3199 unconjugated warhead
8. Frequency of confirmed positive anti-drug antibody (ADA) responses, their associated titers and, if applicable, neutralizing activity to loncastuximab tesirine after treatment with loncastuximab tesirine when given in combination with rituximab
9. Changes in patient-reported outcomes (e.g., symptoms, functions, and overall health status) from baseline as evaluated by Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym)

Investigational products

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

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

ADC Therapeutics S.A.

Sponsor organisation

ADC Therapeutics S.A.

Address

Route De La Corniche 3b

City

Epalinges

Postcode

1066

Country

Switzerland

Scientific contact point

Organisation

ADC Therapeutics S.A.

Contact name

Clinical Operations

Public contact point

Organisation

ADC Therapeutics S.A.

Contact name

Clinical Operations

Third parties 10

Locations

2 EU/EEA countries · 13 investigational sites

By country

Investigational sites

Country notifications

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

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 2 · Art. 38 CTR

Results and documents

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

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 3 files

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

Application history

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