Phase II multicenter single arm study to evaluate the efficacy and safety of ibrutinib in combination to rituximab-CHOP followed by ibrutinib maintenance in untreated patients with Activated-B-Cell (ABC)-DLBCL at intermediate-high and high risk (IPI ≥2)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondazione Italiana Linfomi Ets

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

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

Trial duration

1 Aug 2019 → ongoing

Decision date (initial)

2024-12-02

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Fondazione Roche · Janssen-Cilag S.p.A - Italia

External identifiers

EU CT number

2024-511641-18-00

EudraCT number

2017-005137-23

ClinicalTrials.gov

NCT03731234

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Efficacy

The 2-years PFS of R-CHOP21 in combination with ibrutinib followed by maintenance in untreated patients with ABC-DLBCL, at IPI ≥ 2.

Secondary objectives 5

1. To evaluate the efficacy in terms of EFS and OS;
2. To evaluate the Complete Response (CR) rate and Overall Response Rate (ORR) (Lugano 2014);
3. To evaluate the duration of response (DOR) after the end of treatment.
4. To evaluate the rate of conversion in CR with ibrutinib maintenance for patients in PR after the EOI.
5. To evaluate the safety of R-CHOP in combination with ibrutinib

Conditions and MedDRA coding

Diffuse Large B-cell Lymphoma ABC

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 21

1. Histologically confirmed DLBCL not otherwise specified (NOS). Patients with follicular lymphoma IIIB and large B-cell lymphoma with IRF4 rearrangement can be also included.
2. ABC type defined by Lymph2Cx on the NanoString platform. Note: A formalin fixed paraffin embedded lymph node or tumor biopsy specimen must be submitted to Central Pathology for review during the Screening Period. The specimen must have been acquired by a surgical incision or excision biopsy or from a core needle biopsy
3. Previously untreated disease
4. Age ≥ 18 and < 65 years
5. IPI score ≥ 2
6. Ann Arbor stage II–IV disease
7. Measurable disease ≥ 1.5 cm in longest diameter, and measurable in 2 perpendicular dimensions
8. Normal blood count as defined as: absolute neutrophil count ≥1.0 × 109/L independent of growth factor support, platelet count ≥ 100,000/mm3 or >=50,000/mm3 if bone marrow (BM) involvement independent of transfusion support in either situation
9. Normal organ functions defined as: creatinine ≤2 times the upper limit of normal (ULN) or estimated Glomerular Filtration Rate (Cockroft-Gault) ≥40 ml/min/1.73m2, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤3× the ULN; total bilirubin ≤ 1.5 × the ULN unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin: patients with documented Gilbert disease may be enrolled if total bilirubin is ≤ 3.0 × the ULN; International normalized ratio (INR) < 1.5 × the ULN in the absence of therapeutic anticoagulation; partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) < 1.5 × the ULN in the absence of a lupus anticoagulant”
10. Patients with occult or prior hepatitis B infection (defined as HBsAg negative, anti-HBs positive and /or anti-HBc positive) may be included if hepatitis B virus (HBV) DNA is undetectable. These patients must be willing to undergo bi-monthly DNA testing and they should receive prophylaxis with Lamivudine
11. No active hepatitis C virus (HCV) infection
12. Known availability of biopsy material
13. No Central Nervous System (CNS) disease (meningeal and/or brain involvement by lymphoma)
14. Absence of active infections
15. No peripheral neuropathy or active neurological non-neoplastic disease of CNS
16. No major surgical intervention prior 3 months to enrolment if not due to lymphoma and/or no other disease life-threatening that can compromise chemotherapy treatment
17. No previous malignancies or patient with a history of curatively treated basal or squamous cell carcinoma or melanoma of the skin or in situ carcinoma of the cervix at any time prior to the study or patients with any other malignancy in remission without treatment for at least 5 years prior to enrolment.
18. Women of childbearing potential and men who are sexually active must be practicing a highly effective method of birth control during and after the study consistent with local regulations regarding the use of birth control methods for subjects participating in clinical trials.
19. Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin [-hCG]) or urine pregnancy test at Screening. Women who are pregnant or breastfeeding are ineligible for this study.
20. Life expectancy > 6 months
21. Written informed consent from the patient stating understanding of the purpose and procedures required by the study and willingness to take part in the study.

Exclusion criteria 27

1. DLBCL including High grade B-cell Lymphomas, both with double hit and NOS according to the 2017 Revised WHO Classification of Tumour of Haematopoietic and Lymphoid Tissues
2. GCB-DLBCL after centralized COO profiling
3. Any other histologies than DLBCL: composite or transformed disease,.
4. Primary mediastinal lymphoma (PMBL)
5. Known central nervous system lymphoma
6. Primary testicular lymphoma
7. Any prior lymphoma therapy
8. Contraindication to any drug in the chemotherapy regimen
9. Left ventricular ejection fraction (LVEF) < 50%
10. Neuropathy ≥ grade 2
11. Seropositive for or active viral infection with HBV
12. HBsAg positive
13. HBsAg negative, anti-HBs positive and/or anti-HBc positive with detectable viral DNA
14. Known seropositive active HCV
15. Human immunodeficiency virus (HIV) infection
16. Any of the following abnormal laboratory values (unless any of these abnormalities are due to underlying lymphoma): creatinine > 2 times the ULN (unless creatinine clearance normal, or calculated creatinine clearance < 40 mL/min (using the Cockcroft–Gault formula); AST or ALT >3 × the ULN; total bilirubin >1.5 × the ULN: patients with documented Gilbert disease may be enrolled if total bilirubin is ≤ 3.0 × the ULN; INR > 1.5 × the ULN in the absence of therapeutic anticoagulation; PTT or aPTT > 1.5 × the ULN in the absence of a lupus anticoagulant”
17. History of stroke or intracranial hemorrhage within the past 6 months.
18. Requires anticoagulation with warfarin or equivalent vitamin K antagonists
19. Requires treatment with strong CYP3A inhibitors
20. History of clinically relevant liver or renal insufficiency; significant cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, rheumatologic, hematologic, psychiatric, or metabolic disturbances
21. Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification.
22. Any uncontrolled active systemic infection requiring intravenous (IV) antibiotics
23. Major surgical intervention prior 4 weeks to enrollment if not due to lymphoma and/or other disease life-threatening that can compromise chemotherapy treatment
24. Prior malignancies other than lymphoma in the last 5 years with exception of currently treated basal or squamous cell carcinoma or melanoma of the skin or in situ carcinoma of the cervix
25. Any other medical or psychological condition that might preclude participation in the study or impair the patient's ability to give informed consent.
26. Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator’s opinion, could compromise the subject’s safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk.
27. If female, the patient is pregnant or breast-feeding

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Progression-free survival (PFS) of the high/high-intermediate risk patients from date of enrolment

Secondary endpoints 6

1. Event Free Survival (EFS) and Overall survival (OS)
2. Rate of complete response (CRR) and of overall response (ORR)
3. Duration of response (DOR)
4. Rate of complete response (CRR) before and after maintenance
5. Rate of conversion in CR with Ibrutinib maintenance for patients in PR after the induction with RI-CHOP21
6. Toxicity: all grade of toxicity and severe, life- threatening, fatal (grade 3, 4 and 5) and/or serious adverse events will be defined according to “Common Terminology Criteria for Adverse Events” (CTCAE)

Investigational products

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

Test 7

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

Maurizio Martelli, MD

Public contact point

Organisation

Fondazione Italiana Linfomi Ets

Contact name

Start up office

Locations

1 EU/EEA country · 39 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 22 files

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

Application history

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