Efficacy and Safety of Ibrutinib with Rituximab-CHOP and Maintenance Ibrutinib in Untreated Intermediate-High/High-Risk ABC-DLBCL Patients
- Trial ID
- 2024-511641-18-00
- Protocol
- FIL_RI-CHOP
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase II multicenter single-arm study is to assess the 2-year **Progression-Free Survival (PFS)** of the R-CHOP21 regimen in combination with **ibrutinib**, followed by maintenance therapy in untreated patients with Activated-B-Cell Diffuse Large B-cell Lymphoma (ABC-DLBCL) at an International Prognostic Index (IPI) score of 2 or higher. This objective is clinically relevant as it aims to determine the potential of this combination therapy to improve PFS in a high-risk patient population, which could lead to better management strategies for ABC-DLBCL.
Secondary objectives include:
- Evaluating the efficacy in terms of Event-Free Survival (EFS) and Overall Survival (OS).
- Assessing the Complete Response (CR) rate and Overall Response Rate (ORR) according to the Lugano 2014 criteria.
- Determining the duration of response (DOR) after the end of treatment.
- Evaluating the rate of conversion to CR with ibrutinib maintenance for patients in Partial Response (PR) after the end of induction (EOI).
- Assessing the safety of the R-CHOP regimen in combination with ibrutinib.
Participants
The clinical trial involves participants diagnosed with **Diffuse Large B-cell Lymphoma ABC**. The study population includes both male and female subjects aged between 18 and 65 years. Participants are required to have a life expectancy greater than six months and must not have been previously treated for the disease. The trial does not include a vulnerable population. Participants must have normal organ functions and a normal blood count, with specific parameters outlined for neutrophil and platelet counts. The trial excludes individuals with active infections, central nervous system disease, or significant surgical history unrelated to lymphoma within three months prior to enrollment. Additionally, participants must not have any other malignancies unless in remission for at least five years. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified. The selection criteria ensure that participants have measurable disease and meet specific health standards to participate in the study.
Plans and Procedures
The clinical trial is designed as a **Phase II**, multicenter, single-arm study to evaluate the efficacy and safety of **ibrutinib** in combination with **rituximab-CHOP** followed by ibrutinib maintenance in untreated patients with **Diffuse Large B-cell Lymphoma ABC** at intermediate-high and high risk. The trial is expected to span from August 2019 to August 2028, with the primary endpoint being progression-free survival (PFS) of high/high-intermediate risk patients from the date of enrollment. Secondary endpoints include event-free survival (EFS), overall survival (OS), and the rate of complete response (CRR) before and after maintenance.
The trial involves a sequence of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed DLBCL, absence of active infections, and normal organ functions. Participants will undergo regular follow-up visits to monitor treatment response and adverse events. The end-of-study visit will assess the overall outcomes and any long-term effects of the treatment regimen. The expected length of participant involvement is determined by the treatment period, which can extend up to 673 days for ibrutinib maintenance.
Participants may be subject to early termination from the study if they experience severe adverse events, fail to comply with study protocols, or if the investigator deems it necessary for the participant's safety. The study employs a rigorous methodology to ensure the collection of reliable data, with all treatments administered intravenously or orally as per the protocol. The trial's design and procedures are structured to provide comprehensive insights into the treatment's efficacy and safety profile, contributing valuable information to the field of oncology.
Treatment
The clinical trial involves the administration of several **experimental medications**. **Cyclophosphamide** is administered intravenously with a pharmaceutical form coded as PHF00231MIG. The dosage is calculated based on body surface area, with a maximum daily dose of 750 mg/m² and a total maximum dose of 4500 mg/m² over a treatment period of 6 cycles. Cyclophosphamide is classified as a nitrogen mustard.
**Rituximab** is administered in two forms: intravenously and subcutaneously. The intravenous form, coded as PHF00230MIG, has a maximum daily dose of 375 mg/m² and a total maximum dose of 3000 mg/m² over 8 cycles. The subcutaneous form has a maximum daily dose of 1400 mg and a total maximum dose of 11200 mg over the same period. Rituximab is a monoclonal antibody.
**Prednisolone** is administered orally with a pharmaceutical form coded as PHF00245MIG. The maximum daily dose is 100 mg, with a total maximum dose of 3000 mg over a treatment period of 30 days. Prednisolone is classified as a corticosteroid.
**Vinorelbine** is administered intravenously with a pharmaceutical form coded as PHF00007MIG. The dosage is based on body surface area, with a maximum daily dose of 2 mg/m² and a total maximum dose of 12 mg/m² over 6 cycles. Vinorelbine is a vinka alkaloid.
**Doxorubicin hydrochloride** is administered intravenously with a pharmaceutical form coded as PHF00231MIG. The dosage is calculated based on body surface area, with a maximum daily dose of 50 mg/m² and a total maximum dose of 300 mg/m² over 6 cycles. Doxorubicin is classified as an anthracycline.
**Ibrutinib** is administered orally with a pharmaceutical form coded as PHF00006MIG. The maximum daily dose is 560 mg, with a total maximum dose of 376880 mg over a treatment period of 673 days. Ibrutinib is a Bruton's tyrosine kinase inhibitor and is designated as an orphan drug.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimen. The trial does not include any non-experimental treatments such as standard-of-care therapy or placebo. The administration of these medications is conducted under strict clinical supervision to evaluate their efficacy and safety in patients with Activated-B-Cell Diffuse Large B-Cell Lymphoma (ABC-DLBCL) at intermediate-high and high risk.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is the **Progression-Free Survival (PFS)** of high and high-intermediate risk patients from the date of enrollment. Secondary endpoints include Event-Free Survival (EFS), Overall Survival (OS), the rate of Complete Response (CRR) and Overall Response (ORR), Duration of Response (DOR), and the rate of complete response before and after maintenance. Additionally, the rate of conversion to complete response with Ibrutinib maintenance for patients in partial response after induction with RI-CHOP21 will be evaluated. The assessment of toxicity, including all grades of toxicity and severe, life-threatening, or fatal adverse events, will be conducted according to the Common Terminology Criteria for Adverse Events (CTCAE).
Inclusion and Exclusion Criteria
Inclusion Criteria
- Histologically confirmed DLBCL not otherwise specified (NOS). Patients with follicular lymphoma IIIB and large B-cell lymphoma with IRF4 rearrangement can be also included.
- 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
- Previously untreated disease
- Age ≥ 18 and < 65 years
- IPI score ≥ 2
- Ann Arbor stage II–IV disease
- Measurable disease ≥ 1.5 cm in longest diameter, and measurable in 2 perpendicular dimensions
- 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
- 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”
- 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
- No active hepatitis C virus (HCV) infection
- Known availability of biopsy material
- No Central Nervous System (CNS) disease (meningeal and/or brain involvement by lymphoma)
- Absence of active infections
- No peripheral neuropathy or active neurological non-neoplastic disease of CNS
- 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
- 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.
- 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.
- 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.
- Life expectancy > 6 months
- 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
- 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
- GCB-DLBCL after centralized COO profiling
- Any other histologies than DLBCL: composite or transformed disease,.
- Primary mediastinal lymphoma (PMBL)
- Known central nervous system lymphoma
- Primary testicular lymphoma
- Any prior lymphoma therapy
- Contraindication to any drug in the chemotherapy regimen
- Left ventricular ejection fraction (LVEF) < 50%
- Neuropathy ≥ grade 2
- Seropositive for or active viral infection with HBV
- HBsAg positive
- HBsAg negative, anti-HBs positive and/or anti-HBc positive with detectable viral DNA
- Known seropositive active HCV
- Human immunodeficiency virus (HIV) infection
- 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”
- History of stroke or intracranial hemorrhage within the past 6 months.
- Requires anticoagulation with warfarin or equivalent vitamin K antagonists
- Requires treatment with strong CYP3A inhibitors
- History of clinically relevant liver or renal insufficiency; significant cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, rheumatologic, hematologic, psychiatric, or metabolic disturbances
- 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.
- Any uncontrolled active systemic infection requiring intravenous (IV) antibiotics
- Major surgical intervention prior 4 weeks to enrollment if not due to lymphoma and/or other disease life-threatening that can compromise chemotherapy treatment
- 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
- Any other medical or psychological condition that might preclude participation in the study or impair the patient's ability to give informed consent.
- 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.
- If female, the patient is pregnant or breast-feeding
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Not Recruiting | 01 Aug 2019 | 75 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
RITUXIMAB | Test | — | SUBCUTANEOUS | 1400 | 8 | SUB12570MIG |
DOXORUBICIN | Test | PHF00231MIG | INTRAVENOUS | 50 | 6 | SCP119562649 |
CYCLOPHOSPHAMIDE | Test | PHF00231MIG | INTRAVENOUS | 750 | 6 | SCP106382672 |
VINCRISTINE | Test | PHF00007MIG | INTRAVENOUS | 2 | 6 | SCP1137788 |
RITUXIMAB | Test | PHF00230MIG | INTRAVENOUS | 375 | 8 | SCP872361 |
PREDNISONE | Test | PHF00245MIG | ORAL | 100 | 30 | SCP107216203 |
IBRUTINIB | Test | PHF00006MIG | ORAL | 560 | 673 | SCP31316403 |