Phase III Randomized Study of Shortened vs. Standard Chemotherapy with Rituximab and Drug Combination in High Tumor Burden Follicular Lymphoma Patients
- Trial ID
- 2024-511636-27-00
- Protocol
- FIL_FOLL19
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to demonstrate that in patients with newly diagnosed, advanced stage **Follicular Lymphoma** (FL) with high tumor burden, a treatment strategy that reduces the number of chemotherapy cycles in case of early response to immunochemotherapy is not inferior to standard therapy at full dose in terms of progression-free survival (PFS). This is clinically relevant as it may offer a less intensive treatment option without compromising efficacy, potentially reducing treatment-related toxicity and improving patient quality of life.
Secondary objectives include:
- Comparing the response rates and the rate of adverse events between the standard and experimental treatment.
- Evaluating the impact of a shortened versus full dose program on quality of life (QoL) using the FACT-Lym questionnaire.
- Identifying patient characteristics and biomarkers that indicate suitability for shortened chemotherapy treatment.
- Assessing the role of minimal residual disease (MRD) and cell-free tumor DNA (cfDNA) analysis in predicting patient outcomes and monitoring residual disease.
- Correlating response and survival with clinical and biological prognostic factors.
- Evaluating long-term patient outcomes.
- Complementing heterogeneity information from radiomics analysis with total metabolic tumor value (TMTV) to correlate with prognosis and response.
- Comparing results from PET studies using different reconstruction algorithms with the Lugano classification and TMTV/radiomics analysis.
Participants
The clinical trial involves participants diagnosed with **Follicular Lymphoma**, specifically those with newly diagnosed, advanced-stage disease and a high tumor burden according to the GELF criteria. The study population includes both male and female subjects aged 18 years and older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Participants are required to have adequate hepatic, renal, and hematological function, and a life expectancy of at least six months. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Selection criteria emphasize the presence of measurable nodal disease and the absence of prior immunochemotherapy, except for localized radiotherapy or a maximum of four doses of rituximab monotherapy. Participants must adhere to a study visit schedule and protocol requirements, and those of childbearing potential must agree to use effective contraception. The trial does not impose specific lifestyle considerations such as diet or physical activity.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of a shortened chemotherapy regimen combined with immunotherapy compared to the standard treatment for patients with high tumor burden **Follicular Lymphoma**. This is a randomized, open-label, phase III study. The trial aims to demonstrate that reducing the number of chemotherapy cycles in patients showing early response to immunochemotherapy is not inferior to the standard full-dose therapy in terms of progression-free survival. The trial is expected to run from December 2021 to July 2030.
Participants will be randomly assigned to either the shortened or standard treatment group. The study involves several key medications, including **rituximab**, **doxorubicin hydrochloride**, **vinorelbine**, **prednisolone**, **obinutuzumab**, **bendamustine hydrochloride**, and **cyclophosphamide**, administered through various routes such as subcutaneous, intravenous, and oral. The maximum treatment period for these medications ranges from 12 to 32 weeks, depending on the specific drug and regimen.
The sequence of study visits includes an initial screening visit to confirm eligibility based on criteria such as histologically documented diagnosis, adequate organ function, and high tumor burden as per GELF criteria. Following randomization, participants will undergo regular follow-up visits to monitor treatment response and safety. These visits will include assessments of progression-free survival, overall survival, event-free survival, response rates, molecular response, and quality of life. The end-of-study visit will conclude the participant's involvement, with a comprehensive evaluation of treatment outcomes and any adverse events.
Participant involvement is expected to last up to 32 weeks, depending on the treatment arm and response to therapy. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. The trial's primary endpoint is progression-free survival, with secondary endpoints including overall survival, event-free survival, response rates, molecular response, safety, and quality of life.
Treatment
**Rituximab** is administered in two forms within the clinical trial. As a **solution for injection**, it is delivered subcutaneously with a maximum daily dose of 1400 mg and a total dose of 26600 mg over a treatment period of 32 weeks. Additionally, rituximab is provided as a **solution for infusion** intravenously, with a maximum daily dose of 375 mg/m² and a total dose of 7500 mg/m² over the same treatment period. Rituximab is classified as a monoclonal antibody and is not a paediatric formulation.
**Doxorubicin Hydrochloride** is administered intravenously as an **injection**. The maximum daily dose is 50 mg/m², with a total dose of 200 mg/m² over a 12-week treatment period. Doxorubicin is categorized under anthracyclines and is not formulated for paediatric use.
**Vinorelbine** is delivered intravenously as a **solution for injection**. The maximum daily dose is 2 mg/m², with a total dose of 8 mg/m² over a 12-week treatment period. It is classified as a vinca alkaloid and is not a paediatric formulation.
**Prednisolone** is administered orally in the form of **tablets**. The maximum daily dose is 40 mg/m², with a total dose of 800 mg/m² over a 12-week treatment period. Prednisolone is a corticosteroid and is not intended for paediatric use.
**Obinutuzumab** is administered intravenously as a **concentrate for solution for injection**. The maximum daily dose is 1000 mg, with a total dose of 22000 mg over a 30-week treatment period. It is classified as a monoclonal antibody and is not a paediatric formulation.
**Bendamustine Hydrochloride** is delivered intravenously as a **solution for infusion**. The maximum daily dose is 90 mg/m², with a total dose of 720 mg/m² over a 16-week treatment period. It is categorized as an alkylating agent/purine analogue and is not formulated for paediatric use.
**Cyclophosphamide** is administered intravenously as a **solution for injection/infusion**. The maximum daily dose is 750 mg/m², with a total dose of 3000 mg/m² over a 12-week treatment period. Cyclophosphamide is classified as an alkylating agent and is not a paediatric formulation.
**Vincristine** is delivered intravenously as a **solution for injection**. The maximum daily dose is 2 mg, with a total dose of 12 mg over an 18-week treatment period. It is classified as a vinca alkaloid and is not intended for paediatric use.
**Prednisone** is administered orally in the form of **tablets**. The maximum daily dose is 40 mg/m², with a total dose of 1200 mg/m² over an 18-week treatment period. Prednisone is a corticosteroid and is not formulated for paediatric use.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial includes both experimental and comparator treatments, with the aim of evaluating the efficacy and safety of the treatment strategies in patients with high tumor burden Follicular Lymphoma.
Efficacy
The efficacy of the clinical trial will be assessed using several key endpoints. The primary endpoint is **Progression-Free Survival (PFS)**, which will measure the length of time during and after the treatment that a patient lives with the disease without it getting worse. Secondary endpoints include Overall Survival (OS), Event-Free Survival (EFS), and Response Rate, which encompasses both Overall Response Rate (ORR) and Complete Response Rate (CRR) as defined by Cheson 2014 criteria. Additionally, Molecular Response will be evaluated through polymerase chain reaction (PCR) assessment of Bcl2/IgH rearrangement. Safety of the treatment will be monitored according to the current version of the Common Terminology Criteria for Adverse Events (CTCAE), and Quality of Life will be assessed using Patient Reported Outcomes (PROs) through the FACT-Lym questionnaire.
The collection and analysis of these efficacy parameters will be conducted at specified intervals throughout the trial. The trial is designed to compare a shortened chemotherapy regimen combined with immunotherapy against a standard regimen in patients with high tumor burden Follicular Lymphoma. The study aims to demonstrate that the reduced chemotherapy cycles are not inferior to the standard therapy in terms of PFS. The trial will follow a randomized, open-label, phase III design, ensuring rigorous evaluation of the treatment efficacy.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Histologically documented diagnosis of grade 1-2 or 3a follicular lymphona or classic follicular lymphoma, as defined in the 4 th and 5 th editions of the World Health Organization (WHO) classification respectively;
- Age ≥ 18 years
- ECOG performance status 0-2
- No previous immunochemotherapy for the lymphoma (localized radiotherapy or rituximab monotherapy with max of 4 doses are allowed);
- Ann Arbor stage II-IV
- High tumor burden as per GELF criteria defined as the presence of at least one of the following: - systemic symptoms; - Tumor bulk (any nodal or extranodal tumor mass with diameter > 7 cm); - involvement of ≥ 3 nodal sites, each with a diameter ≥ 3 cm; - splenomegaly; - compressive syndrome (organ compression); - serous effusion; - circulant malignant cells; - cytopenia; - ECOG-PS > 1; - LDH > upper limit of normality (ULN); - β2-microglobulin > 3 mg/L. In the absence of at least one of the GELF criteria, the presence of extranodal disease applies provided that the bone marrow is not the only extranodal site
- At least one site of measurable nodal disease at baseline ≥ 1.5 cm in the longest transverse diameter as determined by CT scan (MRI is allowed if CT scan cannot be performed); or evaluable disease at baseline FDG-PET scan (at least one metabolic active site of disease)
- Adequate hematological counts (unless due to bone marrow involvement by lymphoma) defined as follows: a. Absolute Neutrophil count (ANC) > 1.5 x 109 /L; b. Platelet count ≥ 80 x 109 /L ; c. Hemoglobin ≥ 10 g/dL
- Adequate renal function defined as creatinine ≤ 2 mg/dL, unless secondary to lymphoma;
- Adequate hepatic function defined as bilirubin ≤ 2 mg/dL, unless secondary to lymphoma or Gilbert syndrome
- LVEF > 50% at bidimensional echocardiogram (mandatory only for patients receiving R/G-CHOP);
- Life expectancy ≥ 6 months;
- Subject understands and voluntarily signs an informed consent form approved by the National Ethics Committee (NEC) prior to the initiation of any screening or study-specific procedures;
- Subject must be able to adhere to the study visit schedule and other protocol requirements
- Women of childbearing potential (WOCBP) and men must agree to use effective contraception if sexually active. This applies for the time period between signing of the informed consent form and 12 months after last rituximab dose or 18 months after last obinutuzumab dose. A woman is considered of childbearing potential, i.e. fertile, following menarche and until becoming postmenopausal unless permanently sterile. Permanent sterilization methods include but are not limited to hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for continuous 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. The investigator or a designated associate is requested to advise the patient how to achieve highly effective birth control (failure rate of less than 1%) e.g., intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner. The use of condoms by male patients is required (even if surgically sterilized, i.e., status post vasectomy) unless the female partner is permanently sterile. Full sexual abstinence is admitted when this is in line with the preferred and usual lifestyle of the subject, for the same time period planned for other methods of birth control (see above). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post ovulation methods for the female partner) and withdrawal are not acceptable methods of contraception)
Exclusion Criteria
- Histological diagnosis different from grade 1-3a or cFL, as defined in the WHO classification (4 th and 5 th editions);
- Suspect or clinical evidence of CNS involvement by lymphoma;
- Contraindication to the use of anti-CD20 monoclonal antibodies;
- Subject has received any anticancer therapy (chemotherapy, immunotherapy, investigational therapy, including targeted small molecule agents) within 14 days prior to the first dose of study drug;
- Noteworthy history of neurologic, psychiatric, endocrinological, metabolic, immunologic, or hepatic disease that would preclude participation in the study or compromise ability to give informed consent;
- Any history of other active malignancies within 3 years prior to study entry, with the exception of: adequately treated in situ carcinoma of the cervix uterine; basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin; limited stage surgically removed breast cancer or adequately treated with radiation therapy; limited stage prostate carcinoma surgically removed or adequately treated with radiation therapy; previous malignancy confined and surgically resected with curative intent;
- Evidence of other clinically significant uncontrolled condition(s) including, but not limited to: - Uncontrolled and/or active systemic infection (viral, bacterial or fungal), including active ongoing infection from SARSCoV-2; - 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 negative for HCV-RNA
- HIV seropositivity;
- Women who are pregnant or breastfeeding.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Not Recruiting | 01 Dec 2021 | 602 |
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 | Comparator | — | INTRAVENOUS | 375 | 32 | SUB12570MIG |
CYCLOPHOSPHAMIDE | Comparator | — | INTRAVENOUS | 750 | 18 | SUB06859MIG |
PREDNISONE | Comparator | — | ORAL | 40 | 18 | SUB10020MIG |
BENDAMUSTINE | Test | PHF00230MIG | INTRAVENOUS | 90 | 16 | SCP20211730 |
DOXORUBICIN | Test | PHF00231MIG | INTRAVENOUS | 50 | 12 | SCP138158 |
DOXORUBICIN | Comparator | — | INTRAVENOUS | 50 | 18 | SUB06391MIG |
PREDNISONE | Test | PHF00245MIG | ORAL | 40 | 12 | SCP107216203 |
RITUXIMAB | Test | — | SUBCUTANEOUS | 1400 | 32 | SUB12570MIG |
RITUXIMAB | Comparator | — | SUBCUTANEOUS | 1400 | 32 | SUB12570MIG |
BENDAMUSTINE | Comparator | — | INTRAVENOUS | 90 | 24 | SUB05707MIG |