Randomized Phase III Study of Prednisolone and Vitamin D Supplementation in Elderly Patients with Diffuse Large B-Cell Lymphoma (DLBCL)

Trial ID: 2024-511637-35-00
Sponsor: Fondazione Italiana Linfomi Ets

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Diseases & Conditions

Diffuse large B-cell lymphoma

Objectives

The primary objective of this study is to demonstrate the superiority in terms of **Progression-free survival (PFS)** of a prephase therapy with oral prednisone and **Vitamin D** supplementation versus a prephase therapy with oral prednisone alone. This is followed by six cycles of conventional immunochemotherapy in an elderly patient population diagnosed with **Diffuse Large B-Cell Lymphoma (DLBCL)** and Follicular lymphoma grade IIIb (FL3B). The clinical relevance of this objective lies in potentially improving PFS, which is a critical endpoint in assessing the efficacy of cancer treatments, particularly in elderly patients who may have limited treatment options.

Secondary objectives include: - Assessing the safety of Vitamin D supplementation in terms of hematological and extra-hematological adverse events (AEs) rates. - Evaluating the effect of Vitamin D supplementation on early death rate, response rate, overall survival (OS), and event-free survival (EFS). - Confirming the efficacy of a prephase with Vitamin D supplementation to correct baseline 25(OH)Vitamin D levels. - Correlating baseline clinical, laboratory, and biological features with 25(OH)Vitamin D correction. - Correlating 25(OH)Vitamin D baseline levels with known and novel prognostic biomarkers and with the activity of immunochemotherapy. - Identifying high-risk categories of individuals showing insufficient response to Vitamin D supplementation. - Describing the health-related quality of life (HRQoL) using Patient-Reported Outcomes (PROs) through EORTC-QLQ-C30 and FACT-Lym-LymS questionnaires.

Participants

The clinical trial involves a study population of **elderly patients** diagnosed with **Diffuse Large B-Cell Lymphoma (DLBCL)** and Follicular lymphoma grade IIIb (FL3B). Participants are aged 65 years and older, encompassing both male and female subjects. The trial does not include a vulnerable population. The selection criteria require participants to have a histologically documented diagnosis of DLBCL or FL3B, with adequate hematological, renal, and hepatic function, as well as a life expectancy of at least six months. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 3 or less and be eligible for a six-cycle treatment of an anthracycline-containing regimen. The trial excludes individuals with previous treatment for DLBCL or FL3B. Participants are required to have at least one site of measurable nodal disease or a metabolic active site of disease at baseline. The sponsor has not provided the total number of participants involved in the study.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of a prephase therapy with oral **prednisone** and **Vitamin D** supplementation compared to oral prednisone alone, followed by six cycles of conventional immunochemotherapy in elderly patients diagnosed with Diffuse Large B-Cell Lymphoma (DLBCL) and Follicular lymphoma grade IIIb (FL3B). This is a randomized, open-label, phase III study. The primary objective is to demonstrate the superiority in terms of progression-free survival (PFS) of the combination therapy. The trial is expected to run from March 2021 to August 2026, with participant involvement lasting up to 37 weeks.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically documented diagnosis, adequate hematological, renal, and hepatic function, and a life expectancy of at least six months. Following the screening, participants will be randomized into one of the two treatment arms. The study includes regular follow-up visits to monitor the participants' health status, treatment adherence, and any adverse events. The end-of-study visit will assess the primary and secondary endpoints, including overall survival, event-free survival, and response rates.

Participants are expected to adhere to the study visit schedule and protocol requirements. Conditions that may lead to early termination from the study include significant protocol deviations, withdrawal of consent, or adverse events that compromise participant safety. The trial will ensure that all participants provide informed consent and understand the study's requirements before enrollment. The study aims to provide valuable insights into the potential benefits of Vitamin D supplementation in enhancing the efficacy of prephase therapy in this patient population.

Treatment

The clinical trial involves the administration of **colecalciferol**, commonly known as **Vitamin D3**, in combination with **glycerol**. The pharmaceutical form of this experimental medication is identified as PHF00165MIG. The medication is administered orally, with a maximum daily dose of 25,000 U units and a total maximum dose of 925,000 U units over a treatment period of 37 days. The primary role of this medication in the trial is to serve as a Vitamin D supplement. The active substances, colecalciferol and glycerol, are of chemical origin, with colecalciferol being synonymous with cholecalciferol and Vitamin D3, and glycerol also known as glycerine or glycerin.

In addition to the experimental medication, the trial includes the administration of **prednisolone**, a synthetic glucocorticoid, which is provided in the pharmaceutical form PHF00245MIG. Prednisolone is also administered orally, with a maximum daily dose of 50 mg and a total maximum dose of 350 mg over a 7-day treatment period. The role of prednisolone in the trial is to act as a standard-of-care therapy in the prephase treatment. The active substance, prednisolone, is of chemical origin and is synonymous with delta-hydrocortisone and metacortandrione.

The trial aims to evaluate the efficacy of prephase therapy with oral prednisone and Vitamin D supplementation compared to oral prednisone alone, followed by six cycles of conventional immunochemotherapy, in elderly patients diagnosed with Diffuse Large B-Cell Lymphoma (DLBCL) and Follicular lymphoma grade IIIb (FL3B). Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment regimen.

Efficacy

Efficacy in this clinical trial will be assessed primarily through the measurement of **Progression-Free Survival (PFS)**. This endpoint will evaluate the time from randomization to disease progression or death from any cause, whichever occurs first. Secondary efficacy endpoints include Overall Survival (OS), Event-Free Survival (EFS), and Response Rate (ORR, CRR) as defined by Cheson 2014 criteria. Additionally, the trial will monitor the Early Death Rate (EDR), which accounts for all deaths recorded within 90 days from the date of diagnosis, and the rate of adverse events (AEs) using the CTCAE current version.

Further assessments will include the rate of changes in the Eastern Cooperative Oncology Group (ECOG) performance status after the prephase treatment, and the rate of 25(OH)VitD correction in the Vitamin D supplementation arm, specifically the number of patients with 25(OH)VitD levels above or equal to 20 ng/ml at day 1 of cycle 2. The trial will also evaluate the rate of patients maintaining 25(OH)VitD levels within the normal range at the end of the intervention (EOI).

Patient-reported outcomes (PROs) will be assessed through endpoints such as time-to-deterioration in EORTC QLQ-C30 physical functioning and fatigue, and FACT-Lym-LymS. The proportion of patients in each arm achieving meaningful improvement in these measures will be compared, as well as treatment-related symptoms between the two treatment arms. These efficacy parameters will be collected and analyzed at specified timepoints throughout the trial to determine the impact of the treatment regimens on the patient population diagnosed with Diffuse Large B-Cell Lymphoma (DLBCL) and Follicular lymphoma grade IIIb (FL3B).

Inclusion and Exclusion Criteria

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Inclusion Criteria

Histologically documented diagnosis of Diffuse Large B-cell Lymphoma or Follicular grade IIIb lymphoma, as defined in the 2017 edition of the World Health Organization (WHO) classification
Age ≥ 65 years
Simplified Geriatric Assessment (sGA) performed at baseline, before start of any treatment.
Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤3
Eligibility for 6 cycle treatment of anthracycline containing regimen (R-CHOP or R-miniCHOP)
No previous treatment for DLBCL or Follicular grade IIIb lymphoma
Ann Arbor stage I-IV
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 only if CT scan cannot be performed); or one metabolic active site of disease at baseline FDG-PET scan
Baseline Vitamin D [25(OH)VitD] serum level ≤ 40 ng/ml
Adequate hematological counts defined as follows: - Absolute Neutrophil count (ANC) > 1.5 x 10^9/L unless due to bone marrow involvement by lymphoma - Platelet count ≥ 80.000/mm3 unless due to bone marrow involvement by lymphoma
Adequate renal function defined as follows: - Creatinine ≤ 2 mg/dL, unless secondary to lymphoma
Adequate hepatic function defined as follows: - Bilirubin ≤ 2 mg/dL unless secondary to lymphoma
LVEF > 40% at bidimensionally echocardiogram
Life expectancy ≥ 6 months
Subject understands and voluntarily signs an informed consent form approved by an Independent Ethics Committee (IEC), 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
Men must agree to use one of the below reported acceptable method of contraception (for themselves or female partners if WOCBP) for the duration of the study and for 3 months after receiving the last dose of immunochemotherapy, and to not donate sperm while on study. Acceptable methods for birth control, to be adopted even if male is surgically sterilized (i.e., status post vasectomy) are: - practice effective barrier contraception during the entire study treatment period and through 3 months after the last dose of immunochemotherapy, or - agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post ovulation methods for the female partner] and withdrawal are not acceptable methods of contraception)

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Exclusion Criteria

Histological diagnosis different from Diffuse large B-Cell Lymphoma or Follicular grade IIIb lymphoma, including diagnosis of HGBL, with rearrangement of MYC, BCL2 and/or BCL6 (double-hit)
Use of VitD supplementation as standard of care at dose higher than 10,000 U/week (or higher than 2,000 U/day).
Suspect or clinical evidence of CNS involvement by lymphoma.
Contraindication to the use of rituximab.
Localized stage patients candidates for 3-4 cycles of R-CHOP/R-miniCHOP +RT.
Contraindication to the use of VitD supplementation (Hypercalcemia/Hyperphosphatemia).
Subject has received any anti-cancer therapy including chemotherapy, immunotherapy, radiotherapy, investigational therapy, including targeted small molecule agents within 14 days prior to the first dose of study drug.
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.
Any history of other active malignancies within 2 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 or limited stage surgically removed breast cancer or adequately treated with radiation therapy or limited stage prostate carcinoma surgically removed or adequately treated with radiation therapy or 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) - Chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment. Note: subjects with serologic evidence of prior vaccination to HBV (i.e. hepatitis B surface (HBs) antigen negative, anti-HBs antibody positive and anti-hepatitis B core (HBc) antibody negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) may participate.