Phase II Evaluation of Rituximab and Golcadomide Combination Therapy in Frail Elderly Patients with Diffuse Large B-Cell Non-Hodgkin Lymphoma

Trial ID: 2023-506206-38-00
Protocol: FIL_RICCO
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 evaluate the **efficacy** of the combination of rituximab and golcadomide as a chemo-free approach in older patients newly diagnosed with **Diffuse Large B-cells non-Hodgkin Lymphoma** (DLBCL), who are classified as frail according to a simplified Geriatric Assessment (sGA) and are not candidates for standard R-CHOP (or R-CHOP-like) treatments. This is clinically relevant as it aims to provide an alternative treatment option for a vulnerable patient population that may not tolerate conventional chemotherapy regimens.

Secondary objectives include:

Evaluating the activity in terms of response rate.
Assessing the efficacy in terms of survival.
Determining the rate of grade 3-4 hematological and extra-hematological adverse events, as per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) latest version, and the incidence of death from any cause during treatment.
Evaluating the quality of life (QoL) according to the chemo-free approach.

These secondary objectives aim to provide a comprehensive understanding of the treatment's impact on patient outcomes, safety, and overall well-being.

Participants

The clinical trial involves participants diagnosed with **Diffuse Large B-cells non-Hodgkin Lymphoma** (DLBCL), specifically targeting a population of older, frail patients who are not candidates for standard R-CHOP treatments. The study includes both male and female subjects, with an age range starting from 80 years and above. Participants are characterized by their frailty, defined by specific criteria such as reduced activity of daily living and multiple comorbidities. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Selection criteria emphasize adequate renal and hepatic function, a life expectancy of at least three months, and the ability to adhere to study protocols. Participants must have a histologically confirmed diagnosis of DLBCL and be previously untreated. Lifestyle considerations such as diet and physical activity are not specified in the available data.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of a combination therapy using **rituximab** and **golcadomide** in older frail patients diagnosed with Diffuse Large B-cells non-Hodgkin Lymphoma (DLBCL). This study is a Phase II, randomized, double-blind, controlled trial. The trial aims to provide a chemo-free treatment approach for patients who are not candidates for standard R-CHOP treatments. The trial is expected to commence recruitment on February 1, 2025, and conclude by February 1, 2030, with an estimated duration of five years.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as renal and hepatic function, ability to swallow capsules, and life expectancy of at least three months. Following the screening, eligible participants will be randomized to receive the investigational treatment. The study involves multiple follow-up visits to monitor the participants' response to the treatment, assess progression-free survival, and evaluate overall response rates, including partial and complete responses after the sixth cycle. Quality of life assessments will be conducted at baseline, six months, and twelve months using the EORTC QLQ C-30 and FACT-Lym questionnaires.

The expected length of participant involvement in the study is up to 168 weeks, corresponding to the maximum treatment period for **golcadomide**. Conditions that may lead to early termination from the study include adverse events, treatment intolerance, or disease progression. The primary endpoint of the trial is progression-free survival, while secondary endpoints include overall survival, rate of treatment discontinuation due to adverse events, and changes in quality of life assessments. Participants are required to adhere to the study visit schedule and protocol requirements throughout the trial duration.

Treatment

The clinical trial involves the administration of **Golcadomide**, an experimental medication, in the form of a **capsule**. Golcadomide is chemically synthesized and is identified by the sponsor product code BMS-986369/CC-99282. The active substance, golcadomide, is administered **orally**. The maximum daily dose is 0.4 mg, with a total maximum dose of 49 mg over a treatment period of 168 days. The medication is classified as a CRBN protein modulator and a ubiquitin protein ligase modulator. Participant compliance with the dosing schedule will be monitored throughout the trial.

In addition to Golcadomide, the trial includes the administration of **Rituximab**, a non-experimental treatment, which serves as a comparator in this study. Rituximab is a protein-based therapeutic agent, administered **intravenously**. The maximum daily dose is 375 mg/m², with a total maximum dose of 3000 mg/m² over a treatment period of 8 weeks. Rituximab is classified under the ATC code L01XC02 and is not a pediatric formulation. The administration of Rituximab will be closely monitored to ensure adherence to the dosing schedule and to assess participant compliance.

Efficacy

The efficacy of the combination of **rituximab** and **golcadomide** in treating older frail patients with Diffuse Large B-cells non-Hodgkin Lymphoma (DLBCL) will be assessed through several key endpoints. The primary endpoint for evaluating efficacy is **Progression Free Survival (PFS)**. Secondary endpoints include the **Overall Response Rate** (comprising both partial and complete responses) after the 6th cycle, **Overall Survival (OS)**, the rate of treatment discontinuation due to adverse events or treatment intolerance, and changes in Quality of Life (QoL) assessments from baseline at 6 and 12 months, measured using the EORTC QLQ C-30 and FACT-Lym questionnaires.

Data collection and analysis will be conducted at specified timepoints throughout the trial, with particular attention to the 6-month and 12-month marks for QoL assessments. The trial is designed to provide a comprehensive evaluation of the treatment's efficacy in this specific patient population, using validated tools and methodologies to ensure the reliability and accuracy of the results.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Able to provide written informed consent form approved by the National Ethics Committee (NEC) prior to the initiation of any screening or study-specific procedures and able to understand and to comply with the requirements of the study and the schedule of assessments.
Histologically documented diagnosis of DLBCL as defined in the 5th edition of the World Health Organization (WHO) classification (2022)
Previously untreated
Frail patients defined as follows (Appendix A-D): Age ≥ 80 years: activity of daily living (ADL) < 6 residual functions and/or Instrumental activity of daily living (IADL) < 8 residual functions and/or cumulative illness rating scale (CIRS) > 5 comorbidities of grade 2 and/or one or more comorbidities of grade 3-4
Patient not eligible to anthracycline-based chemotherapy
Ann Arbor Stage I – IV (Appendix E)
Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 3 (Appendix F)
At least one site of measurable nodal disease at baseline [≥ 1.5 cm] in the longest transverse diameter as determined by CT scan
Adequate hematological counts defined as follows: WBC > 2.5 x 10^9/L with ANC > 1.0 x 10^9/L unless due to bone marrow involvement by lymphoma; Platelet count ≥ 75 x 10^9/L unless due to bone marrow involvement by lymphoma; Hemoglobin ≥ 10 g/dL unless anemia related to active lymphoma
Adequate renal function defined as creatinine clearance ≥ 30 mL/min (Appendix G). The same CrCl cutoff applies in case of documented renal involvement by lymphoma
Adequate hepatic function per local laboratory reference range, unless secondary to lymphoma, as follows: Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.0 x ULN; Bilirubin ≤ 2 x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin)
Subject must be able to adhere to the study visit schedule and other protocol requirements
Subject must be able to swallow capsules or tablets
Life expectancy ≥ 3 months
Male subjects must practice complete abstinence or agree to use specified contraceptive methods during sexual contact with a female of childbearing potential while participating in the study, for at least 28 days following investigational product discontinuation, even if he has undergone a successful vasectomy. Furthermore, they do not have to donate sperm during the study and for at least 28 days after receiving the last dose of study drug. If applicable, male subjects must receive study specific Pregnancy Prevention Plan (PPP).

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Exclusion Criteria

Histological diagnosis different from DLBCL
Central nervous system (CNS) involvement with lymphoma
Significant history of cardiac, 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 5 years prior to study entry, except for adequately treated in situ carcinoma of the cervix uterine, basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin, previous malignancy confined and surgically resected with curative intent
Evidence of other clinically significant uncontrolled condition(s) including, but not limited to: a. Uncontrolled and/or active systemic infection (viral, bacterial or fungal), including active ongoing infection from SARS-CoV-2; b. Chronic or acute 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 (Ag) negative, anti-HBs antibody positive and anti-hepatitis B core (HBc) antibody negative, may participate; patients with positive anti-HBc antibody from previous infection or inactive carriers are eligible only with HBV-DNA negative and with concomitant treatment with Lamivudine or Tenofovir; c. Patients with presence of HCV antibody are eligible only if PCR negative for HCV-RNA
Human immunodeficiency virus (HIV) seropositivity
Absence of caregivers in non-autonomous patients