Phase 2 Evaluation of Golcadomide (CC-99282) in Relapsed/Refractory Primary and Secondary Central Nervous System Large B-Cell Lymphoma

Trial ID: 2024-517051-12-00
Protocol: HO176
Sponsor: Hemato-Oncologie voor Volwassenen Nederland (Hovon) Stichting

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Objectives

The primary objective of this phase 2 study is to assess the **overall response rate (ORR)**, including complete remission and partial remission, of 40% in patients with relapsed or refractory primary central nervous system lymphoma (R/R PCNSL) and secondary central nervous system lymphoma (sCNSL). The evaluation will be conducted according to the International Primary CNS Lymphoma Collaborative Group (IPCG) response criteria for R/R PCNSL and both IPCG and Lugano criteria for sCNSL. This objective is clinically relevant as it aims to determine the efficacy of **golcadomide** in achieving significant tumor response in these patient populations, which could potentially lead to improved treatment outcomes.

Secondary objectives include: - Determining toxicity according to the Common Terminology Criteria for Adverse Events (CTCAE) grading. - Evaluating the time to best response. - Assessing progression-free survival (PFS) from the start of study treatment until progression or death. - Evaluating overall survival (OS) from the start of study treatment until death from any cause. - Assessing duration of response (DOR) from the first documentation of response until relapse, progression, or death. - Evaluating functional status and quality of life (QoL). - Exploratory objectives include modeling the pharmacokinetics (PK) of golcadomide in spinal fluid compared to plasma, examining the value of circulating tumor DNA (ctDNA) in plasma and spinal fluid for minimal residual disease (MRD) detection and its correlation with clinical outcomes, and evaluating the correlation between mutational and gene expression profiles (GEP) and response to treatment.

Participants

The clinical trial involves participants diagnosed with **secondary central nervous system lymphoma**, relapsed primary large B-cell lymphoma of the central nervous system, or refractory primary large B-cell lymphoma of the central nervous system. The study population includes both male and female subjects aged 18 years and older, with a **WHO performance status** of 2 or less, indicating a relatively stable general health status. The trial does not include a vulnerable population. Participants were selected based on specific inclusion criteria, such as having received prior high-dose methotrexate-based chemotherapy for cohort A, and a diagnosis of aggressive malignant B-cell lymphoma for cohort B, among other criteria. Lifestyle considerations such as diet and physical activity are not specified. The sponsor has not provided information regarding the total number of participants in the trial.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of **golcadomide** in patients with relapsed and refractory primary large B-cell lymphoma of the central nervous system and secondary central nervous system lymphoma. This is a phase II, randomized, double-blind, controlled study. The trial aims to achieve a best observed overall response rate (ORR) of 40% according to the IPCG response criteria for patients with relapsed/refractory primary central nervous system lymphoma (R/R PCNSL) and the IPCG and Lugano criteria for patients with secondary central nervous system lymphoma (sCNSL). The study is expected to commence recruitment on June 1, 2025, and conclude by June 1, 2028.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, prior treatment history, and specific diagnostic requirements. Following successful screening, participants will be randomized to receive the investigational product, **golcadomide**, administered orally in capsule form. The treatment period will consist of up to 13 cycles, with each cycle lasting 28 days. During this period, participants will attend regular follow-up visits to monitor treatment response, assess toxicity according to CTCAE grading, and evaluate functional status using the MMSE and QoL EORTC QLQ-C30 and EORTC QLQ-BN20.

The end-of-study visit will occur after the completion of the treatment cycles or upon early termination. Participants may be withdrawn from the study if they experience unacceptable toxicity, disease progression, or if they are unable to comply with the study protocol. The expected length of participant involvement is approximately 392 days, corresponding to the maximum treatment period. Secondary endpoints include progression-free survival (PFS), overall survival (OS), duration of response (DOR), and exploratory endpoints such as the pharmacokinetics of **golcadomide** in spinal fluid compared to plasma, and the correlation between mutational and gene expression profiles and treatment response.

Treatment

The clinical trial involves the administration of **Golcadomide**, an experimental medication, for the treatment of relapsed and refractory primary large B-cell lymphoma of the central nervous system and secondary central nervous system lymphoma. **Golcadomide** is provided in a **capsule** form and is intended for **oral use**. The active substance, **Golcadomide**, is of chemical origin and is also known by its synonyms, including CC1007548 and BMS-986369. The maximum daily dose of **Golcadomide** is 0.4 mg, with a total maximum dose of 78.4 mg over a treatment period of 392 days. The medication is manufactured by Celgene Corporation and is designated as an orphan drug under the number EU/3/23/2878.

In this study, **Golcadomide** is the primary investigational product, and no additional non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified. The trial aims to evaluate the best observed overall response rate (ORR) according to the IPCG response criteria for patients with relapsed/refractory primary central nervous system lymphoma (R/R PCNSL) and according to IPCG and Lugano criteria for patients with secondary central nervous system lymphoma (sCNSL). Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the prescribed regimen.

Efficacy

Efficacy in this clinical trial will be assessed primarily through the **Best Overall Response Rate (ORR)**, which includes complete remission and partial remission, evaluated according to the International Primary CNS Lymphoma Collaborative Group (IPCG) response criteria for patients with relapsed/refractory primary central nervous system lymphoma (R/R PCNSL) and according to both IPCG and Lugano criteria for patients with secondary central nervous system lymphoma (sCNSL). The primary endpoint is the best overall response achieved during the first 13 treatment cycles.

Secondary endpoints include the assessment of toxicity using the Common Terminology Criteria for Adverse Events (CTCAE) grading, time to best response, progression-free survival (PFS) measured from the start of study treatment until progression or death, overall survival (OS) measured from the start of study treatment until death from any cause, and duration of response (DOR) measured from the first documentation of response until relapse, progression, or death. Functional status will be evaluated using the Mini-Mental State Examination (MMSE) and quality of life will be assessed with the EORTC QLQ-C30 and EORTC QLQ-BN20 questionnaires.

Exploratory endpoints include the pharmacokinetics (PK) of **golcadomide** in spinal fluid compared to plasma, the value of circulating tumor DNA (ctDNA) in plasma and spinal fluid for detecting minimal residual disease and its correlation with clinical outcomes, and the correlation between mutational and gene expression profiles and response to treatment.

Inclusion and Exclusion Criteria

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Inclusion Criteria

≥ 18 years as minimum age
WHO-performancestatus ≤ 2
Patient must understand and voluntarily sign an Informed Concent Form (ICF) prior to any study related assessments/procedures being conducted
Patient is willing and able to adhere to the study visit schedule and other protocol requirements
Haemoglobin > 5 mmol/l
Absolute neutrophil count (ANC) >1.0x10^9/l without growth factor support for 7 days
Platelet count >75x10^9/l without transfusions for 7 days
Patient agrees not to participate in any other interventional study while on protocol treatment without approval of the Principal Investigator
Additional inclusion criteria cohort A: Additional inclusion criteria cohort A 1 Diagnosis of a R/R PCNSL according to the WHO 2022 classification
Additional inclusion criteria cohort A: Patients must have received prior high-dose methotrexate based chemotherapy.
Additional inclusion criteria cohort B: Diagnosis of aggressive malignant B-cell lymphoma based upon a representative histology specimen according to the WHO 2022 classification: Follicular lymphoma (FL) grade 3B or transformed FL, DLBCL and HGBCL with MYC and BCL2 rearrangements
Additional inclusion criteria cohort B: Progression or relapse with CNS localization with or without systemic relapse
Additional inclusion criteria cohort B: 3 Diagnosis of CNS localization at inclusion based on at least one of the following: Unequivocal morphological and/or immunophenotypically evidence of Cerebrospinal Fluid (CSF) lymphoma, clinical AND Magnetic resonance imaging (MRI) evidence of leptomeningeal localization, brain parenchymal lesion showing homogeneous contrast enhancement suspect for lymphoma, concurrently with systemic progression or recurrence and biopsy-proven brain parenchymal NHL localization of previously diagnosed systemic NHL

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Exclusion Criteria

The following DLBCL subtypes are not allowed: a) Patients with intravitreal lymphoma, b) Primary testicular lymphoma, c) Intravascular lymphoma, d) Epstein-barrvirus (EBV) driven lymphoma, e) Post-transplant LPDs
History of active malignancy (other than lymphoma) requiring ongoing treatment during the past 5 years with the exception of basal carcinoma of the skin or stage 0 cervical carcinoma
Patient is pregnant, breast-feeding patients, or intending to become pregnant during participation in the study
Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule
Patient has received prior therapy with CRBN-modulating drug (eg, lenalidomide, avadomide/CC-122, pomalidomide, golcadomide (CC-99282)) within 5 half-lives or 4 weeks, whichever is shorter, prior to starting investigational product.
Severe cardiovascular disease (arrhythmias not well controlled with medication, congestive heart failure or symptomatic ischemic heart disease)
Severe pulmonary dysfunction
Severe neurological or psychiatric disease
Significant hepatic dysfunction (serum transaminases ≥ 3 times upper limit of normal or bilirubin ≥ 3 x ULN (unless bilirubin rise is due to Gilbert's syndrome))
Significant renal dysfunction (estimated creatinine clearance < 45 ml/min after rehydration according to local practice)
Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, infection, hypertension, cancer, etc.)
Active or uncontrolled viral infection (Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), Human Immunodeficiency Virus (HIV), Coronavirus disease (COVID))
Hypersensitivity to the active substance.
Patients unable to swallow capsules or with diseases significantly affecting the gastrointestinal function.