Golseek-2: A Phase 2 Randomized, Open-Label Study to Evaluate the Efficacy and Safety of Golcadomide in Combination with Rituximab in Participants with Newly Diagnosed Advanced Stage Follicular Lymphoma

Background and Significance

When patients (pts) with follicular lymphoma (FL) present with a high tumor burden, they require systemic treatment with rituximab (R) in combination with chemotherapy (chemo). Given the known cumulative toxicities of chemotherapy and the older age of pts at the time of diagnosis, novel chemo-free treatment approaches are desired by pts as well as physicians. R-lenalidomide (R-Len), a chemo-free alternative to R-based chemoimmunotherapy, has recently been listed as a chemo-free option in the National Comprehensive Cancer Network® (NCCN) guidelines. Golcadomide (GOLCA) is a potential first-in-class oral cereblon E3 ligase modulator (CELMoD™) agent purposefully designed for the treatment of lymphoma. GOLCA co-opts cereblon to induce targeted degradation of the transcription factors Ikaros/Aiolos, inducing deep, rapid, and extensive tumor killing, independent of cell of origin, and enhanced immunostimulatory activity. Compared with immunomodulatory (IMiD) agents like lenalidomide, GOLCA more efficiently drives the cereblon complex to the closed active state resulting in more potent degradation (Watson ER et al, Science 2022), which is expected to translate into improved clinical benefit. In addition, the phase 1/2 study CC-99282-NHL-001 showed that GOLCA alone or in combination with R (GOLCA-R) was well tolerated and showed promising activity in pts with heavily pre-treated relapsed/refractory (R/R) FL, including in those with prior Len-based therapies and/or T cell-redirecting therapies (Chavez et al, EHA 2024). Based on this, GOLSEEK-2 (NCT06425302) is a randomized phase 2 trial assessing the efficacy and safety of GOLCA-R as a chemo-free option in pts with newly diagnosed advanced-stage FL.

Study Design and Methods

After a screening period of ≤ 5 weeks, approximately 90 pts with newly diagnosed advanced-stage FL will be randomized 1:1:1 between GOLCA plus rituximab at a dose of 0.2 mg or 0.4 mg once daily from day 1 to 14 every 28 days for 12 cycles or investigator's choice R-chemo (R-CHOP or R-bendamustine). R maintenance could be considered (as per pt and physician decision) for pts who achieve a partial response or better after completion of initial therapy for up to one year in GOLCA-R arms and up to one and a half years in the R-chemo arm. Pts with histologically confirmed diagnosis of grade 1, 2, 3a FL, or classic FL according to WHO classification would be eligible for the study. Other key inclusion criteria include no prior systemic treatment for FL, stage II-IV disease, the requirement for treatment as per investigator's judgment, and measurable disease as defined by Lugano 2014 criteria. Key exclusion criteria include other lymphoma subtypes, clinical evidence of transformed lymphoma, and documented or suspected central nervous system involvement. The primary endpoint is complete metabolic response (CMR) during the GOLCA plus rituximab combination treatment period, assessed by the investigator and based on Lugano 2014 Response Criteria. Secondary endpoints include progression-free survival, overall survival, overall response rate, duration of response, complete response rate at 30 months, CMR rate at 6 months and 12 months, and safety outcomes.

Villasboas Bisneto:Genentech: Research Funding; Regeneron: Research Funding; Epizyme: Research Funding; Enterome: Research Funding; CRISPR: Research Funding; Aptose: Research Funding. Zinzani:Secura Bio, Celltrion, Gilead, Janssen-Cilag, Bristol Myers Squibb, Servier, Sandoz, MSD, AstraZeneca, Takeda, Roche, Eusapharma, Kyowa Kirin, Novartis, ADC Therapeutics, Incyte, Beigene: Membership on an entity's Board of Directors or advisory committees; MSD, Eusapharma, Novartis: Consultancy; Celltrion, Gilead, Janssen-Cilag, Bristol Myers Squibb, Servier, MSD, AstraZeneca, Takeda, Roche, Eusapharma, Kyowa Kirin, Novartis, Incyte, Beigene: Speakers Bureau. Davies:Bristol Myers Squibb, Roche Pharma, AstraZeneca, MSD, Cellcentric: Research Funding; Bristol Myers Squibb, Roche Pharma, Sobi, AstraZeneca, AbbVie, Johnson & Johnson,: Honoraria; Bristol Myers Squibb, Roche Pharma, Sobi, AstraZeneca, AbbVie,: Membership on an entity's Board of Directors or advisory committees; Roche Pharma,: Other: Travel. Kridel:Abbvie: Research Funding; Roche: Research Funding; Eisai: Other: Travel expenses; BMS: Research Funding; Acerta Pharma: Research Funding; AstraZeneca: Research Funding; Telix Pharmaceuticals: Current equity holder in publicly-traded company; ITM Isotope Technologies Munich SE: Current equity holder in private company. Perini:BMS, Roche, Abbvie, AsstaZeneca, Beigene: Speakers Bureau. Rao:Bristol Myers Squibb: Current Employment. Mikita-Geoffroy:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Sudhindra:Bristol Myers Squibb: Current Employment, Current holder of stock options in a privately-held company. Andreadis:BMS: Consultancy; Roche: Research Funding; Abbvie: Consultancy; Genmab: Research Funding; Merck: Research Funding; Gilead/Kite: Consultancy; Novartis: Research Funding; Astra Zeneca: Consultancy; Seattle Genetics: Consultancy.