Trial in Progress: Phase 1/2 Study of Cereblon-Modulating Agent Golcadomide (BMS-986369/CC-99282) in Relapsed or Refractory (R/R) T-Cell Lymphomas (TCLs) (GOLSEEK-3)
Authors: Izutsu Koji , Fukuhara Noriko , Sugaya Makoto , Baba Yuichi , Hayakawa Jin , Nishio Mitsufumi , Akyol Alev , Sudhindra Akshay , Ishitsuka Kenji 
Published: December 2024

Background and significance:

TCLs are a rare form of non-Hodgkin lymphoma originating from mature T cells. There is a wide diversity of subtypes, based on histological, immunophenotypic, and genetic characteristics, most of which are aggressive lymphomas with a poor prognosis, making treatment challenging. For the last 40 years, the 5-year overall survival (OS) rate for TCLs has remained ~40% in the Surveillance Epidemiology and End Results database (Crozier et al, CLML 2015). Among adult T-cell leukemia/lymphoma (ATL), which is the most common TCL subtype in Japan, the 4-year survival rate of patients with aggressive ATL was 5%-29% (Chihara et al, BJH 2014). There are no standard therapies based on high-level evidence for TCLs, and there is an urgent need for innovative therapeutic agents and regimens.

Golcadomide is a potential first in class oral cereblon E3 ligase modulator (CELMoDTM) agent for the treatment of non-Hodgkin lymphoma that degrades targeted proteins to produce dual immunomodulatory and direct cell killing antitumor activity, with preferential distribution to lymphoid organs. It is much more efficient than lenalidomide at driving the closed, active conformation of cereblon which leads to increased potency (Chavez et al, EHA 2024). In pre-clinical studies, golcadomide induced potent degradation of Ikaros and ZFP91, and demonstrated antiproliferative effects and induced apoptosis in TCL cell lines, including lenalidomide-resistant TCL. Based on pre-clinical and clinical evidence with lenalidomide establishing that Aiolos/Ikaros degrading agents are active in R/R TCL, helping to overcome resistance (Wu et al, Blood 2022), it was anticipated that golcadomide will be active in the treatment of R/R TCL.

Study Design and Methods:

GOLSEEK-3 is a phase 1/2, multicenter, open-label study of golcadomide in approximately 85 participants with R/R TCLs in Japan (NCT06035497). Phase 1 will evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy of oral golcadomide at a daily dose of 0.2 mg or 0.4 mg on the 14 days on/14 days off (14/28-day) schedule. Phase 2 will evaluate the safety, tolerability, PK, and efficacy of oral golcadomide at the recommended phase 2 dose (RP2D) determined in phase 1 on the 14/28-day schedule until clinically significant disease progression, unacceptable toxicity, or participant/physician decision to withdraw. Phase 2 will have 2 cohorts comprising patients with ATL and patients with peripheral T-cell lymphoma (PTCL).

Key inclusion criteria include ≥ 18 years of age with R/R TCL confirmed as one of the following subtypes: ATL, PTCL-not otherwise specified, angioimmunoblastic T-cell lymphoma and other nodal lymphomas of T follicular helper cell origin, anaplastic large cell lymphoma (ALK ± or breast implant-associated), extranodal NK/T-cell lymphoma/nasal type, or advanced stage mycosis fungoides; any other TCL subtypes are exclusionary. Participants must have received ≥1 prior line of therapy, be unresponsive or ineligible to standard therapies (Phase 1 only), have measurable disease, and ECOG performance status of 0-2. Key exclusion criteria include any significant medical condition (eg, infections, laboratory abnormalities, psychiatric illness, impaired cardiac function), life expectancy ≤ 3 months, and active central nervous system involvement.

In phase 1, the primary endpoints are adverse events per CTCAE v5.0, dose-limiting toxicities, and laboratory assessments. Secondary endpoints are PK and preliminary efficacy assessments including objective response rate (ORR), disease control rate, complete response rate, time to response, duration of response, progression-free survival, time to next treatment, and OS. The RP2D will be determined using the modified TPI-2 design.

In Phase 2, the primary endpoint is to assess the efficacy of golcadomide by ORR, with statistical testing using the one sample, exact binomial test. Secondary endpoints are efficacy assessments, safety, and PK. ORR in the ATL cohort is evaluated by assessment per international consensus response criteria for ATL with slight modifications; ORR in the PTCL cohort is evaluated by assessment per response criteria according to Lugano Classification (CT-based).

Status

The trial is ongoing, and patients will be recruited from 40 sites in Japan.