CC-99282 Demonstrates Manageable Safety Profile, Elicits Favorable Responses in Non-Hodgkin Lymphoma

CC-99282 monotherapy displayed encouraging overall response rates (ORR) in patients with non-Hodgkin lymphoma (NHL), including B-cell lymphoma and follicular lymphoma, representing a potentially effective chemotherapy-free treatment option for this population, according to Jean-Marie Michot, MD. 

The phase 1 CC-99282-NHL-001 trial (NCT03930953) is a multicenter, open-label, dose-finding study investigating the novel agent CC-99282 in patients with relapsed/refractory NHL. Michot presented findings from part A evaluating dose escalation in patients with diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma at the 2022 EHA Congress.

Notably, CC-99282 demonstrated a favorable safety profile, with low rates of serious febrile neutropenia. The monotherapy also elicited a 42% ORR in heavily pretreated patients, results which correlated with circulating tumor DNA reduction.1

“For patients with non-Hodgkin B-cell lymphoma, especially patients who are relapsed or refractory to [current] treatments and who have few other options, here we have some research to find new chemotherapy-free treatment options,” Michot said in an interview with OncLive^®.

Michot, a medical oncologist in the Department of Hematology and Innovative Drugs at the Institut de Cancérologie Gustave Roussy in Villejuif, France, discussed the methods and rationale for the CC-99282-NHL-001 study. The efficacy and safety findings show preliminary potential for the drug, underscoring the importance of further study in a dose expansion part of the trial.

OncLive^®: What was the rationale for studying CC-99282 in this patient population?

Michot: CC-99282 is a potential new chemotherapy-free treatment option for patients with relapsed/refractory non-Hodgkin B-cell lymphoma. The drug is based on protein degraders acting as molecular glue degraders, which are innovative treatments. In preclinical models, CC-99282 enhanced apoptotic and antiproliferative activity when compared with other immunomodulatory drugs, so there was a strong rationale to propose this new agent in this phase 1 study.

What methods were used to study this group of patients?

The methods were classical for a phase 1 trial. The population included patients with relapsed or refractory non-Hodgkin B-cell lymphoma [who had received] at least 2 prior lines of treatment and patients with DLBCL who were ineligible for intensive chemotherapy or stem cell transplant.

The study has 2 parts. Part A was the dose escalation portion, and the results were presented at EHA. Part B will be the dose expansion portion. Importantly, in Part A, different schedules of treatment were observed in the study protocol, with different levels of doses ranging from 0.2 mg to 0.8 mg per day.

What results for response rates and pharmacodynamics did you share at EHA?

Efficacy was evaluated in [patients who received doses of at least 0.4 mg per day]. The ORR was 42%, including 17% of patients with complete response [CR]. In patients with follicular lymphoma, the ORR was 75%, with 38% patients achieving CR.

We also observed an encouraging duration of response [DOR] calculated in the interim analysis, as well as a deepening of responses over time. Importantly, we had patients with partial responses who converted to CRs at the last point of follow-up. 

Additionally, interesting pharmacodynamics data show the immune activation of CC-99282 in memory T cells and in activated T cells. We observed a shift of peripheral T cells to activated T cells and a shift of naïve T cells to memory T cells. The drug appears to act as an immune stimulant of T cells, which is an encouraging [aspect of its] mechanism of action.

Did you observe any adverse effects (AEs) of note?

The most frequent AE was neutropenia related to the treatment, [which occurred in] 64% of patients. This is an expected AE with this drug and is manageable with [dose modification] or, eventually, granulocyte colony–stimulating factors.

Did the severity of AEs correlate with number of prior lines of therapy?

Importantly, we investigated the cause of the severe neutropenia. We saw that extensive prior chemotherapy was strongly associated with neutropenia, and that the dose of [CC-99282] by itself was not strongly associated with neutropenia. This is an important point [to consider during patient selection, as it may help] identify patients with risk of severe neutropenia. We also found that regimens with alkylating agents, especially [those with at least 4 alkylating agents used within 3 months prior to treatment with CC-99282], were associated with severe neutropenia.

What main message would you like to leave with colleagues regarding these findings?

The most significant point is the deepening of responses over time and the DOR that was calculated close to the last follow up, indicating a promising durability of response and quality of therapeutic response that we hope to confirm in the next follow-up.

What are the next steps?

The next step is to continue with part B of the study. Part A is now closed, and we are enrolling patients in part B, the dose-expansion part, where 2 different dose levels are being investigated, 0.2 mg and 0.4 mg. We are also enrolling patients to a rituximab [Rituxan] combination cohort, [with additional cohorts to come].

Reference

1. Michot JM, Chavez JC, Carpio C, et al. Clinical activity of CC-99282, a cereblon E3 ligase modulator (celmod) agent, in patients (pts) with relapsed/refractory non-Hodgkin lymphoma (R/R NHL) – results from a phase 1, open-label study. Presented at: 2022 EHA Congress; June 9-12, 2022; Vienna, Austria. Abstract S216.