CC-122 Plus Obinutuzumab: An Effective, Chemotherapy-Free Regimen for Non-Hodgkin Lymphoma?

Results from a phase Ib study of CC-122 (an oral agent that binds the cereblon ubiquitin ligase complex), in combination with obinutuzumab, showed positive response rates in patients with relapsed and refractory B-cell non-Hodgkin lymphoma (NHL), according to a presentation at the 2017 ASH Annual Meeting. At 12-month follow-up, two-thirds of patients responded to this chemotherapy-free regimen without new safety signals.

“Patients with relapsed/refractory NHL, including follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) have a poor prognosis with limited second- and thirdline treatment options,” noted lead author Jean-Marie Michot, MD, of Institut Gustave Roussy in Villejuif, France. “[Patients with FL] experiencing progression within two years of initial diagnosis, and those double-refractory to both rituximab and chemotherapy have particularly poor outcomes,” the researchers noted.

The study enrolled 38 adult patients (median age = 60 years; range = 26-81 years) who had histologically or cytologically confirmed CD20-positive B-cell NHL that relapsed or was refractory to one or more prior treatments for FL/marginal zone lymphoma (MZL), or after two or more regimens and/or autologous hematopoietic cell transplantation (AHCT) for DLBCL. The median number of prior therapies was four (range = 1-12 therapies); 14 patients (37%) had undergone AHCT.

Of the 38 participants, 19 had DLBCL, 18 had FL, and one had MZL. In the FL cohort, 10 people were either double-refractory or relapsed early and were considered “high risk,” the authors noted. Eight patients (42%) with DLBCL had transformed DLBCL, and eight (42%) with FL/MZL had disease that relapsed within 12 months of firstline treatment.

During 28-day cycles, patients received:

  • CC-122 administered orally on days 1-5, followed by 2 days off treatment in escalating doses (1, 2, 3, or 4 mg)
  • intravenous obinutuzumab 1,000 mg on days 2, 8, and 15 of cycle 1, and day 1 of cycles 2-8

As of May 1, 2017 (data cutoff), patients were followed for at least 12 months.

Two patients experienced a dose-limiting toxicity: one grade 4 neutropenia (at CC-122 3 mg) and one grade 5 tumor flare (at CC-122 4 mg). The most common (occurring in ≥10% of patients) grade 3/4 treatment-related adverse events (AEs) included neutropenia (55%) and thrombocytopenia (26%). Eight patients (21%) experienced at least one serious AE related to CC-122, but febrile neutropenia (n=2) was the only serious AE to occur in at least two patients. Three deaths occurred: two related to progressive disease and one related to an AE (tumor flare). “The safety profile [the study’s primary endpoint] was consistent with other studies of CC-122,” the researchers reported.

The 12-month overall response rate (ORR) was 66 percent, with 11 patients (29%) achieving a complete response (CR).

When reviewing data across the subgroups, ORR and CR rates were comparable regardless of disease type:

  • DLBCL: 47% and 11%
  • FL: 83% and 50%

Rates of 12-month progression-free survival (PFS; a secondary efficacy endpoint) appeared to be higher among patients who were double-refractory to rituximab and chemotherapy, compared with those who were not (60% and 51%, respectively; p value not provided). However, PFS rates were higher among patients who had not experienced early relapse, compared with those who did (58% and 51%, respectively; p value not provided).

Overall, the authors concluded that the “chemotherapy-free combination of CC-122 and obinutuzumab was well tolerated with promising response rates, and durable remissions in relapsed/refractory B-cell NHL.”

The small patient population and lack of a comparator arm limit the findings of this early-phase study.

The authors report financial relationships with Celgene (the manufacturer of CC-122) and Roche (the manufacturer of obinutuzumab).


Reference

Michot J, Bouabdallah R, Doorduijn JK, et al. CC-122, a novel cereblon modulating agent, in combination with obinutuzumab (GA101) in patients with relapsed and refractory (R/R) B–cell non–Hodgkin lymphoma (NHL). Abstract #411. Presented at the 2017 American Society of Hematology Annual Meeting, December 10, 2017; Atlanta, GA.

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