Avadomide Shows Promising Clinical Activity and Tolerability in Relapsed/Refractory DLBCL

Avadomide monotherapy demonstrated preliminary clinical efficacy in patients with relapsed and refractory diffuse large B-cell lymphoma (DLBCL), according to results from a phase I study published in Blood. The authors, led by Cecilia Carpio, MD, from the Universitat Autònoma de Barcelona, reported that the investigational drug was well tolerated, with a low incidence of discontinuations due to adverse events (AEs), but added that tolerability could be improved with adjusted dosing schedules.

Avadomide, previously known as CC-122, is a cereblon-modulating agent that exerts direct cell autonomous activity against malignant B cells and immunomodulatory effects, the researchers explained. “In preclinical models, avadomide has demonstrated anti-tumor activities in both germinal center B-cell–like (GCB) and activated B-cell–like (ABC) DLBCL cell lines, indicating that its activity is independent of [cell of origin],” they added.

The multicenter, open-label CC-122-ST-001 study evaluated the safety and efficacy of avadomide in patients with DLBCL who had progressive disease or who were unable to tolerate one or more prior anthracycline- or alkylating-containing regimens. All patients also had:

  • ≥1 measurable lesion
  • Eastern Cooperative Oncology Group performance status of ≤2
  • absolute neutrophil count ≥1.5×109/L
  • platelets ≥60×109/L
  • adequate hepatic and renal function

The trial enrolled a total of 97 patients with relapsed/refractory DLBCL (median age = 62 years; range = 25-91). Patients had previously received a median of three systemic anti-cancer therapies. Evaluable patients also were characterized according to gene expression classifier groups, based on characteristics of the tumor microenvironment: 32 had classifier-positive DLBCL (defined as an enriched infiltration of T cells and macrophages) and 37 had classifier-negative DLBCL (defined as a predominance of intratumoral B cells).

“Based on results of this study, the recommended phase II dose was determined to be avadomide 3 mg formulated capsule, administered on a 5/7-day schedule.”

—Cecilia Carpio, MD

Participants were treated with avadomide at doses ranging from 3 mg to 5 mg in different formulations and in the following schedules:

  • avadomide hydrochloride 3 mg once daily on a continuous schedule in 28-day cycles (n=24)
  • avadomide hydrochloride 4 mg or 5 mg on intermittent schedules (4 mg on 5/7 days [n=39], 4 mg on 21/28 days [n=3], and 5 mg on 5/7 days [n=5])
  • avadomide 3 mg or 4 mg as a formulated capsule on an intermittent schedule (3 mg on 5/7 days [n=18] and 4 mg on 5/7 days [n=8])

Patients were treated until disease progression, unacceptable toxicity, or patient/physician decision to discontinue therapy.

The study found that the intermittent 5/7-day dosing schedule was the most well-tolerated, which allowed for increases in dose intensity. For example, in the continuously dosed avadomide 3 mg group, mean dose intensity was 16.5 mg/week, compared with 19 mg/week in the avadomide 4 mg intermittently dosed group. Seventeen percent of patients experienced a dose-limiting toxicity in cycle 1, which led to dose reduction, interruption, or both in 10 individuals.

Approximately 85% of patients experienced ≥1 grade 3/4 treatment-emergent AE; the most common of these events were neutropenia (51%), infections (24%), anemia (12%), and febrile neutropenia (10%). The most common any-grade treatment-emergent included neutropenia (66%), infections (57%), and asthenia (46%).

The researchers reported that switching from a continuous dosing schedule with avadomide 3 mg to an intermittent 4 mg dosing or avadomide 3 mg as a formulated capsule led to a trend toward less frequent all-grade neutropenia (76% vs. 62% and 56%, respectively), less severe neutropenia (grades 3/4, 64% vs. 39% and 39%, respectively), and less frequent febrile neutropenia (all grades, 12% vs. 5% and 0%, respectively).

The most common reason for treatment discontinuation was disease progression (68%) and, overall, 10% of patients discontinued treatment due to AEs. A total of 25 patients died during study follow-up; 21 of these deaths were considered related to disease progression, 3 to other causes unrelated to study drug, and 1 to grade 5 pneumonia (which was suspected to be related to avadomide). Another 5 patients discontinued treatment when they became eligible for hematopoietic cell transplantation.

“Based on results of this study, the recommended phase II dose was determined to be avadomide 3 mg formulated capsule, administered on a 5/7-day schedule,” the authors wrote.

When investigators assessed preliminary response rates, they found that patients had an overall response rate (ORR) of 28%, including a complete response (CR) rate of 9%. Response rates appeared to differ according to gene expression: Patients in the classifier-positive DLBCL subgroup had a significantly longer median PFS compared with the subgroup of classifier-negative patients (6 months vs. 1.5 months, respectively; hazard ratio = 0.49; 95% CI 0.280-0.857; p=0.0096).

“An understanding of the interplay between avadomide effects and the tumor microenvironment, as well as the biology associated with defined cell types within classifier-positive tumors, can inform patient selection strategies and combination strategies [in future trials],” the researchers concluded.

Limitations of the early-phase study include the small sample size in each of the individual arms and the lack of a randomized control group.

Study authors report relationships with Celgene, which sponsored the trial.

Reference

Carpio C, Bouabdallah R, Ysebaert L, et al. Avadomide monotherapy in relapsed/refractory DLBCL: Safety, efficacy, and a predictive gene classifier. Blood. 2020 January 23. [Epub ahead of print]