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Relapsed and/or refractory (R/R) disease is not rare in patients with non-Hodgkin lymphoma (NHL), and poor prognosis frequently makes the treatment of these patients a challenge. Cereblon modulators induce degradation of transcription factors, such as zinc finger proteins Ikaros and Aiolos, and the cereblon modulator lenalidomide has demonstrated synergistic clinical antitumour activity in patients with R/R NHL when administered in combination with an anti-CD20 monoclonal antibody.
Jean-Marie Michot et al. conducted a phase 1b study, CC-122-NHL-001 (NCT02417285), to investigate the safety and activity of a next-generation cereblon modulating agent, avadomide (CC-122), in combination with obinutuzumab, an anti-CD20 monoclonal antibody. The trial was carried out in patients with R/R B-cell NHL who had not previously received lenalidomide, or were refractory to lenalidomide. Study results have been recently published in The Lancet Haematology, and here we summarize the key points.1
Table 1. A summary of inclusion criteria for dose escalation and expansion phases1
FL, follicular lymphoma; NHL, non-Hodgkin lymphoma; R/R, relapsed/refractory. |
|||
|
Dose escalation (n = 38) |
Dose expansion (n = 35) |
|
---|---|---|---|
Inclusion criteria |
CD20+ tumor |
CD20+ tumor |
|
Confirmed B-cell NHL |
Confirmed FL (Grade 1, 2, or 3a) |
||
R/R NHL with > 2 previous standard therapy regimens* or autologous stem-cell transplantation† |
R/R disease following > 1 previous standard systemic regimen‡ |
||
R/R indolent NHL following > 1 previous standard systemic regimen‡ |
FL1 cohort (n = 4) R/R FL following > 2 cycles of lenalidomide-based therapy |
FL2 cohort (n = 31) Patients with R/R FL who were lenalidomide-naïve and received > 1 standard therapy |
Avadomide and obinutuzumab administration is detailed in Figure 1. Granulocyte colony-stimulating factor (G-CSF) prophylaxis was not allowed, however, G-CSF support was used to treat neutropenia.
Figure 1. Study treatments1
By the cutoff date of March 27, 2019, a total of 73 patients had been treated. The median age was 61 years (range, 26–83), with 37% of patients (n = 27) being > 65 years old. More than half (58%) of the patients had advanced stage (III–IV) disease. Patient characteristics are provided in Table 2.
Table 2. Baseline characteristics
DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma. |
|
Characteristic |
Study population (N = 73) |
---|---|
Disease type |
n (%) |
FL Bendamustine refactory Rituximab refractory Double refractory* Early relapse† Standard risk High risk FL DLBCL Marginal zone lymphoma |
53 (73) 3 (6) 26 (49) 16 (30) 17 (32) 31 (58) 22 (42) 19 (26) 1 (1) |
Previous stem-cell transplantation Patients with FL Patients with DLBCL |
26 (36) 17 (23) 9 (12) |
Bone marrow involvement |
13 (18) |
Number of previous systemic treatments |
|
Median, n (range) 1 2 > 2 |
3 (1–11) 8 (11) 22 (30) 43 (59) |
Of the 73 patients who received study treatment, 30% were still on treatment at the cutoff date. The median treatment durations for avadomide and obinutuzumab were 30 weeks (range, 1–172) and 28 weeks (range, 1.1–34), respectively. Correspondingly, median number of treatment cycles for avadomide and obinutuzumab in the escalation phase were 7.5 and 6.5, respectively.
At least one dose interruption was observed in most patients (90%). The most common reason for dose reduction was adverse events (AEs). 29% of patients required one dose reduction, while 10% required two reductions. Seven patients discontinued treatment due to diarrhea, worsening of fatigue, toxoplasmosis, secondary tumor, and colitis, which were suspected to be related to avadomide treatment. Dose-limiting toxicities included Grade 4 neutropenia (n = 1 in the 3.0 mg AIC cohort; see Figure 1), Grade 3 sepsis (n = 1 in the 3.0 mg F6 cohort; see Figure 1), and Grade 5 tumor flare (n = 1 in 4.0 mg F6 cohort). Most treatment-emergent AEs were Grade 1/2 in severity. The ten most common AEs of any grade were:
In the dose escalation phase, the maximum tolerated dose and the non-tolerated dose were not established. Therefore, based on safety and pharmacokinetic–pharmacodynamic data, the Safety Review Committee established the recommended phase II dose: an oral dose of 3.0 mg avadomide given on a 5–7-day dosing schedule in combination with 1,000 mg obinutuzumab (intravenous) given on Days 2, 8, and 15 in Cycle 1 and on Day 1 in Cycles 2–8.
A summary of safety analysis results is provided in Table 3.
Table 3. Safety outcomes1
AE, adverse event; AML, acute myeloid leukemia; CRS, cytokine release syndrome; SAE, serious adverse event; TEAE, treatment-emergent adverse event. |
||
Outcome |
Patients (N = 73) |
|
---|---|---|
Treatment discontinuation, n (%) Disease progression, n AEs, n Physician decision, n Patient withdrawal, n |
51 (70) 28 8 5 4 |
|
Deaths,* n |
2 |
|
SAEs, n (%) Infusion-related reaction Pyrexia Cytokine release syndrome |
— 5 (7) 4 (5) 4 (5) |
|
Patients experiencing avadomide-related SAEs, n (%) Febrile neutropenia Pyrexia Neutropenia |
23 (32) 3 (4) 3 (4) 2 (3) |
|
Patients experiencing obinutuzumab-related SAEs, n (%) CRS |
20 (27) 4 (5) |
|
Most common Grade 3–4 TEAEs, n (%) |
Grade 3 |
Grade 4 |
Neutropenia |
19 (26) |
22 (30) |
Thrombocytopenia |
14 (19) |
3 (4) |
Most common avadomide-related Grade 3–4 TEAEs, n (%) Neutropenia Thrombocytopenia Pneumonia |
— 16 (22) 11 (15) 4 (6) |
— 21 (29) 1 (1) ― |
Most common obinutuzumab-related Grade 3–4 TEAEs, n (%) Neutropenia Thrombocytopenia Infusion-related reactions |
— 17 (23) 8 (11) 4 (6) |
— 15 (21) 3 (4) ― |
Figure 2. Best response rates among study cohorts1
CR, complete response; ORR, overall response rate; PR, partial response.The combination of avadomide and obinutuzumab has demonstrated a safety profile similar to each agent as monotherapy, and AEs were considered manageable and tolerable. The most common treatment-related AEs included thrombocytopenia, neutropenia, diarrhea (avadomide), infusion-related reactions, and pyrexia (obinutuzumab). Preliminary efficacy data were promising with a high ORR seen at all doses, and especially in patients who experienced early relapse. Pharmacokinetic properties of avadomide were dose proportional, and similar to those observed in preclinical studies. Overall, this study may provide a basis for further evaluation of cereblon modulators with novel anti-CD20 antibodies in patients with FL, who relapse or are refractory to rituximab-containing regimens.
References
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Which of the following would most increase your confidence in referring patients with R/R large B-cell lymphoma for CAR T-cell therapy?