Phase I results suggest a tolerable safety profile for avadomide and obinutuzumab in patients with R/R B-cell NHL

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

Study design

• This was a multi-center, phase Ib dose escalation and dose expansion study (see Table 1).
• The dose expansion phase was done at a recommended phase II dose and excluded patients with R/R diffuse large B-cell lymphoma (DLBCL).

Table 1. A summary of inclusion criteria for dose escalation and expansion phases¹

FL, follicular lymphoma; NHL, non-Hodgkin lymphoma; R/R, relapsed/refractory. *Includes rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone or similar first-line therapy and > 1 salvage therapy. †In patients who were sensitive to chemotherapy. ‡Includes chemotherapy, immunotherapy, or chemoimmunotherapy.
	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

• Eligibility criteria were as follows:
  • Aged ≥ 18 years
  • Measurable disease (with at least one lesion > 1.5 cm in the transverse diameter)
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0–1
  • Sufficient hematological, hepatic, and renal function
• The expansion part did not include patients with DLBCL according to the preliminary safety and efficacy data obtained during phase Ia.
• Primary endpoint was safety and tolerability of the combination. Secondary endpoints included preliminary antitumor activity through tumor response, duration of response, and progression-free survival (PFS), and the pharmacokinetic parameters of avadomide.

Study treatments

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.

Patients

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. *Refractory to both rituximab and an alkylating agent. †Disease progression < 24 months after starting the treatment.
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)

Results

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.

Safety

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:

• diarrhea (30% Grade 1–2; 3%, Grade 3)
• pyrexia (27% Grade 1–2; 1% Grade 3)
• asthenia (27%, Grade 1–2)
• constipation (21%, Grade 1–2)
• cough (21%, Grade 1–2)
• muscle spasms (19%, Grade 1–2)
• thrombocytopenia (18% Grade 1–2; 19% Grade 3; 4% Grade 4)
• anemia (18% Grade 1–2; 5% Grade 3)
• bronchitis (18% Grade 1–2; 1% Grade 3)
• nausea (16%, Grade 1–2).

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. *Tumor flare and AML (n = 1, each) considered related to treatment.
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) ―

Efficacy

• Median duration of follow-up was 253 days.
• Overall response rate (ORR) in all patients was 68% (95% CI, 56.6–78.9) with a median duration of response of 18.9 months (95% CI, 9.7–25.8).
• Both complete and partial response rates were 34% for the entire study population (N = 73), and best response rates among study cohorts are shown in Figure 2.
• ORR in standard-risk and high-risk patients with FL was 81% (range, 62–92) and 68% (range, 45–86), respectively.
• The overall median PFS in all patients was 16.2 months (range, 10.9–22.5), with a median PFS in patients with R/R FL and with R/R DLBCL of 16.6 months (range, 11.4–24.9) and 4.7 months (range, 1.8–13.8), respectively.
• Median PFS was 16.4 months in lenalidomide-naïve patients with R/R FL; it was not reached in four patients who had previously received lenalidomide. The 12-month PFS was 71.9% for lenalidomide-naïve and 75% for lenalidomide-treated patients.
• Tumor volume was reduced in 90% of patients (n = 66) after two cycles of treatment.

Conclusion

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.