A First-in-Human Study of Novel Cereblon Modulator Avadomide (CC-122) in Advanced Malignancies

DOI: 10.1158/1078-0432.CCR-18-1203 Published January 2019

Article Figures & Data

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Figure 1.
Mean (±SD) plasma concentrations of avadomide time profiles for cycle 1, day −1 (A) and for cycle 1, day 15 (B). Abbreviation: SD, standard deviation.
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Figure 2.
Percentage change from baseline in Aiolos protein levels at 1.5 and 5 hours after a single dose of avadomide and exposure–response relationships at 5 hours in CD3⁺ T cells (A) and CD19⁺ B cells (B). Abbreviations: CD, cluster of differentiation; MEFL, molecules of equivalent fluorescence label.
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Figure 3.
Percentage change from baseline in absolute cell counts on cycle 1, day −1 and cycle 1, day 15 at 1.5 hours by cohort, and avadomide exposure–response relationships at cycle 1, day 15; for CD19⁺ B cells (A), CD3⁺ T cells (B), and CD56⁺ NK cells (C) and ex vivo release of IL2 from peripheral blood mononuclear cells (D).

Table 1.

Patient demographics

Characteristic	Patients (N = 34)
Median (range) age, y	57 (31–78)
Age distribution
≤65 y	24 (71)
>65 y	10 (29)
Sex, n (%)
Male	17 (50)
Female	17 (50)
ECOG PS
0	13 (38)
1	21 (62)
Tumor type
Brain cancer	6 (18)
HCC	2 (6)
MM	2 (6)
NHL	5 (15)
Other solid tumors	19 (56)
Prior systemic anticancer therapies
0	1 (3)
1	6 (18)
2	2 (6)
3	8 (24)
4	5 (15)
5	3 (9)
6	6 (18)
7	2 (6)
9	1 (3)

Table 2.

TEAEs suspected to be avadomide-related

AEs, n (%)	Any grade (n = 34)	Grade 3/4 AE (n = 34)
≥1 TEAE	29 (85)	14 (41)
Fatigue	15 (44)	1 (3)
Neutropenia	10 (29)	9 (27)
Diarrhea	5 (15)	–
Alopecia	4 (12)	–
Pruritus	4 (12)	–
Maculopapular rash	4 (12)	–
Abdominal distension	3 (9)	–
Nausea	3 (9)	–
Vomiting	3 (9)	–
Asthenia	3 (9)	–
Decreased appetite	3 (9)	–
Hot flush	3 (9)	–
Anemia	2 (6)	–
Dry mouth	2 (6)	–
Pneumonia	2 (6)	2 (6)
Muscle spasms	2 (6)	–
Dysgeusia	2 (6)	–
Headache	2 (6)	–
Peripheral neuropathy	2 (6)	–
Thrombocytopenia	1 (3)	1 (3)
Cataract	1 (3)	1 (3)
Pyrexia	1 (3)	1 (3)
Pneumocystis jirovecii pneumonia	1 (3)	1 (3)
Muscular weakness	1 (3)	1 (3)
Angioedema	1 (3)	1 (3)

NOTE: Values shown are n (%). Avadomide-related TEAEs of any grade occurring in >1 patient and all grade 3/4 TEAEs are included.

Table 3.

Best overall response to avadomide by investigator assessment per tumor type and cohort

Best response, n (%)	Avadomide (0.5 mg)	Avadomide (1.0 mg)	Avadomide (1.5 mg)	Avadomide (2.0 mg)	Avadomide (2.5 mg)	Avadomide (3.0 mg)	Avadomide (3.5 mg)	Overall
All patients	(n = 3)	(n = 4)	(n = 3)	(n = 3)	(n = 6)	(n = 8)	(n = 7)	(n = 34)
Other solid tumor	(n = 3)	(n = 2)	(n = 2)	(n = 2)	(n = 2)	(n = 4)	(n = 4)	(n = 19)
SD	2 (67)	0	0	1 (50)	1 (50)	0	1 (25)	5 (26)
PD	1 (33)	2 (100)	2 (100)	1 (50)	1 (50)	3 (75)	1 (25)	11 (58)
Not evaluable	0	0	0	0	0	1 (25)	2 (50)	3 (16)
HCC	–	–	(n = 1)	(n = 1)	–	–	–	(n = 2)
SD	–	–	1 (100)	1 (100)	–	–	–	2 (100)
Brain cancer	–	(n = 1)	–	–	(n = 2)	(n = 1)	(n = 2)	(n = 6)
Nonprogression	–	1 (100)	–	–	1 (50)	1 (100)	2 (100)	5 (83)
Progression	–	0	–	–	1 (50)	0	0	1 (17)
NHL	–	–	–	–	(n = 1)	(n = 3)	(n = 1)	(n = 5)
CR	–	–	–	–	0	1 (33)	0	1 (20)
PR	–	–	–	–	0	1 (33)	1 (100)	2 (40)
PD	–	–	–	–	0	1 (33)	0	1 (20)
Not evaluable	–	–	–	–	1 (100)	0	0	1 (20)
MM	–	(n = 1)	–	–	(n = 1)	–	–	(n = 2)
SD	–	1 (100)	–	–	0	–	–	1 (50)
PD	–	0	–	–	1 (100)	–	–	1 (50)

Abbreviations: MM, multiple myeloma; PD, progressive disease; SD, stable disease.

Supplementary Data

Supplementary Data - Supplementary Table S1. Summary of avadomide plasma pharmacokinetic parameters by day and dose level Supplementary Figure S1. Representative flow cytometry analysis of Aiolos degradation in peripheral B cells (A) and T cells (B). Supplementary Figure S2. IL-2 expression correlates with Aiolos degradation in treated primary human T cells in vitro.