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

Rasco, Drew W.; Papadopoulos, Kyriakos P.; Pourdehnad, Michael; Gandhi, Anita K.; Hagner, Patrick R.; Li, Yan; Wei, Xin; Chopra, Rajesh; Hege, Kristen; DiMartino, Jorge; Shih, Kent C.

doi:10.1158/1078-0432.ccr-18-1203

Cited by 78 publications

(95 citation statements)

References 29 publications

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“…The avadomide dose used in this study (single 3‐mg oral dose) was appropriate from a safety perspective because single doses up to 15 mg were well tolerated in healthy subjects . In addition, this dose level is directly relevant to potential clinical usage because it is tested in ongoing cancer studies . Because the accumulation ratios are low in patients (ranging from 0.7 to 1.5), PK findings using single doses of 3 mg plausibly apply to chronic dosing at similar levels.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, this dose level is directly relevant to potential clinical usage because it is tested in ongoing cancer studies . Because the accumulation ratios are low in patients (ranging from 0.7 to 1.5), PK findings using single doses of 3 mg plausibly apply to chronic dosing at similar levels.…”

Section: Discussionmentioning

confidence: 99%

“…Avadomide has multiple pharmacologic activities including potent immune modulation, antiangiogenic, antitumor, and antiproliferative activity. Due to these potent activities, avadomide is being evaluated as an oncology treatment for non‐Hodgkin lymphoma, including diffuse large B‐cell lymphoma; chronic lymphocytic leukemia; multiple myeloma; and/or advanced solid tumors, including glioblastoma multiforme and hepatocellular carcinoma …”

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confidence: 99%

“…The pharmacokinetics (PK) of avadomide was previously evaluated in patients with advanced solid tumors and hematologic malignancies as part of the first‐in‐human study . Plasma avadomide exposure increased in a dose‐dependent manner across the 0.5‐ to 3.5‐mg dose range.…”

mentioning

confidence: 99%

“…Plasma avadomide exposure increased in a dose‐dependent manner across the 0.5‐ to 3.5‐mg dose range. The PK profile of avadomide was characterized by rapid absorption with half‐life ranging from 7.7 to 27.9 hours, and the contribution of renal excretion to the elimination pathway was demonstrated based on the significant urinary recovery of avadomide (18% to 35% recovery of unchanged drug over 24 hours) . Healthy adult subjects receiving a single oral dose ranging from 3 to 15 mg avadomide showed a rapid absorption profile (time to maximum observed plasma concentration, t max approximately 1 hour) and a mean half‐life of 7.6 to 8.9 hours .…”

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confidence: 99%

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Drug‐Drug Interaction Study to Assess the Effect of Cytochrome P450 Inhibition and Induction on the Pharmacokinetics of the Novel Cereblon Modulator Avadomide (CC‐122) in Healthy Adult Subjects

Ogasawara¹,

MacGorman²,

Liu³

et al. 2019

The Journal of Clinical Pharma

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Avadomide (CC‐122) is a novel immunomodulatory drug that binds to cereblon, a member of the Cullin 4‐RING E3 ubiquitin ligase complex. Avadomide has multiple pharmacologic activities including potent immune modulation, antiangiogenic, antitumor, and antiproliferative activity and is being evaluated as an oncology treatment for hematologic malignancies and advanced solid tumors. In vitro study has indicated that cytochrome P450 (CYP) 3A and CYP1A2 appear to be the major enzymes involved in the oxidative metabolism of avadomide. The effects of CYP3A inhibition/induction and CYP1A2 inhibition on the pharmacokinetics of avadomide in healthy adult subjects were assessed in 3 parts of an open‐label, nonrandomized, 2‐period, single‐sequence crossover study. Following a single oral dose of 3 mg, avadomide exposure when coadministered with the CYP1A2 inhibitor fluvoxamine was 154.81% and 107.59% of that when administered alone, for area under the plasma concentration‐time curve from time 0 to infinity (AUC0‐inf) and maximum observed plasma concentration (Cmax), respectively. Avadomide exposures, when coadministered with the CYP3A inhibitor itraconazole, were 100.0% and 93.64% of that when administered alone, for AUC0‐inf and Cmax, respectively. Avadomide exposures when coadministered with the CYP3A inducer rifampin were 62.83% and 88.17% of that when administered alone, for AUC0‐inf and Cmax, respectively. Avadomide was well tolerated when administered as a single oral dose of 3 mg alone or coadministered with fluvoxamine, itraconazole, or rifampin. These results should serve as the basis for avadomide dose recommendations when it is coadministered with strong CYP3A and CYP1A2 inhibitors and with rifampin.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Drug‐Drug Interaction Study to Assess the Effect of Cytochrome P450 Inhibition and Induction on the Pharmacokinetics of the Novel Cereblon Modulator Avadomide (CC‐122) in Healthy Adult Subjects

Ogasawara¹,

MacGorman²,

Liu³

et al. 2019

The Journal of Clinical Pharma

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Mechanistic Basis and Role of Immunomodulatory Drugs

Gribben

2024

Precision Cancer Therapies Vol 2 ‐ Immunologic Approaches for the Treatment of Lymphoid Malignancies ‐ From Concept to Practice

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Single‐Dose Pharmacokinetics, Safety, and Tolerability of Avadomide (CC‐122) in Subjects With Mild, Moderate, or Severe Renal Impairment

Li¹,

MacGorman²,

Liu³

et al. 2019

Clinical Pharm in Drug Dev

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CC-122 (Avadomide) is a nonphthalimide analogue of thalidomide that has multiple pharmacological activities including immune modulation of several immune cell subsets,antigrowth activity,antiproliferative activity,and antiangiogenic activity. CC-122 as monotherapy and in combination with other agents is being evaluated for multiple indications including hematologic malignancies and advanced solid tumors. Given that renal clearance is one of the major routes of elimination for CC-122 and its clearance/exposure could be affected by renal impairment, a total of 50 subjects with various degrees of renal function were enrolled in an open-label, single-dose study to evaluate the impact of renal impairment on CC-122 pharmacokinetic disposition. The study showed that following administration of a single oral dose of 3 mg CC-122, renal impairment reduced both the apparent total plasma clearance and renal clearance of CC-122, but it had less impact on CC-122 absorption, as demonstrated by similar T max and C max among groups with various degrees of renal function. Compared with exposure in subjects with normal renal function, total plasma exposure to CC-122 increased by ß20%, ß50%, and ß120% in subjects with mild, moderate, and severe renal insufficiency, respectively. Results from this study combined with modeling/simulation suggest that dose adjustments are necessary in patients with moderate or severe but not with mild renal impairment. Finally, a single dose of 3 mg CC-122 was safe and well tolerated by healthy subjects and subjects with mild, moderate, and severe renal impairment.

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

Cited by 78 publications

References 29 publications

Drug‐Drug Interaction Study to Assess the Effect of Cytochrome P450 Inhibition and Induction on the Pharmacokinetics of the Novel Cereblon Modulator Avadomide (CC‐122) in Healthy Adult Subjects

Drug‐Drug Interaction Study to Assess the Effect of Cytochrome P450 Inhibition and Induction on the Pharmacokinetics of the Novel Cereblon Modulator Avadomide (CC‐122) in Healthy Adult Subjects

Mechanistic Basis and Role of Immunomodulatory Drugs

Single‐Dose Pharmacokinetics, Safety, and Tolerability of Avadomide (CC‐122) in Subjects With Mild, Moderate, or Severe Renal Impairment

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