Summary
To date, there remains no cure for multiple myeloma, despite numerous advances in treatment over the last 20 years. For patients with this disease, their clinical history often involves the use of several different therapeutic interventions until their disease becomes resistant to that particular therapy.
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Original Article
First-in-Human Clinical Trial Results for Novel CELMoD CC-92480
Oncology Times
By Richard Simoneaux
To date, there remains no cure for multiple myeloma, despite numerous advances in treatment over the last 20 years. For patients with this disease, their clinical history often involves the use of several different therapeutic interventions until their disease becomes resistant to that particular therapy. As a result, there is a constant need for newer therapies to prolong patient lives as their disease becomes resistant to existing treatments.
The initial discovery that thalidomide could be used to treat patients with multiple myeloma gave rise to the immunomodulatory (IMiD) class of anti-myeloma therapeutics. Since then, that class of novel agents has expanded to include compounds with greater activity, such as lenalidomide, and a subsequent highly active, next-generation IMiD, pomalidomide.
Mechanistically, these IMiDs are thought to mediate their anti-myeloma activities by the targeting of the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) for degradation. Subsequent medicinal chemistry efforts around this class of compounds has led to the discovery and design of very potent cereblon E3 ligase modulators, termed CELMoDs.
One compound of particular interest is CC-92480 (J Med Chem 2020;63(13):6648-6676). This compound is currently being evaluated in a phase I clinical trial (NCT03374085).
Recently, as part of the 2020 ASCO Annual Meeting, Paul Richardson, MD, Clinical Program Leader and Director of Clinical Research of the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute, presented the first in-human clinical trial data for CC-92480 (Abstract 8500).
“The response data obtained were especially promising at the optimized dose and schedule with an objective response rate of 54.4 percent; this is especially positive when one considers the heavily pretreated patients enrolled in this study, many of whom had triple-class refractory disease,” Richardson noted. “These are the sort of response rates we see with other state-of-the-art new therapies in patient populations such as this, but typically in combination as compared to single agent.”
CC-92480 at ASH 2019
In a poster presented at the 2019 ASH Annual Meeting, results of in vitro preclinical studies of CC-92480 were revealed (Abstract 1812; Blood 2019;134(Supplement_1):1812).
Cereblon-modulator agents such as CC-92480 mediate the destruction of Ikaros and Aiolos, two transcription factors which contribute to myeloma cell survival. Upon exposure to CC-92480, the degradation of Ikaros and Aiolos was rapid, deep, and prolonged, resulting in significant anti-myeloma activity. In an in vitro binding assay, CC-92480 had a 50 percent inhibitory concentration (IC50) of 30 nM. In comparison, lenalidomide had an IC50 value of 1.27 mM, thus showing that CC-92480 clearly had a greater binding affinity for cereblon. CC-92480 showed more effective recruitment of Ikaros to the cereblon E3 ligase complex, greater cellular ubiquitination (a tagging of proteins with ubiquitin, marking them for proteasomal degradation) of Ikaros and more rapid and efficient degradation of Ikaros and Aiolos than pomalidomide.
Importantly, CC-92480 in multiple myeloma cell lines with acquired lenalidomide or pomalidomide resistance or lowered levels of cereblon displayed efficient degradation of Ikaros and Aiolos, as well as significant decreases in c-Myc and interferon regulatory factor 4 (two crucial transcription factors associated with apoptosis induction). Mechanistic studies revealed that the antimyeloma activity of CC-92480 was cereblon-dependent, as the effect was absent with complete loss of cereblon or stabilization of Ikaros and Aiolos.
“In these studies, CC-92480 displayed broad and potent antiproliferative activity across a large panel of multiple myeloma cell lines that displayed an array of pomalidomide or lenalidomide refractoriness, resistance or susceptibility,” Richardson stated. “In addition, these cell lines had genetic alterations such as an array of chromosomal translocations and oncogenic drivers that are frequently observed in patients with multiple myeloma.”
Roughly half of the MM cell lines tested displayed high sensitivity to CC-92480, having IC50 values ranging from 0.04 to 5 nM, while only two cell lines had IC50 values that were greater than 100 nM. “Importantly, CC-92480 inhibited multiple myeloma cell proliferation and induced apoptosis in those cell lines, which showed insensitivity to standard IMiD therapies (i.e., lenalidomide and pomalidomide).”
At concentrations that produced potent cytotoxicity in multiple myeloma cells, robust degradation of Aiolos and Ikaros occurred in peripheral blood mononuclear cell (PBMC) cultures, leading to increased T-cell activation as well as enhanced cytokine production (e.g., IL-2 and IFNg), ultimately resulting in vigorous immune-mediated multiple myeloma cell destruction in these PBMC co-cultures.
Summarizing the preclinical study results, Richardson noted, “CC-92480 showed potent antiproliferative and pro-apoptotic effects in multiple myeloma cell lines that had varying degrees of sensitivity or refractoriness to standard of care IMiD-based therapies.”
ASH 2019 Abstract 1815
In a poster presented at the ASH 2019 Annual Meeting, the results of in vitro and in vivo preclinical studies of CC-02480 in combination with a variety of standard-of-care therapies for multiple myeloma were revealed (Abstract 1815; Blood 2019; 134(Supplement_1):1815). The combination of CC-92480 plus dexamethasone was evaluated by quantifying caspase-3 activation in multiple myeloma cell line-based in vitro assays. The treatment of multiple myeloma cells with a combination of the proteasome inhibitor bortezomib and CC-92480 yielded data for Ikaros and Aiolos degradation, as well as β5-site proteasome activity.
In addition, the bortezomib plus CC-92480 combination was evaluated for apoptosis and cell viability using flow cytometry; washout experiments were also performed on this combination to more realistically mimic the gradually diminishing proteasome inhibition that occurs with prolonged bortezomib exposure in vivo. Antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) assays were utilized to gauge the effectiveness of the CC-92480-daratumumab combination. A lenalidomide-resistant (H929-1051) xenograft mouse model was utilized to evaluate combinations CC-92480 with dexamethasone or bortezomib.
Synergistic activity was noted in multiple myeloma cell line models for the combination of CC-92480 and dexamethasone. Importantly, that combination showed activity at levels that displayed little to no activity as a single agent.
When the CC-92480-dexamethasone combination was tested in the H929-1051 cell-based xenograft model, significant tumor growth inhibition (84% decrease) was noted. This activity was greater than either agent alone, with 34 percent and 20 percent decreases being noted for CC-92480 and dexamethasone, respectively.
CC-92480 maintained its ability to effect proteasome-mediated degradation of Ikaros and Aiolos despite the use of the proteasome inhibitor bortezomib at clinically relevant levels. Synergy was noted in vitro for the combination of CC-92480 and bortezomib in multiple myeloma cellular assays. This synergy for that combination was also noted for animal models, as complete or nearly complete tumor regression was noted in all animals in the experimental group. In addition six of these nine animals remained tumor-free for the 157-day observation period after termination of control group animals.
Monoclonal antibody therapies such as daratumumab and isatuximab target multiple myeloma cells for elimination by both cytotoxic and phagocytic mechanisms because of their overexpression of CD38. Treatment of a variety of different multiple myeloma cell lines with CC-92480 resulted in two- to three-fold increased surface expression of CD38 relative to controls. Multiple myeloma cells that were pretreated with CC-92480 prior to daratumumab displayed enhanced ADCC and ADCP relative to DMSO-treated controls.
“The strong synergy produced by CC-92480 in combination with dexamethasone, bortezomib, plus an anti-CD38 antibody (equivalent to daratumumab) against multiple myeloma in pre-clinical models shows that these combinations have the potential to be of clinical benefit, and strongly supports the rationale for further testing in a clinical setting,” Richardson noted.
CC-92480-MM-001 Phase I Trial
Among the key eligibility criteria were relapsed and refractory multiple myeloma; resistant to, intolerant to and/or otherwise ineligible for currently available therapies. Among the primary study endpoints were pharmacokinetics assessment, correlatives, safety and determination of the maximum tolerated dosage (MTD), and the recommended phase II dosage (RP2D). Secondary study endpoints included preliminary efficacy assessment.
In the dose-escalation part of the study, both continuous dosing schedules (10/14 days x 2, QD and 21/28 days, QD) and intensive dosing schedules (3/14 days x 2, BID and 7/14 days x 2, BID/QD) were evaluated for the combination of orally dosed CC-92480 plus dexamethasone.
A total of 76 patients were enrolled in this study to date. Regarding the nature of the patients’ clinical histories, Richardson observed, “Clearly, this was a heavily pretreated patient population, with patients having a median number of six prior therapies (range 2-13 prior therapies).
“In addition, most patients (76.3%) had stem cell transplant, while half had disease that was classified as triple-class refractory, that is, disease refractory to one or more IMiD, one proteasome inhibitor, and one anti-CD38-targeting monoclonal antibody. It’s also important to note that all the patients were dexamethasone exposed and refractory.”
Based on the dose-limiting toxicities encountered at the 1.0 mg QD oral dosing level for the 10/14 days x 2 (2 patients, 1-neutropenia plus 1-febrile neutropenia) and 21/28 days (3 patients; 1-neutropenia; 1-febrile neutropenia; 1-sepsis) continuous dosing schedules, the MTD was set at 1.0 mg QD for those respective regimens, while the RP2D was set as 1.0 mg QD for the 21/28 day schedule.
Response data for patients dosed at the RP2D of 1.0 mg QD 21/28 days were particularly promising. The distribution of the 11 patients included at this level (7 of whom had triple-class refractory disease) was as follows: complete response—1; very good partial response—2; partial response—3; minimal response—1; stable disease—4. These data afforded an ORR of 54.5 percent, a clinical benefit rate of 63.6 percent and a disease control rate of 100 percent.
“These levels of response are what we might expect to see in patients receiving more intensive combinations, including cellular therapies. This is very encouraging when one considers the fact that this is an oral therapy and single agent,” Richardson explained. Interestingly, the majority of responders (10 of 16) had disease that was also dual IMiD-refractory (i.e., refractory to both lenalidomide and pomalidomide).
Summarizing their findings, Richardson stated, “The combination of CC-92480 plus dexamethasone displayed a manageable safety profile in a heavily pre-treated patient population. Most treatment-related AEs were related to myelosuppression and proved manageable with dose reduction and supportive care, with a very low rate of discontinuation and no treatment related mortality.”
“The activity we observed at the therapeutic levels used was promising in patients with difficult-to-treat disease characteristics (e.g., pomalidomide-resistant or refractory, triple-class refractory, or extramedullary disease),” Richardson observed. “The study is currently ongoing with a large dose-expansion cohort planned at the RP2D of 1.0 mg QD for 21/28 days.”
When discussing future plans for clinical evaluations of CC-92480, he answered, “The phase I/II CC-92480-MM-002 clinical study (NCT03989414), which is evaluating the safety and efficacy of CC-92480 in combination with other standard antimyeloma therapies, is currently ongoing and enrolling rapidly, despite all the ongoing challenges of the COVID 19 era.”
Richard Simoneaux is a contributing writer.