BET Inhibitor CC-90010 Shows Activity in Advanced Solid Tumors, Relapsed/Refractory Non-Hodgkin Lymphoma

Victor Moreno Garcia, PhD

The reversible BET inhibitor CC-90010 was found to have preliminary antitumor activity in patients with heavily pretreated, advanced solid tumors and relapsed/refractory non-Hodgkin lymphoma, according to the updated results of a phase 1 study (NCT03220347) presented during the 2020 ESMO Virtual Congress.¹

In patients enrolled on part A of the study (n = 69), the agent elicited a clinical benefit rate (CBR) of 17.4% was reported (n = 12; 95% CI, 9.3-28.4) along with an objective response rate (ORR) of 2.9% (n = 2; 0.4-10.1).

During treatment, 1 patient (1.4%) with diffuse astrocytoma achieved a complete response (CR) and continued on the treatment for 18 cycles until before experiencing disease progression. An additional patient with endometrial carcinoma achieved a partial response (PR) and was able to complete 8 cycles of treatment. Ten patients were able to maintain stable disease (SD) for at least 4 months; 3 patients had prolonged SD for 24 cycles, 1 patient had SD for 16 cycles, and 2 patients had SD for 15 cycles. Two patients with stable disease are still receiving treatment at cycles 28 and 24.

In part B of the study (n = 14), CC-90010 induced a CBR of 21.4% (n = 3; 95% CI, 4.7-50.8) along with an ORR of 14.3% (95% CI, 1.8-42.8). One patient with diffuse large B-cell lymphoma (DLBCL) experienced a CR and finished 5 cycles of treatment, while another patient with the same disease achieved a PR and completed 3 cycles. Two patients achieved SD (14.3%), 1 (7.1%) of whom maintained stability for 4 months or longer.

“CC-90010 was well-tolerated and showed preliminary antitumor activity in heavily pretreated patients with advanced solid tumors and relapsed DLBCL,” Victor Moreno Garcia, PhD, director of Clinical Research at the Phase 1 Trials Unit START at University Hospital Fundación Jiménez Díaz, said in a presentation during the meeting. “Treatment-related adverse effects [TRAEs] were mostly mild and manageable with dose interruptions and reductions.”

A potent and reversible small-molecule BET inhibitor, CC-90010 preferentially binds to bromodomain-containing proteins. The agent was found to lead to tumor reduction when evaluated in xenograft models and encouraging activity in patients with advanced malignancies.² Because BET proteins are key players in the regulation of MYC oncogene expression, investigators hypothesized that CC-90010 may represent a potential effective option for patients with high-grade B-cell lymphoma, particularly those who have MYC rearrangements.^3,4

The multicenter, open-label, first-in-human phase 1 trial was comprised of 2 parts; part A focused was the dose-escalation phase of the trial, while the ongoing part B portion is evaluating the safety and efficacy of the agent in an expansion cohort.

To be eligible for the dose-escalation portion of the study, patients needed to be 18 years of age or older with either advanced unresectable solid tumors (n = 67) or relapsed/refractory DLBCL (n = 2). Additionally, patients needed to have an ECOG performance status of 0-1 and have progressed on or were unable to tolerate a standard anticancer treatment.

Numerous doses of CC-90010 were evaluated in part A, although the 45-mg dose, delivered 4 days on and 24 days off, was selected as the recommended phase 2 dose; the 30-mg dose, delivered 3 days on and 11 days off, was selected as an alternative dosing regimen. Dose escalation was completed on December 10, 2018 and the primary objectives of part A were reached.

Two cohorts of patients received the 45-mg dose of CC-90010: cohort 1 was comprised of 14 patients with relapsed/refractory DLBCL and cohort 2 was comprised of 1 patient with advanced basal cell carcinoma and 1 patient with NUT midline carcinomas. Cohort 1 is ongoing and cohort 2 has stopped. The recently-opened third cohort is comprised of patients with relapsed/refractory DLBCL who are receiving the agent at the 30-mg dose.

Patients enrolled on the dose-escalation portion of the trial had a median age of 57 years and were primarily male (n = 38; 55%). Meanwhile, those included in the safety and efficacy portion of the study had a median age of 63.5 years and 57% were male (n = 8). In part A, 48% (n = 33) of patients had an ECOG performance status of 0, while 52% (n = 36) had a status of 1; in part B, these percentages were 21% and 79%, respectively. The median number of previous systemic cancer therapies received was 4 in both parts of the trial.

Moreover, the majority of the patients, of 97% (n = 67) in part A had solid tumors, while 3% (n = 2) had DLBCL. Eighty-six percent (n = 12) of the patients included in part B had DLBCL, while 14% (n = 2) had solid tumors. Notably, at the time of enrollment, stage IV cancer was observed in the majority of patients who had solid tumors.

The median treatment duration was 8 weeks, and the majority of patients were able to receive their planned dose. During the dose-escalation portion of the trial, the monthly dosing schedule of 4 days on and 24 days off was found to have the lowest number of dose modifications compared with other schedules examined. Additionally, the monthly schedule of 4 days on and 24 days off and the biweekly dosing schedules of 3 days on and 11 days off were found to have safety profiles that were more favorable than that of the weekly dosing schedule.

“Adverse effects [AEs] were the most common reason for dose reduction—12% in part A and 14% in part B—and interruption—45% in part A and 43% in part B,” noted Moreno. “One patient in part A discontinued [treatment] due to an AE that was not treatment related.”

In total, 32 patients in part A had progressive disease (46.4%) and 12 were not evaluable (17.4%). Patients on dose escalation portion of the study were additionally reported to have had a median overall survival (OS) of 180 days (95% CI, 161-254) and a median progression-free survival (PFS) of 57 days (95% CI, 52-81). Four patients in part B experienced progressive disease (7.1%) while another 6 were not evaluable (42.9%). Patients enrolled on part B portion reportedly had a median OS of 102 days (95% CI, 92-NE) and a median PFS of 60 days (95% CI, 12-126). One heavily pre-treated patient who had been diagnosed with relapsed/refractory DLBCL experienced a 57% regression of target lesions following treatment.

The majority of treatment-related AEs were found to be mild or moderate in severity, reversible, and easily managed through dose adjustments and/or supportive care. The high rate of thrombocytopenia reported in part B (any grade, 79%; n = 11; grade 3/4, 64%; n = 9) is reflective of the high number of patients with hematologic malignancies on the trial, according to Moreno. Other common AEs reported in part B included anemia (any grade, 43%; grade 3/4 28%), neutropenia (any grade, 29%; grade 3/4 21%), nausea (any grade, 29%), and asthenia (any grade 21%; grade 3/4 7%). No treatment-related deaths occurred.

“This study is ongoing in [patients with] relapsed/refractory DLBCL and advanced solid tumors at the recommended phase 2 doses and relapsed/refractory DLBCL at an alternative dosing regimen," Moreno concluded.

References

1. Moreno V, Braña Im Sepulveda JM, et al. CC-90010, a reversible, oral bromodomain and extra-terminal (BET) inhibitor in patients with advanced solid tumors and relapsed/refractory non-Hodgkin lymphoma: updated results of a phase 1 study. Presented at: 2020 ESMO Virtual Congress; Virtual. September 19-21, 2020. Accessed September 28, 2020. Abstract 5270.
2. Moreno V, Sepulveda JM, Vieito M, et al. Phase I study of CC-90010, a reversible, oral BET inhibitor in patients with advanced solid tumors and relapsed/refractory non-Hodgkin's lymphoma. Ann of Oncol. 2020;S0923-7534(20):36381-X. doi:10.1016/j.annonc.2020.03.294
3. Mertz JA, Conery AR, Bryant BM, et al. Targeting MYC dependence in cancer by inhibiting BET bromodomains. Natl Acad Sci USA. 2011;108(40):16669-16674. doi:10.1073/pnas.1108190108.
4. Delmore JE, Issa GC, Lemieux ME, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011;146(6):904-917. doi:10.1016/j.cell.2011.08.017