CBP/p300 Inhibition Expands Beyond Hematology Field to Show Efficacy in Solid Tumors

Epigenetic modulation of cancer cell plasticity via inhibition of CBP/p300 has shown clinical potential in blocking the underlying transcriptional mechanisms that drive solid tumor growth and treatment resistance to commonly used oncogene-targeting agents, such as KRAS inhibitors and EGFR inhibitors. This approach expands the use of epigenetic therapy beyond its traditional setting in hematologic malignancies.

“Sometimes when we talk about epigenetic therapy, we think hematological malignancies,” Omar Saavedra, MD, said in an interview with OncLive. “It’s important to feel comfortable, or at least to be familiarized with epigenetic therapies. It’s important to know that now we are seeing a signal of response with these kinds of therapies in solid tumors that historically are associated with hematologic malignancies.”

Saavedra is a medical oncologist and clinical investigator at NEXT Oncology in Barcelona, Spain.

Data from several ongoing studies indicate the promise of targeting CBP/p300 across solid tumors, as well as in hematologic malignancies.

How does research with TT125-802 aim to show the potential utility of targeting CBP/p300 in solid tumors?

TT125-802 is a selective bromodomain inhibitor of CBP/p300 that is designed to inhibit the transcriptional pathways that drive treatment resistance and non–oncogene addiction in cancer. The agent is under investigation as monotherapy in patients with solid tumors in an ongoing, first-in-human phase 1 trial (NCT06403436).¹

“Oncogene addiction is important in the evolution of cancer,” Saavedra stated. “Sometimes, if you block this non–oncogene addiction, you can also have responses.”

The completed dose-escalation cohort investigated the fasted administration of TT125-802 across 5 cohorts of patients with solid tumors at doses of 15 mg once daily (n = 5), 30 mg once daily (n = 4), 50 mg once daily (n = 6), 100 mg once daily (n = 5), and 60 mg twice daily (n = 4), as well as the administration of TT125-802 with food at 30 mg once daily in a population of patients enriched for non–small cell lung cancer (NSCLC; n = 4) and at 60 mg once daily in another group patients with NSCLC (n = 6). Tumor types enrolled in this portion of the study included adenoid cystic carcinoma (n = 4), dedifferentiated liposarcoma (n = 1), NSCLC (n = 14), NUT carcinoma (n = 1), cylindroma (n = 1), anal cancer (n = 2), breast cancer (n = 2), colorectal cancer (n = 3), ampullary carcinoma (n = 1), castration-resistant prostate cancer (CRPC; n = 2), thymic cancer (n = 1), pancreatic ductal adenocarcinoma (n = 1), undifferentiated pleomorphic sarcoma (n = 1), and enteroid carcinoma (n = 1).

Based on the outcomes from the dose-escalation portion, 60 mg once daily without food restriction was chosen as the recommended dose for expansion (RDE). The monotherapy enrichment portion of the trial is ongoing in patients with NSCLC and is enrolling a cohort of patients with squamous NSCLC, as well as a cohort of patients with KRAS G12C– and EGFR-mutated NSCLC.

Safety and tolerability, as well as the estimation of the maximum tolerated dose (MTD) and/or RDE, served as the primary end points. Secondary end points include characterization of pharmacokinetics, overall response rate (ORR) per RECIST 1.1 criteria, disease control rate (DCR), duration of response, and progression-free survival. The trial is also assessing pharmacokinetic/pharmacodynamic relationships, as well as biomarkers.

“Epigenetic therapy is common in hematological [malignancies],” Saavedra said about the rationale for exploring TT125-802 in solid tumors. “We have [data showing the] efficacy of epigenetic therapy [with] CBP/p300 inhibitors in multiple myeloma, for example. But if we talk about solid tumors, [our approach should be] different, because the microenvironment is completely different, and we don’t know exactly where this kind of drug could work.”

What findings has TT125-802 demonstrated in patients with solid tumors?

Safety data from the phase 1 trial presented at the 2025 European Society for Medical Oncology Congress showed that the MTD has not yet been reached, and no grade 4 or higher adverse effects (AEs) or thrombocytopenia were reported. The most commonly reported treatment-related AEs (TRAEs) in the total dose-escalation population (n = 34) were dysgeusia (62%), hyperglycemia (35%), fatigue (26%), stomatitis (26%), increased amylase levels (24%), increased aspartate aminotransferase levels (21%), decreased appetite (21%), dry eye (21%), decreased weight (21%), increased alanine aminotransferase levels (18%), conjunctivitis (18%), increased lipase levels (18%), anemia (15%), increased blood creatinine phosphokinase levels (12%), and nausea (12%). Additionally, 2 serious TRAEs (grade 3 hyperglycemia and grade 3 atrial fibrillation) were observed. In total, 3 patients discontinued treatment due to a TRAE.

“When patients stop the treatment, and you give a break from the treatment for 1 or 2 weeks, [AEs are] usually resolved completely,” Saavedra noted. “But how can we manage these AEs? It’s important that the patients have continuous exposure to the drug. It’s an oral medication. If you have to stop for 1 or 2 weeks, we don’t know...if this break could affect the potential efficacy of the drug. We prefer to give the drug to the patients continuously.”

Regarding efficacy, the investigators observed antitumor activity across all dose levels in heavily pretreated patients, including 3 confirmed partial responses among the patients with NSCLC (n = 14). Additionally, the 4-month DCR rate was 36%, and 4 patients remained in the study for longer than 1 year. Notably, the patient with bulky dedifferentiated liposarcoma experienced a tumor shrinkage rate of –27% and remained in the study for 1.5 years.

“We saw clear responses with the monotherapy, and this is important because in the beginning, [we did not] expect monotherapy activity,” Saavedra said. “The evolution of disease [like dedifferentiated liposarcoma] is not very aggressive. Sometimes a patient can have stable disease for a long time, and you can’t be sure whether this stability is related to treating your patient with your drug or whether that is the normal history of the disease. [However], if you have a patient with very aggressive disease like NSCLC, and you see a decrease in the tumor measures, it is a clear signal of response.”

What has targeting CBP/p300 in hematologic malignancies shown?

Another CBP/p300 inhibitor, inobrodib (CCS1477), is under investigation for the treatment of patients with hematologic malignancies. An ongoing phase 1/2 trial (NCT04068597) is evaluating this agent as monotherapy and as part of combination regimens in patients with non-Hodgkin lymphoma, multiple myeloma, acute myeloid leukemia, and high-risk myelodysplastic syndromes.²

Findings from the randomized dose-expansion phase of the trial with inobrodib plus pomalidomide (Pomalyst) and dexamethasone in patients with relapsed/refractory multiple myeloma were presented at the 2025 American Society of Hematology Annual Meeting and Exposition. This cohort enrolled patients with an ECOG performance status of 0 or 1 who had either exhausted standard-of-care treatment options or, if naive to pomalidomide, had received at least 2 prior lines of therapy (including lenalidomide [Revlimid] and a proteasome inhibitor). Patients were randomly assigned to receive intermittent dosing with inotuzumab at 20 mg, 30 mg, or 40 mg in combination with a standard dosing regimen of pomalidomide plus dexamethasone. Patients were permitted to receive inobrodib with or without food.

Among 61 evaluable patients, 95% experienced a TRAE, and 80% had an inobrodib-related AE. Inotuzumab dose reductions (21%), interruptions (44%), and discontinuations (2%) were also observed. The most common grade 3/4 all-cause treatment-emergent AEs were thrombocytopenia (36%), neutropenia (34%), anemia (20%), leukopenia (15%), fatigue (10%), diarrhea (5%), hyperglycemia (3%), pyrexia (3%), and hyponatremia (2%).

Regarding efficacy, at a median follow-up of 105 days (range, 11-294), the ORRs were 69%, 54%, and 33% among 44 total patients who received inobrodib at 20 mg, 30 mg, and 40 mg, respectively. Notably, among heavily pretreated patients whose disease was refractory to pomalidomide and who had prior exposure to BCMA-directed T-cell engagers, the ORRs at 20 mg and 30 mg were 60% and 75%, respectively.

Does inobrodib’s efficacy translate to solid tumors?

Inobrodib has also been evaluated in patients with advanced solid tumors. Recently, a phase 1/2 trial (NCT03568656) assessed the safety and efficacy of this agent as monotherapy and as part of combination regimens in patients with metastatic castrate-resistant prostate cancer (mCRPC), metastatic breast cancer, and NSCLC.³ Notable combination partners included abiraterone acetate (Zytiga), enzalutamide (Xtandi), darolutamide, and olaparib (Lynparza) in mCRPC; olaparib in breast cancer; and atezolizumab (Tecentriq) in NSCLC.

“The combination of epigenetic therapy and immunotherapy is interesting,” Saavedra concluded. “It deserves to be explored. However, we have to focus [our research efforts]. Then, who knows? We [may be able to] explore [this mechanism of action in broader] populations because it’s important personalized medicine.”

References

1. Saavedra O, Garralda E, Boni V, et al. Clinical activity of TT125-802, a highly selective bromodomain inhibitor of CBP/p300, in advanced solid tumors: update on the ongoing phase I study. Ann Oncol. 2025;36(suppl 2):S640. doi:10.1016/j.annonc.2025.08.1547
2. Joseph N, Campbell V, Pawlyn C, et al. Randomized phase II dose optimization study of inobrodib (CCS1477), in combination with pomalidomide and dexamethasone in relapsed/refractory multiple myeloma (RRMM). Blood. 2025;146(suppl 1):4035. doi:10.1182/blood-2025-4035
3. Study to evaluate CCS1477 in advanced tumours. ClinicalTrials.gov. Updated August 8, 2025. Accessed December 23, 2025. https://clinicaltrials.gov/study/NCT03568656