FDA Greenlights Novel Colorectal Cancer Triplet Therapy Trial

Anbogen Therapeutics has received US FDA approval for its investigational new drug (IND) application for ABT-301, paving the way for a phase 1/2 clinical trial in patients with metastatic colorectal cancer (mCRC).¹

The study will evaluate a triplet therapy consisting of the oral histone deacetylase (HDAC) inhibitor ABT-301, the PD-1 monoclonal antibody tislelizumab (Tevimbra), and the antiangiogenic agent bevacizumab (Avastin). This multicenter, international trial aims to assess the safety and preliminary efficacy of this new combination regimen, targeting the majority of mCRC cases that do not respond to existing immunotherapies.

Addressing a Significant Unmet Clinical Need

The trial, an open-label study, plans to enroll 66 patients with proficient mismatch repair (pMMR) or non-microsatellite instability-high (non-MSI-H) mCRC. These tumors, often referred to as "cold tumors," represent approximately 95% of mCRC cases and are known to have poor response rates to current immune checkpoint inhibitors. In contrast, the small subset of patients with deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H) "hot tumors" are the primary beneficiaries of current immunotherapies.

“The only therapies that we have are chemotherapies, which are moderately effective. And so, the principal problem is that there are whole classes of drugs that just don't work in colon cancer,” said Benjamin Schlechter, MD, senior physician specializing in gastrointestinal cancers at Dana-Farber Cancer Center, in a previous interview with Targeted Oncology.

This study, therefore, directly addresses a substantial unmet clinical need within the mCRC patient population. The clinical trial will be conducted in Taiwan and Australia, with tislelizumab being provided by BeOne Medicines as part of a previously announced collaboration.

An estimated 370,000 new patients with pMMR/non-MSI-H in the second line or later settings are diagnosed annually across the US, China, Japan, the United Kingdom, France, Germany, Spain, and Italy. This represents a significant potential market, highlighting the considerable impact of a successful therapy for this patient group.

A Multi-Modality Mechanism of Action

The rationale behind the triplet combination therapy hinges on the unique mechanism of action of ABT-301. As a selective HDAC1/2/3 inhibitor, it operates as a multimodality anticancer agent designed to modulate the tumor microenvironment (TME). Preclinical studies have demonstrated that ABT-301 can effectively convert "cold tumors" into "hot tumors" by promoting the infiltration and activity of CD8-positive cytotoxic T cells, enhancing antigen presentation, and inhibiting myeloid-derived suppressor cells. These effects are crucial for overcoming the immunosuppressive TME that typically prevents checkpoint inhibitors like tislelizumab from being effective.

In addition to its immune-modulating properties, ABT-301 also exhibits pro-apoptotic, antiangiogenic, and tumor metabolic regulation effects, which could provide synergistic benefits when combined with the other agents. The inclusion of bevacizumab, a VEGF inhibitor, complements ABT-301's antiangiogenic effects and further aims to disrupt the tumor's blood supply. The combination of these 3 agents is designed to create a more favorable environment for an effective antitumor immune response.

Differentiated Safety Profile Supports Combination Therapy

The suitability of ABT-301 for a combination regimen is further supported by its favorable safety profile observed in a previous phase 1 monotherapy clinical trial involving 23 patients (NCT02350868).² In that study, ABT-301 did not exhibit dose-limiting toxicities of neutropenia or cardiac toxicity, which are commonly observed adverse effects with other HDAC inhibitors. The absence of these particular toxicities is a key differentiator and a promising indicator for its use in combination with other myelosuppressive or cardiotoxic agents, such as certain chemotherapies often used in mCRC.

With the FDA's IND approval, Anbogen Therapeutics is poised to advance this novel treatment strategy into the clinic. The company's goal is to provide a new therapeutic option for most patients with mCRC who currently have limited choices and poor outcomes with immunotherapy. Anbogen also stated that it is actively pursuing global licensing and strategic partnerships to accelerate the commercialization of its pipeline, including ABT-301.

REFERENCES:

1. Anbogen Receives FDA Clearance to Initiate Phase 1/2 Trial of ABT-301 Triplet Therapy for Advanced Colorectal Cancer. News release. Anbogen Therapeutics. August 4, 2025. Accessed August 4, 2025. https://tinyurl.com/2s3cpuyj

2. Dose-Seeking Study of MPT0E028 in Subjects With Advanced Solid Malignancies Without Standard Treatment. ClinicalTrials.gov. Updated April 11, 2019. Accessed August 4, 2025. https://www.clinicaltrials.gov/study/NCT02350868