AC699 is being evaluated for patients with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2 negative (HER2–), estrogen receptor 1-mutated advanced or metastatic breast cancer with disease progression on or after at least 1 line of endocrine-based therapy.
Trial Name: Study of AC699 in Patients With Estrogen Receptor Positive/Human Epidermal Growth Factor Receptor 2 Negative (ER+/HER2-) Locally Advanced or Metastatic Breast Cancer
ClinicalTrials.gov ID: NCT05654532
Sponsor: Accutar Biotechnology Inc
Completion Date (Estimated): December 31, 2024.
The FDA has granted a fast track designation for the investigation of AC699 (Accutar Biotechnology, Inc) for the treatment of patients who have estrogen receptor-positive (ER+), human epidermal growth factor receptor-2-negative (HER2–), estrogen receptor 1 (ESR1)-mutated advanced or metastatic breast cancer with disease progression on or after at least 1 line of endocrine-based therapy. The investigational treatment is currently being evaluated in a phase 1 clinical trial (NCT05654532).1
AC699 is an investigational bioavailable chimeric degrader of ERα that is administered orally. The treatment has demonstrated potent and selective protein degradation of ERα wild-type and mutants in preclinical studies, demonstrating favorable pharmacological properties. Additionally, AC699 showed promising anti-tumor activities in ER+ animal tumor models.1
Further, the ER+/HER2– subtype is the most common subtype of breast cancer and makes up approximately 70% of cases. Mutations in the ESR1 gene are also common (20% to 40%) among patients with ER+/HER2– breast cancer who have received endocrine therapy in the metastatic setting.1
The ongoing multicenter, open-label phase 1 study is assessing the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of AC699 when used as a treatment in patients with locally advanced or metastatic ER-positive/HER2-negative locally advanced or metastatic breast cancer. To be considered for enrollment, patients were required to receive at least 2 prior lines of endocrine treatment or 1 prior line if combined with a CDK4/6 inhibitor. All patients in the trial will receive an assigned dose of AC699 monotherapy during dose escalation. The treatment will be administered orally once per day in 28-day cycles.1-3
The primary outcomes are the incidence of dose limiting toxicities (DLTs) from AC699 (measured during the first 28 days of treatment) and incidence of treatment-emergent adverse events (TEAEs) and clinically significant grade 3 or higher lab abnormalities (measured at approximately 18 months). Secondary outcomes include objective response rate (ORR), clinical benefit rate (CBR), duration of response, disease control rate, and progression-free survival, all of which will be assessed after approximately 18 months. Another secondary outcomes of the trial is pharmacokinetics, which will be assessed up to approximately 28 weeks.2
Preliminary data presented in an abstract at the 2024 American Society of Clinical Oncology meeting showed that 22 patients (median age: 61 years; median prior lines of therapy: 5 lines) were enrolled. Prior treatments included CDK4/6 inhibitor (100%), aromatase inhibitor (91%), fulvestrant (82%), novel oral selective estrogen receptor degrader or covalent antagonist (23%), and ER chimeric degrader (14%).3
According to the data, 15 patients had at least 1 scan prior to the data cutoff date, and of these, 3 were not evaluable for ORR because they had bone lesions only. In addition, of the 12 evaluable patients, 4 (33%) had achieved partial response (3 confirmed, 1 unconfirmed). The CBR—which required patients to have stable disease at 24 weeks or beyond—was approximately 42% (n = 5). Further, in the subgroup of evaluable patients with a ESR1 mutation, the ORR was approximately 67% (n = 4), the CBR was about 83% (n = 5), and the median time on treatment was 168 days (range: 56-336 days), with 4 of 7 patients still receiving AC699.1,3
Eighteen patients had measurable disease whereas 4 had bone lesions only. There were no DLTs, dose reductions, or discontinuations for TEAEs that were observed; however, the maximum tolerated dose was not reached. The most common TEAEs reported were fatigue (23%), dehydration (18%), and nausea (18%). All TEAEs were grades 1 or 2 in severity, including nausea (18%) and hot flushed (14%).3
"Receiving fast track designation for AC699 from the FDA highlights their recognition of the serious and life-threatening nature of this malignancy, the critical unmet medical needs not fully addressed by existing therapies, and the potential of AC699 to fill in the gap," said Jie Fan, PhD, CEO of Accutar Biotechnology, Inc, in a news release. "We look forward to working closely with the FDA to optimize and expedite the development program."1
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