Samuraciclib, a novel selective CDK7 inhibitor, has demonstrated promising clinical activity and an acceptable safety profile in patients with advanced solid tumors, according to results from a multi-module Phase I clinical trial. The study findings are particularly significant for breast cancer patients who have progressed after CDK4/6 inhibitor therapy, a population with limited treatment options.
Study Design and Patient Population
The clinical investigation was conducted across three modules. Module 1A enrolled 33 patients with various advanced solid tumors to determine the maximum tolerated dose (MTD) of samuraciclib, with an additional 11 breast cancer patients recruited for pharmacodynamic evaluation. Module 1B-1 included 23 patients with locally advanced or metastatic triple-negative breast cancer (TNBC) who received samuraciclib at 360 mg once daily. Module 2A evaluated samuraciclib in combination with fulvestrant in 31 patients with hormone receptor-positive (HR+)/HER2-negative advanced breast cancer who had previously progressed on CDK4/6 inhibitor therapy.
The patient demographics reflected the typical population seen in advanced cancer trials. In Module 1A, the mean age was 59.6 years with 63.6% female participants. Primary malignancies were predominantly breast (30.3%) or colorectal (24.2%), with most patients having received prior chemotherapy (87.9%). All patients in Module 1B-1 were female with a mean age of 53.6 years and had received a median of 2 prior lines of chemotherapy. In Module 2A, all patients were female with a mean age of 60.4 years, and all had previously received aromatase inhibitors in combination with CDK4/6 inhibitors.
Safety Profile and Dose Determination
Dose escalation studies established 360 mg once daily as the MTD for samuraciclib. No dose-limiting toxicities were observed at the 120 mg and 240 mg doses, while the 480 mg dose was not tolerated due to gastrointestinal toxicities. A split dosing regimen of 180 mg twice daily was also explored but was ultimately deemed non-tolerable.
The safety profile was consistent across all modules, with gastrointestinal events being the most common treatment-related adverse events. Nearly all patients (98%) experienced at least one adverse event related to samuraciclib, primarily diarrhea, nausea, and vomiting. These events were generally low-grade, reversible, and manageable with standard medications or dose reductions.
"The gastrointestinal effects were generally low grade, reversible and ameliorated by standard anti-nausea and anti-diarrhea therapies," noted the investigators. Future studies will investigate the benefits of routine anti-emetic prophylaxis, and a switch from multiple instant-release capsules to a single tablet formulation is planned to potentially enhance tolerability.
An interesting observation was a reduction in platelet counts during therapy, with an approximate 20% drop occurring within the first 15 days of treatment before plateauing. This mild thrombocytopenia is likely an on-target consequence of CDK7 inhibition, as increased CDK7 activity in megakaryocytes has been associated with their maturation. Importantly, neither neutropenia nor alopecia were observed even at the highest doses, distinguishing samuraciclib from many conventional chemotherapies.
Clinical Activity
In Module 1A, samuraciclib demonstrated a disease control rate of 52.8% across various advanced solid tumors. Fourteen patients (38.9%) maintained stable disease for 12 weeks or longer. Notably, one heavily pre-treated patient with HR+ breast cancer achieved a partial response sustained for over 24 weeks on samuraciclib monotherapy at 240 mg once daily.
The TNBC cohort in Module 1B-1 showed a clinical benefit rate of 20%, including one partial response with a duration of response of 337 days. Additionally, one patient continued treatment beyond initial progression due to ongoing clinical benefit, remaining on therapy for 64 weeks until developing a new brain lesion.
Perhaps the most promising results came from Module 2A, where samuraciclib was combined with fulvestrant in HR+/HER2- breast cancer patients who had progressed on CDK4/6 inhibitors. In this cohort, the clinical benefit rate was 36%, with partial responses observed in 3 patients (12%) and stable disease in 13 patients (52%). The median progression-free survival was 3.7 months for the overall population, which is approximately double what would be expected for fulvestrant alone in this setting.
Biomarker Analysis
A protocol-specified exploratory analysis identified two factors associated with increased likelihood of benefit: absence of TP53 mutations and absence of liver metastases.
Patients without detectable TP53 mutations in circulating tumor DNA had significantly longer progression-free survival (7.4 months) compared to those with TP53 mutations (1.8 months), with a hazard ratio of 0.14 (95% CI: 0.05-0.45, p<0.001). The clinical benefit rate was 47.4% in patients without TP53 mutations compared to 0% in those with mutations.
Similarly, patients without liver metastases had longer progression-free survival (13.8 months) compared to those with liver metastases (2.8 months), with a hazard ratio of 0.16 (95% CI: 0.04-0.59, p<0.003). The clinical benefit rate was 54.5% for patients without liver metastases versus 21.4% for those with liver metastases.
These findings suggest that TP53 status may serve as a potential biomarker for samuraciclib therapy. The investigators noted, "The impact of lack of TP53 mutation on PFS in Module 2A was greater than that observed previously for fulvestrant alone or in combination with palbociclib, which argues against this being a purely prognostic finding and supports an interaction between samuraciclib treatment and TP53 status."
Pharmacodynamics and Pharmacokinetics
Pharmacodynamic analyses confirmed that samuraciclib inhibits CDK7 activity in tumors. A significant reduction of approximately 30% in phosphorylated RNA polymerase II (a substrate of CDK7) was observed in lymphocytes across all doses. Similar reductions were seen in tumor tissue from the paired biopsy cohort.
Pharmacokinetic results demonstrated that samuraciclib has a half-life of approximately 75 hours after single dosing, supporting once-daily administration. The drug showed dose-proportional exposure, and steady state was achieved between 8 and 15 days of dosing. No pharmacokinetic interactions were observed between samuraciclib and fulvestrant.
Future Directions
The investigators concluded that samuraciclib has the potential to address the significant medical need of patients whose disease has progressed on CDK4/6 inhibitors. They highlighted that while there is currently no consensus regarding standard of care for HR+/HER2- breast cancer patients who progress on CDK4/6 inhibition, the combination of fulvestrant with samuraciclib may provide clinically meaningful activity.
"The potential benefit of combined fulvestrant and samuraciclib is therefore important in its own right, but also because new oral SERDs are currently in clinical trials and may be more effective partner therapies than fulvestrant," the researchers noted. "The efficacy signal of samuraciclib therefore may be further increased in combination with the emerging therapeutic class of oral SERDs."
Several co-administration studies with both fulvestrant and new oral selective estrogen receptor degraders (SERDs) are now being initiated. Additionally, further studies are warranted to evaluate which other cancer types and combination strategies are most promising for samuraciclib therapy.
The researchers acknowledged limitations of the dataset, noting that the studies were uncontrolled, non-randomized, single-arm evaluations in a relatively small number of patients, particularly in the TNBC cohort. Nevertheless, the findings provide a strong rationale for further investigation of samuraciclib in larger, randomized trials.
