Safety and Antitumour Activity of a First-in-Class, Oral, Selective CDK7 Inhibitor

Tolerability, pharmacokinetics and efficacy of samuraciclib were assessed in a first-in-human, modular study. Treatment with this first-in-class, oral, selective inhibitor of CDK7 demonstrated an acceptable safety profile and evidence of antitumour activity in patients with advanced solid tumours, according to Dr. Matthew G. Krebs, a clinical senior lecturer in the Experimental Cancer Medicine Team, The Christie NHS Foundation Trust in Manchester, UK and colleagues who reported the study findings during the mini oral session on metastatic breast cancer at ESMO Congress 2021 (16-21 September).

Dr. Krebs told the audience that CDK7 inhibition is a promising antitumour strategy. CDK7 is a key kinase, regulating cell division, transcription and nuclear receptor function, particularly the oestrogen and androgen receptor.

Together with the colleagues, Dr. Krebs assessed tolerability, pharmacokinetics and efficacy of samuraciclib. They evaluated its ascending doses (M1A), paired tumour biopsy (PB) samples (M1A), effect of food on bioavailability (M4) and expansion cohort (M1B) of triple negative breast cancer (TNBC).

In M1A the investigators recruited 33 patients in 5 cohorts of 120 mg, 240 mg, 360 mg and 480 mg once daily, and 180 mg twice daily. Additionally, 11 patients were dosed in paired tumour biopsy cohorts for pharmacodynamic assessment. In M4 the investigators recruited 15 patients. In M1B they recruited 23 patients.

At 120 mg, 240 mg and 360 mg once daily, most common adverse drug reactions were grade 1-2 nausea, vomiting and diarrhoea.

At 480 mg once daily, 3 of 6 patients experienced a dose limiting toxicity, grade 3 diarrhoea, grade 3 oral mucositis and grade 3 vomiting.

At 180 mg twice daily, 1 of 7 patients experienced a dose limiting toxicity, grade 4 thrombocytopaenia.

The neutropenia and significant myelosuppression associated with inhibitors of other CDKs were not observed.

Once daily 240 mg and 360 mg were determined as clinically relevant doses, with 360 mg once daily as the preliminary recommended phase II dose.

In fasted patients, median T_max was 1.5 to 4 hours and geomean T_1/2 approximately 75 hours. Steady-state was achieved within 8 to 15 days. Plasma exposure increased dose proportionally; pharmacologically active exposures were achieved throughout the entire dosing period. Food had no clinically significant effect on exposure.

In total 36 of 44 patients (82%) were evaluable for response, of which 19 (53%) evidenced disease control by RECIST evaluation at first post baseline scan observed across the ‘all comer’ cohorts in M1A and M4, including a partial response in a patient with hormone receptor-positive breast cancer. PSA reductions were observed in 4 recruited patients with castration-resistant prostate cancer. Preliminary tumour biopsy data supports tumour target engagement. In total, 20 patients with TNBC were evaluable with RECIST assessment; of these 12 had stable disease at first post baseline scan, and 3 patients have been on treatment longer than 1 year.

The authors concluded that samuraciclib demonstrated an acceptable safety profile with evidence of antitumour activity. 

The initial dosing experience for samuraciclib in combination with fulvestrant in patients with advanced hormone receptor positive HER2-negative breast cancer is also presented at the congress (ePoster 265P).

The study was funded by Carrick Therapeutics.

References

• 230MO – Krebs MG, Lord S, Kenny L, et al. First in human, modular study of samuraciclib (CT7001), a first-in-class, oral, selective inhibitor of CDK7, in patients with advanced solid malignancies. ESMO Congress 2021 (16-21 September).
• 265P – Howell S, Krebs MG, Lord S, et al. Study of samuraciclib (CT7001), a first-in-class, oral, selective inhibitor of CDK7, in combination with fulvestrant in patients with advanced Hormone Receptor positive HER2 negative breast cancer (HR+BC). ESMO Congress 2021 (16-21 September).