samuraciclib (CT7001)

Samuraciclib (CT7001), a once-daily oral CDK7 inhibitor, combined with the SERD fulvestrant had a favorable safety profile and clinical activity in patients with HR+/HER2− advanced breast cancer (BC) previously treated with a CDK4/6i [Coombes, 2023]. The most frequent treatment-related AEs were similar to the known safety profiles from both previous samuraciclib and elacestrant studies. With no drug-drug interactions between the treatments, further study of combination treatment in expansion C4 is supported. Preliminary signs of antitumor activity were observed.

P2, N=60, Active, not recruiting, Carrick Therapeutics Limited | Recruiting --> Active, not recruiting

P1/2, N=49, Active, not recruiting, Carrick Therapeutics Limited | Recruiting --> Active, not recruiting

P2 | "Clinical Trial Registration Number: NCT05963984"

P1/2, N=67, Recruiting, Pfizer | Trial completion date: Aug 2027 --> Jan 2027 | Trial primary completion date: Feb 2027 --> Jul 2026

P1/2, N=67, Recruiting, Pfizer | Trial completion date: Feb 2027 --> Aug 2027 | Trial primary completion date: Aug 2026 --> Feb 2027

P1/2, N=67, Recruiting, Pfizer | Phase classification: P2 --> P1/2

P2, N=67, Recruiting, Pfizer

P2, N=67, Recruiting, Pfizer | Not yet recruiting --> Recruiting

P1/2, N=48, Recruiting, Carrick Therapeutics Limited | Phase classification: P1b/2 --> P1/2

P1/2, N=48, Recruiting, Carrick Therapeutics Limited

We show that CDK7i, by samuraciclib, induces a permanent cell-cycle exit, known as senescence, without promoting DNA damage signaling or cell death...Reverting a growth-promoting mutation in PIK3CA to wild type decreases sensitivity to CDK7i. Our work establishes that enhanced growth alone promotes CDK7i sensitivity, providing an explanation for why some cancers are more sensitive to CDK inhibition than normally growing cells.

The cyclin-dependent kinase (CDK)4/6 inhibitors abemaciclib and ribociclib are approved in combination with an aromatase inhibitor or fulvestrant, or as monotherapy (abemaciclib), for ER+/HER2- advanced or metastatic breast cancer...Vepdegestrant is being evaluated in combination with abemaciclib (sub-study A; NCT05548127), ribociclib (sub-study B; NCT05573555), and samuraciclib (sub-study C)...The phase 2 portion of each sub-study will further evaluate the antitumor activity of the combinations; the primary endpoint is objective response and secondary endpoints include antitumor activity (CBR and DOR), PFS, overall survival, safety, plasma concentration of study drugs, and changes in circulating tumor DNA. Future combination sub-studies will be included in TACTIVE-U.

Samuraciclib (CT7001), a once daily oral CDK7 inhibitor has demonstrated a favorable safety profile and clinical activity in combination with fulvestrant (SERD) in patients with HR+/HER2- advanced breast cancer who have previously been treated with a CDK4/6 inhibitor [1]. Secondary endpoints are tolerability, clinical benefit response at 24 weeks, overall response rate, duration of response, best percent change in tumor size, pharmacokinetics and correlations between ctDNA detectable ESR1 and TP53 mutations and efficacy/safety finding in this patient population. The study opened for recruitment in June 2023.

QoL and correlations between ctDNA detectable TP53 mutations and efficacy/safety finding in this patient population will be reported. The study opened for recruitment in June 2023.

Drug sensitivity analysis, conducted using the DepMap database, revealed that colorectal cancer cell lines exhibiting elevated levels of TIMP1 expression were more responsive to certain drugs, such as CC-90003, Pitavastatin, Atuveciclib, and CT7001, compared to those with low levels of TIMP1. Furthermore, TIMP1 expression was positively correlated with that of ferroptosis-related genes, such as GPX4 and HSPA5. TIMP1 can be used as a biomarker for colorectal cancer and is associated with the immunological microenvironment, drug sensitivity, and ferroptosis inhibition in this disease.

Notably, the regulation of condensin subunit gene expression is independent of super-enhancers. Together, these studies reveal a new role for CDK7 in sustaining chromatin configuration by ensuring the expression of condensin genes, including SMC2.

Here we report results from dose escalation and 2 expansion cohorts: Module 1A dose escalation with paired biopsy cohort in advanced solid tumor patients, Module 1B-1 triple negative breast cancer (TNBC) monotherapy expansion, and Module 2A fulvestrant combination in HR+/HER2- breast cancer patients post-CDK4/6-inhibitor. In this study, samuraciclib exhibits tolerable safety and PK is supportive of once-daily oral administration. Clinical activity in TNBC and HR+/HER2-breast cancer post-CDK4/6-inhibitor settings warrants further evaluation.

P2, N=60, Recruiting, Carrick Therapeutics Limited

This study supports CDK7 inhibition as a strategy to target deregulated cell proliferation and demonstrates CT7001 is a promising CRPC therapeutic, alone or in combination with AR-targeting compounds.

Currently, trilaciclib, palbociclib, ribociclib, and abemaciclib that bear dual specificities against CDK4 and CDK6 have been approved for clinical usage, and more CDK4/6 targeted agents are actively under clinical evaluations, among which, TY-302, a novel CDK4/6 inhibitor being developed by TYK Medicines, is under Phase II trial (NCT04433494)...Several CDK7 targeted agents, such as SY-5609 and Samuraciclib (CT7001), are under development...# Shengli Dong and Apeng Liang contributed equally to this work. * Jun Li, Shengli Dong and Apeng Liang are the correspondent authors.

P1/2, N=124, Completed, Carrick Therapeutics Limited | Active, not recruiting --> Completed

P1/2, N=510, Recruiting, Hoffmann-La Roche | Trial completion date: Apr 2027 --> Oct 2026 | Trial primary completion date: Oct 2026 --> Apr 2026

P1/2, N=124, Active, not recruiting, Carrick Therapeutics Limited | N=250 --> 124

No abstract available

P1/2, N=415, Recruiting, Hoffmann-La Roche | N=255 --> 415

Samuraciclib has demonstrated an acceptable safety profile with evidence of anti-tumour activity in combination with fulvestrant for patients with advanced HR+BC who have progressed on their prior CDK4/6i.

No abstract available

Samuraciclib demonstrated an acceptable safety and tolerability profile with evidence of antitumour activity in advanced TNBC. References 1.Patel et al. ICEC0942, an Orally Bioavailable Selective Inhibitor of CDK7 for Cancer Treatment.

Samuraciclib has demonstrated an acceptable safety profile with evidence of anti-tumour activity in combination with fulvestrant for patients with advanced HR+BC who have progressed on their prior CDK4/6i.

Samuraciclib has demonstrated an acceptable safety profile with evidence of anti-tumour activity.

P1/2, N=250, Active, not recruiting, Carrick Therapeutics Limited | Recruiting --> Active, not recruiting | Trial completion date: Dec 2021 --> Mar 2023 | Trial primary completion date: Dec 2021 --> Mar 2023