Samuraciclib (CT7001): A Comprehensive Profile of a Novel CDK7 Inhibitor in Oncology

II. Introduction to Samuraciclib (CT7001)

Overview and Identification

Samuraciclib, also designated CT7001 and ICEC0942, is an investigational small molecule drug candidate currently undergoing clinical evaluation.1 It possesses the Chemical Abstracts Service (CAS) number 1805833-75-3 and the DrugBank identifier DB16061.5 Originally discovered at Imperial College UK, Samuraciclib is being developed by Carrick Therapeutics, an oncology-focused biopharmaceutical company dedicated to discovering and developing highly differentiated therapies.2

Drug Class and Rationale for Targeting CDK7

Samuraciclib functions as a selective, orally available inhibitor of Cyclin-Dependent Kinase 7 (CDK7).1 CDK7 represents a compelling target in oncology due to its multifaceted roles in fundamental cellular processes frequently dysregulated in cancer.1 Firstly, CDK7 is a critical regulator of transcription, particularly for genes involved in oncogenesis and cell survival.1 Secondly, it plays a pivotal role in controlling cell cycle progression.1 Thirdly, CDK7 activity has been implicated in the development of resistance to established cancer therapies, notably anti-hormone treatments in breast and prostate cancers.1 Furthermore, elevated levels of CDK7 have been observed in various cancer types and often correlate with clinical outcomes, suggesting a heightened dependency of tumor cells on CDK7 activity compared to normal tissues.31 Therefore, inhibiting CDK7 offers a promising therapeutic strategy to simultaneously disrupt these key cancer-driving pathways.

Samuraciclib is positioned as a potentially first-in-class or, at minimum, the most advanced oral CDK7 inhibitor currently in clinical development.[7] Its mechanism targets fundamental biological processes—transcription and cell cycle control—distinguishing it from inhibitors focused on single signaling pathways or specific cell cycle checkpoints. This dual mechanism provides a unique approach to cancer therapy, particularly relevant for malignancies driven by aberrant transcriptional programs or those that have developed resistance to other treatments. The advancement of Samuraciclib into Phase 2 and 2b clinical trials underscores its leading position among agents targeting CDK7.[1]

III. Mechanism of Action

The Dual Role of CDK7

Cyclin-Dependent Kinase 7 (CDK7) exerts its influence through two primary mechanisms critical for cell function and often exploited by cancer cells. Firstly, as an integral component of the general transcription factor TFIIH, CDK7 is essential for the initiation and regulation of transcription by RNA Polymerase II (RNAPII).31 It achieves this by phosphorylating specific serine residues (Ser5 and potentially Ser7) within the C-terminal domain (CTD) of RNAPII's largest subunit.4 This phosphorylation is a prerequisite for the transition from transcription initiation to elongation and is particularly crucial for the expression of genes with high regulatory complexity, including key oncogenes like MYC and various anti-apoptotic genes, often located within super-enhancer regions.1

Secondly, CDK7 functions as the catalytic subunit of the CDK-activating kinase (CAK) complex, which also includes Cyclin H and MAT1.[31] The CAK complex is responsible for phosphorylating and thereby activating other cell cycle CDKs, namely CDK1, CDK2, CDK4, and CDK6, at specific threonine residues in their T-loops.[40] This sequential activation of cell cycle CDKs is essential for orderly progression through the different phases of the cell cycle.[1]

Samuraciclib's Inhibitory Action and Selectivity

Samuraciclib acts as a selective, ATP-competitive inhibitor of CDK7.1 It binds to the ATP-binding pocket of CDK7, preventing the kinase from utilizing ATP for phosphorylation reactions.4 This inhibition disrupts both the transcriptional and cell cycle regulatory functions of CDK7.

Regarding selectivity, in vitro kinase assays have shown Samuraciclib to be significantly more potent against CDK7 compared to other related kinases, exhibiting approximately 45-fold selectivity over CDK1, 15-fold over CDK2, 230-fold over CDK5, and 30-fold over CDK9.[39] However, cellular thermal shift assays (CeTSA) conducted in intact LNCaP prostate cancer cells indicated that while Samuraciclib preferentially engages with CDK7 at lower concentrations, it can also engage with CDK2 and CDK9 at higher concentrations.[40] Engagement with CDK4 and CDK1 was not observed in these assays.[40] A broad kinase panel screen showed inhibition of only five additional kinases (ERK8, STK33, CHK2, CLK2, PHK) at a high concentration (10 µM), similar in extent to CDK2 inhibition.[39]

The engagement with CDK2 and CDK9 at higher concentrations, while potentially contributing to the drug's overall anti-cancer activity, needs careful consideration. CDK2 is crucial for the G1/S transition and S-phase progression, while CDK9 (as part of P-TEFb) is vital for transcriptional elongation. Inhibition of these kinases could broaden the therapeutic effect but might also influence the drug's toxicity profile. However, the observed clinical safety data for Samuraciclib, characterized mainly by gastrointestinal adverse events and a lack of significant myelosuppression (a common toxicity associated with less selective CDK inhibitors, particularly those hitting CDK2 or CDK9), suggests that at the clinically relevant dose of 360mg once daily, the effects are predominantly driven by CDK7 inhibition.[26] The precise contribution of off-target CDK2/9 engagement at clinical exposures remains an area for potential further investigation.

Downstream Cellular Consequences

The inhibition of CDK7 by Samuraciclib leads to several key downstream effects within cancer cells:

• Transcriptional Suppression: Inhibition of RNAPII CTD phosphorylation (at Ser2, Ser5, and Ser7) leads to reduced transcription initiation and elongation, particularly affecting the expression of oncogenes like MYC and anti-apoptotic genes.[4]
• Cell Cycle Arrest: Inhibition of CAK activity prevents the activation of cell cycle CDKs (CDK1, CDK2), leading to cell cycle arrest, often observed as an enrichment of cells in the G2/M phase.[2]
• Induction of Apoptosis/Senescence: Disruption of critical transcriptional programs and cell cycle control ultimately triggers programmed cell death (apoptosis), evidenced by the cleavage of caspase-3/7 and PARP [2], or induces cellular senescence, a state of irreversible growth arrest, which may be linked to mTOR signaling pathways in some contexts.[51]
• Inhibition of Hormone Receptor Signaling: In hormone-dependent cancers like estrogen receptor-positive (ER+) breast cancer and castration-resistant prostate cancer (CRPC), CDK7 inhibition interferes with hormone receptor function. CDK7 has been shown to phosphorylate the Androgen Receptor (AR) at Serine-515, affecting its transactivation and stability.[2] By inhibiting CDK7, Samuraciclib can suppress transcription mediated by both full-length AR and constitutively active AR splice variants, contributing to its efficacy in CRPC models.[2] A similar mechanism involving ER phosphorylation or transcriptional co-regulation is implied in HR+ breast cancer.[1]

This dual impact on transcription and cell cycle provides a robust rationale for targeting CDK7, especially in cancers exhibiting transcriptional addiction (e.g., high MYC expression) or dependence on hormone receptor signaling (ER+ breast cancer, CRPC). The resulting cell cycle arrest and induction of apoptosis offer potential for synergy when combined with therapies targeting other cell cycle phases or DNA damage response pathways.[1]

Role in Overcoming Therapy Resistance

A key aspect of the therapeutic rationale for Samuraciclib is its potential to overcome resistance to standard therapies, particularly endocrine therapies in HR+ breast cancer and CRPC.1 Resistance often involves the reactivation or upregulation of hormone receptor signaling pathways or bypass mechanisms involving transcriptional reprogramming. By inhibiting CDK7, Samuraciclib can potentially dampen these resistance mechanisms through direct effects on receptor phosphorylation/activity and broader effects on the transcriptional machinery required for resistance pathways.2 This forms the basis for combining Samuraciclib with various endocrine agents like fulvestrant, oral SERDs (elacestrant, giredestrant), and AR inhibitors (enzalutamide).2

IV. Preclinical Profile

In Vitro Activity

Preclinical investigations have established the in vitro activity profile of Samuraciclib across a range of cancer models. The compound demonstrated potent inhibition of cell proliferation in a panel of 60 cancer cell lines, with a median GI50 (concentration causing 50% growth inhibition) of 0.25 µM.39 Specific cell lines mentioned include breast cancer (MCF-7), colon cancer (HCT116), prostate cancer (LNCaP), and acute myeloid leukemia (AML) models.16 Mechanistically, treatment with Samuraciclib led to decreased phosphorylation of the RNAPII CTD (Ser2/5/7) and key cell cycle CDKs (CDK1 Thr161, CDK2 Thr160) in a dose- and time-dependent manner in HCT116 cells.39 This target engagement translated into functional consequences, including cell cycle arrest (enrichment in G2/M phase) and the induction of apoptosis, as evidenced by caspase 3/7 activation and PARP cleavage after 24 hours of treatment.2 Cellular thermal shift assays (CeTSA) in LNCaP prostate cancer cells confirmed direct engagement with CDK7, and also with CDK2 and CDK9 at higher concentrations.40

In Vivo Activity and Combination Synergy

The in vivo efficacy of Samuraciclib was evaluated in various xenograft models. As a monotherapy, oral administration of Samuraciclib demonstrated antitumor effects, inhibiting tumor growth in xenografts of both breast and colorectal cancers.39 Furthermore, it repressed the growth of CRPC xenografts.2

Crucially, preclinical studies highlighted the synergistic potential of Samuraciclib when combined with endocrine therapies. In ER+ breast cancer models, Samuraciclib showed synergistic activity when combined with tamoxifen or the injectable SERD fulvestrant.[32] Similarly, in CRPC xenografts, the combination of Samuraciclib with the antiandrogen enzalutamide resulted in significantly augmented tumor growth inhibition compared to either agent alone.[2] Preclinical work specifically validated the biological rationale for combining Samuraciclib with SERDs.[10]

These preclinical findings showing synergy with endocrine agents provided a strong foundation for the clinical development strategy. The ability of Samuraciclib to inhibit CDK7, a kinase implicated in both ER and AR signaling pathways [1], offers a mechanistic basis for this synergy. By targeting the hormone receptor pathway both directly (with the endocrine agent) and indirectly (via CDK7 inhibition impacting receptor activity or downstream transcription), these combinations aim to achieve a more profound and durable blockade of tumor growth, particularly in the context of acquired resistance. This rationale directly informed the design of clinical trials combining Samuraciclib with fulvestrant, oral SERDs (elacestrant, giredestrant), and the PROTAC ER degrader vepdegestrant in HR+ breast cancer, and supported its investigation in CRPC.[1]

Pharmacodynamic Markers

Preclinical studies identified the reduction of phosphorylated RNAPII CTD as a key pharmacodynamic marker of CDK7 inhibition by Samuraciclib.39 This marker was subsequently utilized in clinical trials to confirm target engagement in patients.38

V. Clinical Development Program

Overall Strategy and Foundational Trial (NCT03363893)

The clinical development of Samuraciclib commenced with a multi-modular, open-label, multicenter Phase 1/2 study (NCT03363893) initiated in 2017.5 This foundational trial was designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of Samuraciclib both as a monotherapy and in combination with standard therapies across various advanced malignancies.42

Key modules within NCT03363893 included:

• Module 1A (Dose Escalation): Enrolled patients (n=33) with advanced solid tumors to determine the maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), safety, and PK/PD profile of Samuraciclib monotherapy. Ascending doses from 120 mg once daily (OD) up to 480 mg OD, and also 180 mg twice daily (BID), were explored.[37] This module included a paired biopsy cohort (n=11) for PD assessments.[37]
• Module 1B-1 (TNBC Expansion): Evaluated Samuraciclib monotherapy at the determined RP2D (360 mg OD) in patients (n=23) with locally advanced or metastatic triple-negative breast cancer (TNBC) who had received prior systemic therapy.[37]
• Module 2A (HR+ BC Combination): Assessed the safety, tolerability, and preliminary efficacy of Samuraciclib (at 240 mg OD and 360 mg OD) in combination with the standard dose of fulvestrant (an injectable SERD) in patients (n=31) with HR+/HER2- advanced breast cancer whose disease had progressed after prior CDK4/6 inhibitor therapy.[14]
• Module 4 (Food Effect): A randomized crossover study in 15 patients to assess the impact of food on Samuraciclib bioavailability.[37]
• Module 6 (Formulation): Explored the tolerability and PK of a new enteric capsule formulation compared to the original formulation in patients with advanced solid malignancies.[1]

The study also allowed for the investigation of Samuraciclib in other patient groups, including those with Castration-Resistant Prostate Cancer (CRPC), Ovarian Cancer, and Small Cell Lung Cancer (SCLC).[83] The trial was registered on ClinicalTrials.gov (NCT03363893) and the EU Clinical Trials Register (2017-002026-20).[6] Status is listed as completed for Module 1A/1B [5] and active, not recruiting for Module 2A.[38]

Ongoing Combination Trials in HR+/HER2- Breast Cancer (Post-CDK4/6i)

Based on the encouraging results from Module 2A of the initial Phase 1 study, Carrick Therapeutics has launched several Phase 1b/2 and Phase 2b trials focusing on combining Samuraciclib with various endocrine therapy backbones in the HR+/HER2- advanced breast cancer population resistant to prior CDK4/6 inhibitors. This targeted approach leverages the drug's mechanism of action against endocrine resistance pathways and addresses a significant unmet medical need.11

Key ongoing trials include:

• NCT05963984 (SUMIT-BC): A randomized, open-label, multicenter Phase 2b study comparing Samuraciclib plus fulvestrant versus fulvestrant alone.[1] The primary endpoint is Progression-Free Survival (PFS).[11] This trial utilizes a novel single tablet formulation of Samuraciclib, potentially improving gastrointestinal tolerability.[1] It is being conducted with support from Pfizer Ignite.[11] The trial is currently listed as active, not recruiting.[22]
• NCT05963997 (SUMIT-ELA): A Phase 1b/2 open-label study evaluating Samuraciclib in combination with the oral SERD elacestrant.[8] This trial, conducted in collaboration with the Menarini Group (provider of elacestrant), includes an initial dose-escalation phase (Phase 1b) followed by a dose-expansion phase (Phase 2) to assess safety, PK, and efficacy.[8] The trial is listed as active, not recruiting.[51]
• NCT06125522 (TACTIVE-U Sub-Study C): A Phase 1b/2 open-label umbrella study evaluating Samuraciclib in combination with vepdegestrant (ARV-471), an oral PROTAC estrogen receptor degrader.[7] This sub-study is part of the larger TACTIVE-U platform trial sponsored by Arvinas and Pfizer.[9] It involves dose escalation/de-escalation in Phase 1b to determine the RP2D, followed by a Phase 2 expansion.[25] The trial is listed as recruiting.[61]
• NCT04802759 (MORPHEUS-BC): A Phase 1b/2, open-label, multicenter, randomized umbrella study evaluating multiple treatment combinations.[78] One arm of this study, sponsored by Hoffmann-La Roche, investigates the combination of Samuraciclib with Roche's oral SERD, giredestrant, in patients with ER+/HER2- advanced breast cancer post-CDK4/6i.[11] The trial is listed as recruiting.[78]

This focused clinical strategy, investigating Samuraciclib against multiple next-generation endocrine therapies (injectable SERD, oral SERDs, PROTAC degrader) in the well-defined post-CDK4/6i HR+ breast cancer population, reflects a deliberate effort by Carrick Therapeutics. Partnering with established pharmaceutical companies like Pfizer, Menarini, Roche, and Arvinas provides access to these novel endocrine agents and leverages broader development expertise.[7] This approach allows for the identification of the most synergistic and tolerable combination(s) while mitigating the risk associated with dependence on a single combination partner.

Other Potential Indications

Beyond breast cancer, preclinical data and the mechanism of action suggest potential applicability of Samuraciclib in other malignancies. Its demonstrated activity in CRPC xenograft models, coupled with its ability to inhibit AR signaling, supports investigation in prostate cancer.2 Other cancer types mentioned as having potential include pancreatic, ovarian, colorectal, and small cell lung cancer, likely due to the fundamental roles of CDK7 in transcription and cell cycle across various tumor types.8

Table 1: Overview of Key Samuraciclib Clinical Trials

Trial ID (NCT)	Phase	Status (as per snippets)	Combination Agent(s)	Target Population	Primary Endpoint(s) (if available)	Sponsor/Collaborator
NCT03363893	1/2	Module 1A/1B: Completed; Module 2A: Active, not recruiting	Monotherapy (M1A/1B); Fulvestrant (M2A)	Advanced Solid Tumors (M1A); TNBC (M1B); HR+/HER2- BC post-CDK4/6i (M2A)	Safety, Tolerability, MTD (M1A); Safety, Efficacy (M1B, M2A)	Carrick Therapeutics
NCT05963984 (SUMIT-BC)	2b	Active, not recruiting	Fulvestrant	HR+/HER2- BC post-CDK4/6i	PFS	Carrick Therapeutics / Pfizer Ignite
NCT05963997 (SUMIT-ELA)	1b/2	Active, not recruiting	Elacestrant	HR+/HER2- BC post-CDK4/6i	Phase 1b: Safety, RP2D; Phase 2: Efficacy (PFS implied)	Carrick Therapeutics / Menarini Group
NCT06125522 (TACTIVE-U C)	1b/2	Recruiting	Vepdegestrant (ARV-471)	ER+/HER2- Advanced/Metastatic BC (post-endocrine)	Phase 1b: Safety, Tolerability, RP2D; Phase 2: ORR	Arvinas / Pfizer
NCT04802759 (MORPHEUS-BC)	1b/2	Recruiting	Giredestrant	ER+/HER2- Advanced/Metastatic BC (post-CDK4/6i)	ORR, DOR, PFS, OS, Safety	Hoffmann-La Roche

(Note: Status reflects information available in provided snippets, which may not be current. RP2D = Recommended Phase 2 Dose; ORR = Objective Response Rate; CBR = Clinical Benefit Rate; PFS = Progression-Free Survival; OS = Overall Survival; MTD = Maximum Tolerated Dose)

VI. Clinical Efficacy Findings

Monotherapy Activity (NCT03363893)

The initial Phase 1 dose-escalation module (Module 1A) involving patients with various advanced solid tumors provided early signals of Samuraciclib's activity. A disease control rate (DCR) of 53% (19 out of 36 evaluable patients) was observed across the dose levels tested, including one confirmed partial response (PR).38

In the subsequent monotherapy expansion cohort specifically for patients with advanced TNBC (Module 1B-1), treatment with Samuraciclib at the RP2D of 360 mg OD resulted in one confirmed PR, which was notably durable, lasting 337 days.[38] Stable disease was achieved in 14 patients, contributing to a clinical benefit rate (CBR, defined as CR + PR + SD ≥ 24 weeks) of 20.0% (4 out of 20 evaluable patients) at 24 weeks.[42]

Combination Therapy Activity (HR+/HER2- Breast Cancer Post-CDK4/6i)

The most compelling efficacy signals to date have emerged from the combination cohorts, particularly in patients with HR+/HER2- advanced breast cancer whose disease had progressed following treatment with a CDK4/6 inhibitor.

• Samuraciclib + Fulvestrant (NCT03363893 Module 2A): This cohort enrolled 31 patients, primarily treated at the 360 mg OD dose of Samuraciclib.32 Encouragingly, 72% (18 out of 25 evaluable patients) exhibited some degree of tumor shrinkage.32 Three patients achieved a confirmed PR.38 The CBR at 24 weeks was 36.0% (9 out of 25 patients).32 This level of activity is noteworthy considering the poor prognosis typically associated with this patient population, where fulvestrant monotherapy yields a median PFS of only around 2 months (approximately 8 weeks).26 A key finding from this cohort was the apparent predictive value of TP53 mutation status. Patients with wild-type TP53 (n=19) experienced a significantly longer median PFS of 32 weeks compared to 7.9 weeks for those with mutant TP53 (n=6) (HR 0.17; 95% CI, 0.05-0.53; P = 0.0008).32 This aligns with preclinical observations suggesting that intact p53 pathways may be necessary for CDK7 inhibition to efficiently induce apoptosis or senescence.2 Given that approximately 70% of patients in this setting retain wild-type TP53, this biomarker holds significant potential for patient selection.14 Furthermore, the presence of liver metastases at baseline also significantly impacted outcomes. Median PFS was not reached (estimated ≥ 48 weeks) in the 17 patients without liver metastases, whereas it was only 11.9 weeks in the 14 patients with liver metastases (HR 0.16; 95% CI, 0.05-0.59; P = 0.0021).32 The CBR in patients without liver metastases was 55%.32 No significant association was observed between ESR1 mutation status and response to the combination therapy, suggesting patients with ESR1 mutations could still potentially benefit.14
• Samuraciclib + Elacestrant (NCT05963997 Phase 1b): Preliminary data from the dose-escalation phase indicated early signs of antitumor activity. One confirmed PR was reported in a patient with TP53 wild-type, ESR1 wild-type metastatic breast cancer involving liver metastases, treated at the 240 mg Samuraciclib + 300 mg Elacestrant dose level, showing a 37% reduction in target lesions.[36] Longer-term efficacy data from the expansion cohort are awaited.[36]
• Samuraciclib + Giredestrant (NCT04802759 MORPHEUS Arm): An interim analysis presented at ESMO 2024 showed comparable efficacy between the combination arm and giredestrant monotherapy in this specific cohort.[52] The ORR was 6.7% (1/15 PR) for the combination versus 5.6% (1/18 PR) for giredestrant alone. Median PFS was numerically higher for the combination (6.41 months vs 4.67 months), but the difference was not statistically significant (HR 0.68; 95% CI, 0.31-1.46).[52] Biomarker analysis revealed that ESR1 mutations were enriched among patients achieving PR or stable disease (SD) in both treatment arms.[52] Analysis based on TP53 status and liver metastasis was noted as ongoing.[52]

Pharmacodynamic Confirmation

Evidence of target engagement in vivo was obtained during the dose-escalation phase (Module 1A). Analysis of paired tumor biopsies and circulating lymphocytes showed a reduction in the phosphorylation of RNAPII, a direct substrate of CDK7, confirming that Samuraciclib reached its target and exerted its intended biochemical effect in patients.38

Table 2: Summary of Reported Efficacy Outcomes for Samuraciclib

Trial ID (NCT)	Cohort/Combination	Patient Population	Efficacy Metric	Reported Value	Key Context/Notes	Snippet(s)
NCT03363893	Module 1A (Monotherapy Dose Escalation)	Advanced Solid Tumors	DCR	53% (19/36)	Across doses	38
NCT03363893	Module 1A (Monotherapy Dose Escalation)	Advanced Solid Tumors	ORR	~3% (1/36 PR)	Across doses	38
NCT03363893	Module 1B-1 (Monotherapy 360mg OD)	Advanced TNBC	ORR	5% (1/20 PR)	PR duration 337 days	38
NCT03363893	Module 1B-1 (Monotherapy 360mg OD)	Advanced TNBC	CBR @ 24 weeks	20.0% (4/20)		42
NCT03363893	Module 2A (Samuraciclib 360mg + Fulvestrant)	HR+/HER2- BC post-CDK4/6i	ORR	12% (3/25 PR)		14
NCT03363893	Module 2A (Samuraciclib 360mg + Fulvestrant)	HR+/HER2- BC post-CDK4/6i	CBR @ 24 weeks	36.0% (9/25)		32
NCT03363893	Module 2A (Samuraciclib 360mg + Fulvestrant)	HR+/HER2- BC post-CDK4/6i	Median PFS (TP53 WT)	32 weeks	n=19	32
NCT03363893	Module 2A (Samuraciclib 360mg + Fulvestrant)	HR+/HER2- BC post-CDK4/6i	Median PFS (TP53 mutant)	7.9 weeks	n=6	32
NCT03363893	Module 2A (Samuraciclib 360mg + Fulvestrant)	HR+/HER2- BC post-CDK4/6i	Median PFS (No Liver Mets)	Not Reached (≥48 weeks)	n=17	32
NCT03363893	Module 2A (Samuraciclib 360mg + Fulvestrant)	HR+/HER2- BC post-CDK4/6i	Median PFS (Liver Mets)	11.9 weeks	n=14	32
NCT05963997	Phase 1b (Samuraciclib 240mg + Elacestrant 300mg)	HR+/HER2- BC post-CDK4/6i	ORR	1 PR observed	n=6 in cohort, preliminary	36
NCT04802759	MORPHEUS (Samuraciclib + Giredestrant)	ER+/HER2- LA/mBC post-CDK4/6i	ORR	6.7% (1/15 PR)	Interim analysis	52
NCT04802759	MORPHEUS (Giredestrant alone)	ER+/HER2- LA/mBC post-CDK4/6i	ORR	5.6% (1/18 PR)	Interim analysis, comparator arm	52
NCT04802759	MORPHEUS (Samuraciclib + Giredestrant)	ER+/HER2- LA/mBC post-CDK4/6i	Median PFS	6.41 months	Interim analysis (HR 0.68 vs G alone)	52
NCT04802759	MORPHEUS (Giredestrant alone)	ER+/HER2- LA/mBC post-CDK4/6i	Median PFS	4.67 months	Interim analysis, comparator arm	52

(Abbreviations: DCR=Disease Control Rate; ORR=Objective Response Rate; PR=Partial Response; CBR=Clinical Benefit Rate; PFS=Progression-Free Survival; TNBC=Triple-Negative Breast Cancer; HR+=Hormone Receptor Positive; BC=Breast Cancer; CDK4/6i=CDK4/6 inhibitor; WT=Wild Type; Mets=Metastases; LA/mBC=Locally Advanced/Metastatic Breast Cancer; ER+=Estrogen Receptor Positive; OD=Once Daily; HR=Hazard Ratio; CI=Confidence Interval)

VII. Safety and Tolerability

Overall Safety Profile

Across the Phase 1/2 clinical program, Samuraciclib has generally demonstrated a manageable and tolerable safety profile, both as monotherapy and in combination with endocrine agents.1

Maximum Tolerated Dose (MTD) and Dose-Limiting Toxicities (DLTs)

In the initial monotherapy dose-escalation study (Module 1A of NCT03363893), the MTD for Samuraciclib was established at 360 mg administered orally once daily (OD).37 Dose-limiting toxicities (DLTs) were encountered at higher doses. Specifically, at the 480 mg OD dose level, 3 out of 6 patients experienced DLTs, including Grade 3 diarrhea, Grade 3 oral mucositis, and Grade 3 vomiting.37 At the 180 mg twice daily (BID) dose level, 1 out of 7 patients experienced a DLT of Grade 4 thrombocytopenia.37 In the Phase 1b dose escalation of Samuraciclib combined with elacestrant (NCT05963997), one DLT (Grade 3 diarrhea) occurred in the cohort receiving Samuraciclib 360 mg OD plus elacestrant 300 mg OD.36 Based on these findings, 360 mg OD was selected as the preliminary RP2D for monotherapy and further combination studies.36

Common Adverse Events (AEs)

The most frequently reported adverse events associated with Samuraciclib treatment across studies are predominantly gastrointestinal (GI) in nature and typically low-grade (Grade 1-2).1 These include:

• Nausea (reported frequencies ranging from ~81% to 96%)
• Diarrhea (~90-91%)
• Vomiting (~52-74%) Fatigue has also been noted as a common AE (~36%).[32] These AEs were generally reported as reversible and manageable with standard prophylactic measures and patient counseling.[1]

Grade ≥ 3 Adverse Events

While most AEs were low-grade, some Grade 3 or higher events have been reported, although infrequently. The most common Grade ≥ 3 AEs related to Samuraciclib include diarrhea (up to 19% in some cohorts) and nausea (up to 10%).32 Other reported Grade ≥ 3 events include vomiting, fatigue, stomatitis, and anemia.36 In the combination arm of Samuraciclib plus giredestrant (MORPHEUS trial), the most common TRAEs were also low-grade GI events; however, two patients (13.3%) discontinued treatment due to TRAEs (one patient experienced acute myocardial infarction and coronary artery thrombosis, another experienced stomatitis).52

Hematologic Toxicity Profile

A notable characteristic of Samuraciclib's safety profile is the relative absence of significant hematologic toxicities, particularly neutropenia and myelosuppression, which are commonly observed with other classes of CDK inhibitors, such as CDK4/6 inhibitors.26 While Grade 3 anemia and Grade 4 thrombocytopenia were reported as rare DLTs or AEs in specific contexts 37, widespread myelosuppression has not been a feature of Samuraciclib treatment at the doses studied. This distinct safety profile, likely stemming from its selective inhibition of CDK7 rather than broader CDK targets, represents a potential advantage, particularly for combination therapies. It suggests Samuraciclib might be combined more readily with agents known to cause myelosuppression (e.g., certain chemotherapies or PARP inhibitors 14) without significantly increasing the risk of overlapping hematologic toxicities. However, effective management of GI side effects remains a key consideration for patient tolerability.

Management of Adverse Events

Adverse events, primarily GI-related, have led to dose reductions and, in some cases, treatment discontinuations. For instance, in the Samuraciclib plus fulvestrant cohort (Module 2A), 6 patients discontinued due to GI AEs.32 However, dose reductions (e.g., 11 patients in the same cohort) often allowed patients to continue treatment.32

Impact of Formulation

The initial clinical studies utilized an instant release capsule formulation of Samuraciclib. It was hypothesized that the rapid release high in the GI tract might contribute to the observed GI AEs.1 Consequently, a novel single tablet formulation has been developed and is being used in the Phase 2b SUMIT-BC trial (NCT05963984), with the aim of potentially improving GI tolerability.1 An enteric capsule formulation was also explored in Module 6 of the Phase 1 study.83

Table 3: Summary of Common Adverse Events (Grade ≥ 3) Reported for Samuraciclib

Trial ID (NCT)	Cohort/Combination	Adverse Event	Grade ≥ 3 Frequency (%)	Snippet(s)
NCT03363893 (M1A - 480mg OD)	Monotherapy	Diarrhea	1/6 (17%)	37
NCT03363893 (M1A - 480mg OD)	Monotherapy	Oral Mucositis	1/6 (17%)	37
NCT03363893 (M1A - 480mg OD)	Monotherapy	Vomiting	1/6 (17%)	37
NCT03363893 (M1A - 180mg BID)	Monotherapy	Thrombocytopenia	1/7 (14%, G4 DLT)	37
NCT03363893 (M1B-1 - 360mg OD)	Monotherapy (TNBC)	Diarrhea	2/23 (9%)	87
NCT03363893 (M1B-1 - 360mg OD)	Monotherapy (TNBC)	Vomiting	1/23 (4%)	87
NCT03363893 (M1B-1 - 360mg OD)	Monotherapy (TNBC)	Fatigue	1/23 (4%)	87
NCT03363893 (M1B-1 - 360mg OD)	Monotherapy (TNBC)	Stomatitis	1/23 (4%)	87
NCT03363893 (M1B-1 - 360mg OD)	Monotherapy (TNBC)	Anemia	1/23 (4%)	87
NCT03363893 (M2A - 360mg OD)	+ Fulvestrant (HR+ BC)	Diarrhea	19%	32
NCT03363893 (M2A - 360mg OD)	+ Fulvestrant (HR+ BC)	Nausea	10%	32
NCT05963997 (Ph 1b - 360mg OD)	+ Elacestrant (300mg OD)	Diarrhea	1/5 (20%, DLT)	36
NCT05963997 (Ph 1b - 360mg OD)	+ Elacestrant (400mg OD)	Nausea	1/5 (20%)	36
NCT04802759 (MORPHEUS)	+ Giredestrant	TRAEs leading to discontinuation	2/15 (13.3%)	52

(Abbreviations: OD=Once Daily; BID=Twice Daily; G=Grade; DLT=Dose Limiting Toxicity; TNBC=Triple-Negative Breast Cancer; HR+=Hormone Receptor Positive; BC=Breast Cancer; TRAE=Treatment-Related Adverse Event)

VIII. Pharmacokinetics and Pharmacodynamics (PK/PD)

Pharmacokinetics (PK)

The pharmacokinetic profile of Samuraciclib has been characterized through the Phase 1 clinical trial (NCT03363893) and subsequent combination studies.

• Administration and Dosing: Samuraciclib is administered orally, typically once daily (OD).[1] The PK profile supports this OD regimen.[38]
• Absorption: Following oral administration in the fasted state, maximum plasma concentrations (Tmax) are reached between 1.5 and 4 hours.[37]
• Exposure and Dose Proportionality: Plasma exposure (AUC) increases proportionally with dose across the range of 120 mg to 480 mg OD.[37] Pharmacologically active exposures were maintained throughout the dosing period.[37]
• Half-life and Steady State: The geometric mean elimination half-life (T1/2) is approximately 75 hours.[37] Consistent with this long half-life, steady-state plasma concentrations are achieved within 8 to 15 days of continuous dosing.[37]
• Food Effect: A dedicated study (Module 4) demonstrated that food does not have a clinically significant effect on the bioavailability or exposure of Samuraciclib.[37]
• Drug-Drug Interactions (DDI): Clinical data indicate a low potential for significant PK interactions with relevant combination partners. No clinically relevant PK interactions were observed when Samuraciclib was co-administered with fulvestrant [38], elacestrant [36], or giredestrant.[52] Co-administration did not significantly alter the exposure of either Samuraciclib or the partner drug.[36] Furthermore, preliminary data suggest Samuraciclib is not a clinical inhibitor of CYP3A4 at the RP2D.[36]
• Variability: While average exposure was consistent with previous observations, the combination study with elacestrant noted potentially greater inter-individual variability in Samuraciclib exposure compared to monotherapy studies.[36]

The pharmacokinetic properties of Samuraciclib—specifically its oral bioavailability, long half-life supporting once-daily dosing, dose-proportional exposure, lack of significant food effect, and apparent low risk of PK interactions with key endocrine therapy partners—are advantageous for clinical development, particularly for combination regimens. These characteristics simplify dosing schedules and potentially reduce the complexity of managing drug interactions compared to agents with more challenging PK profiles or significant DDI liabilities.

Pharmacodynamics (PD)

Pharmacodynamic studies integrated into the Phase 1 trial confirmed target engagement in vivo. Analysis of paired tumor biopsies and peripheral blood mononuclear cells (PBMCs) from patients in the dose-escalation phase (Module 1A) demonstrated a reduction in the phosphorylation of the C-terminal domain (CTD) of RNA Polymerase II.38 As RNAPII CTD phosphorylation is a direct downstream consequence of CDK7 activity, this reduction serves as a key biomarker confirming that Samuraciclib effectively inhibits its target kinase in patients at clinically relevant exposures.38

IX. Regulatory Status and Future Outlook

Regulatory Designations

Recognizing the potential of Samuraciclib to address significant unmet medical needs, the U.S. Food and Drug Administration (FDA) has granted Fast Track designation for two separate indications:

1. Samuraciclib in combination with fulvestrant for the treatment of HR+, HER2- advanced breast cancer resistant to prior CDK4/6 inhibitor therapy.[7]
2. Samuraciclib in combination with chemotherapy for the treatment of locally advanced or metastatic triple-negative breast cancer (TNBC).[11]

The Fast Track program is designed to facilitate the development and expedite the review of drugs intended for serious conditions with unmet needs.[15] These designations underscore the potential clinical importance of Samuraciclib in these challenging patient populations where effective treatment options are limited. Notably, vepdegestrant (ARV-471), a combination partner for Samuraciclib in trial NCT06125522, has also received FDA Fast Track designation as a monotherapy.[51]

Current Development Status

Samuraciclib is actively progressing through mid-stage clinical development. The primary focus is on HR+/HER2- advanced breast cancer following progression on CDK4/6 inhibitors, with multiple Phase 1b/2 and Phase 2b trials evaluating combinations with different endocrine therapy partners currently underway.1 Key trials initiated in late 2023 and early 2024 include the Phase 2b SUMIT-BC trial (NCT05963984, +Fulvestrant) 11, the Phase 1b/2 SUMIT-ELA trial (NCT05963997, +Elacestrant) 8, and the Phase 1b/2 TACTIVE-U Sub-Study C (NCT06125522, +Vepdegestrant).7 The MORPHEUS-BC arm (NCT04802759, +Giredestrant) is also actively recruiting.78

Future Directions and Outlook

The encouraging safety and preliminary efficacy data from the Phase 1/2 program, particularly the activity observed in the post-CDK4/6i HR+ breast cancer setting, provide a strong rationale for continued development.38 The ongoing randomized Phase 2b SUMIT-BC trial (NCT05963984) is a critical next step, designed to definitively assess the PFS benefit of adding Samuraciclib to fulvestrant compared to fulvestrant alone.11 Results from this trial, along with data from the expansion cohorts of the other combination studies (with elacestrant, vepdegestrant, and giredestrant), will be crucial in determining the optimal endocrine partner and confirming the magnitude of clinical benefit.

Further investigation into biomarkers, especially the predictive potential of TP53 mutation status in HR+ breast cancer, is warranted and planned for future trials.[14] The development and evaluation of new formulations, such as the single tablet and enteric capsule, aim to improve tolerability, potentially enhancing patient compliance and outcomes.[1]

While the primary focus is currently breast cancer, the preclinical rationale and mechanism of action support exploring Samuraciclib in other malignancies, including prostate, pancreatic, ovarian, colorectal, and small cell lung cancers.[8] Potential combinations with other classes of agents, such as chemotherapy or PARP inhibitors, have also been suggested based on its non-myelosuppressive profile.[14]

X. Conclusion

Samuraciclib (CT7001) stands out as the most clinically advanced oral, selective inhibitor of CDK7. Its mechanism of action, targeting the dual roles of CDK7 in regulating oncogenic transcription via RNAPII phosphorylation and controlling cell cycle progression via CAK activity, provides a strong rationale for its development in oncology. Preclinical studies demonstrated potent in vitro and in vivo activity, particularly highlighting synergy with endocrine therapies in hormone-driven cancer models.

The Phase 1/2 clinical program (NCT03363893) established a manageable safety profile for Samuraciclib, primarily characterized by low-grade, reversible gastrointestinal adverse events (nausea, vomiting, diarrhea) and a notable lack of significant myelosuppression often seen with other CDK inhibitors. The maximum tolerated dose was determined to be 360 mg once daily, supported by pharmacokinetic data showing dose proportionality and a long half-life suitable for this schedule, with no significant food effect or interactions with key combination partners like fulvestrant, elacestrant, and giredestrant.

Encouraging preliminary efficacy signals were observed, including monotherapy activity in advanced TNBC (CBR 20%) and, more prominently, in combination with fulvestrant for heavily pretreated HR+/HER2- breast cancer patients who had progressed on CDK4/6 inhibitors (CBR 36%). Within this HR+ BC cohort, TP53 wild-type status and absence of liver metastases emerged as potentially strong positive predictors of clinical benefit, warranting further investigation.

Supported by collaborations with Pfizer/Arvinas, Menarini Group, and Roche, Carrick Therapeutics is now advancing Samuraciclib through multiple Phase 1b/2 and Phase 2b trials, primarily focusing on combinations with next-generation endocrine therapies (fulvestrant, elacestrant, vepdegestrant, giredestrant) in the CDK4/6i-resistant HR+/HER2- breast cancer setting. FDA Fast Track Designations for this indication, as well as for TNBC, underscore the recognized unmet need and the potential of Samuraciclib.

In conclusion, Samuraciclib represents a promising novel therapeutic agent targeting fundamental cancer pathways. While early clinical data are encouraging, particularly in endocrine-resistant breast cancer, definitive assessment of its efficacy awaits results from ongoing randomized Phase 2b studies. Confirmation of PFS benefit, clarification of optimal combination partners, and validation of predictive biomarkers like TP53 status will be critical determinants of its future role in cancer therapy.

XI. Executive Summary

Samuraciclib (CT7001, DB16061) is an investigational, oral, selective small molecule inhibitor of Cyclin-Dependent Kinase 7 (CDK7), developed by Carrick Therapeutics. CDK7 is a key regulator of both cell cycle progression (via activation of other CDKs) and oncogenic transcription (via phosphorylation of RNA Polymerase II), making it a compelling target in oncology, particularly in cancers reliant on specific transcriptional programs or those resistant to endocrine therapies. Samuraciclib functions as an ATP-competitive inhibitor, demonstrating selectivity for CDK7 over other CDKs in preclinical models.

Preclinical studies showed Samuraciclib inhibits proliferation, induces apoptosis, and suppresses hormone receptor signaling in vitro, with in vivo efficacy observed in xenograft models, notably demonstrating synergy with endocrine agents like fulvestrant and enzalutamide.

The foundational Phase 1/2 clinical trial (NCT03363893) established a maximum tolerated dose of 360 mg once daily. The safety profile was characterized primarily by manageable, low-grade gastrointestinal adverse events (nausea, vomiting, diarrhea), with a notable lack of significant myelosuppression. Pharmacokinetics support once-daily oral dosing with no significant food effect or interactions with tested endocrine partners. Preliminary efficacy was observed, including a 20% clinical benefit rate (CBR) at 24 weeks in advanced TNBC monotherapy, and a 36% CBR with the fulvestrant combination in heavily pretreated HR+/HER2- breast cancer patients post-CDK4/6 inhibitors. In the HR+ BC cohort, efficacy appeared significantly greater in patients with wild-type TP53 and without liver metastases.

Samuraciclib has received FDA Fast Track Designations for its combination with fulvestrant in CDK4/6i-resistant HR+/HER2- breast cancer and for its combination with chemotherapy in advanced TNBC. Carrick Therapeutics is actively pursuing Phase 1b/2 and 2b trials evaluating Samuraciclib in combination with various endocrine therapies (fulvestrant, elacestrant, vepdegestrant, giredestrant) in the post-CDK4/6i HR+ breast cancer setting, facilitated by collaborations with Pfizer/Arvinas, Menarini, and Roche.

Samuraciclib holds promise as a novel, potentially first-in-class CDK7 inhibitor targeting areas of high unmet need, particularly endocrine-resistant breast cancer. Its distinct mechanism and safety profile offer potential advantages. However, conclusive evidence of its clinical benefit awaits the results of ongoing randomized trials, particularly regarding progression-free survival and the validation of predictive biomarkers.

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