Cyclacel Pharmaceuticals : A phase 1 study evaluating the safety, pharmacokinetics, and efficacy of fadraciclib, an oral CDK2/9 inhibitor, in patients with advanced solid tumors and lymphoma

#3125: A PHASE 1, EVALUATING THE SAFETY, PHARMACOKINETICS, AND EFFICACY OF

FADRACICLIB, AN ORAL CDK2/9 INHIBITOR, IN SUBJECTS WITH ADVANCED SOLID TUMORS AND LYMPHOMA

Miguel Villalona-Calero1,Do-Youn Oh2, Elena Garralda3, Maria Vieito3, Ying-Hui Huang4, Sarina A. Piha-Paul5

1City of Hope National Medical Center, California, US; 2Seoul National University Hospital, Seoul, Korea; 3Vall d' Hebron Institute of Oncology, Barcelona, Spain; 4Cyclacel, New Jersey, US; 5MD Anderson Cancer Center, Texas, US

BACKGROUND

• Fadraciclib (formerly CYC065) is a highly selective inhibitor of CDK2 (IC50= 5 nM) and CDK9 (IC50= 26 nM) causing mitotic catastrophe and apoptotic death of cancer cells at sub-micromolar concentrations.
• In an earlier Phase 1 study of intravenous (IV) fadraciclib, confirmed CR has been achieved in a heavily pretreated endometrial cancer patient with CDNK2A, CDKN2B and MTAP loss.
• Oral fadraciclib is highly bioavailable allowing flexibility of dosing and schedule.

METHOD

• This is an open-label, multicenter phase 1/2 study in adult subjects with advanced solid tumors and lymphoma (NCT04983810/CYC065-101).
• Phase 1 explores both schedule and dose of oral fadraciclib monotherapy in 28-day cycles to identify maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D). Once RP2D is established, phase 2 will enroll up to 40 subjects in seven tumor specific cohorts and a basket cohort (tumor agnostic but molecularly driven), utilizing a Simon two-stage optimal design to evaluate clinical activity (Figure 1).
• Primary objectives
• • Phase 1: To determine MTD and/or RP2D
  • Phase 2: To evaluate preliminary efficacy of fadraciclib as measured by overall response rate (ORR)
• Secondary objectives
• • Phase 1: To assess safety and tolerability, PK, and ORR
  • Phase 2: To assess safety and tolerability; to evaluate disease control rate (DCR), duration of response (DOR), progression free survival (PFS), and overall survival (OS)
• METHODSExploratory objectives: To investigate clinical pharmacodynamics (PD) and pharmacogenomics (PGx) of fadraciclib

Figure 1: CYC065-101 Study Design

Phase 1 (completed)		Phase 2 (in progress)
(all comer solid tumor and lymphoma; 4 sites; 47 patients enrolled; 29 DLT evaluable)		(Simon 2-stage; ~10 sites)
	Dose Level 6b (n=2)		Cohort 1
	150mg qd tabs 7d (4/4 wk)		Endometrial, Ovarian
	DL6a (n=6)
		Cohort 2
	125mg bid tabs M to F (4/4 wk)
		Cholangiocarcinoma
	DL6 (n=2)
		Cohort 3
	150mg bid caps M to F (4/4 wk)
		Hepatocellular Carcinoma
	DL5 (n=7)		RP2D	Cohort 4
	100mg bid caps M to F (4/4 wk)			Breast (post-CDK4/6i, TNBC, HER-2 refr.)
	DL4 (n=3)
		Cohort 5
	100mg bid caps M to F (3/4 wk)
		B-cell Lymphoma
	Dose Level 3 (n=3)
		Cohort 6 (enrolling)
	75mg bid caps M to F (3/4 wk)
		T-cell Lymphoma (CTCL and PTCL)
	Dose Level 2 (n=3)
		Cohort 7
	50mg bid caps M to F (3/4 wk)
		mCRC (including KRAS mutated)
	Dose Level 1 (n=3)
		Cohort 8 Basket (enrolling):
	50mg bid caps MWF (3/4 wk)
		Solid tumors with alterations in CDKN2A/B

RESULTS

Table 1: Patient Disposition

CONCLUSIONS

• Common adverse events observed across all cohorts include nausea, vomiting and fatigue, while hyperglycemia and platelet decrease were observed primarily at higher dosing cohorts. Dose reductions occurred frequently above the RP2D. DLTs at doses above RP2D were nausea and hyperglycemia.
• Pharmacokinetics were dose-proportional and exceeded the preclinical efficacy target for both CDK2 and CDK9. Pharmacodynamics evaluated in peripheral blood showed suppression of CDKN2A/B by 4 hours post treatment in most patients who received 100 mg bid or higher.
• Clinical benefit was observed across all cohorts in a number of tumor types, including endometrial, NSCLC, ovarian, pancreatic and T-cell lymphoma.
• Based on the totality of safety, pharmacokinetic, pharmacodynamic and preliminary efficacy data, the RP2D of 100 mg bid p.o. Monday to Friday was selected.
• Enrollment of Phase 2 is in progress.

SAFETY

EFFICACY (cont.)

Figure 2: CT Scan of a patient with squamous NSCLC (DL6a)

Baseline scan 7-SEP-23

Cycle 1 scan 9-OCT-23

50y old male with sqNSCLC and CDKN2A and CDKN2B loss. Prior treatments included carboplatin and paclitaxel (from November 2022 to April 2023)

followed by docetaxel and atezolizumab (May 2023) with progression. Patient's first scan after four weeks of therapy showed SD (-22%)

Images kindly provided by the principal investigator.

Figure 3: Best Percentage Change from Baseline in Target Lesions (All Response Types)

*

DL1 (n=3)

DL2 (n=4)

60%

CTCL

DL3 (n=2)

(%)

53%

DL4 (n=3)

*

*

DL5 (n=6)

lesion

40%

**

SGC

*

DL6 (n=1)

TNBC Ovarian

DL6b (n=4)

29%

28%

TNBC

**

*

DL6a (n=9)

24%

BC

HCC

*

*

**

*

20%

19%

*

PR (n=2)

target

20%

17%

MD

EC

SGC

*

*

*

*

*

6%

Prostate

Pancreatic

3%

14%

Sarcoma

4%

3%

PD (n=10)

13%

12%

CRC

10%

CRC

ICC

CRC

*

5%

4%

*

**

SD (n=21)

10%

9%

9%

8%

8%

Pancreatic

BC

AMT

in

0%

CRC

HCC

baselinefromChange

A133TCDKN2A

deletionCDKN2A

CRC

mutantCDKN2A

P114LCDKN2A

lossCDKN2BCDKN2A,

-2%

-2%

CCA

CC

ENDO Ovarian

-4%

-5%

*

**

-8%

-20%

*

-8%

-11%

ENDO

PTCL

*

*

*

-15%

-16% NSCLC

-40%

*

-22%

*: no CDKN2A or CDKN2B alteration (n=23)

-60%

**: Unknown (n=5)

Data cutoff date: 2024-04-29

CTCL

-80%

(DL5)*(PD)026-101

(DL4)(PD)015-201

(DL5)(PD)034-101

(DL6a)(PD)038-101

(DL5)(PD)017-101

(DL1)(PD)003-101

(DL2)(SD)008-102

(DL1)(PD)002-102

(DL6a)(PD)037-101

(DL1)(SD)001-102

(DL6a)(PD)032-302

(DL6b)(PD)060-101

(DL6b)(SD)050-102

(DL6)(SD)029-201

(DL6b)(PD)040-101

(DL6a)(PD)046-101

(DL6b)(SD)053-101

(DL3)(SD)010-101

(DL6a)(SD)055-102

(DL3)(PD)013-101

(DL6a)(SD)042-102

(DL4)(PD)014-101

(DL6b)(SD)047-101

(DL2)(SD)004-102

(DL6a)(SD)031-102

(DL4)(SD)016-302

(DL5)(SD)023-101

(DL6a)(SD)044-101

(DL2)(SD)009-102

(DL5)(SD)020-302

(DL5)*(PR)021-102

(DL6a)(SD)051-102

(DL2)**(PR)006-102

-73%

*

Response Criteria by RECIST 1.1 (N=30), mSWAT (N=1), Lugano (N=2)

101-012 (SD)(DL3): no target lesion); 102-062 (SD)(DL6b): target lesion data pending entry

AMT = Appendix; BC; Breast; CC = Cervix; CCA = Cholangiocarcinoma; CRC = Colon and Rectum; CTCL = Cutaneous T cell Lymphoma; EC = Uterus; ICC = Intrahepatic bile ducts; ENDO = Endometrial; HCC = Hapatocellular Carcinoma; MD = Mandible; SGC = Salivary gland; TNBC = Triple-Negative Breast Cancer

	50mg BID MWF 50mg BID M-F	75mg BID M-F 100mg BID M-F 100mg BID M-F 150mg BID M-F 125mg BID M-F	150mg QD	Total
	Wk 1-3	Wk 1-3	Wk 1-3	Wk 1-3	Wk 1-4	Wk 1-4	Wk 1-4	Wk 1-4
Patients who received at least one dose of	3 (100)	4 (100)	3 (100)	3 (100)	9 (100)	2 (100)	13 (100)	10 (100)	47 (100)
treatment, n (%)
DLT evaluable Patients [a], n	3	3	3	3	7	2	6	2		29
Patients who discontinued the treatment, n (%)	3 (100)	4 (100)	3 (100)	3 (100)	9 (100)	2 (100)	13 (100)	9 (90.0)	46	(97.8)
Primary reason for treatment discontinuation, n (%)
Withdrawal of consent	0	0	0	0	1 (11.1)	0 (0)	5 (38.5)	3 (30.0)	9 (19.1)
Adverse event	1 (33.3)	1 (25.0)	0	0	1 (11.1)	0 (0)	1 (7.7)	2 (20.0)	6 (12.8)
Disease progression	2 (66.7)	3 (75.0)	2 (66.7)	3 (100)	6 (66.7)	1 (50.0)	6 (46.2)	4 (40.0)	27	(57.4)
Pregnancy	0	0	0	0	0	0	0	0		0
Investigator decision	0	0	0	0	1 (11.1)	0	0	0	1	(2.1)
Sponsor decision	0	0	0	0	0	0	0	0		0
Other	0	0	1 (33.3)	0	0	1 (50.0)	1 (7.7)	0	3	(6.4)
All-Treated Subjects Set [b]	3	4	3	3	9	2	13	10		47
DLT-Evaluable Patients Set	3	3	3	3	7	2	6	2		29
Full Analysis Set [c]	3	4	3	3	6	1	9	6		35

[a] DLT-Evaluable Patients: All patients who received at least 80% of the doses and completed all safety evaluations required for initiating Cycle 2. [b] All-Treated Subjects Set: All enrolled patients who received at least 1 dose of study drug.

[c] Full Analysis Set: All treated patient's subset with measurable disease at baseline and have at least one post-baseline disease assessment.

• The most common treatment related adverse events reported were nausea (66.0%), vomiting (46.8%), diarrhea (31.9%) fatigue (25.5%), and hyperglycemia (21.3%).
• Fadraciclib was well tolerated with good compliance between dose levels 1-5. A total of 4 DLT were reported at dose levels 6 (nausea, n=1; and hyperglycemia, n=1) and 6a (hyperglycemia, n=2).
• A total of 25 drug-related SAEs were reported in 8 patients with most common being hyperglycemia (n=4), platelet count decrease (n=3), and accidental overdose (n=3). There were no drug-related SAEs in dose level 5 (100 mg bid) the RP2D.
• Three deaths were reported on treatment. None were related to treatment.

EFFICACY

PHARMACOKINETICS

Figure 4: Plasma Concentration of CYC065 post Treatment

Day 1

			CYC065 conc. C1D1
	1200				DL5 100mg BID C1D1
	1000				DL6a 125mg BID C1D1
(ng/ml)	800				DL6 150mg BID C1D1
				DL6b 150mg QD C1D1
[CYC065]	600
400
	200
	0
	0	5	10	15	20	25
			Time post dosing (hrs)

Day 17/18

			CYC065 conc.
	1200				DL5 100mg BID C1D17/18
	1000				DL6a 125mg BID C1D17/18
(ng/ml)	800				DL6b 150mg QD C1D17/18
[CYC065]	600
400
	200
	0
	0	5	10	15	20	25
			Time post dosing (hrs)

Table 2: Patient Demographics and Baseline Characteristics - All Treated Subjects (N=47)

(A)	Total (N=47)		(B)	Total (N=47)
Age (years)			Primary tumor site, n (%)
Mean (SD)	58.6 (12.60)		Appendix	3
Median	60.0		BTC	4
Min, Max	36, 81		Breast	9
Sex, n (%)			CRC	6
		CUP	1
Female	30 (63.8)
	Gyn	7
Male	17 (36.2)
	H&N	3
ECOG performance status, n (%)
		HCC	2
0	9 (19.1)
	Lung	3
1	38 (80.9)
	Melanoma	1
Number of Prior Anti-cancer therapy, n (%)
5.43 (3.67)		Pancreatic	2
Mean (SD)
	Prostate	2
Median	4.0
	Testis	1
Min, Max	1; 17		T cell lymphoma	3

• A total of 35 patients were evaluable for efficacy (34 with measurable target lesions at baseline) as of April 29th, 2024. Tumor evaluations were conducted at baseline, end of Cycle 1 and then every 2 cycles. Response criteria of RECIST 1.1 were used for solid tumors (n=32), Lugano (n=2) and mSWAT (n=1) for PTCL and CTCL patients enrolled in the study.
• Two PRs were reported at dose levels 2 and 5 in patients with T-cell lymphomas.
• A heavily pretreated NSCLC patient with CDKN2A/B loss achieved 22% reduction in tumor burden at 4 weeks (Figure 2).
• Clinical benefit was reported in 7 patients (2 each with T-Cell lymphomas and endometrial cancer, and 1 with NSCLC, ovarian, and pancreatic respectively.)

CDK9 target engagement CDK2 target engagement

PK samples were collected in patients on Cycle 1 Day 1 and Cycle 1 Day 17/18. Dose proportional PK with CDK2 and 9 coverage at higher dose levels.

PHARMACODYNAMICS

Figure 5: Fadraciclib Suppressed CDKN2A/B Transcription in Patients

DL5: 100 mg bid

CDKN2A

P017 D01 H01

P017 D01 H04

P017 D01 H08

P017 D01 H24

P019 D01 H01

P019 D01 H04

P019 D01 H08

P019 D01 H24

P020 D01 H01

P020 D01 H04

P020 D01 H08

P020 D01 H24

P020 D17 H01

P020 D17 H04

P020 D17 H08

P020 D17 H24

P021 D01 H01

P021 D01 H08

P021 D01 H24

P023 D01 H01

P023 D01 H04

P023 D01 H08

P023 D01 H24

P023 D17 H01

P023 D17 H04

P023 D17 H08

P023 D17 H24

P024 D01 H01

P024 D01 H04

P024 D01 H08

P024 D01 H24

P026 D01 H01

P026 D01 H04

P026 D01 H08

P026 D01 H24

P026 D17 H01

P026 D17 H04

P026 D17 H08

P026 D17 H24

P027 D01 H01

P027 D01 H04

P027 D01 H24

P027 D17 H01

P027 D17 H04

P027 D17 H08

P027 D17 H24

P034 D01 H01

P034 D01 H04

P034 D01 H08

P034 D01 H24

P034 D17 H01

P034 D17 H04

P034 D17 H08

P034 D17 H24

CDKN2B

Peripheral blood PD samples were collected at baseline and at 1, 4, 8, and 24 h post-treatment on Cycle 1 Day 1 and Cycle 1 Day 17/18.

TPM (transcripts per million) was determined by mRNAseq and differential gene expression levels were determined relative to baseline after normalization to housekeeping genes. Samples are labelled by "Subject No._Day_Hour"

Log2

(HxH0)

+3

0 -3