Constellation Pharmaceuticals : Poster Presentation of Phase 1/2 First-in-Human (FIH) Study of CPI-0209 in Patients With Advanced Tumors, Presented at ACRO, June 4, 2021

Phase 1/2 First-in-Human (FIH) Study of CPI-0209, a Novel Small Molecule Inhibitor of Enhancer of Zeste Homolog 2 (EZH2) in Patients With Advanced Tumors

Poster #

3104

Nehal J. Lakhani, MD, PhD1, Martin Gutierrez, MD2, Linda Duska, MD3, Khanh Do, MD4, Manish Sharma, MD1, Leena Gandhi, MD, PhD5, Kyriakos P. Papadopoulos, MD6, Jennifer Truong, MD7, Xiaolin Fan, PhD7, Ji Hyun Lee, MD7, Suresh Bobba, MD7, Ronda Rippley, PhD7, Rentian Wu, PhD7, Jike Cui, PhD7, Kaiming Sun, PhD7, Jing Wang, PhD7, Patrick Trojer, PhD7, Drew Rasco, MD6

1START - Midwest, Grand Rapids, MI; 2Hackensack University Medical Center, Hackensack, NJ; 3University of Virginia, Charlottesville, VA; 4Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, MA; 5Dana-Farber Cancer Institute, Boston, MA; 6START - San Antonio, San Antonio, TX; 7Constellation Pharmaceuticals, Cambridge, MA

BACKGROUND

EZH2 "Writer" Activity Suppresses Gene Transcription

Patient Disposition

RESULTS

Platelet Count Change

Treatment Duration by Dose Level

Polycomb Repressive Complex 2 (PRC2)	Broad Implications in Cancer
	Activating mutations

EZH2	PRC2	Oncogenic driver synergy
	H3K27me3	Synthetic lethal relationships
	OFF

	N (%)
Enrolled	41
Treated	40
Ongoing*	9 (22)
Discontinued	32	(78)
Reason for treatment discontinuation
Progressive disease	31	(76)
Adverse event	1	(2)
Treatment duration (days) - median (min, max)	43 (1, 324)
Total number of cycles - median (min, max)	2 (1, 12)

Analysis Set	N
Safety Analysis Set	40
Efcacy Analysis Set	34

CPI-0209 Dose	N
50 mg	4
100 mg	6
137.5 mg	6
187.5 mg	6
225 mg	7
275 mg	4
375 mg*	8
Total	41

% Change in Platelets from Baseline to End of Cycle 1 by Cohort

Count	30
	20
Platelet	10
0
	-10
in	-20
-30
Change
-40
	-50
%	-60
-70
Median
-80
	-90

	50 mg	100 mg	137.5 mg	187.5 mg	225 mg	275 mg	375 mg
N	4	6	5	6	7	4	7
Median	-1.0	-21.6	-32.6	-33.6	-43.2	-61.6	-60.1

x

	x
		Dose level:
x			50 mg
		100 mg
			137.5 mg
			187.5 mg
			225 mg
			275 mg

	Drug resistance
EZH2 trimethylates histone H3 at lysine 27	Tumor immunity
and suppresses transcription

EZH2i - enhancer of zeste homolog 2 (EZH2) inhibitor

CPI-0209: Durable and Complete Tumor Regression in Xenograft Model

H3K27me3 and Efficacy

HT1376 ARID1A Mutant Bladder Cancer Xenograft Model

The Safety Analysis Set is dened as all patients who received any amount of study drug

The Efcacy Analysis Set is dened as all patients who received the study drug and had at least 1 post-baseline tumor assessment

*1 patient (375 mg) - treatment not started as of 09Mar21

Baseline Demographics and Disease Characteristics

Safety Analysis Set (N=40)

	Mean (SD) or n (%) or Median (Min, Max)
Total (N)	40
Age (years)	64 (11)
Gender
Male/Female	17 (43)/23 (58)
Time since initial diagnosis (days)	925 (88, 9159)
Cancer Type

% Change

A dose dependent platelet count decrease was observed that was manageable and reversible

Summary of TEAEs by Dose Cohorts

• 43% of pts had at least 1 ≥ Grade 3 TEAE; these occurred at 25% in dose-cohort 50 mg; 50% in 100 mg, 137.5 mg, and 187.5 mg; 75% in 275 mg, and 57% in 375 mg dose cohort
• 28% of pts had at least 1 serious AE; these occurred at 14% in 375 mg, 33% in 100 mg and
  137.5 mg, 50% in 187.5 mg, and 75% in 275 mg; no pts in 50 mg and 225 mg had a serious AE
• 68% of pts had at least 1 TEAE considered possibly related to CPI-0209

− TEAEs considered possibly related in more than 2 pts were anemia, diarrhea, nausea, vomiting, fatigue,

platelet count decrease, dysgeusia, and alopecia

• 3 pts experienced Grade 4 TEAEs

− Worsening lipase increased (137.5 mg), lung infection (275 mg), and thrombocytopenia (375 mg)

375 mg

Treatment ongoing

Mesothelioma patients x BAP1 loss [local testing]

	SD
x	PR
PD

A		160	Vehicle (PO QD)				B
						3000
		140	CPI-0209 75 mg/kg PO QD from D1-13
	H3K27me3/H3(%)						(mmVolumeTumor3)	2500
RatioRelativeof	120
					500
		100							2000
		80							1500
		60							1000
		40
		20
		0							0
			D13 (0)	D14 (1)	D15 (2)	D16 (3)	D19 (6)	D24 (11)	0
			Days Post Treatment Start (Days Post Dose Suspension)

Vehicle (PO QD)

CPI-0209 (75 mg/kg PO QD)

>100% TGI

10

20

30

40

50

60

Time (Day)

Ovarian cancer	7 (18)
Mesothelioma*	6 (15)
Pancreatic cancer	6 (15)
Breast cancer	5 (13)
Colon cancer	5 (13)
Endometrial cancer	2	(5)
Leiomyosarcoma	2	(5)
Other†	7 (18)
Prior lines of cancer therapies
1	3	(8)
2	9 (23)
3	12	(30)
>3	16	(40)

CPI-0209 Pharmacokinetics in Patients Exhibit Durable Exposure and Half-Life of ~8 hrs

Cycle 1 Day 1

Cycle 2 Day 1 (QD×28 Days)

in

in

50 mg

1000

1000

100 mg

137.5 mg

100

100

187.5 mg

225 mg

275 mg

10

10

375 mg

1

1

ConcentrationCPI-0209

(ng/mL)Plasma

ConcentrationCPI-0209

(ng/mL)Plasma

0	1	2	3	4	5	6	7	8	9	10	11	12
						Month

Preliminary Evidence of CPI-0209 Activity in Mesothelioma With BAP1 Loss

Baseline

After 2 Cycles

After 4 Cycles

• Significant reduction (>90%) of global H3K27me3 levels
• Reduction of H3K27me3 maintained for days after dose suspension
• Tumor regression seen with 75 mg/kg QD dosing
• Long residence time
• Increased potency
• Sustained target engagement allows for QD dosing

STUDY DESIGN

*4 mesothelioma patients had BAP1 loss

† Other - bladder cancer, cholangiocarcinoma, gastric cancer, melanoma, prostate cancer, tonsil carcinoma, and uterine carcinoma

Summary of Treatment Emergent Adverse Events

			• CPI-0209 was generally well tolerated
	All Grades	Grades ≥3
TEAEs1	N=402	N=402	• 37 pts (93%) reported at least 1 treatment-
	n (%)	n (%)	emergent adverse event (TEAE)
			• 17 pts (43%) reported at least 1 ≥Grade 3 TEAE
Hematological Events
			− Reported in ≥2 pts were thrombocytopenia,
Thrombocytopenia3	11 (28)	2 (5)
			anemia, abdominal pain, pneumonia, amylase ↑,
Anemia	8 (20)	2 (5)
AST ↑, ALP ↑, pulmonary embolism, and back pain
Non-hematological Events		• 1 dose-limiting toxicity (DLT) (Grade 4
Gastrointestinal Events			thrombocytopenia) was reported by 1 pt from 375 mg
			dose cohort
Diarrhea	11 (28)	0

0.1 0	4	8	12	16	20	24	28	0.1 0	4	8	12	16	20	24	28
			Time (Hours)							Time (Hours)

• Plasma concentrations increase with increases in dose
• Estimated mean half-life ~8 hrs (range 4-11 hrs)
• Exposure is durable over time
• • Accumulation after 1 cycle ~10-50% across cohorts, consistent with estimated half-life
  • Trough concentrations are stable, no evidence for net autoinduction

			CPI-0209 Reduces H3K27me3 in Monocytes
			CPI-0209 Impact on H3K27me3 in Monocytes in Patients
H3		0
H3K27me3/Total	to Baseline	-20	• Comprehensive target engagement was
-40	observed after 7 days of treatment within the first
-60	cycle at all dose levels in monocytes

Phase 1 - Escalation

Monotherapy - Advanced Tumor

3+3 Design

Dose Level 7

375 mg

Dose Level 6

275 mg

Dose Level 5

225 mgRP2D

Phase 2 - Expansion at RP2D* (350 mg QD)

Monotherapy

Disease-Specific Cohorts

		Urothelial Carcinoma				Lymphoma (either B-cell
M1			M4		or T-cell histology, EZH2
	(ARID1A mutant)
						mutant and wildtype)

M2	Ovarian Clear Cell	M5	Pleural or Peritoneal
Carcinoma	Mesothelioma

Nausea	9 (23)	0	• 9 pts (23%) reported TEAEs leading to CPI-0209 dose
reduction or interruption
Abdominal pain	6 (15)	2 (5)
− Grade 2 diarrhea (2) and Grade 3 anemia (1)
Other Non-hematological Events
	were related TEAEs leading to dose interruption
Asthenic conditions4	11 (28)	0	in 3 pts
			• 4 pts (10%) reported TEAEs leading to CPI-0209
Dysgeusia	8 (20)	0
			discontinuation
Alopecia	6 (15)	0
− Grade 2 dysgeusia was the related TEAE leading to
1TEAEs of all grades that occurred in ≥15% of patients		discontinuation in 2 pts
2Safety evaluable population: received at least 1 dose of study drug	• 1 pt experienced Grade 5 TEAE (progressive malignant
as of the data cut-off
3Includes TEAE platelet count decrease			neoplasm)
4Includes TEAEs of fatigue and malaise

Change	Compared	-80				• CPI-0209 reduces H3K27me3 over 90% in
-100				monocytes at doses ≥100 mg
-120
%		100 mg	137.5 mg	187.5 mg	225 mg 275 mg 375 mg
	50 mg
					Dose

Change of H3K27me3/total H3 ratio at cycle 1 day 8 (C1D8) compared to baseline (C1D1)

CPI-0209 Increased the Expression of PRC2-Controlled Gene Sets in

Patient Whole Blood in an Exposure-Dependent Manner

• Diagnosed with biphasic mesothelioma BAP1 bi-allelic mutation and IHC negative
• Patient had rapid progression through 2 prior lines of therapy
• Partial response after 4 cycles (225 mg QD), conrmed at cycle 5

CONCLUSIONS

Dose Level 4

187.5 mg

Dose Level 3

137.5 mg

Dose Level 2

100 mg

Dose Level 1

50 mg

Mono

(ARID1A mutant)

(BAP1 loss)

M3		Endometrial Carcinoma		M6		Metastatic Castration
			Resistant Prostate Cancer
		(ARID1A mutant)

*RP2D - recommended Phase 2 dose

TEAEs Occurring in ≥15% Overall by Dose Cohorts

	CPI-0209CPI-0209CPI-0209	CPI-0209CPI-0209	CPI-0209	CPI-0209	Overall
TEAEs	50 mg	100 mg	137.5 mg	187.5 mg	225 mg	275 mg	375 mg	Total
	(N=4)	(N=6)	(N=6)	(N=6)	(N=7)	(N=4)	(N=7)	(N=40)
Total Patients with	3 (75%)	6 (100%)	6 (100%)	6 (100%)	6 (86%)	4 (100%)	6 (86%)	37 (93%)
at least 1 TEAE
Total Number of TEAEs	8	26	27	52	44	30	37	224
Thrombocytopenia1	0	1 (17%)	0	2 (33%)	2 (29%)	2 (50%)	4 (57%)	11 (28%)
Diarrhea	1 (25%)	1 (17%)	0	1 (17%)	4 (57%)	1 (25%)	3 (43%)	11 (28%)

A

Decreased

N=510

	B		Pearson's Correlation	C
		r=0.91	-Log10(P Value)
			p=2.8E-10
	Changes	0.75		0	20	40	60	80
		Dose	Meissner Brain HCP With H3K4me3 and H3K27me3
		50	Lee BMP2 Targets Up
Increased	0.50	100
137.5
N=1403	Fold		187.5	Dodd Nasopharyngeal Carcinoma Up
	225	Wong Adult Tissue Stem Module
		275
	Log2
	0.25	Gender	Benporath ES With H3K27me3
		Female	Liu Prostate Cancer DN
	Mean
		Male
			Lim Mammary Stem Cell Up
		0.00		Perez TP53 Targets
				Benporath EED Targets

• Comprehensive target engagement as assessed by global reduction in H3K27me3 levels was

observed within the rst cycle after 7 days of treatment at all dose levels in monocytes

• CPI-0209 increased the expression of PRC2-controlled gene sets in whole blood in an

exposure-dependent manner

• CPI-0209 pharmacokinetics in patients exhibit durable exposure and a half-life of ~8 hrs

• CPI-0209 showed a manageable safety prole with dose dependent thrombocytopenia

• There was 1 DLT in 375 mg cohort (Grade 4 thrombocytopenia)

• The MTD has not been reached. The RP2D was chosen as 350 mg QD based on collective

• Phase 1 primary objective is to determine the maximum tolerated dose (MTD) and/or RP2D of CPI-0209 in patients with advanced tumors
• Phase 2 primary objective is to evaluate the antitumor activity of CPI-0209 in patients with

selected tumors

Asthenic conditions2	0	1 (17%)	1 (17%)	3 (50%)	4 (57%)	1 (25%)	1 (14%)	11 (28%)
Nausea	0	1 (17%)	2 (33%)	1 (17%)	2 (29%)	1 (25%)	2 (29%)	9 (23%)
Anemia	0	0	1 (17%)	3 (50%)	0	1 (25%)	3 (43%)	8 (20%)
Dysgeusia	0	0	1 (17%)	0	4 (57%)	1 (25%)	2 (29%)	8 (20%)
Abdominal pain	1 (25%)	1 (17%)	1 (17%)	2 (33%)	1 (14%)	0	0	6 (15%)
Alopecia	0	1 (17%)	0	1 (17%)	3 (43%)	0	1 (14%)	6 (15%)

1Includes TEAE thrombocytopenia and platelet count decrease

2Includes TEAEs of fatigue and malaise

						Benporath SUZ12 Targets
1.0	1.5	2.0	2.5	3.0	3.5

Log10 AUC Exposure of C1D1

• RNAseq analysis of patient whole blood (Day 1 vs 22) identified expression changes on 1913 genes
• • 1403 up-regulated genes and 510 down-regulated genes
• Expression changes of CPI-0209up-regulated genes correlate with exposure in plasma
• Up-regulatedgenes are mechanism-related: gene set enrichment analysis of up-regulated genes identified PRC2 related gene sets

safety assessments

• Of the 4 BAP1 loss mesothelioma patients, 1 patient had a durable PR and 2 had SD ≥2 months