• 141 subjects received treatment with SRA737 (+LDG) across both escalation and expansion cohorts. Of the subjects treated, 81/141 (57%) were considered evaluable for RECIST target tumor response.

• The largest number of subjects (n=35) were enrolled in the anogenital/cervical cancer cohort with the next largest number in the HGSOC (n=28) cohort.

• Partial responses (PR) were observed in 6 subjects (Figure 3). Overall, 41 subjects had a best response of stable disease (SD); durable SD lasting ≥ 4 months was recorded in 32 subjects and was observed in all expansion cohorts. 22 subjects remained on study treatment at the time of the data cut off.

• Anogenital cancer was identified as the indication most sensitive to SRA737+LDG in this clinical study (ORR=30%; DCR=60%) (Figure 7). Several subjects with anogenital cancer had noteworthy durations of response: 5/10 (50%) subjects remained on study treatment for ≥ 4 months with a maximal duration of ~11 months.

• In keeping with the signal seeking objective of this study, tumor responses were further examined with respect to the genetic profiles determined for the tumor types

enrolled and treated (Figure 4).• Alterations in several gene networks correlated either

positively, or negatively, with response to SRA737+LDG across multiple indications (Table 1). Subjects whose tumors harbored multiple gene network alterations tended to have more favorable tumor reductions and longer DOS.

• Several of the robust responses observed in this study were associated with genomic alterations in the FA/BRCA network and related factors involved in replication fork repair (Figure 5). A putative mechanistic model correlates observed activity with the FA/BRCA gene network (Figure 6)

• Tumor mutational burden (TMB): 3 of 4 subjects with anogenital cancer presenting with elevated TMB (a hallmark of genomic instability) had robust responses, encompassing some of the most profound tumor decreases observed in the SRA737-02 study (Figure 7).

• Results data cut off: 03 May 2019; Data not final

Authors and AffiliationsUdai Banerji1, Ruth Plummer2, Victor Moreno3, Joo Ern Ang1, Amy Quinton4, Yvette Drew2, Tatiana Hernandez3, Desamparados Rhoda Perez5, Louise Carter6, Alex Navarro7, Rebecca Kristeleit8, Tobias Arkenau9, Debashis Sarker10, Daniel Castellano11, Harriet Walter12, Patricia Roxburgh13, Sarah Blagden14, Alan Anthoney15, Mark Kowalski16, Ines Verdon16, Robert Jones4

1Royal Marsden Hospital, London, UK; 2Freeman Hospital, Newcastle, UK; 3Hospital Fundacion Jimenez Diaz, Madrid, Spain; 4Velindre Cancer Centre, Cardiff, UK; 5Biomedical Research Institute INCLIVA, Valencia, Spain; 6The Christie Hospital, Manchester, UK; 7Hospital Universitario Vall d’Hebron, Barcelona, Spain; 8University College Hospital, London, UK; 9Sarah Cannon Research Institute, London, UK; 10Guy’s Hospital, London, UK 11Hospital Universitario 12 de Octubre, Madrid, Spain; 12Leicester Royal Infirmary, Leicester, UK; 13The Beatson West of Scotland Cancer Center, Glasgow, UK; 14Oxford University Hospital, Oxford, UK; 15Leeds Teaching Hospitals, Leeds, UK; 16Sierra Oncology, Vancouver, Canada

A Phase 1/2 First-in-Human Trial of Oral SRA737 (a Chk1 Inhibitor) Given in Combination with Low Dose Gemcitabine in Subjects with Advanced Cancer Abstract #3095

SRA737 is a potent, highly selective and orally-bioavailable small molecule inhibitor of Checkpoint kinase 1 (Chk1).

Chk1 is a serine/threonine protein kinase in the DNA Damage Response (DDR) network that is critically important in reducing elevated replication stress in tumor cells.

Replication stress (RS) is manifested by the stalling of replication forks which results in DNA prone to damage. Increased RS results in genomic instability, which affords survival advantages to tumor cells, however, if not properly managed, can result in extensive DNA damage and cell death.

Consequently, tumor cells increase reliance on Chk1 to manage elevated intrinsic RS. It is hypothesized that cancer cells with higher RS may have increased sensitivity to Chk1 inhibitor therapy.

Intrinsic sources of RS can include genetic alterations in tumor suppressors, oncogenes or DNA damage repair

genes. Tumors harboring defects in these functional gene networks are hypothesized to have higher levels of intrinsic RS (Figure 1). Additionally, it has been shown that certain extrinsic sources of RS such as sub-therapeutic doses of gemcitabine (low dose gemcitabine; LDG) can further exacerbate replication fork instability and enhance Chk1 inhibitor mediated anti-tumor activity (Figure 2). This signal-seeking Phase 1/2 study (NCT02797977) was designed to investigate the safety and tolerability of SRA737+LDG as well as to evaluate preliminary anti-tumor activity in tumors with genetic alterations predicted to confer increased intrinsic RS and Chk1i sensitivity in order to delineate potential genetic signatures and/or tumor indications that might warrant additional therapeutic investigation.

Prospective genetic screening was performed to identify and select subjects harboring one or more of these genetic alterations.

A total of 58 subjects received SRA737 in 13 escalation cohorts at doses of 40 to 600 mg SRA737 variously combined with LDG doses of 50 to 300 mg/m2.

No protocol-defined dose limiting toxicities (DLTs) were observed, but intolerability was notably evident at the highest doses tested.

The pharmacokinetic profile of SRA737 revealed AUC0-24 and Cmax of 3550 ng∙h/mL and 548 ng/mL at 150 mg SRA737. At this dose, the Cmin (52 ng/mL) exceeded that determined in preclinical models to be effective. 

Enrollment into the expansion cohorts was initiated at 500 mg SRA737 + 100 mg/m2 LDG.

Based on overall tolerability, the recommended dose to be employed in the expansion cohorts was determined to be 500 mg SRA737 + 250 mg/m2 LDG (RP2D).Of 335 subjects prospectively identified, 204 were screened for genetic alterations associated with Chk1 sensitivity. Of these subjects 176 (86%) met genetic eligibility criteria, and 85 were treated in the four expansion cohorts.

In the Dose Escalation phase, subjects with solid tumors in cohorts of 3 to 6 subjects received escalating doses of SRA737 in combination with varying sub-therapeutic doses of gemcitabine. SRA737 was administered for 2 days after LDG administration on days 1, 8 and 15 of a 28 day cycle. A lead-in dose for Pharmacokinetic (PK) analysis was performed 4-7 days prior to Cycle 1 (C1). 

The Cohort Expansion phase was contemporaneously initiated when circulating plasma concentrations of SRA737 exceeded the minimum effective concentration of SRA737 modelled from murine efficacy studies. Thereafter, experience gained in the ongoing Dose Escalation phase informed the dose selection for the expansion cohorts. 

The Cohort Expansion phase enrolled subjects with genetically defined tumors that harbored genomic alterations hypothesized to confer sensitivity to Chk1 inhibition, which were prospectively selected by next-generation sequencing (FoundationOne). Subjects with the following tumors were eligible for enrollment: i) soft tissue sarcoma, ii) high grade serous ovarian (HGSOC), iii) small cell lung, and iv) anogenital/cervical cancers. Subjects with anogenital or cervical cancer were eligible for enrollment without prospective genetic profiling based on the near ubiquitous prevalence of HPV-positivity in this population.

• Overall, these data provide clear evidence of SRA737+LDG anti-tumor activity. Multiple partial responses were observed, generally first recorded at the first on-study scan (end of cycle 2).

• In this first-in-human trial of SRA737+LDG, the RP2D was determined to be 500 mg SRA737 plus 250 mg/m2  gemcitabine. Consistent with the RS-inducing properties of LDG, this combination utilized a gemcitabine dose substantially below (10-25%) standard of care dose levels. The

combination of SRA737+LDG was generally well tolerated.

• In aggregate, the safety and efficacy data determined in this study support that SRA737+LDG is readily conducive to development as a standalone therapy and appears potentially combinable with other therapeutics.

• This signal-seeking study surveyed broadly across tumor indications and tumor RS-driver genetics to

identify potential SRA737-sensitive settings in the context of the potentiating effect of the extrinsic RS-inducer, LDG.

• FA/BRCA network mutations were associated with the most favorable outcomes in this study (ORR=25%; DCR=81%). The FA/BRCA gene network encodes a series of Fanconi Anemia and other proteins involved directly or indirectly in replication fork metabolism and management of RS. 

• Importantly, the sensitivity of SRA737+LDG associated with mutations in the FA/BRCA gene network observed in this study were consistent with similar findings from the SRA737 monotherapy clinical study (NCT02797964). 

• Striking anti-tumor activity was observed in subjects with advanced anogenital cancer (ORR = 30%; DCR=60%), encompassing noteworthy tumor decreases (e.g. -66% tumor decrease; resolution

of pleural effusion) and promising durations of treatment (e.g. ~11 months).

• Second line metastatic anogenital cancer represents a significant unmet medical need, with no approved therapies and a significantly abrogated life expectancy.  These promising data suggest that SRA737+LDG could represent a potentially efficacious treatment option for these patients and warrants additional registration-intent studies. 

Oncogenic drivers Dysregulation of replication,

transcription/replication collision

Defective DNA damage repair

Single strand breaks, double strand breaks

Depleted replica building blockstion Low dose gemcitabine (LDG)

Cell cycle dysregulation

Loss of G1/S

MYC*

Defective G1 / S

Checkpoint

TP53*

HPV*

BRCA 1/2*

CCNE1*

Increased reliance on Chk1 in tumor

High RS results in:

Chk1

regulates RS

I n t r ins ic RS Inducers Ext r ins ic RS Inducers

*Illustrative genes and drivers only

e.g.

e.g.

e.g.

Figure 1. Intrinsic and Extrinsic Sources of RS Elevate Genomic Instability and Increase Reliance on Chk1 for Tumor Cell Survival. RS-driver genes can be divided into several functional categories including G1/S tumor suppressors, oncogenes and DNA repair genes. Research in the DDR field has implicated mutations in G1/S guardian genes, including RB1, TP53 and genes functioning in these pathways, as potentially contributing to intrinsic RS. Certain viral infections that impact these same pathways, e.g. HPV, have also been implicated in increasing cellular RS. In addition, activating mutations in several oncogenes, including MYC, CCNE1 and others, have been suggested to dysregulate replication origin firing and transcriptional programs resulting in elevated RS.  Similarly, tumor genetic alterations in certain DNA repair factors, such as those in the Fanconi Anemia and BRCA pathways, have been demonstrated to compromise replication fork stability or repair of damaged forks, exacerbating intrinsic RS. Additional RS can be generated by treatment with LDG, a drug that depletes DNA replication building blocks (dNTP) resulting in extrinsic RS and increased Chk1 reliance.

Figure 2. Low Dose Gemcitabine (LDG) Profoundly Potentiates SRA737. Gemcitabine is a potent and irreversible inhibitor of ribonucleotide reductase (RNR), the rate-limiting enzyme responsible for generating the deoxyribonucleotide (dNTP) supply needed for DNA replication. Very low, non-cytotoxic concentrations of gemcitabine result in dNTP depletion, stalled replication forks and activation of Chk1 (pChk1). Once activated, Chk1 manages RS by pausing cell cycle progression and limiting further replication origin firing.  In addition, activated Chk1 triggers increased RNR expression to recover the diminished dNTP pool.  As such, simultaneous inhibition of Chk1 by SRA737 results in profound synergy with LDG, leading to catastrophic RS and tumor cell death. 

• The majority of TEAEs were mild to moderate in severity (91% Grade 1/Grade 2).

• No evidence of emergent or cumulative toxicity and/or declining tolerability with up to 13 cycles.

CharacteristicOverall SRA737+LDG(Escalation & Expansion)

Tumor Types of Interest

Anogenital Cervical Rectal cancer HGSOC

Number of subjects treated 141 18 17 14 28

Age / years (min, max)

62.0 (18, 81)

61.5 (48, 74)

45.0 (34, 75)

63.5 (40, 81)

64.5 (44, 79)

Gender (M/F) 55 (39%) / 86 (61%)

5 (28%) / 13 (72%)

0 / 17 (100%)

10 (71%) / 4 (29%)

0 / 28 (100%)

WHO performance status (PS0 / PS1) 61 / 80 6 / 12 8 / 9 11 / 3 14 / 14

Prior systemic therapy regimens; mean (min, max)

2.8 (1, 9) 2.0 (1, 5) 2.2 (1, 4) 3.5 (2, 5) 4.2 (1, 9)

Prior radiation therapy regimens; mean (min, max)

1.6 (1, 3)n=76

1.6 (1, 3)n=14

1.9 (1, 3)n=14

1.4 (1, 2)n=8

1.0 (1, 1)n=2

Treatment delay from consent to C1D1; median (min, max)

24 (7, 157) 26 (11, 147) 43 (8, 89) 22 (13, 36) 28 (8, 84)

Subjects evaluable for target-tumor response*; [# with genetic profile available]

81[54]

10[7]

12#[9]

8[6]

15[10]

* Subjects with pre- and post-treatment target tumor measurements who received ≥ 83% of total planned SRA737 in C1 at ≥ 150mg SRA737 and ≥ 100 mg/m2 GEM, or continued on-study after 3 cycles of treatment at any dose level

# 8/12 subjects were noted to be squamousData cut off: 03 May 2019

dNDP NDP

Converted to dNTP andincorporated as buildingblocks into DNA strands

Chk1

RNR

dNDP NDP

Activated pChk1 pausesfurther DNA replication(origin firing) to avoid

increasing RS

Chk1 P

Activated pChk1 feedsback to express more

RNR for increaseddNTP manufacturing

Replication stress (RS)

Insu�cient dNTPresulting in stalledreplication forks

SRA737 + LDG

No Treatment

RNR Gemcitabine

LDG

NA

0 0 NA

0 0

Chromatin

Mismatch Repair

9 8 38%

8 7 71%

17 16 81%

75%PI3K

FA/BRCA

HR/NHEJ

67%

RAS

CCNE

44%

0%MYC

6 6

9 NA

1 1

64%

G1/S 60%

29 25

10 10

19 16

p53 Pathway

DNA Damage Response and Repair Network

Cell Cycle Dysregulation

Oncogenic Drivers

DNA Pol

MDM2

TP53

RB1

CDKN1A/B

CDKN2A/B/C

CCNE1

FBXW7

PARK2

KRAS

NRAS

HRAS

MYC

MYCN

MYCL1

PIK3CA

PTEN

AKT1/2/3

CDK12

FANC*

RAD**

ATR

BRCA1/2

RAD51B

RAD51C

PRKDC

PALB2

ATM

MLL2

ARID1A

ARID1B

MLH1

MSH2

MSH6

PMS2

POLD1

POLE

Functional Gene Category Gene

Number of Subjects

Number of RAS Wild-Type

SubjectsDCR‡

(%)

NA

NA

13%

29%

25%

13%

17%

0%

0%

8%

0%

Response Rate‡ (%)

Gene Network

V VVV V

VV

VATR

PRKDCBRCA1BRCA2CDK12FANC*RAD**

Bes

t %

Cha

nge

fro

m B

asel

ine

in S

um o

f Ta

rget

Tum

or

Dia

met

ers

HGSOC HGSOC CRC Mesothelioma HGSOC CRC HGSOC HGSOC CRC HGSOC mCRPC mCRPC HGSOC HGSOC mCRPC HGSOC CRC HGSOC mCRPC HGSOC HGSOC 031-019 141-015 149-010 031-007 031-011 031-038 143-061 144-031 146-001 144-026 146-008 149-015 141-017 031-100 011-010 144-029 146-002 143-033 031-053 031-013 140-007

V VV V V V

V

VV

V

V V V

VV

-40% -30% -20% -10%

0% 10% 20% 30% 40% 50% 60% 70% 80% 90%

SD

PD

Subject Ongoing

Adjudicated VUSV

‡ Rate for RAS Wild-Type subjects

Table 1. Response & Disease Control Rates Vary Across Gene Networks Summary of DCR and response rates across 11 gene networks within three functional gene categories: Cell Cycle Dysregulation, Oncogenic Drivers and DNA Damage Response and Repair Network. Mutations in the RAS gene network were associated with relatively poor response. Alterations in the CCNE network were associated with directionally positive DCR (67%) and a partial response (HGSOC), albeit CCNE network alterations were observed in only a limited number of subjects (n=6). Alterations in PI3K and FA/BRCA gene networks correlated with favorable DCR and were associated with several PRs.

Figure 4. Frequency of Gene Network Alterations Across Indications Heatmap displays the frequency of observed gene network alterations observed in SRA737-02 across key treatment cohorts, represented by percent of subjects with specified gene alterations.

Gene Network HGSOC Rectal Anogenital Cervical

p53 Pathway

G1/S

 CCNE

RAS

MYC 0%

PI3K

HR/NHEJ

FA/BRCA

Chromatin 100%

70 yo male with anal cancer; extensive liver metastasisPrior therapy: radiation and 1 line of systemic therapy Genetic Profile:  FA/BRCA, PI3K and TMB-IBest tumor response: -41% Duration on treatment: 11 cycles (response ongoing at discontinuation; patient decision)

59 yo female with anal cancer; mediastinal mass compression & pleural effusionPrior therapy: 3 lines of systemic therapy Genetic Profile: FA/BRCA and TMB-IBest tumor response: -26% + resolution of pleural effusionDuration on treatment: 7 cycles; ongoing

Figure 3. SRA737+LDG Demonstrates Anti-Cancer Activity Across Multiple Indications Data shown represent the best % tumor change from baseline among evaluable subjects within the four tumor types showing sensitivity to SRA737+LDG (cervical, anogenital, HGSOC and rectal). Partial responses (PR) were observed in 6 subjects. These included 3 subjects with anogenital cancer and one subject each with rectal, cervical, and ovarian cancer. In general, tumor responses were first recorded at the end of Cycle 2 (first on-study scan).

-80%

-60%

-40%

-20%

0%

20%

40%

60%

80%

100%

Rectal

HGSOC

Cervical

Anogenital

Subject Ongoing

Confirmed partial response*

*

*

Figure 6. Anti-Cancer Activity With SRA737+LDG Correlates with Mutations in the FA/BRCA Gene Network.

FA/BRCA gene network encodes for proteins that respond to RS by stabilizing and repairing stalled replication forks and HRR in conjunction with Chk1 and other DDR checkpoint kinases. Genetic alterations in these complexes contribute directly to RS, increasing genomic instability that manifests as increased TMB in certain contexts. Notably, elevated TMB was associated with certain tumor responses to SRA737+LDG, particularly in subjects with anogenital and rectal cancer.

-80%

-60%

-40%

-20%

0%

20%

40%

60%

60%

100%

Eso

pha

gea

l

Ano

gen

ital

Co

lon

Eso

pha

gea

l

SC

C S

kin

Cer

vica

l

Ano

gen

ital

Mes

oth

elio

ma

HG

SO

C

HG

SO

C

Uro

thel

ial

Ano

gen

ital

HG

SO

C

Rec

tal

Ano

gen

ital

Ano

gen

ital

Adjudicated VUSV

ATRPRKDCBRCA1BRCA2CDK12FANC*RAD**

V

V V V V V

V VVV

V

V V

SD PD PR

Subject Ongoing Confirmed partial response*

*

*

Figure 5. FA/BRCA Replication Fork Gene Network Associated With SRA737+LDG Activity

Several PRs and robust SDs were associated with tumors harboring alterations in the FA/BRCA gene network; many also carried a secondary alteration in one of two DDR checkpoint kinase genes (ATR, PRKDC). These findings suggest that multiple replication fork-associated mutations may exacerbate intrinsic RS and genomic instability, and/or be a consequence thereof.

Dose escalation (unselected)

Dose optimization(unselected)

Phase 2cohorts

Ovarian

Small Cell Lung

Sarcoma

Anogenital / Cervical

Prospective patient selection using NGS technology

Administered weekly for 3 weeks on a 28-day cycle

Tumor SuppresorTP53, RAD50...

Oncogenic DriversCCNE1, MYC...

DNA Repair MachineryBRCA1, FANCA...

Replicative StressATR, CHEK1...

Dosing Schedule

Day 1 2 3 4 5 6 7

• • • SRA737

LDG

InformationFor more information, email info@sierraoncology.com or visit www.sierraoncology.com

Acknowledgments This study was sponsored by Sierra Oncology. We would like to thank all participating patients and their families. Investigators thank Cancer Research UK, the Experimental Cancer Medicine Centre (ECMC) and the National Institute of Health Research for research infrastructure support.

Figure 7. SRA737+LDG Demonstrates Promising 30% Response Rate In Anogenital Cancer Data shown represent the best % tumor change from baseline among evaluable subjects with anogenital cancer. The magnitude of target tumor decrease in anogenital tumors was notable; as of the data cutoff two subjects achieved ongoing decreases of -66% and -51% respectively, and a third subject achieved a decrease of -41%. In addition, several subjects with anogenital cancer had noteworthy durations of response: 5/10 (50%) subjects remained on study treatment for ≥ 4 months with a maximal duration of ~11 months. The ORR for subjects in the broader cohort of squamous anogenital/cervical cancer was 22% (4/18).

SD PD PR

Subject Ongoing

Genetic Reports were not available Confirmed partial response*

**

FA/BRCAPI3K

HPV+TMB H/I

-80%

-60%

-40%

-20%

0%

20%

40%

60%

80%

100%

J

D2

N

I

Q P

FA core complex

F

CB

E

L

A

MG

Partial Response

Durable SD ≥ 5 cycles

A l te ra t ions ident ifiedin responders

Nuclear repair focus

BRCA1

Increased RS

Genomic instability

TMB

Cell Nucleus

CDK12

Defective stalled forkprocessing/repair

BRCA2

RAD51/C

Chk1

ATR

ATMDNA-PK

Chk1

Introduction

Methods

Subject Characteristics and Dose Evaluation

Conclusions

Treatment-Emergent Adverse Events (TEAEs)

Occurring in ≥ 20% of subjects N=139 n (%)

≥ Grade 3 N=139, n (%)

Subjects with any TEAE 137 (98.6%) 88 (63.4%)

Nausea 83 (59.7%) 1 (0.7%)

Vomiting 70 (50.4%) 3 (2.2%)

Diarrhea 63 (45.3%) 3 (2.2%)

Fatigue 60 (43.2%) 3 (2.2%)

Anemia 46 (33.1%) 8 (5.8%)

Pyrexia 43 (30.9%) 1 (0.7%)

Neutropenia 36 (25.9%) 13 (9.4%)

Decreased appetite 33 (23.7%) 0

Thrombocytopenia 33 (23.7%) 5 (3.6%)

ALT increased 31 (22.3%) 8 (5.8%)

AST increased 28 (20.1%) 7 (5.0%)

Constipation 28 (20.1%) 2 (1.4%)

TEAEs regardless of the investigator’s assessment of causality; Data cut off: 23 March 2019

Safety

40/ 300

80/ 100

150/ 100

300/ 100

300/ 50

500/ 100

500/ 50

500/ 150

600/ 100

500/ 250

500/ 200

600/ 250

600/ 200

SRA737/ Gem dose

Cohort

SR

A73

7 D

ose

(m

g)

Gem

citabine D

ose (m

g/m

2)

SRA737 DoseGemcitabine Dose

1 2 43 5 6 7 8 9 10 11 13

4080

150

300

500

600

12

50100150200250300

MED

MED: minimum e�ective dose of SRA737 modeled from preclinical studies

0

250

500

750

1000

1250

Gemcitabine dose range in SRA737-02

Relative to standard-of-care, gemcitabine doses tested in SRA737-02 were approximately 10-25% of a standard cytotoxic dose

Gem

cita

bin

e D

ose

(m

g/m

2 )

Standard-of-Care

40/ 300

80/ 100

150/ 100

300/ 100

300/ 50

500/ 100

500/ 50

500/ 150

600/ 100

500/ 250

500/ 200

600/ 250

600/ 200

SRA737/ Gem dose

Cohort

SR

A73

7 D

ose

(m

g)

Gem

citabine D

ose (m

g/m

2)

SRA737 DoseGemcitabine Dose

1 2 43 5 6 7 8 9 10 11 13

4080

150

300

500

600

12

50100150200250300

MED

MED: minimum e�ective dose of SRA737 modeled from preclinical studies

0

250

500

750

1000

1250

Gemcitabine dose range in SRA737-02

Relative to standard-of-care, gemcitabine doses tested in SRA737-02 were approximately 10-25% of a standard cytotoxic dose

Gem

cita

bin

e D

ose

(m

g/m

2 )

Standard-of-Care

Results