NuTide:701 A first-in-human study of NUC-7738,a 3'-dA phosphoramidate, in patients with advanced solid tumours

SN Symeonides1, F Aroldi2, N Md Haris3, S Kestenbaumum1, ER Plummer3, SP Blagden2

1) Edinburgh ECMC, Western General Hospital, Edinburgh UK2) Oxford ECMC; University of Oxford, UK3) Newcastle ECMC: Northern Centre for Cancer Care, Freeman Hospital, Newcastle upon Tyne, UK

BACKGROUND NUTIDE:701 STUDY DESIGN PATIENT CASE STUDIES

CONCLUSION

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REFERENCES: Chen LS et al 2008. Br J Haematol:140:682-691ABBREVIATIONS: 3’-dA: 3’-deoxyadenosine 3’-dATP: 3’-deoxyadenosine triphosphate ADA: adenosine deaminase AE: adverse event AK: adenosine kinase AMPK: 5' adenosine monophosphate-activated protein kinase AUC: area under the curve Cmax: maximum concentration DLT: dose-limiting toxicity DNA: deoxyribonucleic acid hENT1: human equilibrative nucleoside transporter 1 IV: intravenous mTOR: mammalian target of rapamycin pAMPK: phospho-AMPK PBMC: peripheral blood mononuclear cell q1w: weekly dosing RNA: ribonucleic acid RP2D: recommended phase 2 dose

• Nucleoside analogs form the backbone therapy for solid and haematological malignancies• 3’-deoxyadenosine (3’-dA; cordycepin) isolated from Cordyceps sinensis• 3’-deoxyadenosine triphosphate (3’-dATP) causes cell death by inhibiting DNA and RNA replication1

• 3’-dA not successful in clinical studies due to cancer resistance mechanisms, including: • Rapid enzymatic breakdown by adenosine deaminase (ADA) • Cellular uptake dependent on nucleoside transporters (hENT1) • Reliance on adenosine kinase (AK) for activation

NUC-7738: Multiple potential anti-cancer modes of action

NUC-7738: A ProTide transformation of 3'-dA• Overcomes 3’-dA resistance mechanisms: • Protected from breakdown by ADA • Cellular uptake independent of nucleoside transporters (hENT1) • 3’-dATP generation independent of enzymatic activation by AK

NUC-7738 has potent anti-cancer activity across a broad range of malignant cell lines (up to 185-times greater than 3’-dA)

Study status • 14 patients treated• Dose range 14 - 400 mg/m2 (IV infusion from 30-120 mins) q1w• Intrapatient dose escalation continuing

Safety profile• NUC-7738 is well tolerated: • No Grade 3 or 4 treatment-related AEs • No discontinuations due to AEs • No DLTs

Presentation Number:600TiP

NCT Number:NCT03829254

EudraCT Number:2018-003417-17

Email:Stefan.Symeonides@ed.ac.uk

Pharmacokinetic profile

• NUC-7738 is a novel nucleotide analog with multiple potential anti-cancer mechanisms of action• NUC-7738 is designed to overcome key cancer resistance mechanisms of 3’-dA (cordycepin)• NuTide:701 will establish the RP2D of NUC-7738 in patients with solid tumours• Interim data from NuTide:701 demonstrate: • Signals of anti-cancer activity at low doses • Favourable tolerability profile • Generation of intracellular 3'-dATP• NuTide:701 recruitment ongoing

Patients (n=9) dosed between 14 - 400 mg/m2

• NUC-7738 has a predictable PK profile: • Dose proportional increase in Cmax and AUC • Preliminary intracellular (PBMCs) data indicate: • Efficient conversion of NUC-7738 to 3’-dATP • Persistence of 3’-dATP post-infusion

0.0

MCF-7(Breast cancer)

26.8

47.8

76.8

72.5

55.7

67.0

88.7

2.3

7.1

7.4

8.6

5.0

14.6

0.5

HepG2(Liver cancer)

MiaPaCa-2(Pancreatic cancer)

OVCAR 3(Ovarian cancer)

K562(CML)

HL-60(AML)

MOLT(ALL)

10.0 20.0 30.0 40.0 50.0 60.0 70.0 80.0 90.0 100.0IC50 µM

Advanced solid

tumours(n 20)

Lymphomas(n 12)

NUC-7738 AUCNUC-7738 Cmax

Expansion3 + 31 + 1Enrolment

Establish RP2D

+Schedule

DLT

3+3Fortnightly

3+3 Weekly

1+1 Weekly DLT

Metastatic Lung Adenocarcinoma - 2 Prior Lines

Original lesion identified (2015)

Diagnosed as T4 N0 M0 lung adenocarcinoma at thoracoscopy

and wedge biopsy (2015)

HISTORY

PRIOR TREATMENTRadical radiotherapy (2016)

55Gy in 20 fractions

CT relapse with multiple lungmetastases (2017)

Disease now T4 N0 M1

Carboplatin & pemetrexed (Apr-Oct 2018)Partial response

25% dose reduction: neutropaenia

Docetaxel (Apr-Jul 2019)Progressive disease (low volume)

Cycle 2 dose reduction: diarrhoea and fatigue

Metastatic Melanoma - 2 Prior Lines

Original lesion identified T2b N(unknown) M0 melanoma

Stage III Received lymphadenectomy and routine therapy

Stage IV metastatic disease Lung metastases

Starting Dose: 14 mg/m2

Highest Dose Received: 400 mg/m2

Number of Dose Escalations: 7

Treatment-related AEs: Dysgeusia (G2, successfully treated with artificial saliva spray); Nausea (G2, resolved); Fatigue (G1, resolved); Muscular pain (G1, resolved); Hypoglycemia (G1, resolved)

Target Lesion: 1 (pelvic side wall)

Target Lesions: 2 (both lung)

Tumour volume• Reduction in of 14% following 8 weeks of treatment• Stable Disease maintained for 12 months• Treatment continued beyond progression due to ongoing clinical benefit (see below)

• Disease control re-established from month 12 to 15 (ongoing)

Pleural effusion resolved• Patient had ongoing pleural effusion at the time of study entry which required regular drainage• Following initiation of NUC-7738, pleural effusion resolved: no drainage required and lung function normalised

Tumour volume• Increased between Week 1 and Week 8, but patient remained on treatment due to ongoing clinical benefit (asymptomatic of disease)• Reduced between Week 8 and Week 16 in one lesion and changes in character observed in the other (see below)

Target Lesion 1: Encouraging signs of anti-tumour activity

with a 46% reduction in lesion between Week 8 and Week 16 (41mm to 22mm)

STUDY TREATMENT

TREATMENT DURATION

SAFETY

NUC-7738HISTORY

PRIOR TREATMENT

15 Months(ongoing)

Starting Dose: 42 mg/m2

Highest Dose Received: 273 mg/m2

Number of Dose Escalations: 4

Treatment-related AEs: No AEs observed One Grade 3 pneumonia not related to NUC-7738 resulted in a dose omission

STUDY TREATMENT

TREATMENT DURATION

SAFETY

NUC-7738

6 Months

Primary resectionRight leg, cutaneous melanoma

Radiation therapy Right groin

Nivolumab & ipilumumab (Oct-Nov 2018)Discontinued due to toxicity

Investigational CK7 inhibitor (Mar-Apr 2019)Discontinued due to progression

Clinical Benefit

Clinical Benefit

65 Years, Male

62 Years, Female

Patients with advanced

solid tumours

No immunotherapy offered due to pulmonary fibrosis and PD-L1 0%

mTOR

AMPK

pAMPKP

3’-dAMP

Inhibition of mTOR pathway

Activation of AMPK

Cancer cell membrane

Inhibition of metastasis

Inhibition of platelet aggregation

Plateletaggregation

Blood Vessel

Tumor cells

Inhibition of RNA polyadenylation

Inhibition of gene expression

AAA

Inhibition of DNA replication

Misincorporation of nucleotides

ADA

Breakdown

Breakdown

ADATRANSPORTER

3’-dAMP 3’-dADP 3’-dATP

Deprotection

3’-dA

5,000

10,000

15,000

20,000

0 200 400 600

Mea

n NU

C-77

38 C

max

(ng.

h/m

L)

Actual dose (mg)

r2 = 0.968

Actual dose (mg)

10,000

5,000

0 200 400 600

Mea

n NU

C-77

38 A

UC (n

g.h/

mL)

r2 = 0.926

Wee

k16

Wee

k 8

Target Lesion 2: Lesion changed in character, with a smaller dense core surrounded by a

larger diffuse “ground-glass” periphery

Wee

k16

Wee

k 8