NuTide:701 A first-in-human study of NUC-7738, · • NUC-7738 is a novel nucleotide analog with...
Transcript of NuTide:701 A first-in-human study of NUC-7738, · • NUC-7738 is a novel nucleotide analog with...
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:[email protected]
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