A first-in-human study of NUC-7738, a 3’-dA ... · NUC-7738 Maintains Cytotoxicity Under Cancer...
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14-day cycles Expansion at the RP2D & schedule determined by Part 1 TREATMENT A first-in-human study of NUC-7738, a 3’-dA phosphoramidate, in patients with advanced solid tumors or lymphoma (NuTide:701) HP Schwenzer 1 , SN Symeonides 2 , ER Plummer 3 , GP Bond 4 , SP Blagden 1 1) University of Oxford, Oxford, UK 2) Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, UK 3) Northern Centre for Cancer Care, Newcastle-upon-Tyne, UK 4) Ludwig Institute, Oxford, UK Background • Nucleoside analogs form backbone therapy for solid and hematological malignancies • 3’-deoxyadenosine (3’-dA; cordycepin): adenosine derivative first isolated from Cordyceps sinensis • Adenosine required for many molecular processes, including DNA and RNA synthesis • 3’-deoxyadenosine triphosphate (3’-dATP), the anti-cancer metabolite of 3’dA, causes cell death by incorporation into RNA and DNA • 3’-dA not successful in clinical studies to date due to cancer resistance mechanisms, including: • Rapid enzymatic degradation by adenosine deaminase (ADA) • Cellular uptake dependent on nucleoside transporters (hENT1) • Conversion to the active metabolite (3’-dATP) dependent on rate limiting phosphorylation by adenosine kinase (AK) • Resistance to chemotherapy associated with poor survival prognosis • Effective new agents are required ProTides: NucleoTide Analogs • A new class of anti-cancer agents • Transformative phosphoramidate chemistry • Increase intracellular levels of anti-cancer metabolites • Broad clinical utility NUC-7738: A ProTide Transformation of 3’-dA • ProTide transformation of 3’-dA • Overcomes key 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 Maintains Cytotoxicity Under Cancer Resistance Conditions • NUC-7738 up to 185-times greater anti-cancer activity than 3’-dA across a range of human cancer cell lines • NUC-7738 generated up to 19-times higher levels of the active anti-cancer metabolite, 3’-dATP, than 3’-dA in human cancer cell lines • Unlike 3’-dA, NUC-7738 cytotoxicity was not affected by the key cancer resistance conditions First-in-human Phase I study of NUC-7738 NuTide:701 Study Design 14-day cycles NUC-7738 starting dose: 14 mg/m 2 Dose-escalation in weekly (Days 1 & 8) and fortnightly (Day 1) schedules RP2D & Schedule PART 1 Patients with advanced solid tumors not amenable to standard chemotherapy TREATMENT PART 2 Patients with advanced solid tumors or lymphoma NUC-7738 overcomes the key cancer resistance mechanisms of 3’dA PRIMARY OBJECTIVES • Safety & tolerability • Recommended Phase II dose STUDY OPEN TO RECRUITMENT SECONDARY OBJECTIVES • Pharmacokinetics • Anti-cancer activity (BOR, ORR, DoR, DCR, DoSD & PFS) EXPLORATORY OBJECTIVES • Biomarker evaluation • Pharmacodynamics 1+1 Weekly dose escalation 3+3 Weekly 3+3 Fortnightly Establish RP2D & Schedule Advanced solid tumors Lymphomas 1+1 3+3 Expansion DEPROTECTION AK TRANSPORTER ADA ADA Copies of this poster obtained through Quick Response (QR) Code are for personal use only and may not be reproduced without permission from ASCO ® and the author of this poster. Abstract Number: TPS3147 Registry Number: NCT03829254 Email: sarah.blagden@ oncology.ox.ac.uk Summary • NUC-7738 designed to overcome the key cancer resistance mechanisms associated with 3’-dA • NuTide:701 study will determine the RP2D and schedule of NUC-7738 in patients with advanced solid tumors or lymphoma BOR: Best overall response DCR: Disease control rate DoR: Duration of response DoSD: Duration of stable disease PFS: Progression-free survival
Transcript of A first-in-human study of NUC-7738, a 3’-dA ... · NUC-7738 Maintains Cytotoxicity Under Cancer...
14-day cyclesExpansion at the RP2D &
schedule determined by Part 1
TREATMENT
A first-in-human study of NUC-7738, a 3’-dA phosphoramidate, in patients with advanced solid tumors or lymphoma (NuTide:701)
HP Schwenzer1, SN Symeonides2, ER Plummer3, GP Bond4, SP Blagden1
1) University of Oxford, Oxford, UK 2) Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, UK3) Northern Centre for Cancer Care, Newcastle-upon-Tyne, UK 4) Ludwig Institute, Oxford, UK
Background• Nucleoside analogs form backbone therapy for solid and hematological malignancies• 3’-deoxyadenosine (3’-dA; cordycepin): adenosine derivative first isolated from Cordyceps sinensis• Adenosine required for many molecular processes, including DNA and RNA synthesis• 3’-deoxyadenosine triphosphate (3’-dATP), the anti-cancer metabolite of 3’dA, causes cell death by incorporation into RNA and DNA• 3’-dA not successful in clinical studies to date due to cancer resistance mechanisms, including: • Rapid enzymatic degradation by adenosine deaminase (ADA) • Cellular uptake dependent on nucleoside transporters (hENT1) • Conversion to the active metabolite (3’-dATP) dependent on rate limiting phosphorylation by adenosine kinase (AK)• Resistance to chemotherapy associated with poor survival prognosis• Effective new agents are required
ProTides: NucleoTide Analogs• A new class of anti-cancer agents • Transformative phosphoramidate chemistry• Increase intracellular levels of anti-cancer metabolites• Broad clinical utility
NUC-7738: A ProTide Transformation of 3’-dA • ProTide transformation of 3’-dA• Overcomes key 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 Maintains Cytotoxicity Under Cancer Resistance Conditions• NUC-7738 up to 185-times greater anti-cancer activity than 3’-dA across a range of human cancer cell lines• NUC-7738 generated up to 19-times higher levels of the active anti-cancer metabolite, 3’-dATP, than 3’-dA in human cancer cell lines• Unlike 3’-dA, NUC-7738 cytotoxicity was not affected by the key cancer resistance conditions
First-in-human Phase I study of NUC-7738
NuTide:701 Study Design
14-day cyclesNUC-7738 starting dose: 14 mg/m2
Dose-escalation in weekly (Days 1 & 8) and fortnightly (Day 1) schedules
RP2D & Schedule
PART 1Patients with advanced solid tumors
not amenable to standard chemotherapy
TREATMENT
PART 2Patients with advanced solid tumors
or lymphoma
NUC-7738 overcomes the key cancer resistance mechanisms of 3’dA
PRIMARY OBJECTIVES
• Safety & tolerability • Recommended Phase II dose
STUDY OPEN TO RECRUITMENT
SECONDARYOBJECTIVES
• Pharmacokinetics • Anti-cancer activity (BOR, ORR, DoR, DCR, DoSD & PFS)
EXPLORATORY OBJECTIVES
• Biomarker evaluation • Pharmacodynamics
1+1Weekly dose
escalation
3+3Weekly
3+3Fortnightly
EstablishRP2D
&Schedule
Advancedsolid tumors
Lymphomas
1+1 3+3 Expansion
SUPERIOR TUMOR APOPTOSISTRANSPORTER INDEPENDENT ACTIVE ANTI-CANCER METABOLITES
DEPROTECTION
Phosphoramidate
TUMOR APOPTOSIS
3’-dADP3’-dAMP 3’-dATP
ACTIVE ANTI-CANCER METABOLITES
AK
ACTIVATIONBREAKDOWNTRANSPORTER
DEPENDENT
TRANSPORTER
BREAKDOWN
3'-dA
ADA
ADA
Copies of this poster obtained through Quick Response (QR) Code are for personal use only and may not be reproduced without permission from ASCO® and the author of this poster.
Abstract Number:TPS3147
Registry Number:NCT03829254
Email:sarah.blagden@
oncology.ox.ac.uk
Summary• NUC-7738 designed to overcome the key cancer resistance mechanisms associated with 3’-dA
• NuTide:701 study will determine the RP2D and schedule of NUC-7738 in patients with advanced solid tumors or lymphoma
BOR: Best overall response DCR: Disease control rate DoR: Duration of response DoSD: Duration of stable disease PFS: Progression-free survival
