Simon Smith

The impact of germline mutations on targeted therapy.

Targeted therapies provide clinical benefit and improved therapeutic index. They have a growing prominence in patient management and focus in drug development. Their development is fuelled by our deepening knowledge of complex disease phenotypes and the need for improvement in new therapeutic efficacy. Extrapolation of the biological discovery through to new therapy targeting the causal biological variants to drive clinical gain is challenging. Here, we review the impact of germline mutations on targeted therapies. Historically, germline changes have contributed most to our understanding of disease mechanisms, drug metabolism and exposure, the latter of which has enabled safer positioning of therapies, such as clopidogrel and irinotecan. Similarly, prescreening for germline variants can avoid potentially fatal hypersensitivity reactions with abacavir. However, germline mutations continue to emerge as a central player in targeting therapeutics; ivacaftor drives partial restoration of mucus secretion in cystic fibrosis patients harbouring specific mutations, and treatment with olaparib exploits germline mutations in BRCA genes to drive synthetic lethality as an anti‐cancer mechanism. Central is definition of the causal link, association or contribution to the biological variance – and that we believe it is drugable for therapeutic gain. The demand for better therapies to treat modern diseases provides the appetite for continued investigation of the biological variance associated with germline mutations, inevitably leading to increased impact on the development of targeted therapeutics. Copyright

PATRIOT: A phase I study to assess the tolerability, safety and biological effects of a specific ataxia telangiectasia and Rad3-related (ATR) inhibitor (AZD6738) as a single agent and in combination with palliative radiation therapy in patients with solid tumours

Highlights • Summary of a protocol for a phase I study combining the ATR inhibitor and palliative radiotherapy.• Study design is discussed.• Study aims and objectives, brief eligibility criteria, DLT criteria and dose escalation is discussed.• Brief summary of translational research to be carried out.

Abstract CT084: A Phase I dose-escalation study of ATR inhibitor monotherapy with AZD6738 in advanced solid tumors (PATRIOT Part A)

Many cancers have high levels of replication stress and a poorly functional G1/S DNA damage checkpoint. This may render them more susceptible than normal tissues to inhibition of ATR, an apical kinase in the DNA damage response and critical part of the response to DNA replication stress. We report the early results of the monotherapy dose-escalation phase of the PATRIOT study of AZD6738, an orally active ATR inhibitor in patients (pts) with advanced solid tumors (NCT02223923), whose endpoints were MTD, safety, tolerability, pharmacokinetics (PK) and preliminary efficacy. 26 pts were enrolled between July 2014 and July 2016 in a 3+3 design. Pts received continuous BD dosing. PK analyses were performed. Dose limiting toxicities (table 1) were thrombocytopenia (G3 with epistaxis, 1 participant; G4, 2 participants), pancytopenia (G4, 1 participant), increased amylase (G3, 1 participant). Other treatment-related AEs (probably or definitely caused by AZD6738) affecting ≥2 participants were fatigue (9; 35% G1-4, 0% G3-4), anemia (7; 23% G1-4, 12% G3-4), nausea (4; 15% G1-4, 0% G3-4), thrombocytopenia (5; 19% G1-4, 15% G3-4), anorexia (3; 12% G1-4, 0% G3-4), dysgeusia (3; 12% G1-4, 0% G3-4), vomiting (2; 8% G1-4, 0% G3-4). The MTD was 160 mg BD, given continuously. Two RECIST partial responses were observed in pts with SCCHN and nasopharyngeal carcinoma, one confirmed. Median duration taking AZD6738 was 97 days, range 30-279 days (evaluable patients only). Two pts remain on treatment, three pts discontinued due to treatment-related toxicity. Expansion cohorts have been initiated at 160mg BD, exploring a number of alternative treatment schedules designed to offset cumulative toxicity and test efficacy of AZD6738 monotherapy and the presence of high replication stress, DNA damage response deficiencies or ATM loss. Schedules include: AZD6738 given at 160mg BD for 21 of a 28 day cycle and 5 days on, 2 days off. A parallel study is investigating AZD6738 in combination with palliative radiotherapy.[Funded by CRUK CRUKD/14/007] Citation Format: Magnus T. Dillon, Aude Espinasse, Sally Ellis, Kabir Mohammed, Lorna G. Grove, Lyndall McLellan, Simon A. Smith, Graham Ross, Sola Adeleke, Kin Woo, Eleni Josephides, James F. Spicer, Martin D. Forster, Kevin J. Harrington. A Phase I dose-escalation study of ATR inhibitor monotherapy with AZD6738 in advanced solid tumors (PATRIOT Part A) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT084. doi:10.1158/1538-7445.AM2017-CT084

Abstract CT118: PK-Biomarker-Safety modelling aids choice of recommended Phase II dose and schedule for AZD6738 (ATR inhibitor)

Introduction: AZD6738 is a potent inhibitor of the ATR protein kinase that is being tested in patients with solid malignancies. In Phase I dose escalation studies, AZD6738 was dosed as monotherapy (continuous schedule from 40 - 480 mg per day), or in combination (intermittent schedule from 80 - 320 mg per day) with olaparib, durvalumab, carboplatin, or radiation. In those studies, thrombocytopenia was the main dose limiting toxicity and changes in peripheral monocytes and proliferating T-cells were seen with AZD6738, with up to 80% decrease on-drug and return to baseline upon cessation of dosing. This effect on monocytes and proliferating T cells was not observed with either single agent olaparib or durvalumab. Based on these observations, we developed two PKPD models linking AZD6738 dose, AZD6738 plasma exposure, and differential blood cell counts to support dose and schedule selection. Methods and Results: The first model characterized the quantitative relationship between the plasma exposure of AZD6738 monotherapy, and the difference between monocyte decrease (on-target activity) and platelet decrease (on-target toxicity). This model was a sigmoid function and predicted biological activity starting at exposures of 2.5 ug/mL (aligned with the in vitro IC90 in LoVo cells, and obtained in ≥ 50% of patients with 80 mg per day) increasing in a concentration dependent manner to 10 ug/mL (obtained in almost all patients dosed at 480 mg per day), after which negligible monocyte response over platelet decrease was observed. Those data were consistent with the preclinical observations which showed tumour regression after at least 3-day concomitant treatment of olaparib and AZD6738 at exposure maintaining IC90[1]. The second model was a PK-safety model describing the temporal relationship between circulating platelets and exposure of AZD6738 administered in combination with olaparib dosed at 300 mg twice daily continuously. This model allowed generation of various platelet/ time profiles in the most sensitive patient group (10% of the patients) for different AZD6738 doses and schedules. The simulations indicated that, for doses considered biologically relevant by the first model, a period of 21-days free of AZD6738 is needed to give full recovery of potential thrombocytopenia in a 28-day cycle. Conclusion: Using monocyte and proliferative T-cell decreases as biological activity indicators and platelet decrease as a safety indicator, we quantified the exposure/activity/safety relationship for AZD6738. The recommended Phase II dose of AZD6738 (in combination with olaparib) was then driven by maintaining maximally active exposure consistent with manageable safety. Reference: [1]. 2017 AACR Abstract 2494. Acknowledgements: T.A. Yap (The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London, UK) and J.C. Soria (Institut Gustave Roussy, Paris, France) Citation Format: Alienor Berges, S. Y. Amy Cheung, Andrew J. Pierce, Emma Dean, Brunella Felicetti, Nathan Standifer, Simon Smith, James Yates, Alan Lau, Christine Stephens, Matthew Krebs, Kevin Harrington, Simon J. Hollingsworth. PK-Biomarker-Safety modelling aids choice of recommended Phase II dose and schedule for AZD6738 (ATR inhibitor) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT118.

Abstract 311: Development of AZD2811, an aurora kinase B inhibitor, incorporated into an AccurinTM nanoparticle for use in haematological and solid cancers

A nanoparticle formulation of AZD2811, a selective aurora kinase B inhibitor, is currently under clinical development for the treatment of both haematological and solid tumour disease. AZD2811 is the active derivative of the prodrug Barasertib (AZD1152) which gave promising clinical activity in elderly AML patients delivered as a 7-day infusion (Kantarjian et al, Cancer, 119, 2611-2619, 2013). To address the limitations associated with the clinical utility of Barasertib and other cell cycle inhibitors in the clinic, AZD2811 has been incorporated into an AccurinTM nanoparticle using a pamoic acid ion pairing approach to optimise drug release rate (Song et al, Journal of Controlled Release, 229, 106-119, 2016), improve the drug exposure to tumour and reduce the duration of administration. A proof of principle formulation of AZD2811 as an AccurinTM nanoparticle established the principle that anti-tumour activity and improved therapeutic index could be achieved (Ashton et al, Science Translational Medicine, 325, 1-10, 2016). The clinical nanoparticle formulation of AZD2811 has been optimised for drug loading and release rate. In pre-clinical models, the clinical formulation can be used flexibly to optimise drug delivery for use in both haematological disease such as AML, or in solid tumour settings. Anti-tumour activity in solid tumours can be achieved at doses where bone marrow toxicity is reduced compared to Barasertib. In sensitive xenograft and PDX solid tumour models greater than 90% tumour regression is observed after a total dose of 50mg/kg with no tumour progression for greater than 40 days. In contrast, for AML, increasing the dose intensity by 2-4 fold leads to neutropenia and to complete tumour regression in a range of AML xenograft models for greater than 60 days. These data establish the concept that drug delivery using nanoparticles is able to resolve therapeutic index challenges, and is able to do so across different disease types. AZD2811 is currently in Phase 1 clinical trial (D6130C0000). The current pre-clinical and clinical data with this novel approach to inhibition of the cell cycle will be discussed. Citation Format: Susan Ashton, Nicholas Floch, Paula Taylor, Colin Howes, Doug Ferguson, Matthew Ling, Maureen Hattersley, Shenghua Wen, Kim Maratea, Adina Hughes, Sean Redmond, Wolfram Brugger, Simon Smith, Alexander MacDonald, Keith Parry, Howard Burris, Young-Ho Song, Jim Nolan, Elizabeth Pease, Simon T. Barry. Development of AZD2811, an aurora kinase B inhibitor, incorporated into an AccurinTM nanoparticle for use in haematological and solid cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 311. doi:10.1158/1538-7445.AM2017-311

Clinical pharmacology profile of an oral selective androgen receptor down-regulator, AZD3514: Implications on the design of ongoing castrate-resistant prostate cancer clinical studies

Purpose: To describe the pharmacokinetics (PK) and pharmacodynamics (PD) of AZD3514 and how the design of the first-time-in-human study was adapted based on the emerging clinical PK. Patients and methods: Data were collected from 77 patients with castrate-resistant prostate cancer from two dose-escalation studies, in Europe (NCT01162395) and Japan (NCT01351688). PK parameters were derived from plasma and urine data and exploration of PK-PD relationships were performed. Post hoc analysis was conducted to investigate time-dependent changes and interand intra-patient variability in PK. Results: AZD3514 was rapidly absorbed and plasma levels declined in a bi-phasic manner with no ethnic differences. Plasma exposure to AZD3514 was dose proportional. Generally, overall exposures were similar between visits within each patient, but varied between patients within each cohort. A switch to twice-daily dosing, to increase exposure, produced a marked time-dependent reduction in area under the curve of 30% and an increase in apparent clearance (from 17 to 25 L/h) at steady state compared to single doses. Emerging study data showed that low baseline testosterone may influence prostate-specific antigen (PSA) reductions by AZD3514. Combination cohorts with abiraterone acetate, a drug that decreases testosterone in CRPC patients, did not result in meaningful decreases in PSA. Discussion and conclusions: Despite adaptation of the clinical strategy from emerging PK and PD data, the hypothesis around androgen receptor (AR) modulation through AR down-regulation could not be tested due to the time-dependent effect on AZD3514 PK, which prevented coverage above the target concentration. Further testing of this hypothesis is warranted.