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Poster Discussion session - Developmental therapeutics / investigational immunotherapy

4732 - Phase I clinical and translational evaluation of AZD6738 in combination with durvalumab in patients (pts) with lung or head and neck carcinoma

Date

20 Oct 2018

Session

Poster Discussion session - Developmental therapeutics / investigational immunotherapy

Topics

Clinical Research;  Immunotherapy

Tumour Site

Head and Neck Cancers

Presenters

Matthew Krebs

Citation

Annals of Oncology (2018) 29 (suppl_8): viii133-viii148. 10.1093/annonc/mdy279

Authors

M. Krebs1, J. Lopez2, A. El-Khoueiry3, Y. Bang4, S. Postel-Vinay5, W. Abidah6, S. Im7, L.T. Khoja8, N. Standifer9, G.N. Jones10, P. Marco-Casanova10, P. Frewer11, A. Berges12, A. Cheung12, C. Stephens8, B. Felicetti8, E. Dean8, A. Pierce10, S. Hollingsworth13

Author affiliations

  • 1 Phase I Unit, The Christie NHS Foundation Trust, M20 4BX - Manchester/GB
  • 2 Phase I Unit, The Royal Marsden Hospital, SM2 - London/GB
  • 3 Medical Oncology, Norris cancer centre, Los Angeles/US
  • 4 Internal Medicine (medical Oncology), Seoul National University Hospital, 110-744 - Seoul/KR
  • 5 Drug Development Department, Institute Gustav Roussy, Paris/FR
  • 6 Medical Oncology, Memorial Sloan Kettering Hospital, New York/US
  • 7 Internal Medicine, Seoul National University Hospital, 3080 - Seoul/KR
  • 8 Early Clinical Development, Imed Biotech Unit, AstraZeneca UK, Cambridge/GB
  • 9 Clinical Immunology & Bioanalysis, medimmune plc, san francisco/US
  • 10 Translational Science, Imed Biotech Unit, AstraZeneca UK, Cambridge/GB
  • 11 Early Clinical Biometrics, Ecd, Imed Biotech Unit, AstraZeneca UK, Cambridge/GB
  • 12 Quantitative Clinical Pharmacology, Early Clinical Development, Imed Biotech Unit, AstraZeneca UK, Cambridge/GB
  • 13 Oncology, Imed Biotech Unit, AstraZeneca UK, Cambridge/GB
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Resources

Abstract 4732

Background

AZD6738 is a potent oral selective inhibitor of ATR (ataxia telangiectasia Rad3-related). The ongoing dose escalation Phase I study D5330C00004 (NCT02264678) combines AZD6738 with Durvalumab (Durva) to exploit ATR-dependent cycle arrest and DNA damage-induced immune responses.

Methods

Five cohorts with 1-2 weeks monotherapy run-in, followed by Durva 1500 mg on D1 + AZD6738 80-240 mg od or bd for 1 (D22-28) or 2 (D15-28) weeks have completed (cohort 6 is ongoing), with concurrent translational blood borne and biomarker assessment.

Results

Twenty-five pts have been treated to date with either NSCLC, or HNSCC cancer. Toxicities that occurred in ≥ 20% subjects included: anemia (≥G3 in 1 pt), fatigue, nausea, decreased appetite, cough, vomiting, dizziness, pruritus, constipation, diarrhea, musculoskeletal chest pain and dyspnea. One DLT of thrombocytopenia was observed, an on-target AZD6738 effect. Of 21 pts, 1 RECIST CR, 2 PRs and 1 uPR were observed in advanced NSCLC (3 pts) and HNSCC (1 pt) with no clear correlation with tumor PD-L1 or ATM expression. Expansion of the final cohort 6 is ongoing with one reported DLT in the initial 3 of the planned 6 pts. Preliminary PK data showed rapid absorption of AZD6738 with peak plasma concentration ≈1.5h post dose, a biphasic decline with an elimination half-life of 11h. Despite ≈45% variability in clearance, there was dose proportionality and no evidence of drug-drug interaction with Durva.

Peripheral monocytes and proliferating T-cells were suppressed during the AZD6738 dosing interval; both rebounding to levels ≥ baseline during the off-drug interval; the immunostimulatory cytokine IL-12 behaved similarly. These cyclical changes were observed across multiple treatment cycles. GM-CSF increased reciprocally to on-target decreases in monocytes. Durvalumab was dosed to saturation and therefore these changes are attributable to AZD6738. AZD6738 consistently increased pRAD50 in post treatment tumour biopsies.

Conclusions

The combination of AZD6738 with Durva was tolerated in dose escalation with signals of antitumor activity and pharmacodynamic evidence of AZD6738 target engagement.

Clinical trial identification

NCT02264678.

Legal entity responsible for the study

AstraZeneca plc.

Funding

AstraZeneca plc.

Editorial Acknowledgement

not applicable

Disclosure

Y-J. Bang: Consultancy work: AstraZeneca plc; Research funding to institution: AstraZeneca. W. Abidah: Consulting: Clovis Pharmaceuticals. L.T. Khoja, G.N. Jones, P. Marco-Casanova: Full time employee: AstraZeneca plc. N. Standifer: Full time employee: Medimmune/AstraZeneca plc. P. Frewer, A. Berges, A. Cheung, C. Stephens, B. Felicetti, E. Dean, A. Pierce, S. Hollingsworth: Full time employee and shareholder: AstraZeneca plc. All other authors have declared no conflicts of interest.

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