Ph II Trial of Carboplatin and Pemetrexed With or Without AZD1775 for Untreated Lung Cancer

A Phase II Study of AZD1775 Plus Pemetrexed and Carboplatin Followed by a Randomised Comparison of Pemetrexed and Carboplatin With or Without AZD1775 in Patients With Previously Untreated Stage IV Non-Squamous Non-Small-Cell Lung Cancer

The aim of this study is to combine AZD1775 with standard front-line chemotherapy in subjects with advanced NSCLC.

This is a randomised, phase II trial comparing AZD1775 plus pemetrexed and carboplatin followed by maintenance AZD1775 and pemetrexed versus pemetrexed and carboplatin followed by maintenance pemetrexed in patients with previously untreated metastatic non-squamous NSCLC with TP53 mutations. The primary endpoint of the trial is assessment of progression-free survival (PFS).

Inclusion Criteria

• Provision of informed consent prior to any study specific procedures
• Histologic or cytologic diagnosis of advanced NSCLC, Recurrent or Stage IV disease (according to American Joint Committee on Cancer (AJCC) staging system, v7.0).
• No prior chemotherapy for locally advanced or metastatic disease
• Subjects with a known EGFR mutation must have received previous treatment with an EGFR tyrosine kinase inhibitor; and subjects with a known ALK translocation must have received previous treatment with an ALK inhibitor.
• No prior radiation therapy to the whole pelvis or to ≥25% of the total bone marrow area.
• At least one measurable lesion according to Response Evaluation Criteria in Solid Tumours (RECIST) v1.1
• Mandatory availability of tumour tissue (archival or fresh if archival is not available) for TP53 determination.
• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0 or 1.
• Absolute neutrophil count (ANC) ≥1500/μL
• Hemoglobin (Hgb) ≥10 g/dL
• Platelets ≥100,000/μL
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST), ≤3.0 x the upper limit of normal (ULN); 5 x ULN if known hepatic metastases
• Total bilirubin ≤1.5 x ULN, unless secondary to Gilbert's disease
• Serum creatinine ≤1.5 x ULN and a calculate creatinine clearance (CrCl) ≥45 mL/min by the Cockcroft-Gault method
• Ability to swallow oral medication
• Fertile male subjects willing to use at least one medically acceptable form of birth control for the duration of the study and for 2 weeks after treatment stops
• Female subjects who are not of childbearing potential and fertile female subjects of childbearing potential who agree to use adequate contraceptive measures who are not breastfeeding, and who have a negative serum or urine pregnancy test within 72 hours prior to start of study treatment
• Predicted life expectancy ≥12 weeks
• Must be ≥18 years of age
• Willingness and ability to comply with study and follow-up procedures
• Ability to understand the nature of this trial and give written informed consent Exclusion criteria
• Use of a study drug ≤21 days or 5 half-lives (whichever is shorter) prior to the first dose of AZD1775
• Major surgical procedures ≤28 days of beginning AZD1775, or minor surgical procedures ≤7 days
• Known central nervous system (CNS) disease
• Subject has had prescription or non-prescription drugs or other products (i.e. grapefruit juice) known to be sensitive CYP3A4 substrates
• Any known hypersensitivity or contraindication to the components of study treatment
• Any of the following cardiac diseases currently or within the last 6 months as defined by New York Heart Association ([NYHA] Appendix G) ≥ Class 2
• Corrected QT interval (QTc) >470 msec (as calculated by Fridericia correction formula) at study entry or congenital long QT syndrome.
• Pregnant or lactating
• Any serious, active underlying medical condition that would impair the ability of the subjects to receive study treatment
• Unable or unwilling to take folic acid or vitamin B12
• Presence of other active cancers, or history of treatment for invasive cancer ≤3 years
• Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol