Effects of AZD1775 on the PK Substrates for CYP3A, CYP2C19, CYP1A2 and on QT Interval in Patients With Advanced Cancer

Involvement in the planning and/or conduct of the study (applies to both AstraZeneca personnel and/or personnel at the study centre).

Previous enrolment or randomisation and received study treatment in the present study. Patients can, however, be re-screened if the reason for the screen failure no longer exists.

Known malignant central nervous system (CNS) disease other than neurologically stable, treated brain metastases - defined as metastasis having no evidence of progression or haemorrhage for at least 2 weeks after treatment (including brain radiotherapy). Must be off any systemic corticosteroids for the treatment of brain metastases for at least 14 days prior to enrolment.

Use of any anti-cancer treatment drug ≤21 days or 5 half-lives (whichever is shorter) prior to the first dose of AZD1775. For drugs for which 5 half-lives is ≤21 days, a minimum of 10 days between termination of the prior treatment and administration of AZD1775 treatment is required.

No other anticancer-therapy (chemotherapy, immunotherapy, hormonal anti-cancer therapy, radiotherapy \[except for palliative local radiotherapy\]), biological therapy or other novel agent is to be permitted while patient is receiving study treatment. Patients on LHRH analogue treatment for more than 6 months are allowed entry into the study and may continue at the discretion of the Investigator.

Previous radiation therapy completed ≤7 days prior to the start of study treatment (i.e., first administration of cocktail \[Part A Day -8\]).

Major surgical procedures ≤28 days of beginning study treatment (i.e., first administration of cocktail \[Part A Day -8\]), or minor surgical procedures ≤7 days. No waiting period required following port-a-cath placement or other central venous access placement.

Grade \>1 toxicities from previous cancer therapy, according to the Common Terminology Criteria for Adverse Events \[CTCAE\]), excluding alopecia or anorexia.

Patient has an inability to swallow oral medications. Note: Patient may not have a percutaneous endoscopic gastrostomy tube or be receiving total parenteral nutrition.

Patients suffering from conditions which are likely to adversely affect gastrointestinal motility and/or transit (for example, diarrhoea, vomiting or nausea, gastroparesis, irritable bowel syndrome and malabsorption), or patients with gastrointestinal resection (e.g., partial or total gastrectomy) likely to interfere with absorption of study treatment).

Patients who are not non-smokers or light smokers (no more than 5 cigarettes per day) and who cannot abstain from smoking from 2 weeks prior to first dose of cocktail until after the last PK sample collection in Part B.

Any intake of grapefruit, grapefruit juice, Seville oranges, Seville orange marmalade, or other products containing grapefruit or Seville oranges within 7 days of the start of treatment (i.e., first administration of cocktail \[Part A Day -8\]).

Excessive intake of caffeine (more than 6 cups of coffee or equivalent per day) and/or consumption of any caffeine containing drinks or food, e.g., coffee, tea, chocolate, caffeine-containing energy drinks (e.g., Red Bull), or cola within 36 hours of administration of the cocktail on Day -8.

Patient has had prescription or non-prescription drugs or other products known to be sensitive to CYP3A4 substrates or CYP3A4 substrates with a narrow therapeutic index, which cannot be discontinued 2 weeks prior to the first administration of AZD1775 (Part A Day 1), or to be moderate to strong inhibitors/inducers of CYP3A4 which cannot be discontinued 2 weeks prior to beginning study treatment (i.e., first administration of cocktail \[Part A Day -8\]) and withheld throughout the study until 2 weeks after the last administration of AZD1775. Co-administration of aprepitant or fosaprepitant during this study is prohibited. Any patient taking an oral contraceptive must be discussed with the Medical Monitor to ensure that there will be no interaction with the brand of oral contraceptive and cocktail of drugs prior to trial entry to confirm eligibility.

Patient has had prescription or non-prescription drugs or other products known to be moderate to strong inhibitors/inducers of CYP1A2 or CYP2C19 which cannot be discontinued 2 weeks prior to beginning study treatment (ie, first administration of cocktail \[Part A Day -8\]) and withheld through Day 4 of Part A

Patient has had adjustments to prescription or non-prescription drugs or other products known to be mild inhibitors and/or inducers of CYP3A4 within 1 week prior to the first dose of the cocktail (Part A Day -8).

Herbal preparations taken within 7 days beginning study treatment (i.e., first administration of cocktail \[Part A Day -8\]). However, in the case of St John's wort, patients cannot have taken this herbal preparation 21 days prior to first dose of cocktail (Part A Day -8). In the case of Angelica root (Bhai Zhi), patients cannot have taken this herbal preparation 2 weeks prior to beginning study treatment (ie, first administration of cocktail \[Part A Day -8\]).

Patients taking any concomitant medications that might affect QT/QTc intervals.

Patients who have taken any proton pump inhibitors (omeprazole, lansoprazole, esomeprazole, pantoprazole, etc.) within 7 days of beginning study treatment (i.e., first administration of cocktail \[Part A Day -8\]).

Patients who cannot withhold antacids for 6 hours or H2-antagonists (cimetidine, ranitidine, famotidine, nizatidine) for up to 96 hours at a time (24 hours prior to and following cocktail administration and 24 hours prior to and following AZD1775 administration) .

Patients who have received midazolam and/or omeprazole (or esomeprazole) within 14 days of beginning study treatment (i.e., first administration of cocktail \[Part A Day -8\]).

Any known hypersensitivity or contraindication to the cocktail drugs (caffeine, omeprazole and midazolam) or AZD1775, or to the components thereof.

Any of the following cardio-vascular conditions currently or within the last 6 months:

* Unstable angina pectoris.

* Congestive heart failure ≥ Class 2 as defined by the New York Heart Association

* Acute myocardial infarction.

* Significant conduction abnormalities, e.g., atrioventricular block II and III, sick sinus syndrome even if controlled with medication, as well as complete left bundle branch block (complete LBBB).

* Ventricular or supraventricular arrhythmias.

* Insufficiently controlled hypertension, i.e., \>160/100 mm Hg.

* Cardiac devices (pacemaker, implantable cardioverter defibrillator, cardiac resynchronisation therapy device, etc.) that can affect the ST-T wave morphology and has a subsequent negative impact on the accuracy of the QTc measurement

Patients with centrally reviewed QT interval (specifically QTc calculated using the Fridericia formula) \>450 ms \[QTcF\]) obtained from 3 dECGs 2 to 5 minutes apart at study entry, or congenital long QT syndrome.

AZD1775 should not be given to patients who have a history of Torsades de pointes unless all risk factors that contributed to Torsades have been corrected. AZD1775 has not been studied in patients with ventricular arrhythmias or recent myocardial infarction.

Pregnant or lactating female patients.

Serious, symptomatic active infection at the time of study entry, or another serious underlying medical condition that would impair the ability of the patient to receive study treatment.

Presence of other active invasive cancers.

Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.

Active infection with hepatitis B, hepatitis C, or human immunodeficiency virus (HIV).

Any of the following is regarded as a criterion for exclusion from the optional pharmacogenetic part of the study:

Previous bone marrow transplant.

Non-leukocyte depleted whole blood product within 120 days of the genetic sample collection.

Effects of AZD1775 on the PK Substrates for CYP3A, CYP2C19, CYP1A2 and on QT Interval in Patients With Advanced Cancer

What this study is about

Effects of AZD1775 on the PK Substrates for CYP3A, CYP2C19, CYP1A2 and on QT Interval in Patients With Advanced Cancer

What this study is about