Effects of AZD1775 on the PK Substrates for CYP3A, CYP2C19, CYP1A2 and on QT Interval in Patients With Advanced Cancer
Condition: Solid Tumours
Study type: Interventional
Phase: Phase 1

Summary: 
      The purpose of this study is to determine whether AZD1775 has any effect on the
      pharmacokinetics (PK) of three compounds (caffeine, omeprazole, and midazolam) that are
      probes for common drug-metabolizing enzymes (caffeine-CYP1A2, omeprazole-CYP2C19,
      midazolam-CYP3A). The study also seeks to determine the effect of AZD1775 on the QTc
      interval, which is a common measure of cardiac (heart) function.
    

Detailed description: 
      This is a Phase I, 2-part study (Part A and Part B) in patients with advanced solid tumours.

      Part A: Part A of this study is an open-label, non-randomised, 2-period design. The treatment
      starts with the administration of a cocktail of 3 medications:

      caffeine, omeprazole and midazolam (Day -8), followed by pharmacokinetic (PK) sampling for 24
      hours (Period 1) and a washout period of at least 7, but no more than 14 days. In Period 2,
      AZD1775 will be administered twice daily (bid) until steady state for 2.5 days (total of 5
      doses) and the final dose will be administered in combination with the cocktail in the
      morning of Day 3.

      Part B: Part B is an open-label, non-randomised study in the same patients who participated
      in Part A. On Day -1, baseline dECG assessments will be performed at clock times matched to
      planned/scheduled dECG assessment times on Days 1 and 3.

      Starting on Day 1, each patient will receive AZD1775 (225 mg) bid for 2.5 days and will
      undergo dECG and PK assessments pre-dose and for 12 hours post AZD1775 dose.

      On Day 3, patients will receive their final AZD1775 dose and undergo dECG and PK assessments
      pre-dose and for 12 hours post-dose. On completion of Part B (ie, collection of the 24-hour
      PK sample/dECG and safety assessments on Day 4) patients will enter a 4-day washout period
      relative to the last dose of AZD1775. Within 3 days after the washout period, patients will
      be required to attend an end of treatment (EoT) visit. Patients will be evaluated for their
      eligibility and interest to enrol into the open-label continued access (CA) study
      (D6014C00007).
    

Intervention name(s): CYP1A2 (caffeine); CYP2C19 (omeprazole); CYP3A (midazolam); Kytril (granisetron); Wee-1 kinase inhibitor AZD1775
Intervention type(s): Drug; Drug; Drug; Drug; Drug
Intervention description(s): In Part A, Period 1, patients will be administered a 3 drug cocktail of caffeine, omeprazole and midazolam on Day -8 followed by a washout period of at least 7 but no more than 14 days. In Part A, Period 2, AZD1775 capsules will be administered orally, 225 mg bid, until steady state for 2.5 days (total of 5 doses) and administered together with the cocktail on the morning of Day 3.; In Part A, Period 1, patients will be administered a 3 drug cocktail of caffeine, omeprazole and midazolam on Day -8 followed by a washout period of at least 7 but no more than 14 days. In Part A, Period 2, AZD1775 capsules will be administered orally, 225 mg bid, until steady state for 2.5 days (total of 5 doses) and administered together with the cocktail on the morning of Day 3.; In Part A, Period 1, patients will be administered a 3 drug cocktail of caffeine, omeprazole and midazolam on Day -8 followed by a washout period of at least 7 but no more than 14 days. In Part A, Period 2, AZD1775 capsules will be administered orally, 225 mg bid, until steady state for 2.5 days (total of 5 doses) and administered together with the cocktail on the morning of Day 3.; Patients should be administered Kytril (granisetron) 1 mg orally, under fasted conditions (-2 to 2 hours away from meals), 30 minutes prior to administration of the AZD1775 capsules with a small amount of water.; Multiple doses of 225 mg AZD1775, (3 x 75 mg, printed capsules) administered orally. The drug class of AZD1775 is Wee-1 kinase inhibitor.
Intervention MeSH terms: Midazolam; Granisetron; Caffeine; Omeprazole; Adavosertib
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Pharmacokinetics, Cardiac Conduction, Mitotic Checkpoint inhibitor, QTc interval