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

This study is not yet open for participant recruitment.
Verified November 2017 by AstraZeneca
Sponsor:
ClinicalTrials.gov Identifier:
NCT03333824
First Posted: November 7, 2017
Last Update Posted: November 27, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborator:
Quintiles, Inc.
Information provided by (Responsible Party):
AstraZeneca
  Purpose
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.

Condition Intervention Phase
Solid Tumours Drug: CYP1A2 (caffeine) Drug: CYP2C19 (omeprazole) Drug: CYP3A (midazolam) Drug: Kytril (granisetron) Drug: Wee-1 kinase inhibitor AZD1775 Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Open-label Study to Evaluate the Effect of Multiple Doses of AZD1775 on the Pharmacokinetics of Substrates for CYP3A, CYP2C19, CYP1A2 and to Provide Data on the Effect of AZD1775 on QT Interval in Patients With Advanced Solid Tumours

Resource links provided by NLM:


Further study details as provided by AstraZeneca:

Primary Outcome Measures:
  • Part A: Area under the plasma concentration-time curve from zero to infinity for cocktail parent compounds (midazolam, omeprazole and caffeine) [ Time Frame: Blood samples are collected on Day -8 and Day 3 of Part A at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post cocktail dose ]
    To assess the effect of AZD1775 on the PK of probe substrates for CYP1A2 (caffeine), CYP2C19 (omeprazole), and CYP3A (midazolam)

  • Part A: Area under the plasma concentration-time curve from time zero to the time "t" of the last quantifiable concentration for cocktail parent compounds (midazolam, omeprazole and caffeine) [ Time Frame: Blood samples are collected on Day -8 and Day 3 of Part A at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post cocktail dose ]
    To assess the effect of AZD1775 on the PK of probe substrates for CYP1A2 (caffeine), CYP2C19 (omeprazole), and CYP3A (midazolam)

  • Part A: maximum plasma drug concentration for cocktail parent compounds (midazolam, omeprazole and caffeine) [ Time Frame: Blood samples are collected on Day -8 and Day 3 of Part A at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post cocktail dose ]
    To assess the effect of AZD1775 on the PK of probe substrates for CYP1A2 (caffeine), CYP2C19 (omeprazole), and CYP3A (midazolam)

  • Part B: dECG intervals (QTcF) for absolute values and time-matched change from baseline [ Time Frame: dECGs are measured on Day -1, Day 1 and Day 3 of Part B at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours post AZD1775 dose ]
    To assess the effect on QT interval corrected for heart rate (QTc) following multiple oral doses of AZD1775


Secondary Outcome Measures:
  • Time to reach maximum plasma concentration for cocktail parent compounds (midazolam, omeprazole and caffeine) [ Time Frame: Blood samples are collected on Day -8, and Day 3 of Part A at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post dose ]
    To describe the PK of midazolam, omeprazole and caffeine and their metabolites (1'-hydroxy-midazolam, 5-hydroxy-omeprazole, and paraxanthine) in the absence and presence of AZD1775

  • Terminal half-life for cocktail parent compounds (midazolam, omeprazole and caffeine) [ Time Frame: Blood samples are collected on Day -8, and Day 3 of Part A at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post dose ]
    To describe the PK of midazolam, omeprazole and caffeine and their metabolites (1'-hydroxy-midazolam, 5-hydroxy-omeprazole, and paraxanthine) in the absence and presence of AZD1775

  • Elimination rate constant for cocktail parent compounds (midazolam, omeprazole and caffeine) [ Time Frame: Blood samples are collected on Day -8, and Day 3 of Part A at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post dose ]
    To describe the PK of midazolam, omeprazole and caffeine and their metabolites (1'-hydroxy-midazolam, 5-hydroxy-omeprazole, and paraxanthine) in the absence and presence of AZD1775

  • Apparent clearance following oral administration for cocktail parent compounds (midazolam, omeprazole and caffeine) [ Time Frame: Blood samples are collected on Day -8, and Day 3 of Part A at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post dose ]
    To describe the PK of midazolam, omeprazole and caffeine and their metabolites (1'-hydroxy-midazolam, 5-hydroxy-omeprazole, and paraxanthine) in the absence and presence of AZD1775

  • Apparent volume of distribution for cocktail parent compounds (midazolam, omeprazole and caffeine) [ Time Frame: Blood samples are collected on Day -8, and Day 3 of Part A at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post dose ]
    To describe the PK of midazolam, omeprazole and caffeine and their metabolites (1'-hydroxy-midazolam, 5-hydroxy-omeprazole, and paraxanthine) in the absence and presence of AZD1775

  • Area under the plasma concentration-time curve from zero to infinity for cocktail metabolites [ Time Frame: Blood samples are collected on Day -8, and Day 3 of Part A at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post dose ]
    To describe the PK of midazolam, omeprazole and caffeine and their metabolites (1'-hydroxy-midazolam, 5-hydroxy-omeprazole, and paraxanthine) in the absence and presence of AZD1775

  • Area under the plasma concentration-time curve from time zero to the time "t" of the last quantifiable concentration for cocktail metabolites [ Time Frame: Blood samples are collected on Day -8, and Day 3 of Part A at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post dose ]
    To describe the PK of midazolam, omeprazole and caffeine and their metabolites (1'-hydroxy-midazolam, 5-hydroxy-omeprazole, and paraxanthine) in the absence and presence of AZD1775

  • Time to reach maximum plasma concentration for cocktail metabolites [ Time Frame: Blood samples are collected on Day -8, and Day 3 of Part A at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post dose ]
    To describe the PK of midazolam, omeprazole and caffeine and their metabolites (1'-hydroxy-midazolam, 5-hydroxy-omeprazole, and paraxanthine) in the absence and presence of AZD1775

  • Maximum plasma drug concentration for cocktail metabolites [ Time Frame: Blood samples are collected on Day -8, and Day 3 of Part A at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post dose ]
    To describe the PK of midazolam, omeprazole and caffeine and their metabolites (1'-hydroxy-midazolam, 5-hydroxy-omeprazole, and paraxanthine) in the absence and presence of AZD1775

  • Terminal half-life for cocktail metabolites [ Time Frame: Blood samples are collected on Day -8, and Day 3 of Part A at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post dose ]
    To describe the PK of midazolam, omeprazole and caffeine and their metabolites (1'-hydroxy-midazolam, 5-hydroxy-omeprazole, and paraxanthine) in the absence and presence of AZD1775

  • Elimination rate constant for cocktail metabolites [ Time Frame: Blood samples are collected on Day -8, and Day 3 of Part A at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post dose ]
    To describe the PK of midazolam, omeprazole and caffeine and their metabolites (1'-hydroxy-midazolam, 5-hydroxy-omeprazole, and paraxanthine) in the absence and presence of AZD1775

  • Day 1, Part B Only: Area under the plasma concentration-time curve from time zero to 12 hours for AZD1775 [ Time Frame: Blood samples are collected on Day 1 of Part B at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10 and 12 hours post dose ]
    To describe the PK of AZD1775 following single and multiple dose administration

  • Day 1, Part B only: Time to reach maximum plasma concentration for AZD1775 [ Time Frame: Blood samples are collected on Day 1 of Part B at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10 and 12 hours post dose ]
    To describe the PK of AZD1775 following single and multiple dose administration

  • Day 1, Part B only: Maximum plasma drug concentration for AZD1775 [ Time Frame: Blood samples are collected on Day 1 of Part B at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10 and 12 hours post dose ]
    To describe the PK of AZD1775 following single and multiple dose administration

  • Day 3, Parts A & B: Area under the plasma concentration-time curve from time zero to 12 hours for AZD1775 [ Time Frame: Blood samples are collected on Day 3 of Part A and B at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10 and 12 hours post dose ]
    To describe the PK of AZD1775 following single and multiple dose administration

  • Day 3, Parts A & B: Time to reach maximum plasma concentration for AZD1775 [ Time Frame: Blood samples are collected on Day 3 of Part A and B at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post dose ]
    To describe the PK of AZD1775 following single and multiple dose administration

  • Day 3, Parts A & B: Maximum plasma drug concentration for AZD1775 [ Time Frame: Blood samples are collected on Day 3 of Part A and B at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post dose ]
    To describe the PK of AZD1775 following single and multiple dose administration

  • Day 3, Parts A & B: Minimum plasma drug concentration for AZD1775 [ Time Frame: Blood samples are collected on Day 3 of Part A and B at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post dose ]
    To describe the PK of AZD1775 following single and multiple dose administration

  • Day 3, Parts A & B: Average concentration over a dosing interval for AZD1775 [ Time Frame: Blood samples are collected on Day 3 of Part A and B at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post dose ]
    To describe the PK of AZD1775 following single and multiple dose administration

  • Day 3, Parts A & B: Apparent clearance at steady state for AZD1775 [ Time Frame: Blood samples are collected on Day 3 of Part A and B at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post dose ]
    To describe the PK of AZD1775 following single and multiple dose administration

  • Day 3, Parts A & B: Fluctuation index (FI) over a dosing interval for AZD1775 [ Time Frame: Blood samples are collected on Day 3 of Part A and B at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post dose ]
    To describe the PK of AZD1775 following single and multiple dose administration

  • Part B only: Accumulation ratio for area under the plasma concentration-time curve from time zero to twelve hours for AZD1775 [ Time Frame: Blood samples are collected on Day 1 and 3 of Part B at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post dose ]
    To describe the PK of AZD1775 following single and multiple dose administration

  • Part B only: Accumulation ratio for maximum plasma drug concentration for AZD1775 [ Time Frame: Blood samples are collected on Day 1 and 3 of Part B at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post dose ]
    To describe the PK of AZD1775 following single and multiple dose administration

  • dECG intervals (heart rate, RR, PR, QRS, QTcB, QTcF and QT) for absolute values and time-matched change from baseline [ Time Frame: dECG intervals are performed on Day -1, Day 1, and Day 3 of Part B at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose ]
    To evaluate the effect of single and multiple doses of AZD1775 on cardiac (ECG) parameters

  • Changes in dECG morphology [ Time Frame: dECG intervals are performed on Day -1, Day 1, and Day 3 of Part B at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose ]
    To evaluate the effect of single and multiple doses of AZD1775 on cardiac (ECG) parameters

  • Area under the plasma concentration-time curve from time zero to infinity ratios in relation to parent compound [ Time Frame: Blood samples are collected on Day -8, and Day 3 of Part A at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post dose ]
    To describe the PK of midazolam, omeprazole and caffeine and their metabolites (1'-hydroxy-midazolam, 5-hydroxy-omeprazole, and paraxanthine) in the absence and presence of AZD1775

  • Maximum plasma drug concentration ratios in relation to parent compound [ Time Frame: Blood samples are collected on Day -8, and Day 3 of Part A at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post dose ]
    To describe the PK of midazolam, omeprazole and caffeine and their metabolites (1'-hydroxy-midazolam, 5-hydroxy-omeprazole, and paraxanthine) in the absence and presence of AZD1775


Estimated Enrollment: 30
Anticipated Study Start Date: November 30, 2017
Estimated Study Completion Date: July 18, 2018
Estimated Primary Completion Date: July 18, 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Wee-1 kinase inhibitor AZD1775
To evaluate the effect of multiple doses of AZD1775 on the PK of substrates for CYP3A (midazolam), CYP2C19 (omeprazole), CYP1A2 (caffeine) and to evaluate the effect of multiple doses of AZD1775 on QT interval
Drug: CYP1A2 (caffeine)
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.
Drug: CYP2C19 (omeprazole)
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.
Drug: CYP3A (midazolam)
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.
Drug: Kytril (granisetron)
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.
Drug: Wee-1 kinase inhibitor AZD1775
Multiple doses of 225 mg AZD1775, (3 x 75 mg, printed capsules) administered orally. The drug class of AZD1775 is Wee-1 kinase inhibitor.

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).

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 99 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Has read and understands the informed consent form (ICF) and has given written informed consent prior to any study procedures.
  • Histologically or cytologically documented, locally advanced or metastatic solid tumour, excluding lymphoma, for which standard therapy does not exist or has proven ineffective or intolerable.
  • Any prior palliative radiation must have been completed at least 7 days prior to the start of study treatment (first administration of cocktail [Part A Day -8]), and patients must have recovered from any acute adverse effects prior to the start of study treatment.
  • Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0 to 1.
  • Baseline laboratory values within 7 days of study treatment initiation (first administration of cocktail [Part A Day -8]):

    • Absolute neutrophil count (ANC) ≥1500/μL.
    • Haemoglobin ≥9 g/dL.
    • Platelets ≥100,000/μL.
    • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 x upper limit of normal (ULN) or ≤5 x ULN if known hepatic metastases.
    • Serum bilirubin within normal limits (WNL) or ≤1.5 x ULN in patients with liver metastases; or total bilirubin ≤3.0 x ULN with direct bilirubin WNL in patients with well documented Gilbert's Syndrome.
    • Serum creatinine ≤1.5 x ULN, or measured creatinine clearance (CrCl) calculated by Cockcroft-Gault method ≥45 mL/min (confirmation of creatinine clearance is only required when creatinine is >1.5 x ULN).

CrCl (glomerular filtration rate) = (140-age) x (weight/kg) x F (72 x serum creatinine mg/dL)

awhere F = 0.85 for females and F = 1 for males

  • Female patients who are not of childbearing potential and fertile females of childbearing potential who agree to use adequate contraceptive measures that are in place during screening (or consent), for the duration of the study, and for 1 month after treatment stops, and who are not breastfeeding, and who have a negative serum or urine pregnancy test prior to the start of study treatment (first administration of cocktail [Part A Day -8]).
  • Male patients should be willing to use barrier contraception (ie, condoms) for the duration of the study and for 3 months after study treatment discontinuation.
  • Female and/or male patients ≥18 years of age.
  • Willingness and ability to comply with the study and follow-up procedures.

For inclusion in the optional genetic component of the study for all the patients:

o Provision of informed consent for genetic research. If a patient declines to participate in the genetic component of the study, there will be no penalty or loss of benefit to the patient. The patient will not be excluded from other aspects of the study, as long as all the eligibility criteria are met.

Exclusion Criteria:

  • 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, 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.
  • 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).
  • 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 48 hours.
  • 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 cardiac diseases currently or within the last 6 months as defined by the New York Heart Association ≥ Class:

    • Unstable angina pectoris.
    • Congestive heart failure.
    • 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.
    • Patients with 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.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03333824


Contacts
Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com

Locations
United States, Arizona
Research Site Not yet recruiting
Tucson, Arizona, United States, 85724
United States, California
Research Site Not yet recruiting
Los Angeles, California, United States, 90048
Research Site Not yet recruiting
Pasadena, California, United States, 91105
United States, Maryland
Research Site Not yet recruiting
Silver Spring, Maryland, United States, 20910
United States, Michigan
Research Site Not yet recruiting
Bingham Farms, Michigan, United States, 48025
Research Site Not yet recruiting
Detroit, Michigan, United States, 48202
United States, New Hampshire
Research Site Not yet recruiting
Lebanon, New Hampshire, United States, 03756
United States, Ohio
Research Site Not yet recruiting
Cincinnati, Ohio, United States, 45229
United States, Rhode Island
Research Site Not yet recruiting
Providence, Rhode Island, United States, 02903
United States, South Carolina
Research Site Not yet recruiting
Greenville, South Carolina, United States, 29605
United States, Texas
Research Site Not yet recruiting
Dallas, Texas, United States, 75251
Research Site Not yet recruiting
Houston, Texas, United States, 77030-4004
Sponsors and Collaborators
AstraZeneca
Quintiles, Inc.
Investigators
Study Director: Lone Ottesen, MD AstraZeneca
Principal Investigator: Ding Wang, MD Henry Ford Hospital
  More Information

Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT03333824     History of Changes
Other Study ID Numbers: D6014C00006
First Submitted: October 23, 2017
First Posted: November 7, 2017
Last Update Posted: November 27, 2017
Last Verified: November 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by AstraZeneca:
Pharmacokinetics, Cardiac Conduction, Mitotic Checkpoint inhibitor, QTc interval

Additional relevant MeSH terms:
Omeprazole
Midazolam
Caffeine
Granisetron
Adjuvants, Anesthesia
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
GABA Modulators
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Central Nervous System Stimulants
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Purinergic P1 Receptor Antagonists
Purinergic Antagonists
Purinergic Agents
Anti-Ulcer Agents
Gastrointestinal Agents
Proton Pump Inhibitors
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents