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

NCT03333824 | Completed Phase 1 FDA Drug

• 1 other identifier: D6014C00006
• Study Type: interventional
• Target: 33
• Locations: 1 country
• Sites: 7

Brief 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.

Conditions

Solid Tumours

Keywords

Pharmacokinetics, Cardiac Conduction, Mitotic Checkpoint inhibitor, QTc interval

Outcome Measures

Primary Outcomes (4)

• Part A: Area under the plasma concentration-time curve from zero to infinity for cocktail parent compounds (midazolam, omeprazole and caffeine)

  To assess the effect of AZD1775 on the PK of probe substrates for CYP1A2 (caffeine), CYP2C19 (omeprazole), and CYP3A (midazolam)

  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

• 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)

  To assess the effect of AZD1775 on the PK of probe substrates for CYP1A2 (caffeine), CYP2C19 (omeprazole), and CYP3A (midazolam)

  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

• Part A: maximum plasma drug concentration for cocktail parent compounds (midazolam, omeprazole and caffeine)

  To assess the effect of AZD1775 on the PK of probe substrates for CYP1A2 (caffeine), CYP2C19 (omeprazole), and CYP3A (midazolam)

  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

• Part B: dECG intervals (QTcF) for absolute values and time-matched change from baseline

  To assess the effect on QT interval corrected for heart rate (QTc) following multiple oral doses of AZD1775

  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

Secondary Outcomes (27)

• Time to reach maximum plasma concentration for cocktail parent compounds (midazolam, omeprazole and caffeine)

  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

• Terminal half-life for cocktail parent compounds (midazolam, omeprazole and caffeine)

  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

• Elimination rate constant for cocktail parent compounds (midazolam, omeprazole and caffeine)

  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

• Apparent clearance following oral administration for cocktail parent compounds (midazolam, omeprazole and caffeine)

  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

• Apparent volume of distribution for cocktail parent compounds (midazolam, omeprazole and caffeine)

  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

Study Arms (1)

Wee-1 kinase inhibitor AZD1775

EXPERIMENTAL

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); Drug: CYP2C19 (omeprazole); Drug: CYP3A (midazolam); Drug: Kytril (granisetron); Drug: Wee-1 kinase inhibitor AZD1775

Interventions

CYP1A2 (caffeine) DRUG

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.

Wee-1 kinase inhibitor AZD1775

CYP2C19 (omeprazole) DRUG

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.

Wee-1 kinase inhibitor AZD1775

CYP3A (midazolam) DRUG

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.

Wee-1 kinase inhibitor AZD1775

Kytril (granisetron) DRUG

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.

Wee-1 kinase inhibitor AZD1775

Wee-1 kinase inhibitor AZD1775 DRUG

Multiple doses of 225 mg AZD1775, (3 x 75 mg, printed capsules) administered orally. The drug class of AZD1775 is Wee-1 kinase inhibitor.

Wee-1 kinase inhibitor AZD1775

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 \[Part A Day -8\]). 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.
• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• AstraZeneca: lead
• Quintiles, Inc.: collaborator

Study Sites (7)

Research Site

Bingham Farms, Michigan, 48025, United States

Location

Research Site

Detroit, Michigan, 48202, United States

Location

Research Site

Lebanon, New Hampshire, 03756, United States

Location

Research Site

Cincinnati, Ohio, 45229, United States

Location

Research Site

Providence, Rhode Island, 02903, United States

Location

Research Site

Greenville, South Carolina, 29605, United States

Location

Research Site

Dallas, Texas, 75251, United States

Location

Related Publications (2)

• Nagard M, Ah-See ML, Strauss J, Wise-Draper T, Safran HP, Nadeau L, Edenfield WJ, Lewis LD, Ottesen LH, Li Y, Mugundu GM. Phase I study to assess the effect of adavosertib (AZD1775) on the pharmacokinetics of substrates of CYP1A2, CYP2C19, and CYP3A in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2023 Sep;92(3):193-203. doi: 10.1007/s00280-023-04554-3. Epub 2023 Jul 2.

  PMID: 37394627 DERIVED

• Nagard M, Ah-See ML, Strauss J, Wise-Draper T, Safran HP, Nadeau L, Edenfield WJ, Lewis LD, Rekic D, Dota C, Ottesen LH, Li Y, Mugundu GM. Adavosertib (AZD1775) does not prolong the QTc interval in patients with advanced solid tumors: a phase I open-label study. Cancer Chemother Pharmacol. 2023 Aug;92(2):141-150. doi: 10.1007/s00280-023-04555-2. Epub 2023 Jun 27.

  PMID: 37368100 DERIVED

MeSH Terms

Interventions

Cytochrome P-450 CYP1A2; Caffeine; Cytochrome P-450 CYP2C19; Omeprazole; Cytochrome P-450 CYP3A; Midazolam; Granisetron

Intervention Hierarchy (Ancestors)

Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 Enzyme System; Cytochromes; Enzymes and Coenzymes; Cytochrome P450 Family 1; Mixed Function Oxygenases; Oxygenases; Oxidoreductases; Enzymes; Hemeproteins; Proteins; Amino Acids, Peptides, and Proteins; Xanthines; Alkaloids; Heterocyclic Compounds; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Limonene Hydroxylases; Cytochrome P450 Family 2; 2-Pyridinylmethylsulfinylbenzimidazoles; Sulfoxides; Sulfur Compounds; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Benzimidazoles; Cytochrome P450 Family 3; Oxidoreductases, N-Demethylating; Oxidoreductases Acting on CH-NH Group Donors; Benzodiazepines; Benzazepines; Azabicyclo Compounds; Aza Compounds; Indazoles; Pyrazoles; Azoles; Bridged Bicyclo Compounds, Heterocyclic; Heterocyclic Compounds, Bridged-Ring

Study Officials

• Lone Ottesen, MD

  AstraZeneca

  STUDY DIRECTOR

• Ding Wang, MD

  Henry Ford Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 23, 2017
• First Posted: November 7, 2017
• Study Start: December 1, 2017
• Primary Completion: January 22, 2019
• Study Completion: January 22, 2019
• Last Updated: March 25, 2019

Record last verified: 2019-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (7)