MC# 21-18 - A Phase I, Open-label, Non-randomised Study to Assess the Effect of Itraconazole (a CYP3A4 Inhibitor), Rifampicin (a CYP3A4 Inducer), and Omeprazole (a Proton Pump Inhibitor) on the Pharmacokinetics of a Single Oral Dose of Adavosertib in Patients with Advanced Solid Tumours (D601HC00006 & Adavosertib

  • Agent(s): Adavosertib
  • Disease Type(s):
  • Phase(s): I
  • Drug Classification(s): Targeted Therapy, Small Molecule
  • Molecular Target(s): WEE1

Mechanism of Action

AZD1775 is a highly selective, adenosine-triphosphate (ATP) competitive, small-molecule inhibitor of the DNA damage checkpoint kinase WEE1 that sensitizes tumor cells to cytotoxic agents by abrogating cell-cycle arrest and proper DNA repair.

Purpose

In this study, the sponsor and investigators want to learn:

  • The individual effects on metabolism, safety, and tolerability of Adavosertib when given with either Itraconazole, Rifampicin, or Omeprazole
  • How much of Adavosertib is absorbed into the blood and how fast it is removed when given in combination with Itraconazole, Rifampicin, or Omeprazole and with or without food.
  • If research tests can be used in the future to predict who will benefit from Adavosertib
Inclusion Criteria
  1. Participant must be at least 18 years of age, at the time of signing the ICF
  2. 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
  3. ECOG PS score of 0 or1 with no deterioration over the previous 2 weeks prior to baseline or day of first dosing
  4. Predicted life expectancy ≥ 12 weeks
  5. Adequate organ and marrow function as follows:
    1. Absolute neutrophil count ≥ 1.5 × 109/L
    2. Hemoglobin ≥ 9.0 g/dL
    3. Platelets count ≥ 100 × 109/L
    4. ALT and AST ≤ 2.5 × ULN; for participants with hepatic metastases, ALT and AST ≤ 5 × ULN
    5. Total bilirubin ≤ 1.5 × ULN or ≤ 3 × ULN in the presence of documented Gilbert’s Syndrome (unconjugated hyperbilirubinemia)
    6. Calculated CrCl > 50 mL/min as determined by Cockcroft-Gault method (using actual body weight)
  6. Male and female: Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
  7. Negative pregnancy test (serum) for women of childbearing potential
  8. Female patients must be post-menopausal, surgically sterile, or using one highly effective form of birth control (a highly effective method of contraception is defined as one that can achieve a failure rate of less than 1% per year when used consistently and correctly.)  Women of childbearing potential must agree to use one highly effective method of birth control.  They should have been stable on their chosen method of birth control for a minimum of 3 months before entering the study to 1 month after the last dose.  Non sterilized male partners of a woman of childbearing potential must use a male condom plus spermicide (condom alone in countries where spermicides are not approved) throughout this period.
  9. Non-sterilized male patients who intend to be sexually active with a female partner of childbearing potential must be surgically sterile or using an acceptable method of contraception from the time of screening throughout the total duration of the study and the drug washout period (3 months after the last dose of study intervention) to prevent pregnancy in a partner.  Male participants must not donate or bank sperm during this same time period.
  10. Capable of and giving signed informed consent as described in Appendix C which includes compliance with the requirements and restrictions listed in the ICF and in this CSP
  11. Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of samples for optional genetic research that supports Genomic Initiative
Exclusion Criteria
  1. Persistent toxicities (CTCAE Grade ≥ 2) caused by previous anti-cancer therapy, excluding alopecia and CTCAE Grade 2 peripheral neuropathy.  Participants with irreversible toxicity that is not reasonably expected to be exacerbated by study intervention may be included (eg, hearing loss) after consultation with the AstraZeneca Medical Monitor.
  2. Persistent toxicities (CTCAE Grade ≥ 2) caused by previous anti-cancer therapy, excluding alopecia and CTCAE Grade 2 peripheral neuropathy.  Participants with irreversible toxicity that is not reasonably expected to be exacerbated by study intervention may be included (eg, hearing loss) after consultation with the AstraZeneca Medical Monitor.
  3. Spinal cord compression or brain metastases unless asymptomatic, stable, and not requiring steroids for at least 4 weeks prior to start of study intervention
  4. Any of the following cardiac diseases currently or within the last 6 months:
    1. Unstable angina pectoris
    2. Acute myocardial infarction
    3. Congestive heart failure ≥ Class 2
  5. History of arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia.  Participants with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers may be permitted upon discussion with the Medical Monitor.
  6. Investigator judgment of 1 or more of the following:
    1. Mean resting corrected QT interval > 480 msec, obtained from triplicate ECGs performed at screening
    2. History of QT prolongation associated with other medications that required discontinuation of that medication, or any current concomitant medication known to prolong the QT interval and cause Torsades de Pointes.
    3. Congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives.
  7. Known to have tested positive for human immunodeficiency virus or active tuberculosis infection (clinical evaluation that may include clinical history, physical examination and radiographic findings, or tuberculosis testing in line with local practice)
  8. Known active hepatitis infection, positive hepatitis C antibody, hepatitis B virus surface antigen or hepatitis B virus core antibody, at screening
  9. As judged by the investigator, any evidence of diseases (such as severe or uncontrolled systemic diseases, including uncontrolled hypertension, renal transplant, active infections, and active bleeding diseases) which, in the investigator’s opinion, makes it undesirable for the participant to participate in the study or that would jeopardise compliance with the CSP
  10. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the CSP
  11. Receipt of live virus and live bacterial vaccines whilst the patient is receiving the study intervention and during the 30-day follow-up period. Inactivated flu vaccines are permitted
  12. Known history of drug or alcohol abuse within 12 months of screening or positive test results of drug or alcohol abuse screen
  13. Use of an anti-cancer treatment drug ≤ 21 days (≤ 6 weeks for nitroureas or mitomycin C) or use of an investigational product within 5 half-lives prior to the first dose of adavosertib.  For PD-1/PD-L1 inhibitors, a minimum of 28 days since last dose is required.  For drugs for which 5 half-lives is ≤ 21 days, a minimum of 10 days between termination of the prior treatment and administration of adavosertib treatment is required.  Patients on luteinizing hormone-releasing hormone analogue treatment for more than 6 months are allowed entry into the study and may continue at the discretion of the investigator.
  14. Other anti-cancer-therapy (chemotherapy, immunotherapy, hormonal anti-cancer therapy, radiotherapy [except for palliative local radiotherapy]), biological therapy or other novel agent are not permitted until the last PK sampling is completed
  15. Palliative radiotherapy with a limited field of radiation within 2 weeks or with wide field of radiation or to more than 30% of the bone marrow within 4 weeks before the first dose of study intervention
  16. Major surgical procedure (excluding placement of vascular access) or significant traumatic injury within 4 weeks of the first dose of study intervention or an anticipated need for major surgery during the study
  17. 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 or 5 half-lives (whichever is longer) prior to Day 1 of dosing and withheld  throughout the study until 2 weeks after the last dose of the study intervention
  18. Herbal preparations are not allowed throughout the study.  These herbal medications include but are not limited to: St. John’s wort, kava, ephedra (ma hung), gingko biloba, DHEA, yohimbe, saw palmetto and ginseng.  Patients should stop using these herbal medications 7 days prior to first dose of study intervention.
  19. Participants with a known hypersensitivity to adavosertib, itraconazole, rifampicin, or omeprazole or any of the excipients of the products
  20. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
  21. Judgement by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions, and requirements
  22. Previous enrolment in the present study
  23. Currently pregnant (confirmed with positive pregnancy test) or breast-feeding

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City
More Info: https://clinicaltrials.gov/ct2/show/NCT04959266

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Re: MC# 21-18