MC# 21-30 - An Open-label, Fixed-sequence Study to Assess the Effect of Repeated Doses of Capivasertib on the Pharmacokinetics of Oral Midazolam (a CYP450 3A Probe) in Patients With Advanced Solid Tumours

  • Agent(s): Capivasertib
  • Disease Type(s): Solid Tumor
  • Phase(s): I
  • Drug Classification(s): Small Molecule, Targeted Therapy
  • Molecular Target(s): AKT, MTOR, PI3K

Mechanism of Action

Capivasertib binds to and inhibits all AKT isoforms.  Inhibition of AKT prevents the phosphorylation of AKT substrates that mediate cellular processes, such as cell division, apoptosis, and glucose and fatty acid metabolism.  A wide range of solid and hematological malignancies show dysregulated PI3K/AKT/mTOR signaling due to mutations in multiple signaling components.


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

  • The effects of Capivasertib (good and bad) alone and in combination with Midazolam
  • How much of Capivasertib is absorbed into the blood and how fast it is removed alone and in combination with Midazolam
  • How Capivasertib is acting on your body
Inclusion Criteria
  1. Patient must be at least 18 years of age inclusive, at the time of signing the informed consent
  2. Patients with documented evidence of locally advanced inoperable or metastatic solid tumours, who may be suitable for capivasertib treatment. Note: Patients harbouring any of the following mutations as determined by local testing, will be eligible for capivasertib monotherapy or capivasertib in combination with standard of care treatment, at the Investigator’s discretion in Part B. Patients who do not harbour any of these mutations (or where the mutation status is unknown) are recommended receive capivasertib in addition to standard of care treatment in Part B, at the Investigator’s discretion.
    1. activating mutations, indels or gene amplifications in PIK3CA, AKT1, AKT2, or AKT3
    2. deleterious mutations, gene deletions, or protein deficiency of PTEN
    3. deleterious mutations in PIK3R1, PIK3R2, INPP4A, INPP4B, PHLPP1, or PHLPP2
  3. Eastern Cooperative Oncology Group/World Health Organization performance status 0 to 1 with no deterioration over the previous 2 weeks and minimum life expectancy of 12 weeks, as assessed at Day -1
  4. At least one lesion (measurable and/or non-measurable) that can be accurately assessed at baseline by CT/MRI or plain X-ray and is suitable for repeated assessment
  5. Body mass index within the range 18 to 32 kg/m2 (inclusive)
  6. Male and female patients
  7. Women of childbearing potential must either abstain from sexual activity with male partners or be willing to use 2 forms of highly effective methods of contraception from the time of screening until 4 weeks after discontinuing study intervention.  OR  Patients must have evidence of an inability to bear children by fulfilling 1 of the following criteria at screening:
    1. Post-menopausal – defined as aged > 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments
    2. Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy, but not tubal ligation
  8. Female patients must not be breastfeeding and women of childbearing potential must have a negative pregnancy test prior to start of dosing
  9. Male patients must use barrier contraception (ie, condoms) or abstain from sexual activity with female partners from the time of screening until 16 weeks after discontinuation of study drug
  10. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol
  11. Provision of signed and dated, written ICF prior to any mandatory study specific procedures, sampling and analyses
  12. 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. Radiotherapy with a wide field of radiation within 4 weeks of the first dose of capivasertib and/or radiotherapy with a limited field of radiation for palliation within 2 weeks prior to study intervention initiation
  2. Major surgery (excluding placement of vascular access) within 4 weeks of the first dose of capivasertib
  3. Any unresolved toxicity from prior therapies higher than CTCAE grade 2 or any unresolved toxicity that may interfere with PK assessment at the time of study intervention initiation
  4. Spinal cord compression or brain metastases unless asymptomatic, treated and stable and not requiring steroids for at least 4 weeks before the first dose of capivasertib
  5. Any of the following cardiac criteria at screening:
    1. Mean resting QTc > 470 ms obtained from 3 consecutive ECGs
    2. Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (eg, complete left bundle branch block, third degree heart block)
    3. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, potential for Torsades de Pointes, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age or any concomitant medication known to prolong the QT interval
    4. Experience of any of the following procedures or conditions in the preceding months: coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, angina pectoris, congestive heart failure NYHA Grade ≥ 2
    5. Uncontrolled hypotension – SBP < 90 mmHg and/or DBP < 50 mmHg
    6. Cardiac ejection fraction outside institutional range of normal or < 50% (whichever is higher) as measured by ECHO (or MUGA scan if an ECHO cannot be performed or is inconclusive)
  6. Clinically significant abnormalities of glucose metabolism as defined by any of the following at screening:
    1. Patients with diabetes mellitus type I or patients with diabetes mellitus type II requiring insulin treatment
    2. HbA1c >7.5% (58.5 mmol/mol)
  7. Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values:
    1. Absolute neutrophil count < 1.5 × 109/L
    2. Platelet count < 100 × 109/L
    3. Haemoglobin < 9 g/dL (< 5.59 mmol/L)
    4. Note: any blood transfusion must be > 14 days prior to the determination of a haemoglobin ≥ 9 g/dL (≥ 5.59 mmol/L)
    5. Alanine aminotransferase and AST > 2.5 × ULN if no demonstrable liver metastases or > 5 × ULN in the presence of liver metastases.  Elevated ALP is not exclusionary if due to the presence of bone metastasis and liver function is otherwise considered adequate in the Investigator’s judgement
    6. Total bilirubin > 1.5 × ULN (patients with confirmed Gilbert’s syndrome may be included in the study)
    7. Creatinine > 1.5 × ULN concurrent with creatinine clearance <50 mL/min (measured or calculated by Cockcroft and Gault equation); confirmation of creatinine clearance is only required when creatinine is > 1.5 × ULN
  8. As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diatheses, or clinically significant active infection including hepatitis B, hepatitis C, HIV, and COVID-19.  Screening for chronic conditions is not required.
  9. Known history of drug or alcohol abuse within 2 years of screening, as judged by the Investigator
  10. Known immunodeficiency syndrome
  11. Previous allogeneic bone marrow transplant or solid organ transplant
  12. Evidence of dementia, altered mental status or any psychiatric condition that would prohibit understanding or rendering of informed consent
  13. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that, in the Investigator’s opinion, gives reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, may affect the interpretation of the results, render the patient at high risk from treatment complications or interferes with obtaining informed consent
  14. Refractory nausea and vomiting, malabsorption syndrome, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection, or other condition that would preclude adequate absorption of capivasertib
  15. Prior treatment with any of the following:
    1. Nitrosourea or mitomycin C within 6 weeks of the first dose of study intervention
    2. Any investigational agents or study drugs from a previous clinical study within 30 days of the first dose of study intervention
    3. Any chemotherapy, immunotherapy, immunosuppressant medication (other than corticosteroids), or anticancer agents other than hormonal therapy with LHRH analogues (in patients with breast or prostate cancer) within 2 weeks or 5 half-lives of the first dose of study intervention, whichever is longer
    4. Potent and moderate inhibitors or inducers of CYP3A4 within 2 weeks (or 5 half-lives, whichever is longer) prior to the first dose of study intervention (3 weeks for St John’s wort, and 4 weeks for enzalutamide), or sensitive substrates of CYP3A4, with a narrow therapeutic window within 1 week prior to the first dose of study intervention
    5. 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 1st dose of midazolam
  16. Participation in another clinical study with an IMP administered in the last 30 days or 5 half-lives, whichever is longer
  17. History of hypersensitivity to active or inactive excipients of capivasertib or drugs with a similar chemical structure or class to capivasertib
  18. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
  19. 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
  20. Currently pregnant (confirmed with positive pregnancy test) or breastfeeding
  21. 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 study intervention


  • Dallas, TX - Mary Crowley Cancer Research - Medical City
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Re: MC# 21-30