Solid Tumour
Conditions
Keywords
CYP3A inhibitor, Pharmacokinetics, Safety
Brief summary
This is an open-label, fixed-sequence study to evaluate the effect of capivasertib on the pharmacokinetics (PK) of midazolam, a sensitive CYP3A substrate. The PK of midazolam will be assessed when administered alone and in combination with repeated doses of capivasertib.
Detailed description
This is 2 part study: Part A and Part B. Part A of the study consists of a screening period and 3 treatment periods (midazolam alone, capivasertib alone, and midazolam + capivasertib). During Part A, the PK profile of midazolam will be determined with and without capivasertib.All participants will receive capivasertib treatment (4 days on/3 days off); however, at the Investigator's discretion, ER positive breast cancer patients may also receive fulvestrant in addition to capivasertib and midazolam. Participants completing Part A without disease progression or unacceptable toxicity, who are considered likely to continue to benefit from further capivasertib treatment (with or without certain standard of care treatment) in the opinion of the Investigator will enter Part B. Part B of the study consists of an extended treatment period with capivasertib, with or without certain standard of care treatment, followed by a 30-day safety follow-up. Part A of the study may be extended to allow the administration of midazolam on a rescheduled Cycle 1 Day 8(C1D8) and Cycle 1 Day 12(C1D12 ) visit.
Interventions
DRUGCapivasertib
Capivasertib (tablet) will be given as an intermittent schedule (4 days on/3 days off) from Cycle 1 Day 2 until discontinuation. Capivasertib will be administrated in both Part A and Part B.
DRUGMidazolam
Single doses of midazolam (syrup, 1 mg) will be given on cycle 1 Days 1, 8, and 12.
Sponsors
AstraZeneca
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
1. Participants with documented evidence of locally advanced inoperable or metastatic solid tumours who may be suitable to receive capivasertib treatment. 2. Eastern Cooperative Oncology Group/World Health Organization performance status 0 to 1 and with minimum life expectancy for 12 weeks. 3. Participant should have at least one lesion that can be assessed by computed tomography/magnetic resonance imaging or plain X-ray at baseline. 4. Body mass index within the range 18 to 32 kg/m\^2
Exclusion criteria
Participants are excluded from the study if any of the following criteria apply: 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. Participants with diabetes mellitus type I or participants with diabetes mellitus type II requiring insulin treatment. 3. Undergone a major surgery within 4 weeks of the first dose of capivasertib. 4. Any unresolved toxicities 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. 5. Participants with spinal cord compression or brain metastases. 6. Participants with severe or uncontrolled systemic diseases, active bleeding diatheses, or active infection. 7. Previous allogeneic bone marrow transplant or solid organ transplant. 8. Known immunodeficiency syndrome.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Midazolam AUCinf | Cycle 1 Day 1, Cycle 1 Day 2, Cycle 1 Day 8, Cycle 1 Day 9, Cycle 1 Day 12 and Cycle 1 Day 13 (Cycle 1 is 29 days) | Area under the plasma concentration-time curve from zero to infinity |
| Midazolam Cmax | Cycle 1 Day 1, Cycle 1 Day 2, Cycle 1 Day 8, Cycle 1 Day 9, Cycle 1 Day 12 and Cycle 1 Day 13 (Cycle 1 is 29 days) | Maximum observed plasma (peak) drug concentration |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Capivasertib metabolite AZ14102143 t½λz | Cycle 1 Day 12 and Cycle 1 Day 13 (Cycle 1 is 29 days) | Half-life associated with terminal slope (λz) of a semilogarithmic concentration-time curve |
| Midazolam AUClast | Cycle 1 Day 1, Cycle 1 Day 2, Cycle 1 Day 8, Cycle 1 Day 9, Cycle 1 Day 12 and Cycle 1 Day 13 (Cycle 1 is 29 days) | Area under plasma concentration-time curve from zero to the last quantifiable concentration |
| Midazolam t½λz | Cycle 1 Day 1, Cycle 1 Day 2, Cycle 1 Day 8, Cycle 1 Day 9, Cycle 1 Day 12 and Cycle 1 Day 13 (Cycle 1 is 29 days) | Half-life associated with terminal slope (λz) of a semilogarithmic concentration-time curve |
| Midazolam tmax | Cycle 1 Day 1, Cycle 1 Day 2, Cycle 1 Day 8, Cycle 1 Day 9, Cycle 1 Day 12 and Cycle 1 Day 13 (Cycle 1 is 29 days) | Time to reach peak or maximum observed concentration |
| Capivasertib Ctrough | Cycle 1 Day 9 and Cycle 1 Day 13 (Cycle 1 is 29 days) | Observed lowest drug concentration reached before the next dose is administered |
| Capivasertib Cmax | Cycle 1 Day 12 and Cycle 1 Day 13 (Cycle 1 is 29 days) | Maximum observed plasma (peak) drug concentration |
| Capivasertib metabolite AZ14102143 tmax | Cycle 1 Day 12 and Cycle 1 Day 13 (Cycle 1 is 29 days) | Time to reach peak or maximum observed concentration |
| Capivasertib t½λz | Cycle 1 Day 12 and Cycle 1 Day 13 (Cycle 1 is 29 days) | Half-life associated with terminal slope (λz) of a semilogarithmic concentration-time curve |
| Capivasertib tmax | Cycle 1 Day 12 and Cycle 1 Day 13 (Cycle 1 is 29 days) | Time to reach peak or maximum observed concentration |
| Capivasertib CL/F | Cycle 1 Day 12 and Cycle 1 Day 13 (Cycle 1 is 29 days) | Apparent total body clearance of drug from plasma after extravascular administration |
| Capivasertib metabolite AZ14102143 Ctrough | Cycle 1 Day 9 and Cycle 1 Day 13 (Cycle 1 is 29 days) | Observed lowest drug concentration reached before the next dose is administered |
| Capivasertib metabolite AZ14102143 Cmax | Cycle 1 Day 12 and Cycle 1 Day 13 (Cycle 1 is 29 days) | Maximum observed plasma (peak) drug concentration |
| Number of participants with adverse events and serious adverse events | From screening to disease progression or discontinuation from the study (up to 15 months) | Assessment of safety and tolerability of capivasertib (with or without the use of standard of care)and in combination with midazolam. |
| Capivasertib AUCτ | Cycle 1 Day 12 and Cycle 1 Day 13 (Cycle 1 is 29 days) | Area under plasma concentration-time curve in the dose interval |
| Capivasertib metabolite AZ14102143 AUCτ | Cycle 1 Day 12 and Cycle 1 Day 13 (Cycle 1 is 29 days) | Area under plasma concentration-time curve in the dose interval |
Countries
United States
Outcome results
None listed