A Study to Assess the Effect of Capivasertib on Midazolam in Patients With Advanced Solid Tumours

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Solid Tumour

Intervention / Treatment
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* Drug: Capivasertib
* Drug: Midazolam


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants with documented evidence of locally advanced inoperable or metastatic solid tumours who may be suitable to receive capivasertib treatment. Eastern Cooperative Oncology Group/World Health Organization performance status 0 to 1 and with minimum life expectancy for 12 weeks. Participant should have at least one lesion that can be assessed by computed tomography/magnetic resonance imaging or plain X-ray at baseline. 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: 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. Participants with diabetes mellitus type I or participants with diabetes mellitus type II requiring insulin treatment. Undergone a major surgery within 4 weeks of the first dose of capivasertib. 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. Participants with spinal cord compression or brain metastases. Participants with severe or uncontrolled systemic diseases, active bleeding diatheses, or active infection. Previous allogeneic bone marrow transplant or solid organ transplant. Known immunodeficiency syndrome.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (Midazolam + Capivasertib)<br>Midazolam will be administered on Cycle 1 Day 1 and Cycle 1 Day 8. Capivasertib will be administrated from Cycle 1 Day 2 as an intermittent schedule (4 days on/3 days off) until discontinuation. On Cycle 1 Day 12, Midazolam will be administrated with Capivasertib. | Drug: Capivasertib<br>* 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.<br>Drug: Midazolam<br>* Single doses of midazolam (syrup, 1 mg) will be given on cycle 1 Days 1, 8, and 12.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Midazolam AUCinf | Area under the plasma concentration-time curve from zero to infinity | 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) | 
| Midazolam Cmax | Maximum observed plasma (peak) drug concentration | 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) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Midazolam AUClast | Area under plasma concentration-time curve from zero to the last quantifiable concentration | 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) | 
| Midazolam t½λz | Half-life associated with terminal slope (λz) of a semilogarithmic concentration-time curve | 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) | 
| Midazolam tmax | Time to reach peak or maximum observed concentration | 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) | 
| Capivasertib Ctrough | Observed lowest drug concentration reached before the next dose is administered | Cycle 1 Day 9 and Cycle 1 Day 13 (Cycle 1 is 29 days) | 
| Capivasertib Cmax | Maximum observed plasma (peak) drug concentration | Cycle 1 Day 12 and Cycle 1 Day 13 (Cycle 1 is 29 days) | 
| Capivasertib AUCτ | Area under plasma concentration-time curve in the dose interval | Cycle 1 Day 12 and Cycle 1 Day 13 (Cycle 1 is 29 days) | 
| Capivasertib t½λz | Half-life associated with terminal slope (λz) of a semilogarithmic concentration-time curve | Cycle 1 Day 12 and Cycle 1 Day 13 (Cycle 1 is 29 days) | 
| Capivasertib tmax | Time to reach peak or maximum observed concentration | Cycle 1 Day 12 and Cycle 1 Day 13 (Cycle 1 is 29 days) | 
| Capivasertib CL/F | Apparent total body clearance of drug from plasma after extravascular administration | Cycle 1 Day 12 and Cycle 1 Day 13 (Cycle 1 is 29 days) | 
| Capivasertib metabolite AZ14102143 Ctrough | Observed lowest drug concentration reached before the next dose is administered | Cycle 1 Day 9 and Cycle 1 Day 13 (Cycle 1 is 29 days) | 
| Capivasertib metabolite AZ14102143 Cmax | Maximum observed plasma (peak) drug concentration | Cycle 1 Day 12 and Cycle 1 Day 13 (Cycle 1 is 29 days) | 
| Capivasertib metabolite AZ14102143 AUCτ | Area under plasma concentration-time curve in the dose interval | Cycle 1 Day 12 and Cycle 1 Day 13 (Cycle 1 is 29 days) | 
| Capivasertib metabolite AZ14102143 t½λz | Half-life associated with terminal slope (λz) of a semilogarithmic concentration-time curve | Cycle 1 Day 12 and Cycle 1 Day 13 (Cycle 1 is 29 days) | 
| Capivasertib metabolite AZ14102143 tmax | Time to reach peak or maximum observed concentration | Cycle 1 Day 12 and Cycle 1 Day 13 (Cycle 1 is 29 days) | 
| Number of participants with adverse events and serious adverse events | Assessment of safety and tolerability of capivasertib (with or without the use of standard of care)and in combination with midazolam. | From screening to disease progression or discontinuation from the study (up to 15 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CYP3A inhibitor, Pharmacokinetics, Safety