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

Solid Tumour Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04958226
• Other study ID #: D3614C00003
• Status: Completed
• Phase: Phase 1
• Start date: October 15, 2021
• Est. completion date: February 15, 2023

Study information

• Verified date: January 2024
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 21
• Est. completion date: February 15, 2023
• Est. primary completion date: February 6, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 130 Years

Eligibility

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.

Related Conditions & MeSH terms

• Neoplasms
• Solid Tumour

Intervention

Drug:
• Capivasertib
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.
• Midazolam
Single doses of midazolam (syrup, 1 mg) will be given on cycle 1 Days 1, 8, and 12.

Locations

Country	Name	City	State
United States	Research Site	Aurora	Colorado
United States	Research Site	Cleveland	Ohio
United States	Research Site	Dallas	Texas
United States	Research Site	Durham	North Carolina
United States	Research Site	Pittsburgh	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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	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)
Secondary	Midazolam t½?z	Half-life associated with terminal slope (?z) 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)
Secondary	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)
Secondary	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)
Secondary	Capivasertib Cmax	Maximum observed plasma (peak) drug concentration	Cycle 1 Day 12 and Cycle 1 Day 13 (Cycle 1 is 29 days)
Secondary	Capivasertib AUCt	Area under plasma concentration-time curve in the dose interval	Cycle 1 Day 12 and Cycle 1 Day 13 (Cycle 1 is 29 days)
Secondary	Capivasertib t½?z	Half-life associated with terminal slope (?z) of a semilogarithmic concentration-time curve	Cycle 1 Day 12 and Cycle 1 Day 13 (Cycle 1 is 29 days)
Secondary	Capivasertib tmax	Time to reach peak or maximum observed concentration	Cycle 1 Day 12 and Cycle 1 Day 13 (Cycle 1 is 29 days)
Secondary	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)
Secondary	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)
Secondary	Capivasertib metabolite AZ14102143 Cmax	Maximum observed plasma (peak) drug concentration	Cycle 1 Day 12 and Cycle 1 Day 13 (Cycle 1 is 29 days)
Secondary	Capivasertib metabolite AZ14102143 AUCt	Area under plasma concentration-time curve in the dose interval	Cycle 1 Day 12 and Cycle 1 Day 13 (Cycle 1 is 29 days)
Secondary	Capivasertib metabolite AZ14102143 t½?z	Half-life associated with terminal slope (?z) of a semilogarithmic concentration-time curve	Cycle 1 Day 12 and Cycle 1 Day 13 (Cycle 1 is 29 days)
Secondary	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)
Secondary	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)