Clinical trial NCT04958226: A Study to Assess the Effect of Capivasertib on Midazolam in Patients With Advanced Solid Tumours
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Solid Tumour
Keywords: CYP3A inhibitor
Pharmacokinetics
Safety
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2021-07-12
Enrollment: 21
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Midazolam AUCinf
timeFrame: 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)
measure: Midazolam Cmax
timeFrame: 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 outcomes:
measure: Midazolam AUClast
timeFrame: 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)
measure: Midazolam t½λz
timeFrame: 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)
measure: Midazolam tmax
timeFrame: 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)
measure: Capivasertib Ctrough
timeFrame: Cycle 1 Day 9 and Cycle 1 Day 13 (Cycle 1 is 29 days)
measure: Capivasertib Cmax
timeFrame: Cycle 1 Day 12 and Cycle 1 Day 13 (Cycle 1 is 29 days)
measure: Capivasertib AUCτ
timeFrame: Cycle 1 Day 12 and Cycle 1 Day 13 (Cycle 1 is 29 days)
measure: Capivasertib t½λz
timeFrame: Cycle 1 Day 12 and Cycle 1 Day 13 (Cycle 1 is 29 days)
measure: Capivasertib tmax
timeFrame: Cycle 1 Day 12 and Cycle 1 Day 13 (Cycle 1 is 29 days)
measure: Capivasertib CL/F
timeFrame: Cycle 1 Day 12 and Cycle 1 Day 13 (Cycle 1 is 29 days)
measure: Capivasertib metabolite AZ14102143 Ctrough
timeFrame: Cycle 1 Day 9 and Cycle 1 Day 13 (Cycle 1 is 29 days)
measure: Capivasertib metabolite AZ14102143 Cmax
timeFrame: Cycle 1 Day 12 and Cycle 1 Day 13 (Cycle 1 is 29 days)
measure: Capivasertib metabolite AZ14102143 AUCτ
timeFrame: Cycle 1 Day 12 and Cycle 1 Day 13 (Cycle 1 is 29 days)
measure: Capivasertib metabolite AZ14102143 t½λz
timeFrame: Cycle 1 Day 12 and Cycle 1 Day 13 (Cycle 1 is 29 days)
measure: Capivasertib metabolite AZ14102143 tmax
timeFrame: Cycle 1 Day 12 and Cycle 1 Day 13 (Cycle 1 is 29 days)
measure: Number of participants with adverse events and serious adverse events
timeFrame: From screening to disease progression or discontinuation from the study (up to 15 months)
Other outcomes:
Locations:
city: Aurora
country: United States
facility: Research Site
state: Colorado
city: Durham
country: United States
facility: Research Site
state: North Carolina
city: Cleveland
country: United States
facility: Research Site
state: Ohio
city: Pittsburgh
country: United States
facility: Research Site
state: Pennsylvania
city: Dallas
country: United States
facility: Research Site
state: Texas
Study officials:
References: