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

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

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.

Study Overview

• Status: Completed
• Conditions: Solid Tumour
• Intervention / Treatment: Drug: Capivasertib; Drug: Midazolam

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.

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Research Site
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Research Site
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Research Site
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • Research Site
  • Texas
    • Dallas, Texas, United States, 75251
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 130 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (Midazolam + Capivasertib); 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; 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.; Drug: Midazolam; Single doses of midazolam (syrup, 1 mg) will be given on cycle 1 Days 1, 8, and 12.

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: AstraZeneca

Study record dates

Study Major Dates

• Study Start (Actual): October 15, 2021
• Primary Completion (Actual): February 6, 2023
• Study Completion (Actual): February 15, 2023

Study Registration Dates

• First Submitted: July 1, 2021
• First Submitted That Met QC Criteria: July 1, 2021
• First Posted (Actual): July 12, 2021

Study Record Updates

• Last Update Posted (Estimated): January 25, 2024
• Last Update Submitted That Met QC Criteria: January 24, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Safety; Pharmacokinetics; CYP3A inhibitor
• Additional Relevant MeSH Terms: Neoplasms; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Midazolam
• Other Study ID Numbers: D3614C00003

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No