NCT05538312

A Study to Understand the Effect of Itraconazole on the Levels of a Study Medicine Called ARV-471 in Healthy Adults

Completed Phase 1 Results posted Last updated 23 September 2024

What this trial tests

Phase 1 trial testing vepdegestrant in Healthy in 12 participants. Completed in 22 May 2023.

Timeline

23 February 2023

Primary endpoint
24 April 2023

22 May 2023

Quick facts

Lead sponsor	Pfizer
Phase	Phase 1
Status	Completed
Study type	INTERVENTIONAL
Allocation	na
Design	crossover
Masking	none
Primary purpose	other
Enrollment	12
Start date	23 February 2023
Primary completion	24 April 2023
Estimated completion	22 May 2023
Sites	1 location across Belgium

Drugs / interventions tested

• vepdegestrant — full drug profile →
• Itraconazole — full drug profile →

Conditions studied

• Healthy — all drugs for Healthy →

Sponsor

Pfizer — full company profile →

Who can join

Adults 18 to 65, any sex, with Healthy. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Area Under the Plasma Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUCinf) of ARV-471 Primary · Period 1 Day 1: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose; Period 2 Day 5: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours post-dose

AUCinf was defined as area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUCinf) of ARV-471. AUCinf was calculated by AUClast + (Clast/kel), where Clast was the predicted plasma concentration at the last quantifiable time point from the log-linear regression analysis and kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration time curve.

Group	Value	95% CI
Period 1: ARV-471 200 mg	18960	± 23
Period 2: ARV-471 200 mg + Itraconazole 200 mg	32020	± 24

Maximum Observed Plasma Concentration (Cmax) of ARV-471 Primary · Period 1 Day 1: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose; Period 2 Day 5: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours post-dose

Cmax was defined as maximum plasma concentration. Cmax of ARV-471 was observed directly from data.

Group	Value	95% CI
Period 1: ARV-471 200 mg	517.9	± 22
Period 2: ARV-471 200 mg + Itraconazole 200 mg	788.2	± 19

Area Under the Plasma Concentration-Time Profile From Time 0 to 120 Hours (AUC120) of ARV-473 Primary · Period 1 Day 1: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose; Period 2 Day 5: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose

ARV-473 was the epimer of ARV-471. AUC120 was defined as area under the plasma concentrationtime profile from time zero to 120 hours. AUC120 was calculate by Linear/Log trapezoidal method.

Group	Value	95% CI
Period 1: ARV-471 200 mg	4734	± 30
Period 2: ARV-471 200 mg + Itraconazole 200 mg	7668	± 28

Cmax of ARV-473 Primary · Period 1 Day 1: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose; Period 2 Day 5: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours post-dose

ARV-473 was the epimer of ARV-471. Cmax was defined as maximum plasma concentration. Cmax of ARV-473 was observed directly from data.

Group	Value	95% CI
Period 1: ARV-471 200 mg	56.37	± 26
Period 2: ARV-471 200 mg + Itraconazole 200 mg	86.31	± 27

Area Under the Plasma Concentration Time Profile From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of ARV-471 Secondary · Period 1 Day 1: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose; Period 2 Day 5: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours post-dose

AUClast was defined as area under the plasma concentrationtime profile from time zero to the time of the last quantifiable concentration (Clast). AUClast was calculated by Linear/Log trapezoidal method.

Group	Value	95% CI
Period 1: ARV-471 200 mg	16730	± 24
Period 2: ARV-471 200 mg + Itraconazole 200 mg	28710	± 21

AUC120 of ARV-471 Secondary · Period 1 Day 1: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose; Period 2 Day 5: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose

AUC120 was defined as area under the plasma concentrationtime profile from time zero to 120 hours. AUC120 was calculate by Linear/Log trapezoidal method.

Group	Value	95% CI
Period 1: ARV-471 200 mg	16730	± 24
Period 2: ARV-471 200 mg + Itraconazole 200 mg	26400	± 20

Time for Cmax (Tmax) of ARV-471 Secondary · Period 1 Day 1: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose; Period 2 Day 5: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours post-dose

Time for Cmax of ARV-471 was observed directly from data as time of first occurrence.

Group	Value	95% CI
Period 1: ARV-471 200 mg	6.00	2.00 – 8.00
Period 2: ARV-471 200 mg + Itraconazole 200 mg	6.00	4.00 – 8.00

Terminal Half-Life (t1/2) of ARV-471 Secondary · Period 1 Day 1: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose; Period 2 Day 5: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours post-dose

Terminal half-life (t1/2) was calculated by Loge(2)/kel, where kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.

Group	Value	95% CI
Period 1: ARV-471 200 mg	42.64	± 4.0800
Period 2: ARV-471 200 mg + Itraconazole 200 mg	61.57	± 9.1196

Apparent Clearance After Oral Dose (CL/F) of ARV-471 Secondary · Period 1 Day 1: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose; Period 2 Day 5: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours post-dose

CL/F was defined as apparent oral clearance and calculated by dose/AUCinf. AUCinf was defined as area under the plasma concentration-time curve from time 0 extrapolated to infinite time.

Group	Value	95% CI
Period 1: ARV-471 200 mg	10.54	± 23
Period 2: ARV-471 200 mg + Itraconazole 200 mg	6.245	± 24

Apparent Volume of Distribution After Oral Dose (Vz/F) of ARV-471 Secondary · Period 1 Day 1: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose; Period 2 Day 5: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours post-dose

Vz/F was defined as apparent volume of distribution calculated by dose/(AUCinf \* kel). AUCinf was defined as area under the plasma concentration-time curve from time 0 extrapolated to infinite time and kel was defined as the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.

Group	Value	95% CI
Period 1: ARV-471 200 mg	645.6	± 29
Period 2: ARV-471 200 mg + Itraconazole 200 mg	549.5	± 20

AUClast of ARV-473 Secondary · Period 1 Day 1: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose; Period 2 Day 5: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours post-dose

ARV-473 was the epimer of ARV-471. AUClast was defined as area under the plasma concentration-time profile from time zero to the time of the last quantifiable concentration (Clast). AUClast was calculated by Linear/Log trapezoidal method.

Group	Value	95% CI
Period 1: ARV-471 200 mg	4734	± 30
Period 2: ARV-471 200 mg + Itraconazole 200 mg	9129	± 31

Tmax of ARV-473 Secondary · Period 1 Day 1: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose; Period 2 Day 5: pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours post-dose

ARV-473 was the epimer of ARV-471. Time for Cmax of ARV-473 was observed directly from data as time of first occurrence.

Group	Value	95% CI
Period 1: ARV-471 200 mg	24.0	24.0 – 48.1
Period 2: ARV-471 200 mg + Itraconazole 200 mg	35.9	12.0 – 47.8

Adverse events — posted to ClinicalTrials.gov

Time frame: From the first dose (Day 1) up to 35 days after the last dose of study intervention (up to 52 days).. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

ARV-471 200 mg

Serious: 0/12 (0%)

Deaths: 0/12

Itraconazole 200 mg

Serious: 0/12 (0%)

Deaths: 0/12

ARV-471 200 mg + Itraconazole 200 mg

Serious: 0/12 (0%)

Deaths: 0/12

Other adverse events (7 terms — click to expand)

Reaction	System	ARV-471 200 mg	Itraconazole 200 mg	ARV-471 200 mg + Itraconaz…
Abdominal pain	Gastrointestinal disorders	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—
Gingival discomfort	Gastrointestinal disorders	—	—	—
Fatigue	General disorders	—	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—	—
Somnolence	Nervous system disorders	—	—	—
Nasal congestion	Respiratory, thoracic and mediastinal disorders	—	—	—

Data from ClinicalTrials.gov NCT05538312 adverse events section.

Sponsor's own description

The purpose of this study is to understand if a strong CYP3A4 inhibitor (itraconazole) affects how ARV-471 is processed and eliminated in healthy adults.

All participants in this study will receive one dose of ARV-471 alone by mouth in Period 1. In Period 2, everyone will receive itraconazole by mouth once a day for multiple days. Participants will also receive one dose of ARV-471 by mouth. The levels of ARV-471 in Period 1 will be compared to the levels of ARV-471 in Period 2 to determine if the CYP3A4 inhibitor affects how ARV-471 is processed differently in healthy adults.

Publications & conference data

5 peer-reviewed publications reference this trial (live from Europe PMC):

1. PROTAC Technology as a New Tool for Modern Pharmacotherapy.
   Kubryń N, Fijałkowski Ł, Nowaczyk J, Jamil A, et al · · 2025 · cited 13× · PMID 40430296 · DOI 10.3390/molecules30102123
2. Proteolysis-Targeting Chimera (PROTAC): Current Applications and Future Directions.
   Fan G, Chen S, Zhang Q, Yu N, et al · · 2025 · cited 6× · PMID 41049269 · DOI 10.1002/mco2.70401
3. The Effect of Itraconazole on the Pharmacokinetics of Vepdegestrant, a PROteolysis TArgeting Chimera Estrogen Receptor Degrader, in Healthy Adult Participants.
   Tran L, Winton JA, Matschke KT, Stouffs A, et al · · 2026 · cited 2× · PMID 41558883 · DOI 10.1016/j.clinthera.2025.12.007
4. PROTAC-based protein degradation: a window of opportunity for melanoma therapy.
   Gentile G, D'Aguanno S, Di Martile M, Petricca A, et al · · 2026 · PMID 41761284 · DOI 10.1186/s12929-026-01225-2
5. Recent advances in targeting protein degradation for tumor immunotherapy.
   Li S, Jin Y, Wu H, Yuan H, et al · · 2025 · PMID 41345706 · DOI 10.1186/s13045-025-01765-4