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NCT02317016

Study to Assess the Effect of AZD9291 on the Blood Levels of Rosuvastatin, in Patients With EGFRm+ Non-small Cell Lung Cancer

Completed Phase 1 Results posted Last updated 31 July 2018
What this trial tests

Phase 1 trial testing Pharmacokinetic sampling - AZD9291 in Non Small Cell Lung Cancer in 44 participants. Completed in 22 May 2018.

Timeline
10 March 2015
Primary endpoint
11 July 2015
22 May 2018

Quick facts

Lead sponsorAstraZeneca
PhasePhase 1
StatusCompleted
Study typeINTERVENTIONAL
Allocationna
Designsingle group
Maskingnone
Primary purposetreatment
Enrollment44
Start date10 March 2015
Primary completion11 July 2015
Estimated completion22 May 2018
Sites13 locations across France, United Kingdom, United States, Spain

Drugs / interventions tested

Conditions studied

Sponsor

AstraZeneca — full company profile →

Who can join

Adults 18 to 99, any sex, with Non Small Cell Lung Cancer. 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.

Assessment of Maximum Plasma Concentration (Cmax) for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291 Primary · Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.

Rate and extent of absorption of rosuvastatin by assessment of Cmax. Single rosuvastatin doses were first without, then with AZD9291 (Day 1 \[Period 1\] and Day 32 \[Period 3\], respectively).

GroupValue95% CI
Rosuvastatin Alone (Period 1 [Day 1])13.96± 66.7
AZD9291 + Rosuvastatin (Period 3 [Day 32])24.03± 70.5
Assessment of AUC From Time Zero Extrapolated to Infinity for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291 Primary · Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.

Rate and extent of absorption of rosuvastatin by assessment of AUC from time zero extrapolated to infinity. Single rosuvastatin doses were first without, then with AZD9291 (Day 1; Period 1 and Day 32; Period 3, respectively).

GroupValue95% CI
Rosuvastatin Alone (Period 1 [Day 1])139.1± 49.0
AZD9291 + Rosuvastatin (Period 3 [Day 32])185.7± 60.9
Assessment of Time to Maximum Plasma Concentration (Tmax) for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291 Secondary · Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.

Rate and extent of absorption of rosuvastatin by assessment of tmax. Single rosuvastatin doses were first without, then with AZD9291 (Day 1; Period 1 and Day 32; Period 3, respectively).

GroupValue95% CI
Rosuvastatin Alone (Period 1 [Day 1])2.050.48 – 5.95
AZD9291 + Rosuvastatin (Period 3 [Day 32])2.070.47 – 6.00
Assessment of Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration at Time "t" (AUC0-t) for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291 Secondary · Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.

Rate and extent of absorption of rosuvastatin by assessment of AUC0-t. Single rosuvastatin doses were first without, then with AZD9291 (Day 1; Period 1 and Day 32; Period 3, respectively).

GroupValue95% CI
Rosuvastatin Alone (Period 1 [Day 1])130.6± 51.1
AZD9291 + Rosuvastatin (Period 3 [Day 32])183.7± 58.3
Assessment of Apparent Plasma Clearance (CL/F) for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291 Secondary · Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.

Rate and extent of absorption of rosuvastatin by assessment of CL/F. Single rosuvastatin doses were first without, then with AZD9291 (Day 1; Period 1 and Day 32; Period 3, respectively).

GroupValue95% CI
Rosuvastatin Alone (Period 1 [Day 1])143.8± 49.0
AZD9291 + Rosuvastatin (Period 3 [Day 32])107.7± 60.9
Assessment of Apparent Volume of Distribution (Vz/F) for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291 Secondary · Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.

Rate and extent of absorption of rosuvastatin by assessment of Vz/F. Single rosuvastatin doses were first without, then with AZD9291 (Day 1; Period 1 and Day 32; Period 3, respectively).

GroupValue95% CI
Rosuvastatin Alone (Period 1 [Day 1])3890± 65.0
AZD9291 + Rosuvastatin (Period 3 [Day 32])2874± 77.9
Assessment of Terminal Elimination Half-life (t1/2[lambda_z]) for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291 Secondary · Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.

Rate and extent of absorption of rosuvastatin by assessment of t1/2(lambda\_z). Single rosuvastatin doses were first without, then with AZD9291 (Day 1; Period 1 and Day 32; Period 3, respectively).

GroupValue95% CI
Rosuvastatin Alone (Period 1 [Day 1])18.75± 29.5
AZD9291 + Rosuvastatin (Period 3 [Day 32])18.51± 37.4
Assessment of Area Under the Plasma Concentration-time Curve During the Dosing Interval (AUCtau) for AZD9291, and AZ5104 and AZ7550 (Metabolites) Following Administration of AZD9291 and Rosuvastatin Together Secondary · Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.

Rate and extent of absorption for AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of AUCtau. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).

AZD9291 AUCtau
GroupValue95% CI
AZD9291 + Rosuvastatin (Period 3 [Day 32])15800± 45.0
AZ5104 AUCtau
GroupValue95% CI
AZD9291 + Rosuvastatin (Period 3 [Day 32])1655± 62.1
AZ7550 AUCtau
GroupValue95% CI
AZD9291 + Rosuvastatin (Period 3 [Day 32])1418± 44.7
Assessment of Maximum Plasma Concentration at Steady State (Css,Max) for AZD9291, and AZ5104 and AZ7550 (Metabolites) Following Administration of AZD9291 and Rosuvastatin Together Secondary · Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.

Rate and extent of absorption for AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of Css,max after multiple dosing. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).

AZD9291 Css,max
GroupValue95% CI
AZD9291 + Rosuvastatin (Period 3 [Day 32])897.9± 47.2
AZ5104 Css,max
GroupValue95% CI
AZD9291 + Rosuvastatin (Period 3 [Day 32])86.20± 60.3
AZ7550 Css,max
GroupValue95% CI
AZD9291 + Rosuvastatin (Period 3 [Day 32])73.73± 47.3
Assessment of Time to Reach Maximum Plasma Concentration at Steady State (Tss,Max) for AZD9291, and AZ5104 and AZ7550 (Metabolites) Following Administration of AZD9291 and Rosuvastatin Together Secondary · Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.

Rate and extent of absorption for AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of tss,max after multiple dosing. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).

AZD9291 tss,max
GroupValue95% CI
AZD9291 + Rosuvastatin (Period 3 [Day 32])5.002.00 – 8.17
AZ5104 tss,max
GroupValue95% CI
AZD9291 + Rosuvastatin (Period 3 [Day 32])5.000.50 – 24.33
AZ7550 tss,max
GroupValue95% CI
AZD9291 + Rosuvastatin (Period 3 [Day 32])5.051.50 – 12.05
Assessment of Minimum Plasma Concentration at Steady State (Css,Min) for AZD9291, and AZ5104 and AZ7550 (Metabolites) Following Administration of AZD9291 and Rosuvastatin Together Secondary · Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.

Rate and extent of absorption for AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of Css,min over the dosing interval. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).

AZD9291 Css,min
GroupValue95% CI
AZD9291 + Rosuvastatin (Period 3 [Day 32])485.6± 47.3
AZ5104 Css, min
GroupValue95% CI
AZD9291 + Rosuvastatin (Period 3 [Day 32])54.60± 63.6
AZ7550 Css, min
GroupValue95% CI
AZD9291 + Rosuvastatin (Period 3 [Day 32])46.46± 46.3
Assessment of Apparent Plasma Clearance at Steady State (CLss/F) for AZD9291 Following Administration of AZD9291 and Rosuvastatin Together Secondary · Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.

Rate and extent of absorption for AZD9291 by assessment of CLss/F after multiple dosing. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).

GroupValue95% CI
AZD9291 + Rosuvastatin (Period 3 [Day 32])10.14± 45.0

Adverse events — posted to ClinicalTrials.gov

Time frame: Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined).. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Overall Safety Population
Serious: 7/44 (16%)
Deaths:
Part A Safety Population
Serious: 2/44 (5%)
Deaths:
Part B Safety Population
Serious: 6/42 (14%)
Deaths:

Serious adverse events (9 terms)

ReactionSystemOverall Safety PopulationPart A Safety PopulationPart B Safety Population
Gastrooesophageal reflux diseaseGastrointestinal disorders
FatigueGeneral disorders
PneumoniaInfections and infestations
Pneumonia pseudomonalInfections and infestations
Blood creatine phosphokinase increasedInvestigations
Transaminases increasedInvestigations
Transient ischaemic attackNervous system disorders
Chronic obstructive pulmonary diseaseRespiratory, thoracic and mediastinal disorders
Pleural effusionRespiratory, thoracic and mediastinal disorders
Other adverse events (32 terms — click to expand)

ReactionSystemOverall Safety PopulationPart A Safety PopulationPart B Safety Population
Decreased appetiteMetabolism and nutrition disorders
DiarrhoeaGastrointestinal disorders
DyspnoeaRespiratory, thoracic and mediastinal disorders
CoughRespiratory, thoracic and mediastinal disorders
AstheniaGeneral disorders
FatigueGeneral disorders
NauseaGastrointestinal disorders
ConstipationGastrointestinal disorders
ArthralgiaMusculoskeletal and connective tissue disorders
PyrexiaGeneral disorders
ParonychiaInfections and infestations
Back painMusculoskeletal and connective tissue disorders
HeadacheNervous system disorders
Dry skinSkin and subcutaneous tissue disorders
Muscle spasmsMusculoskeletal and connective tissue disorders
Musculoskeletal painMusculoskeletal and connective tissue disorders
Neck painMusculoskeletal and connective tissue disorders
Pain in extremityMusculoskeletal and connective tissue disorders
Dermatitis acneiformSkin and subcutaneous tissue disorders
AnaemiaBlood and lymphatic system disorders
RhinitisInfections and infestations
Urinary tract infectionInfections and infestations
InsomniaPsychiatric disorders
VomitingGastrointestinal disorders
Blood creatine phosphokinase increasedInvestigations
VertigoEar and labyrinth disorders
Dry eyeEye disorders
Abdominal painGastrointestinal disorders
StomatitisGastrointestinal disorders
XerosisGeneral disorders
EpistaxisRespiratory, thoracic and mediastinal disorders
Palmar-plantar erythrodysaesthesia syndromeSkin and subcutaneous tissue disorders

Most-reported serious reactions: Gastrooesophageal reflux disease, Fatigue, Pneumonia, Pneumonia pseudomonal, Blood creatine phosphokinase increased, Transaminases increased, Transient ischaemic attack, Chronic obstructive pulmonary disease.

Data from ClinicalTrials.gov NCT02317016 adverse events section.

Sponsor's own description

This is a Phase I, open-label, 2-part study in patients with a confirmed diagnosis of epidermal growth factor receptor (EGFR) mutation positive (EGFRm+) non-small cell lung cancer (NSCLC), who have progressed following prior therapy with an approved EGFR tyrosine kinase inhibitor (TKI) agent. Part A will assess the effect of AZD9291 on the pharmacokinetic (PK) parameters of rosuvastatin, following multiple oral dosing of AZD9291 in the fasted state. Part B will allow patients further access to AZD9291 after the PK phase (Part A) and will provide for additional safety data collection. All patients from Part A who completed treatment may continue to receive AZD9291 80 mg once daily as a single agent until: disease progression; they are no longer deriving clinical benefit; or any other reason.

Publications & conference data

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

  1. Inflammation and tumor progression: signaling pathways and targeted intervention.
    Zhao H, Wu L, Yan G, Chen Y, et al · · 2021 · cited 1932× · PMID 34248142 · DOI 10.1038/s41392-021-00658-5
  2. Drug repurposing for cancer therapy.
    Xia Y, Sun M, Huang H, Jin WL. · · 2024 · cited 229× · PMID 38637540 · DOI 10.1038/s41392-024-01808-1
  3. Development, Verification, and Prediction of Osimertinib Drug-Drug Interactions Using PBPK Modeling Approach to Inform Drug Label.
    Pilla Reddy V, Walker M, Sharma P, Ballard P, et al · · 2018 · cited 48× · PMID 29468841 · DOI 10.1002/psp4.12289
  4. Effect of multiple-dose osimertinib on the pharmacokinetics of simvastatin and rosuvastatin.
    Harvey RD, Aransay NR, Isambert N, Lee JS, et al · · 2018 · cited 27× · PMID 30171779 · DOI 10.1111/bcp.13753
  5. Novel Effects of Statins on Cancer via Autophagy.
    Mengual D, Medrano LE, Villamizar-Villamizar W, Osorio-Llanes E, et al · · 2022 · cited 15× · PMID 35745567 · DOI 10.3390/ph15060648
  6. Erratum: Development, Verification, and Prediction of Osimertinib Drug-Drug Interactions Using PBPK Modeling Approach to Inform Drug Label.
    · 2019 · PMID 30901159 · DOI 10.1002/psp4.12386

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Other trials of Pharmacokinetic sampling - AZD9291

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Drug Landscape aggregates and links these public records for informational use only. Always verify against the primary source before clinical or regulatory decisions. Canonical URL: https://druglandscape.com/trial/NCT02317016.

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