Study to Assess Osimertinib in Patients w/ Adv Solid Tumours & Normal Kidney Function or Severe Kidney Impairment
- Conditions
- Solid Tumours
- Interventions
- Drug: Osimertinib; AZD9291
- Registration Number
- NCT02923947
- Lead Sponsor
- AstraZeneca
- Brief Summary
The purpose of this study is to assess the effect of severe renal impairment on the levels of AZD9291 in the blood in patients with advanced solid tumours compared to patients with normal renal function
- Detailed Description
This is a 3-part study (Part A, Part B and continued access) in patients with advanced solid tumours (excluding lymphoma) that are refractory to standard therapies or for which no standard therapies exist.
Part A will have a non-randomised, open-label, parallel group, multi-centre design to investigate the pharmacokinetics (PK) of a single dose of osimertinib in patients with severe renal impairment compared with patients with normal renal function. Patients with severe renal impairment will be recruited before those with normal renal function to allow the cohorts to be matched as closely as possible in terms of demographic characteristics (ie, age, body mass index \[BMI\] and sex).
Approximately 16 patients (8 with severe renal impairment and 8 with normal renal function) are planned to be enrolled to obtain at least 12 evaluable patients (6 with severe renal impairment and 6 with normal renal function) in Part A. A patient with severe renal impairment (as measured by the Cockcroft-Gault equation) is defined as having a creatinine clearance (CrCl) of \<30 mL/min whilst a patient with normal renal function has a CrCl of ≥90 mL/min. Both the severe renal impairment and normal renal function patients will be recruited such that both groups will be matched for age, sex, and BMI to the maximum extent possible.
In Part A, each patient will receive a single oral dose of osimertinib 80 mg (given as a tablet). Where possible, patients will check into the clinic on Day -1, the evening prior to dosing (Day 1), and remain resident until 24 hours after the dose of osimertinib (Day 2) for collection of blood samples and 24-hour pooled urine for PK analysis during this time. Samples will be analysed to determine the concentrations of osimertinib and metabolites (AZ5104 and AZ7550) in plasma, urine, and plasma ultrafiltrate (PUF). Patients will then return to the clinic as outpatients for assessments on Day 3 (48 hours), Day 4 (72 hours), Day 6 (120 hours), Day 8 (168 hours) and Day 10 (216 hours).
Part B will allow patients with severe renal impairment, who complete Part A, to continue to receive osimertinib 80 mg once daily for 12 weeks and will provide additional safety data. Patients should start Part B after the last PK sample collected in Part A (ie, 216 hours after receiving the single dose of osimertinib in Part A).
If a patient does not immediately continue into Part B, this should be discussed on a case by case basis with the AstraZeneca physician or representative. Patients who enter Part B, will have weekly clinic visits for the first 3 weeks; thereafter visits will be every 3 weeks until Week 12. Safety assessments will be collected and there will be no formal evaluation of efficacy.
At the end of Part B, those patients with severe renal impairment who are deemed to be gaining clinical benefit from osimertinib will enter the continued access phase. Patients with normal renal function can enter the continued access phase immediately after completing Part A (ie, collection of the last PK sample scheduled on Day 10 of Part A). During the continued access phase, patients may continue to take osimertinib 80 mg once daily, if patients and the Investigator deem it appropriate, or until such time as their disease progresses, the Investigator believes the patients are no longer deriving clinical benefit, or patients stop taking osimertinib for any other reason. No clinical data, other than serious adverse events (SAEs) that may be related to the investigational product (IP), will be collected during this phase.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 16
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Normal renal function Osimertinib; AZD9291 For inclusion in the study as a patient with normal renal function, patients must have creatinine clearance ≥90 mL/min. Severe renal impairment Osimertinib; AZD9291 For inclusion in the study as a patient with severe renal impairment, patients must have stable severe renal impairment (creatinine clearance \<30 mL/min), as defined by the Cockcroft Gault equation, for at least 2 months prior to Day 1.
- Primary Outcome Measures
Name Time Method Area under the plasma concentration-time curve from zero to infinity for osimertinib On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168, 216hrs post-dose Part A: To investigate the PK of osimertinib after a single oral dose of 80 mg in patients with advanced solid tumours and normal renal function or severe renal impairment.
Maximum plasma concentration for osimertinib On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168, 216hrs post-dose Part A: To investigate the PK of osimertinib after a single oral dose of 80 mg in patients with advanced solid tumours and normal renal function or severe renal impairment.
- Secondary Outcome Measures
Name Time Method Apparent volume of distribution for osimertinib On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168, 216hrs for osimertinib post-dose Part A: To investigate the PK of osimertinib and metabolites (AZ5104 and AZ7550) after a single oral dose of 80 mg in patients with advanced solid tumours and normal renal function or severe renal impairment.
Time to maximum plasma concentration for AZ7550 On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168, 216hrs for osimertinib post-dose Part A: To investigate the PK of osimertinib and metabolites (AZ5104 and AZ7550) after a single oral dose of 80 mg in patients with advanced solid tumours and normal renal function or severe renal impairment.
Terminal rate constant for AZ7550 On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168, 216hrs for osimertinib post-dose Part A: To investigate the PK of osimertinib and metabolites (AZ5104 and AZ7550) after a single oral dose of 80 mg in patients with advanced solid tumours and normal renal function or severe renal impairment.
Time to maximum plasma concentration for osimertinib On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168, 216hrs for osimertinib post-dose Part A: To investigate the PK of osimertinib and metabolites (AZ5104 and AZ7550) after a single oral dose of 80 mg in patients with advanced solid tumours and normal renal function or severe renal impairment.
Terminal rate constant for osimertinib On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168, 216hrs for osimertinib post-dose Part A: To investigate the PK of osimertinib and metabolites (AZ5104 and AZ7550) after a single oral dose of 80 mg in patients with advanced solid tumours and normal renal function or severe renal impairment.
Amount excreted in urine from time zero to 24 hours post-dose for osimertinib On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24hrs for osimertinib post-dose Part A: To investigate the PK of osimertinib and metabolites (AZ5104 and AZ7550) after a single oral dose of 80 mg in patients with advanced solid tumours and normal renal function or severe renal impairment.
Maximum plasma concentration for AZ7550 On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168, 216hrs for osimertinib post-dose Part A: To investigate the PK of osimertinib and metabolites (AZ5104 and AZ7550) after a single oral dose of 80 mg in patients with advanced solid tumours and normal renal function or severe renal impairment.
Area under the plasma concentration-time curve from zero to the last quantifiable time point for AZ7550 On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168, 216hrs for osimertinib post-dose Part A: To investigate the PK of osimertinib and metabolites (AZ5104 and AZ7550) after a single oral dose of 80 mg in patients with advanced solid tumours and normal renal function or severe renal impairment.
Metabolite to parent ratios for area under the plasma concentration time curve from zero to infinity On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168, 216hrs for osimertinib post-dose Part A: To investigate the PK of osimertinib and metabolites (AZ5104 and AZ7550) after a single oral dose of 80 mg in patients with advanced solid tumours and normal renal function or severe renal impairment.
Area under the plasma concentration-time curve from zero to the last quantifiable time point for osimertinib On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168, 216hrs for osimertinib post-dose Part A: To investigate the PK of osimertinib and metabolites (AZ5104 and AZ7550) after a single oral dose of 80 mg in patients with advanced solid tumours and normal renal function or severe renal impairment.
Apparent clearance following oral administration for osimertinib On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168, 216hrs for osimertinib post-dose Part A: To investigate the PK of osimertinib and metabolites (AZ5104 and AZ7550) after a single oral dose of 80 mg in patients with advanced solid tumours and normal renal function or severe renal impairment.
Renal clearance for osimertinib On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24hrs post-dose for osimertinib plasma and 24 hour urine collection. Part A: To investigate the PK of osimertinib and metabolites (AZ5104 and AZ7550) after a single oral dose of 80 mg in patients with advanced solid tumours and normal renal function or severe renal impairment.
Maximum plasma concentration for AZ5104 On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168, 216hrs for osimertinib post-dose Part A: To investigate the PK of osimertinib and metabolites (AZ5104 and AZ7550) after a single oral dose of 80 mg in patients with advanced solid tumours and normal renal function or severe renal impairment.
Time to maximum plasma concentration for AZ5104 On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168, 216hrs for osimertinib post-dose Part A: To investigate the PK of osimertinib and metabolites (AZ5104 and AZ7550) after a single oral dose of 80 mg in patients with advanced solid tumours and normal renal function or severe renal impairment.
Area under the plasma concentration time curve from zero to infinity for AZ7550 On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168, 216hrs for osimertinib post-dose Part A: To investigate the PK of osimertinib and metabolites (AZ5104 and AZ7550) after a single oral dose of 80 mg in patients with advanced solid tumours and normal renal function or severe renal impairment.
Amount excreted in urine from time zero to 24 hours post-dose for AZ5104 24 hour pooled collection starting from time of dosing on Day 1 Part A: To investigate the PK of osimertinib and metabolites (AZ5104 and AZ7550) after a single oral dose of 80 mg in patients with advanced solid tumours and normal renal function or severe renal impairment.
Amount excreted in urine from time zero to 24 hours post-dose for AZ7550 24 hour pooled collection starting from time of dosing on Day 1 Part A: To investigate the PK of osimertinib and metabolites (AZ5104 and AZ7550) after a single oral dose of 80 mg in patients with advanced solid tumours and normal renal function or severe renal impairment.
Terminal rate constant for AZ5104 On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168, 216hrs for osimertinib post-dose Part A: To investigate the PK of osimertinib and metabolites (AZ5104 and AZ7550) after a single oral dose of 80 mg in patients with advanced solid tumours and normal renal function or severe renal impairment.
Renal clearance for AZ7550 On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24 hours post-dose for AZ7550 plasma and 24 hour urine collection. Part A: To investigate the PK of osimertinib and metabolites (AZ5104 and AZ7550) after a single oral dose of 80 mg in patients with advanced solid tumours and normal renal function or severe renal impairment.
Part A: evaluation of laboratory Until 30 days following the final dose of osimertinib Part A: To investigate the safety and tolerability of a single oral dose of osimertinib in patients with advanced solid tumours and normal renal function or severe renal impairment.
Area under the plasma concentration-time curve from zero to 24 hours post-dose for osimertinib On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24hrs for osimertinib post-dose Part A: To investigate the PK of osimertinib and metabolites (AZ5104 and AZ7550) after a single oral dose of 80 mg in patients with advanced solid tumours and normal renal function or severe renal impairment.
Terminal half-life for osimertinib On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168, 216hrs for osimertinib post-dose Part A: To investigate the PK of osimertinib and metabolites (AZ5104 and AZ7550) after a single oral dose of 80 mg in patients with advanced solid tumours and normal renal function or severe renal impairment.
Area under the plasma concentration-time curve from zero to the last quantifiable time point for AZ5104 On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168, 216hrs for osimertinib post-dose Part A: To investigate the PK of osimertinib and metabolites (AZ5104 and AZ7550) after a single oral dose of 80 mg in patients with advanced solid tumours and normal renal function or severe renal impairment.
Terminal half-life for AZ7550 On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168, 216hrs for osimertinib post-dose Part A: To investigate the PK of osimertinib and metabolites (AZ5104 and AZ7550) after a single oral dose of 80 mg in patients with advanced solid tumours and normal renal function or severe renal impairment.
Renal clearance for AZ5104 On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24hrs post-dose for AZ5104 plasma and 24 hour urine collection. Part A: To investigate the PK of osimertinib and metabolites (AZ5104 and AZ7550) after a single oral dose of 80 mg in patients with advanced solid tumours and normal renal function or severe renal impairment.
Part A: physical exam Until 30 days following the final dose of osimertinib Part A: To investigate the safety and tolerability of a single oral dose of osimertinib in patients with advanced solid tumours and normal renal function or severe renal impairment.
Part A: vital signs Until 30 days following the final dose of osimertinib Part A: To investigate the safety and tolerability of a single oral dose of osimertinib in patients with advanced solid tumours and normal renal function or severe renal impairment.
Part B - ECG Until 30 days following the final dose of osimertinib Part B: To investigate the safety and tolerability of multiple oral doses of osimertinib in patients with advanced solid tumours and severe renal impairment.
Area under the plasma concentration time curve from zero to infinity for AZ5104 On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168, 216hrs for osimertinib post-dose Part A: To investigate the PK of osimertinib and metabolites (AZ5104 and AZ7550) after a single oral dose of 80 mg in patients with advanced solid tumours and normal renal function or severe renal impairment.
Terminal half-life for AZ5104 On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168, 216hrs for osimertinib post-dose Part A: To investigate the PK of osimertinib and metabolites (AZ5104 and AZ7550) after a single oral dose of 80 mg in patients with advanced solid tumours and normal renal function or severe renal impairment.
Part A: echocardiogram/MUGA. Until 30 days following the final dose of osimertinib Part A: To investigate the safety and tolerability of a single oral dose of osimertinib in patients with advanced solid tumours and normal renal function or severe renal impairment.
Part B - Adverse events, graded CTCAE v4.0 Until 30 days following the final dose of osimertinib Part B: To investigate the safety and tolerability of multiple oral doses of osimertinib in patients with advanced solid tumours and severe renal impairment.
Part B - vital signs Until 30 days following the final dose of osimertinib Part B: To investigate the safety and tolerability of multiple oral doses of osimertinib in patients with advanced solid tumours and severe renal impairment.
Metabolite to parent ratios for maximum plasma concentration On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168, 216hrs for osimertinib post-dose Part A: To investigate the PK of osimertinib and metabolites (AZ5104 and AZ7550) after a single oral dose of 80 mg in patients with advanced solid tumours and normal renal function or severe renal impairment.
Part A: Adverse Events's, graded by the National Cancer Institute Common Terminology Criteria for Adverse Event's (CTCAE v4.0) Until 30 days following the final dose of osimertinib Part A: To investigate the safety and tolerability of a single oral dose of osimertinib in patients with advanced solid tumours and normal renal function or severe renal impairment.
Part B - evaluation of laboratory parameters. Until 30 days following the final dose of osimertinib Part B: To investigate the safety and tolerability of multiple oral doses of osimertinib in patients with advanced solid tumours and severe renal impairment.
Part A: ECG Until 30 days following the final dose of osimertinib Part A: To investigate the safety and tolerability of a single oral dose of osimertinib in patients with advanced solid tumours and normal renal function or severe renal impairment.
Part B -physical exam Until 30 days following the final dose of osimertinib Part B: To investigate the safety and tolerability of multiple oral doses of osimertinib in patients with advanced solid tumours and severe renal impairment.
Trial Locations
- Locations (1)
Research Site
🇪🇸Sevilla, Spain