Study to assess Osimertinib in patients w/ adv solid tumours & normal kidney function or severe kidney impairment

Study identifier:D5160C00035

ClinicalTrials.gov identifier:NCT02923947

EudraCT identifier:2016-002564-14

CTIS identifier:N/A

Study Complete

Official Title

Open-label,Non-randomised,Multicentre,Phase I study to assess the Pharmacokinetics, Safety & Tolerability of Osimertinib Following a Single Oral 80mg Dose to Patients w/ Adv Solid Tumours & Normal Renal Function or Severe Renal Impairment.

Medical condition

Solid tumours

Phase

Phase 1

Healthy volunteers

Study drug

Osimertinib; AZD9291

Sex

All

Actual Enrollment

Study type

Interventional

Age

18 Years - 130 Years

Date

Study Start Date: 04 May 2017

Primary Completion Date: 20 Sept 2018

Study Completion Date: 28 Oct 2022

Study design

Allocation: Non-randomized
Endpoint Classification: Pharmacokinetics
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment

Verification:

Verified 01 Nov 2023 by AstraZeneca

Collaborators

Quintiles

Inclusion and exclusion criteria

Inclusion Criteria

:
1. For inclusion as a patient with severe renal impairment patient must have stable severe renal impairment (CrCl <30 mL/min at screening), for at least 2 months prior to the study.
2. For inclusion as a patient with normal renal function, patient must have CrCl ≥90 mL/min at screening.
3. >18 years old
4. Histological or cytological confirmation of a solid, malignant tumour (excluding lymphoma) that is refractory to standard therapies or for which no standard therapies exist. Tumours in which inhibition of the EGFR pathway is considered relevant by the Investigator are not mandated but are encouraged.
5. ECOG performance status ≤2
6. Life expectancy of ≥12 weeks
7. BMI 18-35.
8. Females should be using adequate contraceptive measures and must have a negative pregnancy test prior to dosing if of child-bearing potential or must have evidence of non-child bearing potential
9. Males should use barrier contraception until 6 months after the last study drug is taken.

Exclusion Criteria

1. Participation in another clinical study with an IP during the last 14 days (or a longer period, depending on the agents used).
2. Treatment with any of the following:
- Treatment with a 1st or 2nd generation EGFR-TKI within 8 days or approximately 5 half-lives, prior to the first dose of study drug.
- Any cytotoxic chemotherapy, investigational agents or anticancer drugs within 14 days of the first dose of study drug.
- Osimertinib in the present study or has previously received a 3rd generation EGFR-TKI (eg, CO 1686).
- Major surgery within 4 weeks of the first dose of study drug.
- Radiotherapy with a limited field of radiation for palliation within 1 week of the first dose of study treatment
- Currently receiving medications or herbal supplements known to be potent inducers of CYP3A4. Patients in Part B and continued access must avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known potent inducer effects on CYP3A4.
3. Patients with severe renal impairment only: use of concurrent medication known to affect CrCl within 7 days of the first dose
4. Unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of starting study treatment; with the exception of alopecia and Grade 2 prior platinum-therapy related neuropathy
5. Spinal cord compression or brain metastases, unless asymptomatic, stable and not requiring steroids for at least 4 weeks prior to start of study treatment
6. Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values:
- Absolute neutrophil count <1.5 x 109/L
- Platelet count <100 x 109/L
- Haemoglobin <90 g/L
- ALT >2.5 times the ULN if no demonstrable liver metastases or >5xULN in the presence of liver metastases
- AST >2.5xULN if no demonstrable liver metastases or > 5xULN in the presence of liver metastases
- Total bilirubin >1.5 times ULN if no liver metastases or >3xULN in the presence of liver metastases
7. Any of the following cardiac criteria:
- Mean resting QT interval QTcF >470 msec, obtained from 3 ECGs.
- Abnormalities in rhythm, conduction or morphology of resting ECG
- Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age or any concomitant medication known to prolong the QT interval
8. Unable to swallow oral medication or patients with GI disorders or significant GI resection.
9. Medical history of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD.
10. Severe portal hypertension or surgical porto-systemic shunts.
11. Kidney transplant
12. On dialysis

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.

Location

Research Site

Saint Herblain, France, 44805

Location

Research Site

Madrid, Spain, 28050

Location

Research Site

Sevilla, Spain, 41013

Location

Research Site

Dijon, France, 21079

Location

Research Site

Seoul, Republic of Korea, 03080

Location

Research Site

Seoul, Republic of Korea, 05505

Location

Research Site

Madrid, Spain, 28040

Location

Research Site

Bordeaux, France, 33000

Arms	Assigned Interventions
Experimental: Normal renal function For inclusion in the study as a patient with normal renal function, patients must have creatinine clearance ≥90 mL/min.	Drug: Osimertinib; AZD9291 80mg tablet dose to be taken orally – single dose in part A, daily dosing in Part B and continued access until progression or no longer receiving benefit Other Name: TAGRISSO™
Experimental: Severe renal impairment 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.	Drug: Osimertinib; AZD9291 80mg tablet dose to be taken orally – single dose in part A, daily dosing in Part B and continued access until progression or no longer receiving benefit Other Name: TAGRISSO™

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
First patient enrolled: 04May17; Last patient last visit Part A: 20Sep18; Part B: 10May18. Study performed at 12 sites in Europe and Asia. Part A assessed effect of severe renal impairment on pharmacokinetics (PK) of osimertinib (AZD9291) after single oral dosing; Part B allowed patients with severe renal impairment further access to osimertinib.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Patients with advanced solid tumours that were refractory to standard therapies or for which no standard therapies exist were enrolled and assigned to either the normal renal function group or severe renal impairment group (defined as having a creatinine clearance of <30 millilitres per minute, as measured by the Cockcroft-Gault equation).

Reporting Groups

	Description
Normal renal function	Patients with normal renal function received a single oral dose of 80 milligrams (mg) osimertinib on Day 1 in Part A of the study. Patients in the normal renal function group did not enter Part B but could enter the continued access phase immediately after completing Part A to receive osimertinib 80 mg orally once daily for the duration of their participation.
Severe renal impairment	Patients with severe renal impairment received a single oral dose of 80 mg osimertinib on Day 1 in Part A of the study.

Participant Flow for 2 periods

Period 1: Part A: Day 1-10 (PK phase)

	Normal renal function	Severe renal impairment
STARTED	9	7
Received treatment	9	7
PK analysis set	8	7
COMPLETED	7^[1]	6^[2]
NOT COMPLETED	2	1
Death	1	0
Progressive disease	1	0
Physician Decision	0	1

[1]	Entered continued access
[2]	Entered Part B

Period 2: Part B: Day 10 to end Part B

	Normal renal function	Severe renal impairment
STARTED	0^[1]	6
COMPLETED	0	3^[2]
NOT COMPLETED	0	3
Adverse Event	0	1
Progressive disease	0	1
Physician Decision	0	1

[1]	Patients in the normal renal function group did not enter Part B of the study.
[2]	Entered continued access

Baseline Characteristics

Analysis Population Description -- Explanation of how the number of participants for analysis was determined.

All patients in the safety analysis set who received at least one dose of osimertinib were included in the baseline analysis.

Reporting Groups

	Description
Normal renal function	Patients with normal renal function received a single oral dose of 80 mg osimertinib on Day 1 in Part A of the study. Patients in the normal renal function group did not enter Part B but could enter the continued access phase immediately after completing Part A to receive osimertinib 80 mg orally once daily for the duration of their participation.
Severe renal impairment	Patients with severe renal impairment received a single oral dose of 80 mg osimertinib on Day 1 in Part A of the study.

Baseline Measures

	Normal renal function	Severe renal impairment	Total
Number of Participants [units: Participants]	9	7	16
Age Continuous [units: Years] Mean ± Standard Deviation	64.0 ± 4.33	74.9 ± 7.86	68.8 ± 8.10
Sex: Female, Male [units: Participants]
Female	4	4	8
Male	5	3	8
Race/Ethnicity, Customized ^[1] [units: Participants]
White	4	5	9
Asian	2	2	4
Unknown	3	0	3
Ethnicity (NIH/OMB) [units: Participants]
Hispanic or Latino	0	0	0
Not Hispanic or Latino	6	7	13
Unknown or Not Reported	3	0	3

Outcome Measures

1. Primary Outcome Measure: Area under the plasma concentration-time curve from zero to infinity (AUC) for osimertinib [ Time Frame: Blood samples were collected on Days 1 to 10 (pre-dose, and at 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168 and 216 hours post-dose) in Part A of the study. ]

Measure Type	Primary
Measure Name	Area under the plasma concentration-time curve from zero to infinity (AUC) for osimertinib
Measure Description	Assessment of AUC for osimertinib following administration of osimertinib as a single oral dose.
Time Frame	Blood samples were collected on Days 1 to 10 (pre-dose, and at 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168 and 216 hours post-dose) in Part A of the study.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK analysis set included all patients who received an osimertinib dose and had at least 1 post-dose quantifiable plasma osimertinib or metabolite (AZ5104 or AZ7550) concentration without important protocol deviations/violations or events thought to significantly affect the PK. Only patients with data available for analysis are presented.

Reporting Groups

	Description
Normal renal function	Patients with normal renal function received a single oral dose of 80 mg osimertinib on Day 1 in Part A of the study.
Severe renal impairment	Patients with severe renal impairment received a single oral dose of 80 mg osimertinib on Day 1 in Part A of the study.

Measured Values

	Normal renal function	Severe renal impairment
Number of Participants Analyzed [units:participants]	8	7
Area under the plasma concentration-time curve from zero to infinity (AUC) for osimertinib [units: nanomolar * hour (nM*h)] Geometric Mean (Geometric Coefficient of Variation)	11070 (87.5%)	20460 (69.4%)

Statistical Analysis 1 for Area under the plasma concentration-time curve from zero to infinity (AUC) for osimertinib

Groups^[1]	All groups
Other^[5]	184.78
90% Confidence Interval	( 93.85 to 363.80 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Natural log-transformed AUC values were compared between renal function groups using an analysis of variance (ANOVA) model, with renal function group as a fixed effect. LS = least-squares.
[5]	Other relevant estimation information:
	Severe versus Normal

2. Primary Outcome Measure: Maximum plasma concentration (Cmax) for osimertinib [ Time Frame: Blood samples were collected on Days 1 to 10 (pre-dose, and at 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168 and 216 hours post-dose) in Part A of the study. ]

Measure Type	Primary
Measure Name	Maximum plasma concentration (Cmax) for osimertinib
Measure Description	Assessment of Cmax for osimertinib following administration of osimertinib as a single oral dose.
Time Frame	Blood samples were collected on Days 1 to 10 (pre-dose, and at 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168 and 216 hours post-dose) in Part A of the study.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK analysis set included all patients who received an osimertinib dose and had at least 1 post-dose quantifiable plasma osimertinib or metabolite (AZ5104 or AZ7550) concentration without important protocol deviations/violations or events thought to significantly affect the PK.

Reporting Groups

	Description
Normal renal function	Patients with normal renal function received a single oral dose of 80 mg osimertinib on Day 1 in Part A of the study.
Severe renal impairment	Patients with severe renal impairment received a single oral dose of 80 mg osimertinib on Day 1 in Part A of the study.

Measured Values

	Normal renal function	Severe renal impairment
Number of Participants Analyzed [units:participants]	8	7
Maximum plasma concentration (Cmax) for osimertinib [units: nM] Geometric Mean (Geometric Coefficient of Variation)	195.5 (57.7%)	233.4 (74.8%)

Statistical Analysis 1 for Maximum plasma concentration (Cmax) for osimertinib

Groups^[1]	All groups
Other^[5]	119.36
90% Confidence Interval	( 68.88 to 206.85 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Natural log-transformed Cmax values were compared between renal function groups using an ANOVA model, with renal function group as a fixed effect.
[5]	Other relevant estimation information:
	Severe versus Normal

3. Secondary Outcome Measure: AUC for osimertinib metabolites, AZ5104 and AZ7550 [ Time Frame: Blood samples were collected on Days 1 to 10 (pre-dose, and at 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168 and 216 hours post-dose) in Part A of the study. ]

Measure Type	Secondary
Measure Name	AUC for osimertinib metabolites, AZ5104 and AZ7550
Measure Description	Assessment of AUC for metabolites of osimertinib (AZ5104 and AZ7550) following administration of osimertinib as a single oral dose.
Time Frame	Blood samples were collected on Days 1 to 10 (pre-dose, and at 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168 and 216 hours post-dose) in Part A of the study.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK analysis set included all patients who received an osimertinib dose and had at least 1 post-dose quantifiable plasma osimertinib or metabolite (AZ5104 or AZ7550) concentration without important protocol deviations/violations or events thought to significantly affect the PK. Only patients with data available for analysis are presented.

Reporting Groups

	Description
Normal renal function	Patients with normal renal function received a single oral dose of 80 mg osimertinib on Day 1 in Part A of the study.
Severe renal impairment	Patients with severe renal impairment received a single oral dose of 80 mg osimertinib on Day 1 in Part A of the study.

Measured Values

	Normal renal function	Severe renal impairment
Number of Participants Analyzed [units:participants]	8	7
AUC for osimertinib metabolites, AZ5104 and AZ7550 [units: nM*h] Geometric Mean (Geometric Coefficient of Variation)
AZ5104	1202 (79.7%)	1953 (68.7%)
AZ7550	563.0 (28.1%)	417.7 (17.8%)

Statistical Analysis 1 for AUC for osimertinib metabolites, AZ5104 and AZ7550

Groups^[1]	All groups
Other^[5]	162.46
90% Confidence Interval	( 81.51 to 323.77 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Natural log-transformed AUC values for AZ5104 were compared between renal function groups using an ANOVA model, with renal function group as a fixed effect.
[5]	Other relevant estimation information:
	Severe versus Normal

Statistical Analysis 2 for AUC for osimertinib metabolites, AZ5104 and AZ7550

Groups^[1]	All groups
Other^[5]	74.20
90% Confidence Interval	( 52.98 to 103.91 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Natural log-transformed AUC values for AZ7550 were compared between renal function groups using an ANOVA model, with renal function group as a fixed effect.
[5]	Other relevant estimation information:
	Severe versus Normal

4. Secondary Outcome Measure: Cmax for osimertinib metabolites, AZ5104 and AZ7550 [ Time Frame: Blood samples were collected on Days 1 to 10 (pre-dose, and at 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168 and 216 hours post-dose) in Part A of the study. ]

Measure Type	Secondary
Measure Name	Cmax for osimertinib metabolites, AZ5104 and AZ7550
Measure Description	Assessment of Cmax for metabolites of osimertinib (AZ5104 and AZ7550) following administration of osimertinib as a single oral dose.
Time Frame	Blood samples were collected on Days 1 to 10 (pre-dose, and at 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168 and 216 hours post-dose) in Part A of the study.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK analysis set included all patients who received an osimertinib dose and had at least 1 post-dose quantifiable plasma osimertinib or metabolite (AZ5104 or AZ7550) concentration without important protocol deviations/violations or events thought to significantly affect the PK.

Reporting Groups

	Description
Normal renal function	Patients with normal renal function received a single oral dose of 80 mg osimertinib on Day 1 in Part A of the study.
Severe renal impairment	Patients with severe renal impairment received a single oral dose of 80 mg osimertinib on Day 1 in Part A of the study.

Measured Values

	Normal renal function	Severe renal impairment
Number of Participants Analyzed [units:participants]	8	7
Cmax for osimertinib metabolites, AZ5104 and AZ7550 [units: nM] Geometric Mean (Geometric Coefficient of Variation)
AZ5104	10.15 (59.0%)	8.763 (76.6%)
AZ7550	4.556 (47.9%)	2.618 (58.9%)

Statistical Analysis 1 for Cmax for osimertinib metabolites, AZ5104 and AZ7550

Groups^[1]	All groups
Other^[5]	86.32
90% Confidence Interval	( 49.29 to 151.16 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Natural log-transformed Cmax values for AZ5104 were compared between renal function groups using an ANOVA model, with renal function group as a fixed effect.
[5]	Other relevant estimation information:
	Severe versus Normal

Statistical Analysis 2 for Cmax for osimertinib metabolites, AZ5104 and AZ7550

Groups^[1]	All groups
Other^[5]	57.46
90% Confidence Interval	( 36.38 to 90.78 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Natural log-transformed Cmax values for AZ7550 were compared between renal function groups using an ANOVA model, with renal function group as a fixed effect.
[5]	Other relevant estimation information:
	Severe versus Normal

5. Secondary Outcome Measure: Area under the plasma concentration-time curve from time zero to the last quantifiable time point (AUC0-t) for osimertinib and metabolites (AZ5104 and AZ7550) [ Time Frame: Blood samples were collected on Days 1 to 10 (pre-dose, and at 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168 and 216 hours post-dose) in Part A of the study. ]

Measure Type	Secondary
Measure Name	Area under the plasma concentration-time curve from time zero to the last quantifiable time point (AUC0-t) for osimertinib and metabolites (AZ5104 and AZ7550)
Measure Description	Assessment of AUC0-t for osimertinib and metabolites (AZ5104 and AZ7550) following administration of osimertinib as a single oral dose.
Time Frame	Blood samples were collected on Days 1 to 10 (pre-dose, and at 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168 and 216 hours post-dose) in Part A of the study.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK analysis set included all patients who received an osimertinib dose and had at least 1 post-dose quantifiable plasma osimertinib or metabolite (AZ5104 or AZ7550) concentration without important protocol deviations/violations or events thought to significantly affect the PK.

Reporting Groups

	Description
Normal renal function	Patients with normal renal function received a single oral dose of 80 mg osimertinib on Day 1 in Part A of the study.
Severe renal impairment	Patients with severe renal impairment received a single oral dose of 80 mg osimertinib on Day 1 in Part A of the study.

Measured Values

	Normal renal function	Severe renal impairment
Number of Participants Analyzed [units:participants]	8	7
Area under the plasma concentration-time curve from time zero to the last quantifiable time point (AUC0-t) for osimertinib and metabolites (AZ5104 and AZ7550) [units: nM*h] Geometric Mean (Geometric Coefficient of Variation)
Osimertinib	10370 (82.3%)	16610 (70.2%)
AZ5104	1058 (69.6%)	1295 (70.3%)
AZ7550	561.8 (41.6%)	378.9 (63.2%)

Statistical Analysis 1 for Area under the plasma concentration-time curve from time zero to the last quantifiable time point (AUC0-t) for osimertinib and metabolites (AZ5104 and AZ7550)

Groups^[1]	All groups
Other^[5]	160.07
90% Confidence Interval	( 85.78 to 298.72 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Natural log-transformed AUC0-t values for osimertinib were compared between renal function groups using an ANOVA model, with renal function group as a fixed effect.
[5]	Other relevant estimation information:
	Severe versus Normal

Statistical Analysis 2 for Area under the plasma concentration-time curve from time zero to the last quantifiable time point (AUC0-t) for osimertinib and metabolites (AZ5104 and AZ7550)

Groups^[1]	All groups
Other^[5]	122.39
90% Confidence Interval	( 68.64 to 218.24 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Natural log-transformed AUC0-t values for AZ5104 were compared between renal function groups using an ANOVA model, with renal function group as a fixed effect.
[5]	Other relevant estimation information:
	Severe versus Normal

Statistical Analysis 3 for Area under the plasma concentration-time curve from time zero to the last quantifiable time point (AUC0-t) for osimertinib and metabolites (AZ5104 and AZ7550)

Groups^[1]	All groups
Other^[5]	67.45
90% Confidence Interval	( 43.01 to 105.77 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Natural log-transformed AUC0-t values for AZ7550 were compared between renal function groups using an ANOVA model, with renal function group as a fixed effect.
[5]	Other relevant estimation information:
	Severe versus Normal

6. Secondary Outcome Measure: Area under the plasma concentration-time curve from time zero to 24 hours post-dose (AUC0-24) for osimertinib and metabolites (AZ5104 and AZ7550) [ Time Frame: Blood samples were collected on Days 1 to 10 (pre-dose, and at 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168 and 216 hours post-dose) in Part A of the study. ]

Measure Type	Secondary
Measure Name	Area under the plasma concentration-time curve from time zero to 24 hours post-dose (AUC0-24) for osimertinib and metabolites (AZ5104 and AZ7550)
Measure Description	Assessment of AUC0-24 for osimertinib and metabolites (AZ5104 and AZ7550) following administration of osimertinib as a single oral dose.
Time Frame	Blood samples were collected on Days 1 to 10 (pre-dose, and at 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168 and 216 hours post-dose) in Part A of the study.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK analysis set included all patients who received an osimertinib dose and had at least 1 post-dose quantifiable plasma osimertinib or metabolite (AZ5104 or AZ7550) concentration without important protocol deviations/violations or events thought to significantly affect the PK.

Reporting Groups

	Description
Normal renal function	Patients with normal renal function received a single oral dose of 80 mg osimertinib on Day 1 in Part A of the study.
Severe renal impairment	Patients with severe renal impairment received a single oral dose of 80 mg osimertinib on Day 1 in Part A of the study.

Measured Values

	Normal renal function	Severe renal impairment
Number of Participants Analyzed [units:participants]	8	7
Area under the plasma concentration-time curve from time zero to 24 hours post-dose (AUC0-24) for osimertinib and metabolites (AZ5104 and AZ7550) [units: nM*h] Geometric Mean (Geometric Coefficient of Variation)
Osimertinib	3109 (67.4%)	4129 (84.8%)
AZ5104	162.7 (47.1%)	146.5 (58.3%)
AZ7550	79.94 (44.8%)	45.44 (62.5%)

No statistical analysis provided for Area under the plasma concentration-time curve from time zero to 24 hours post-dose (AUC0-24) for osimertinib and metabolites (AZ5104 and AZ7550)

7. Secondary Outcome Measure: Time to reach maximum plasma concentration (tmax) for osimertinib and metabolites (AZ5104 and AZ7550) [ Time Frame: Blood samples were collected on Days 1 to 10 (pre-dose, and at 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168 and 216 hours post-dose) in Part A of the study. ]

Measure Type	Secondary
Measure Name	Time to reach maximum plasma concentration (tmax) for osimertinib and metabolites (AZ5104 and AZ7550)
Measure Description	Assessment of tmax for osimertinib and metabolites (AZ5104 and AZ7550) following administration of osimertinib as a single oral dose.
Time Frame	Blood samples were collected on Days 1 to 10 (pre-dose, and at 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168 and 216 hours post-dose) in Part A of the study.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK analysis set included all patients who received an osimertinib dose and had at least 1 post-dose quantifiable plasma osimertinib or metabolite (AZ5104 or AZ7550) concentration without important protocol deviations/violations or events thought to significantly affect the PK.

Reporting Groups

	Description
Normal renal function	Patients with normal renal function received a single oral dose of 80 mg osimertinib on Day 1 in Part A of the study.
Severe renal impairment	Patients with severe renal impairment received a single oral dose of 80 mg osimertinib on Day 1 in Part A of the study.

Measured Values

	Normal renal function	Severe renal impairment
Number of Participants Analyzed [units:participants]	8	7
Time to reach maximum plasma concentration (tmax) for osimertinib and metabolites (AZ5104 and AZ7550) [units: hours] Median (Full Range)
Osimertinib	5.03 (2.00 to 6.05)	6.00 (4.00 to 10.07)
AZ5104	35.92 (6.00 to 48.42)	24.17 (24.00 to 49.33)
AZ7550	24.04 (9.92 to 71.75)	24.30 (6.00 to 72.83)

No statistical analysis provided for Time to reach maximum plasma concentration (tmax) for osimertinib and metabolites (AZ5104 and AZ7550)

8. Secondary Outcome Measure: Apparent plasma clearance following oral administration (CL/F) for osimertinib [ Time Frame: Blood samples were collected on Days 1 to 10 (pre-dose, and at 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168 and 216 hours post-dose) in Part A of the study. ]

Measure Type	Secondary
Measure Name	Apparent plasma clearance following oral administration (CL/F) for osimertinib
Measure Description	Assessment of CL/F for osimertinib following administration of osimertinib as a single oral dose.
Time Frame	Blood samples were collected on Days 1 to 10 (pre-dose, and at 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168 and 216 hours post-dose) in Part A of the study.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK analysis set included all patients who received an osimertinib dose and had at least 1 post-dose quantifiable plasma osimertinib or metabolite (AZ5104 or AZ7550) concentration without important protocol deviations/violations or events thought to significantly affect the PK. Only patients with data available for analysis are presented.

Reporting Groups

	Description
Normal renal function	Patients with normal renal function received a single oral dose of 80 mg osimertinib on Day 1 in Part A of the study.
Severe renal impairment	Patients with severe renal impairment received a single oral dose of 80 mg osimertinib on Day 1 in Part A of the study.

Measured Values

	Normal renal function	Severe renal impairment
Number of Participants Analyzed [units:participants]	8	7
Apparent plasma clearance following oral administration (CL/F) for osimertinib [units: Litres per hour (L/h)] Mean (Standard Deviation)	17.87 (10.60)	9.241 (6.079)

No statistical analysis provided for Apparent plasma clearance following oral administration (CL/F) for osimertinib

9. Secondary Outcome Measure: Apparent volume of distribution (Vz/F) for osimertinib [ Time Frame: Blood samples were collected on Days 1 to 10 (pre-dose, and at 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168 and 216 hours post-dose) in Part A of the study. ]

Measure Type	Secondary
Measure Name	Apparent volume of distribution (Vz/F) for osimertinib
Measure Description	Assessment of Vz/F for osimertinib following administration of osimertinib as a single oral dose.
Time Frame	Blood samples were collected on Days 1 to 10 (pre-dose, and at 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168 and 216 hours post-dose) in Part A of the study.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK analysis set included all patients who received an osimertinib dose and had at least 1 post-dose quantifiable plasma osimertinib or metabolite (AZ5104 or AZ7550) concentration without important protocol deviations/violations or events thought to significantly affect the PK. Only patients with data available for analysis are presented.

Reporting Groups

	Description
Normal renal function	Patients with normal renal function received a single oral dose of 80 mg osimertinib on Day 1 in Part A of the study.
Severe renal impairment	Patients with severe renal impairment received a single oral dose of 80 mg osimertinib on Day 1 in Part A of the study.

Measured Values

	Normal renal function	Severe renal impairment
Number of Participants Analyzed [units:participants]	8	7
Apparent volume of distribution (Vz/F) for osimertinib [units: Litres] Mean (Standard Deviation)	1159 (573.9)	951.3 (581.8)

No statistical analysis provided for Apparent volume of distribution (Vz/F) for osimertinib

10. Secondary Outcome Measure: Terminal rate constant (λz) for osimertinib and metabolites (AZ5104 and AZ7550) [ Time Frame: Blood samples were collected on Days 1 to 10 (pre-dose, and at 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168 and 216 hours post-dose) in Part A of the study. ]

Measure Type	Secondary
Measure Name	Terminal rate constant (λz) for osimertinib and metabolites (AZ5104 and AZ7550)
Measure Description	Assessment of λz for osimertinib and metabolites (AZ5104 and AZ7550) following administration of osimertinib as a single oral dose.
Time Frame	Blood samples were collected on Days 1 to 10 (pre-dose, and at 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168 and 216 hours post-dose) in Part A of the study.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK analysis set included all patients who received an osimertinib dose and had at least 1 post-dose quantifiable plasma osimertinib or metabolite (AZ5104 or AZ7550) concentration without important protocol deviations/violations or events thought to significantly affect the PK. Only patients with data available for analysis are presented.

Reporting Groups

	Description
Normal renal function	Patients with normal renal function received a single oral dose of 80 mg osimertinib on Day 1 in Part A of the study.
Severe renal impairment	Patients with severe renal impairment received a single oral dose of 80 mg osimertinib on Day 1 in Part A of the study.

Measured Values

	Normal renal function	Severe renal impairment
Number of Participants Analyzed [units:participants]	8	7
Terminal rate constant (λz) for osimertinib and metabolites (AZ5104 and AZ7550) [units: 1/h] Mean (Standard Deviation)
Osimertinib	0.014894 (0.0036852)	0.010032 (0.0018674)
AZ5104	0.012823 (0.0040847)	0.0097610 (0.0022986)
AZ7550	0.010347 (0.0029315)	0.0084164 (0.0010357)

No statistical analysis provided for Terminal rate constant (λz) for osimertinib and metabolites (AZ5104 and AZ7550)

11. Secondary Outcome Measure: Terminal half-life (t1/2λz) for osimertinib and metabolites (AZ5104 and AZ7550) [ Time Frame: Blood samples were collected on Days 1 to 10 (pre-dose, and at 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168 and 216 hours post-dose) in Part A of the study. ]

Measure Type	Secondary
Measure Name	Terminal half-life (t1/2λz) for osimertinib and metabolites (AZ5104 and AZ7550)
Measure Description	Assessment of t1/2λz for osimertinib and metabolites (AZ5104 and AZ7550) following administration of osimertinib as a single oral dose.
Time Frame	Blood samples were collected on Days 1 to 10 (pre-dose, and at 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168 and 216 hours post-dose) in Part A of the study.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK analysis set included all patients who received an osimertinib dose and had at least 1 post-dose quantifiable plasma osimertinib or metabolite (AZ5104 or AZ7550) concentration without important protocol deviations/violations or events thought to significantly affect the PK. Only patients with data available for analysis are presented.

Reporting Groups

	Description
Normal renal function	Patients with normal renal function received a single oral dose of 80 mg osimertinib on Day 1 in Part A of the study.
Severe renal impairment	Patients with severe renal impairment received a single oral dose of 80 mg osimertinib on Day 1 in Part A of the study.

Measured Values

	Normal renal function	Severe renal impairment
Number of Participants Analyzed [units:participants]	8	6
Terminal half-life (t1/2λz) for osimertinib and metabolites (AZ5104 and AZ7550) [units: hours] Mean (Standard Deviation)
Osimertinib	49.29 (13.02)	71.38 (14.81)
AZ5104	59.00 (18.17)	74.33 (17.83)
AZ7550	71.11 (18.15)	83.15 (9.630)

No statistical analysis provided for Terminal half-life (t1/2λz) for osimertinib and metabolites (AZ5104 and AZ7550)

12. Secondary Outcome Measure: Amount excreted in urine from time zero to 24 hours post-dose (Ae0-24) for osimertinib and metabolites (AZ5104 and AZ7550) [ Time Frame: Urine samples were collected on Day 1 (24-hour pooled urine collection preceded by a pre-dose void) in Part A of the study. ]

Measure Type	Secondary
Measure Name	Amount excreted in urine from time zero to 24 hours post-dose (Ae0-24) for osimertinib and metabolites (AZ5104 and AZ7550)
Measure Description	Assessment of Ae0-24 for osimertinib and metabolites (AZ5104 and AZ7550) following administration of osimertinib as a single oral dose.
Time Frame	Urine samples were collected on Day 1 (24-hour pooled urine collection preceded by a pre-dose void) in Part A of the study.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK analysis set included all patients who received an osimertinib dose and had at least 1 post-dose quantifiable plasma osimertinib or metabolite (AZ5104 or AZ7550) concentration without important protocol deviations/violations or events thought to significantly affect the PK. Only patients with data available for analysis are presented.

Reporting Groups

	Description
Normal renal function	Patients with normal renal function received a single oral dose of 80 mg osimertinib on Day 1 in Part A of the study.
Severe renal impairment	Patients with severe renal impairment received a single oral dose of 80 mg osimertinib on Day 1 in Part A of the study.

Measured Values

	Normal renal function	Severe renal impairment
Number of Participants Analyzed [units:participants]	8	7
Amount excreted in urine from time zero to 24 hours post-dose (Ae0-24) for osimertinib and metabolites (AZ5104 and AZ7550) [units: nanomoles] Mean (Standard Deviation)
Osimertinib	284.3 (276.3)	387.7 (350.6)
AZ5104	73.84 (58.24)	16.96 (5.482)
AZ7550	71.05 (65.77)	15.99 (5.244)

No statistical analysis provided for Amount excreted in urine from time zero to 24 hours post-dose (Ae0-24) for osimertinib and metabolites (AZ5104 and AZ7550)

13. Secondary Outcome Measure: Renal clearance (CLR) for osimertinib and metabolites (AZ5104 and AZ7550) [ Time Frame: Blood samples were collected on Days 1 to 10 (pre-dose, and at 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168 and 216 hours post-dose) in Part A of the study. ]

Measure Type	Secondary
Measure Name	Renal clearance (CLR) for osimertinib and metabolites (AZ5104 and AZ7550)
Measure Description	Assessment of CLR for osimertinib and metabolites (AZ5104 and AZ7550) following administration of osimertinib as a single oral dose.
Time Frame	Blood samples were collected on Days 1 to 10 (pre-dose, and at 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168 and 216 hours post-dose) in Part A of the study.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK analysis set included all patients who received an osimertinib dose and had at least 1 post-dose quantifiable plasma osimertinib or metabolite (AZ5104 or AZ7550) concentration without important protocol deviations/violations or events thought to significantly affect the PK. Only patients with data available for analysis are presented.

Reporting Groups

	Description
Normal renal function	Patients with normal renal function received a single oral dose of 80 mg osimertinib on Day 1 in Part A of the study.
Severe renal impairment	Patients with severe renal impairment received a single oral dose of 80 mg osimertinib on Day 1 in Part A of the study.

Measured Values

	Normal renal function	Severe renal impairment
Number of Participants Analyzed [units:participants]	8	7
Renal clearance (CLR) for osimertinib and metabolites (AZ5104 and AZ7550) [units: L/h] Mean (Standard Deviation)
Osimertinib	0.1223 (0.1053)	0.09421 (0.07079)
AZ5104	0.5159 (0.4248)	0.1408 (0.01780)
AZ7550	0.8580 (0.6490)	0.3266 (0.09460)

No statistical analysis provided for Renal clearance (CLR) for osimertinib and metabolites (AZ5104 and AZ7550)

14. Secondary Outcome Measure: Metabolite to parent ratios of Cmax (MRAUC) for AZ5104 and AZ7550 [ Time Frame: Blood samples were collected on Days 1 to 10 (pre-dose, and at 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168 and 216 hours post-dose) in Part A of the study. ]

Measure Type	Secondary
Measure Name	Metabolite to parent ratios of Cmax (MRAUC) for AZ5104 and AZ7550
Measure Description	Assessment of MRAUC for each metabolite following administration of osimertinib as a single oral dose. Ratios were calculated for AZ5104 to osimertinib and for AZ7550 to osimertinib.
Time Frame	Blood samples were collected on Days 1 to 10 (pre-dose, and at 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168 and 216 hours post-dose) in Part A of the study.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK analysis set included all patients who received an osimertinib dose and had at least 1 post-dose quantifiable plasma osimertinib or metabolite (AZ5104 or AZ7550) concentration without important protocol deviations/violations or events thought to significantly affect the PK. Only patients with data available for analysis are presented.

Reporting Groups

	Description
Normal renal function	Patients with normal renal function received a single oral dose of 80 mg osimertinib on Day 1 in Part A of the study.
Severe renal impairment	Patients with severe renal impairment received a single oral dose of 80 mg osimertinib on Day 1 in Part A of the study.

Measured Values

	Normal renal function	Severe renal impairment
Number of Participants Analyzed [units:participants]	8	7
Metabolite to parent ratios of Cmax (MRAUC) for AZ5104 and AZ7550 [units: Ratio] Mean (Standard Deviation)
AZ5104	0.1187 (0.05913)	0.09554 (0.02037)
AZ7550	0.07533 (0.02658)	0.02730 (0.02137)

No statistical analysis provided for Metabolite to parent ratios of Cmax (MRAUC) for AZ5104 and AZ7550

15. Secondary Outcome Measure: Metabolite to parent ratios of Cmax (MRCmax) for AZ5104 and AZ7550 [ Time Frame: Blood samples were collected on Days 1 to 10 (pre-dose, and at 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168 and 216 hours post-dose) in Part A of the study. ]

Measure Type	Secondary
Measure Name	Metabolite to parent ratios of Cmax (MRCmax) for AZ5104 and AZ7550
Measure Description	Assessment of MRCmax for each metabolite following administration of osimertinib as a single oral dose. Ratios were calculated for AZ5104 to osimertinib and for AZ7550 to osimertinib.
Time Frame	Blood samples were collected on Days 1 to 10 (pre-dose, and at 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168 and 216 hours post-dose) in Part A of the study.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK analysis set included all patients who received an osimertinib dose and had at least 1 post-dose quantifiable plasma osimertinib or metabolite (AZ5104 or AZ7550) concentration without important protocol deviations/violations or events thought to significantly affect the PK.

Reporting Groups

	Description
Normal renal function	Patients with normal renal function received a single oral dose of 80 mg osimertinib on Day 1 in Part A of the study.
Severe renal impairment	Patients with severe renal impairment received a single oral dose of 80 mg osimertinib on Day 1 in Part A of the study.

Measured Values

	Normal renal function	Severe renal impairment
Number of Participants Analyzed [units:participants]	8	7
Metabolite to parent ratios of Cmax (MRCmax) for AZ5104 and AZ7550 [units: Ratio] Mean (Standard Deviation)
AZ5104	0.05659 (0.02739)	0.03982 (0.01347)
AZ7550	0.02552 (0.01250)	0.01239 (0.005550)

No statistical analysis provided for Metabolite to parent ratios of Cmax (MRCmax) for AZ5104 and AZ7550

Serious Adverse Events

Time Frame	Approximately 1 month for Part A (from first dose in Part A and up to and including 30 days post-last dose in Part A and prior to first dose in either Part B or continued access). Up to approximately 4 months for Part B (from first dose in Part B and up to and including 30 days post-last dose in Part B and prior to first dose in continued access).
Additional Description	All-Cause Mortality and adverse events (AEs) are reported for the safety analysis set which included all patients who received at least one dose of osimertinib. All-Cause Mortality is reported for the overall study period.

Reporting Groups

	Description
Part A: Normal renal function	Patients with normal renal function received a single oral dose of 80 mg osimertinib on Day 1 in Part A of the study.
Part A: Severe renal impairment	Patients with severe renal impairment received a single oral dose of 80 mg osimertinib on Day 1 in Part A of the study.
Part B: Severe renal impairment	Patients with severe renal impairment who completed Part A entered Part B where they received osimertinib 80 mg orally once daily for 12 weeks. The first dose in Part B was 10 days after the single dose of osimertinib in Part A and after completion of the PK assessments.

Serious Adverse Events

Part A: Normal renal function

Part A: Severe renal impairment

Part B: Severe renal impairment

Total, serious adverse events

# participants affected / at risk

0/9 (0.00%)

2/7 (28.57%)

2/6 (33.33%)

Vascular disorders

Hypotension¹,^†

# participants affected / at risk

0/9 (0.00%)

1/7 (14.29%)

0/6 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Dyspnoea¹,^†

# participants affected / at risk

0/9 (0.00%)

0/7 (0.00%)

1/6 (16.67%)

# events

General disorders

Asthenia¹,^†

# participants affected / at risk

0/9 (0.00%)

0/7 (0.00%)

1/6 (16.67%)

# events

Injury, poisoning and procedural complications

Rib fracture¹,^†

# participants affected / at risk

0/9 (0.00%)

1/7 (14.29%)

0/6 (0.00%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA version 21.0

Other Adverse Events

Time Frame	Approximately 1 month for Part A (from first dose in Part A and up to and including 30 days post-last dose in Part A and prior to first dose in either Part B or continued access). Up to approximately 4 months for Part B (from first dose in Part B and up to and including 30 days post-last dose in Part B and prior to first dose in continued access).
Additional Description	All-Cause Mortality and adverse events (AEs) are reported for the safety analysis set which included all patients who received at least one dose of osimertinib. All-Cause Mortality is reported for the overall study period.

Frequency Threshold

Threshold above which other adverse events are reported	5%

Reporting Groups

	Description
Part A: Normal renal function	Patients with normal renal function received a single oral dose of 80 mg osimertinib on Day 1 in Part A of the study.
Part A: Severe renal impairment	Patients with severe renal impairment received a single oral dose of 80 mg osimertinib on Day 1 in Part A of the study.
Part B: Severe renal impairment	Patients with severe renal impairment who completed Part A entered Part B where they received osimertinib 80 mg orally once daily for 12 weeks. The first dose in Part B was 10 days after the single dose of osimertinib in Part A and after completion of the PK assessments.

Other Adverse Events

Part A: Normal renal function

Part A: Severe renal impairment

Part B: Severe renal impairment

Total, other (not including serious) adverse events

# participants affected / at risk

3/9 (33.33%)

3/7 (42.86%)

6/6 (100.00%)

Infections and infestations

Conjunctivitis¹,^†

# participants affected / at risk

0/9 (0.00%)

0/7 (0.00%)

1/6 (16.67%)

# events

Infections and infestations

Paronychia¹,^†

# participants affected / at risk

0/9 (0.00%)

0/7 (0.00%)

1/6 (16.67%)

# events

Blood and lymphatic system disorders

Anaemia¹,^†

# participants affected / at risk

0/9 (0.00%)

1/7 (14.29%)

3/6 (50.00%)

# events

Metabolism and nutrition disorders

Decreased appetite¹,^†

# participants affected / at risk

0/9 (0.00%)

1/7 (14.29%)

2/6 (33.33%)

# events

Psychiatric disorders

Depression¹,^†

# participants affected / at risk

0/9 (0.00%)

0/7 (0.00%)

2/6 (33.33%)

# events

Psychiatric disorders

Hallucination¹,^†

# participants affected / at risk

0/9 (0.00%)

0/7 (0.00%)

1/6 (16.67%)

# events

Nervous system disorders

Headache¹,^†

# participants affected / at risk

0/9 (0.00%)

0/7 (0.00%)

1/6 (16.67%)

# events

Eye disorders

Eye irritation¹,^†

# participants affected / at risk

0/9 (0.00%)

1/7 (14.29%)

1/6 (16.67%)

# events

Eye disorders

Lacrimation increased¹,^†

# participants affected / at risk

0/9 (0.00%)

1/7 (14.29%)

0/6 (0.00%)

# events

Cardiac disorders

Cardiomyopathy¹,^†

# participants affected / at risk

0/9 (0.00%)

0/7 (0.00%)

1/6 (16.67%)

# events

Vascular disorders

Hypertension¹,^†

# participants affected / at risk

1/9 (11.11%)

0/7 (0.00%)

0/6 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Nasal dryness¹,^†

# participants affected / at risk

0/9 (0.00%)

0/7 (0.00%)

1/6 (16.67%)

# events

Gastrointestinal disorders

Constipation¹,^†

# participants affected / at risk

0/9 (0.00%)

1/7 (14.29%)

1/6 (16.67%)

# events

Gastrointestinal disorders

Diarrhoea¹,^†

# participants affected / at risk

0/9 (0.00%)

1/7 (14.29%)

1/6 (16.67%)

# events

Gastrointestinal disorders

Dry mouth¹,^†

# participants affected / at risk

1/9 (11.11%)

0/7 (0.00%)

0/6 (0.00%)

# events

Gastrointestinal disorders

Dyspepsia¹,^†

# participants affected / at risk

0/9 (0.00%)

0/7 (0.00%)

1/6 (16.67%)

# events

Gastrointestinal disorders

Flatulence¹,^†

# participants affected / at risk

0/9 (0.00%)

0/7 (0.00%)

1/6 (16.67%)

# events

Gastrointestinal disorders

Nausea¹,^†

# participants affected / at risk

1/9 (11.11%)

1/7 (14.29%)

1/6 (16.67%)

# events

Gastrointestinal disorders

Vomiting¹,^†

# participants affected / at risk

1/9 (11.11%)

1/7 (14.29%)

1/6 (16.67%)

# events

Musculoskeletal and connective tissue disorders

Back pain¹,^†

# participants affected / at risk

0/9 (0.00%)

0/7 (0.00%)

1/6 (16.67%)

# events

Musculoskeletal and connective tissue disorders

Pain in extremity¹,^†

# participants affected / at risk

0/9 (0.00%)

0/7 (0.00%)

1/6 (16.67%)

# events

Renal and urinary disorders

Nephrolithiasis¹,^†

# participants affected / at risk

1/9 (11.11%)

0/7 (0.00%)

0/6 (0.00%)

# events

Renal and urinary disorders

Renal failure¹,^†

# participants affected / at risk

0/9 (0.00%)

0/7 (0.00%)

1/6 (16.67%)

# events

General disorders

Asthenia¹,^†

# participants affected / at risk

0/9 (0.00%)

1/7 (14.29%)

3/6 (50.00%)

# events

General disorders

Fatigue¹,^†

# participants affected / at risk

0/9 (0.00%)

0/7 (0.00%)

1/6 (16.67%)

# events

General disorders

General physical health deterioration¹,^†

# participants affected / at risk

0/9 (0.00%)

0/7 (0.00%)

1/6 (16.67%)

# events

General disorders

Mucosal dryness¹,^†

# participants affected / at risk

0/9 (0.00%)

0/7 (0.00%)

1/6 (16.67%)

# events

General disorders

Oedema peripheral¹,^†

# participants affected / at risk

0/9 (0.00%)

0/7 (0.00%)

2/6 (33.33%)

# events

General disorders

Pyrexia¹,^†

# participants affected / at risk

1/9 (11.11%)

0/7 (0.00%)

0/6 (0.00%)

# events

Investigations

Weight decreased¹,^†

# participants affected / at risk

1/9 (11.11%)

1/7 (14.29%)

0/6 (0.00%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA version 21.0

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days . The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: The Investigator shall provide the Sponsor with copies of any materials intended for publication, submission or presentation, at least 30 days in advance. At request of the Sponsor, the Investigator shall not include in or shall remove from any proposed publication any Confidential Information, errors or inaccuracies; and shall withhold publication or presentation for a period of 90 days to allow the Sponsor to preserve its proprietary rights and/or protect its Confidential Information.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
At end of Part B, the continued access phase allowed patients to continue receiving osimertinib if still deriving clinical benefit. No clinical data was databased during this phase; thus AE data is presented to end of Part B only.

Results Point of Contact

Name/Title:	Global Clinical Lead
Organization:	AstraZeneca
Phone	+1 302 885 1180
E-mail:	[email protected]

Documents available

https://filehosting-v2.pharmacm.com/api/Attachment/Download?tenantId=80217111&parentIdentifier=D5160C00035&attachmentIdentifier=538889f3-f2fb-46d8-8c8c-ea789a666c31&fileName=D5160C00035_CSR_Synopsis_Redacted.pdf&versionIdentifier=
Download
Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

information.center@astrazeneca.com

Investigators

Principal Investigator

Philippe Ravaud

COLUMBIA UNIVERSITY

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

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Trial Results Summaries

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