Clinical trial NCT02923947: Study to Assess Osimertinib in Patients w/ Adv Solid Tumours & Normal Kidney Function or Severe Kidney Impairment
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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Solid Tumours
Keywords: Pharmacokinetics,
Renal impairment,
Safety assessments,
Solid tumours,
EGFRm+
EGFRm+/T790M+ inhibitor
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Quintiles, Inc.
First posted: 2016-10-05
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: Area under the plasma concentration-time curve from zero to infinity for osimertinib
timeFrame: On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168, 216hrs post-dose
measure: Maximum plasma concentration for osimertinib
timeFrame: On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168, 216hrs post-dose
Secondary outcomes:
measure: Area under the plasma concentration-time curve from zero to the last quantifiable time point for osimertinib
timeFrame: On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168, 216hrs for osimertinib post-dose
measure: Area under the plasma concentration-time curve from zero to 24 hours post-dose for osimertinib
timeFrame: On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24hrs for osimertinib post-dose
measure: Time to maximum plasma concentration for osimertinib
timeFrame: On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168, 216hrs for osimertinib post-dose
measure: Apparent clearance following oral administration for osimertinib
timeFrame: On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168, 216hrs for osimertinib post-dose
measure: Apparent volume of distribution for osimertinib
timeFrame: On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168, 216hrs for osimertinib post-dose
measure: Terminal rate constant for osimertinib
timeFrame: On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168, 216hrs for osimertinib post-dose
measure: Terminal half-life for osimertinib
timeFrame: On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168, 216hrs for osimertinib post-dose
measure: Amount excreted in urine from time zero to 24 hours post-dose for osimertinib
timeFrame: On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24hrs for osimertinib post-dose
measure: Renal clearance for osimertinib
timeFrame: 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.
measure: Maximum plasma concentration for AZ5104
timeFrame: On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168, 216hrs for osimertinib post-dose
measure: Maximum plasma concentration for AZ7550
timeFrame: On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168, 216hrs for osimertinib post-dose
measure: Time to maximum plasma concentration for AZ5104
timeFrame: On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168, 216hrs for osimertinib post-dose
measure: Time to maximum plasma concentration for AZ7550
timeFrame: On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168, 216hrs for osimertinib post-dose
measure: Area under the plasma concentration time curve from zero to infinity for AZ5104
timeFrame: On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168, 216hrs for osimertinib post-dose
measure: Area under the plasma concentration time curve from zero to infinity for AZ7550
timeFrame: On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168, 216hrs for osimertinib post-dose
measure: Area under the plasma concentration-time curve from zero to the last quantifiable time point for AZ5104
timeFrame: On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168, 216hrs for osimertinib post-dose
measure: Area under the plasma concentration-time curve from zero to the last quantifiable time point for AZ7550
timeFrame: On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168, 216hrs for osimertinib post-dose
measure: Amount excreted in urine from time zero to 24 hours post-dose for AZ5104
timeFrame: 24 hour pooled collection starting from time of dosing on Day 1
measure: Amount excreted in urine from time zero to 24 hours post-dose for AZ7550
timeFrame: 24 hour pooled collection starting from time of dosing on Day 1
measure: Terminal rate constant for AZ5104
timeFrame: On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168, 216hrs for osimertinib post-dose
measure: Terminal rate constant for AZ7550
timeFrame: On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168, 216hrs for osimertinib post-dose
measure: Terminal half-life for AZ5104
timeFrame: On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168, 216hrs for osimertinib post-dose
measure: Terminal half-life for AZ7550
timeFrame: On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168, 216hrs for osimertinib post-dose
measure: Renal clearance for AZ5104
timeFrame: 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.
measure: Renal clearance for AZ7550
timeFrame: 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.
measure: Metabolite to parent ratios for maximum plasma concentration
timeFrame: On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168, 216hrs for osimertinib post-dose
measure: Metabolite to parent ratios for area under the plasma concentration time curve from zero to infinity
timeFrame: On Day of dosing in Part A - predose, 1, 2, 4, 6, 8, 10, 24, 48, 72, 120, 168, 216hrs for osimertinib post-dose
measure: Part A: Adverse Events's, graded by the National Cancer Institute Common Terminology Criteria for Adverse Event's (CTCAE v4.0)
timeFrame: Until 30 days following the final dose of osimertinib
measure: Part A: physical exam
timeFrame: Until 30 days following the final dose of osimertinib
measure: Part A: vital signs
timeFrame: Until 30 days following the final dose of osimertinib
measure: Part A: ECG
timeFrame: Until 30 days following the final dose of osimertinib
measure: Part A: evaluation of laboratory
timeFrame: Until 30 days following the final dose of osimertinib
measure: Part A: echocardiogram/MUGA.
timeFrame: Until 30 days following the final dose of osimertinib
measure: Part B - Adverse events, graded CTCAE v4.0
timeFrame: Until 30 days following the final dose of osimertinib
measure: Part B -physical exam
timeFrame: Until 30 days following the final dose of osimertinib
measure: Part B - vital signs
timeFrame: Until 30 days following the final dose of osimertinib
measure: Part B - ECG
timeFrame: Until 30 days following the final dose of osimertinib
measure: Part B - evaluation of laboratory parameters.
timeFrame: Until 30 days following the final dose of osimertinib
Other outcomes:
Locations:
city: Angers Cedex 2
country: France
facility: Research Site
city: Bordeaux
country: France
facility: Research Site
city: Dijon
country: France
facility: Research Site
city: Lille Cedex
country: France
facility: Research Site
city: Saint Herblain
country: France
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Sevilla
country: Spain
facility: Research Site
Study officials:
affiliation: Columbia University
name: Philippe Ravaud, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Vishwanathan K, Sanchez-Simon I, Keam B, Penel N, de Miguel-Luken M, Weilert D, Mills A, Marotti M, Johnson M, Ravaud A. A multicenter, phase I, pharmacokinetic study of osimertinib in cancer patients with normal renal function or severe renal impairment. Pharmacol Res Perspect. 2020 Aug;8(4):e00613. doi: 10.1002/prp2.613.