A Phase I, Open-Label, Two Parts Study to Assess the Safety, Tolerability,Pharmacokinetics and Preliminary Anti-tumour Activity of AZD9291 in Chinese Patients with Advanced Non-Small Cell Lung Cancer who have Progressed Following Prior Therapy with an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Agent Study Objective: 1, Primary Objective To characterise the pharmacokinetics (PK) of AZD9291 and its metabolites (AZ5104 and AZ7550) after single then multiple doses of AZD9291 administered orally once daily in Chinese patients with locally advanced or metastatic non small cell lung Cancer (NSCLC) who have progressed following prior therapy with an approved Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR TKI) agent. 2, Secondary objective(s) To investigate the safety and tolerability of AZD9291 when given orally to Chinese patients with locally advanced or metastatic NSCLC who have progressed following prior therapy with an approved EGFR TKI agent. To obtain a preliminary assessment of the anti-tumour activity of AZD9291 by evaluation of tumour response using Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1.
Name: AZD9291 40 mg
Name: AZD9291 80 mg
Description: Pharmacokinetics of AZD9291 after single dosing by assessment of maximum plasma AZD9291 concentration
Measure: Cmax of AZD9291 After Single Dosing Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.Description: Pharmacokinetics of AZD9291 metabolites (AZ5104) after single dosing by assessment of maximum plasma concentration
Measure: Cmax of AZ5104 After Single Dosing Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.Description: Pharmacokinetics of AZD9291 metabolites (AZ7550) after single dosing by assessment of maximum plasma concentration
Measure: Cmax of AZ7550 After Single Dosing Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.Description: Pharmacokinetics of AZD9291 after single dosing by assessment of area under the plasma concentration time curve from zero to infinity
Measure: AUC of AZD9291 After Single Dosing Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.Description: Pharmacokinetics of AZD9291 metabolites (AZ5104) after single dosing by assessment of area under the plasma concentration time curve from zero to infinity
Measure: AUC of AZ5104 After Single Dosing Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.Description: Pharmacokinetics of AZD9291 metabolites (AZ7550) after single dosing by assessment of area under the plasma concentration time curve from zero to infinity
Measure: AUC of AZ7550 After Single Dosing Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.Description: Rate and extent of absorption of single dose AZD9291 by assessment of apparent clearance following oral administration
Measure: CL/F of AZD9291 After Single Dosing Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.Description: Pharmacokinetics of AZD9291 after multiple dosing by assessment of maximum plasma concentration at steady state
Measure: C(ss, Max) of AZD9291 After Multiple Dosing Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.Description: Pharmacokinetics of AZD9291 metabolites (AZ5104) after multiple dosing by assessment of maximum plasma concentration at steady state
Measure: C(ss, Max) of AZ5104 After Multiple Dosing Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.Description: Pharmacokinetics of AZD9291 metabolites (AZ7550) after multiple dosing by assessment of maximum plasma concentration at steady state
Measure: C(ss, Max) of AZ7550 After Multiple Dosing Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.Description: Pharmacokinetics of AZD9291 after multiple dosing by assessment of area under the plasma concentration curve from time zero to the end of the dosing interval
Measure: AUC(ss) of AZD9291 After Multiple Dosing Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.Description: Pharmacokinetics of AZD9291 metabolites (AZ5104) after multiple dosing by assessment of area under the plasma concentration curve from time zero to the end of the dosing interval
Measure: AUC(ss) of AZ5104 After Multiple Dosing Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.Description: Pharmacokinetics of AZD9291 metabolites (AZ7550) after multiple dosing by assessment of area under the plasma concentration curve from time zero to the end of the dosing interval
Measure: AUC(ss) of AZ7550 After Multiple Dosing Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.Description: Pharmacokinetics of AZD9291 after multiple dosing by assessment of apparent plasma clearance at steady state
Measure: CL(ss)/F of AZD9291 After Multiple Dosing Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR (according to independent review) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.
Measure: Objective Response Rate (ORR) Time: Treatment discontinuation plus 28 days or 12 months after last subject first dose (LSFD). Results are based on data cut off of 2 Nov 2016.Allocation: Non-Randomized
Parallel Assignment
There are 3 SNPs
In addition other lines of therapy may have been given - Documented EGFR mutation (at any time since the initial diagnosis of NSCLC) known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) 6. World Health Organisation (WHO) performance status 0-1 7. --- L858R ---
In addition other lines of therapy may have been given - Documented EGFR mutation (at any time since the initial diagnosis of NSCLC) known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) 6. World Health Organisation (WHO) performance status 0-1 7. --- L858R --- --- L861Q ---
At least one lesion suitable for accurate repeated measurements 8. Females - Child bearing potential : should not be breast feeding, use adequate contraceptive measures for female patients with child-bearing potential, OR - Have evidence of non-child-bearing potential that meet one of the following criteria at screening: - Post-menopausal defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments - Women below 50 years old would be consider postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and with luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in the post-menopausal range for the institution - Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation 9. Male patients should be willing to use barrier contraception ie, condoms Exclusion Criteria: 1. Treatment with any of the following (prior to first dose of study treatment) - Treatment with an EGFR TKI within 8 days - Any investigational agents or other anticancer drugs from a previous treatment regimen or clinical study within 14 days - Previous treatment with AZD9291, or a Thr790Met (T790M) directed EGFR TKIs - Major surgery (excluding placement of vascular access) within 4 weeks - Radiotherapy : - Within 1 week if limited field of radiation for palliation of the first dose of study treatment - Within 4 weeks if receiving radiation to more than 30% of the bone marrow or with a wide field of radiation - Patients currently receiving (or unable to stop use at least 1 week) medications or herbal supplements known to be potent inhibitors or inducers of cytochrome P450 3A4 (CYP3A4) - Treatment with an investigational drug within five half-lives of the compound 2. Any 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 3. Spinal cord compression or brain metastases unless asymptomatic, stable and not requiring steroids for at least 4 weeks prior to start of study treatment 4. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardise compliance with the protocol, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). --- Thr790Met ---
At least one lesion suitable for accurate repeated measurements 8. Females - Child bearing potential : should not be breast feeding, use adequate contraceptive measures for female patients with child-bearing potential, OR - Have evidence of non-child-bearing potential that meet one of the following criteria at screening: - Post-menopausal defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments - Women below 50 years old would be consider postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and with luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in the post-menopausal range for the institution - Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation 9. Male patients should be willing to use barrier contraception ie, condoms Exclusion Criteria: 1. Treatment with any of the following (prior to first dose of study treatment) - Treatment with an EGFR TKI within 8 days - Any investigational agents or other anticancer drugs from a previous treatment regimen or clinical study within 14 days - Previous treatment with AZD9291, or a Thr790Met (T790M) directed EGFR TKIs - Major surgery (excluding placement of vascular access) within 4 weeks - Radiotherapy : - Within 1 week if limited field of radiation for palliation of the first dose of study treatment - Within 4 weeks if receiving radiation to more than 30% of the bone marrow or with a wide field of radiation - Patients currently receiving (or unable to stop use at least 1 week) medications or herbal supplements known to be potent inhibitors or inducers of cytochrome P450 3A4 (CYP3A4) - Treatment with an investigational drug within five half-lives of the compound 2. Any 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 3. Spinal cord compression or brain metastases unless asymptomatic, stable and not requiring steroids for at least 4 weeks prior to start of study treatment 4. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardise compliance with the protocol, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). --- Thr790Met --- --- T790M ---