Cancer, Advanced Solid Malignancies
Conditions
Keywords
Cancer, Tumour, Advanced Solid Malignancies, FGFR, Squamous NSCLC, Gastric adenocarcinoma
Brief summary
This study is primarily designed to assess the safety and tolerability of AZD4547 at increasing doses in patients with advanced solid malignancies and for whom no standard medication options are available. It also assesses the blood levels and action of AZD4547 in the body over a period of time.
Interventions
DRUGAZD4547
Single dose is followed by washout 5-10 days before multiple dose, and at dose of 80mg twice daily
Sponsors
AstraZeneca
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
25 Years to 149 Years
Healthy volunteers
No
Inclusion criteria
* Minimum life expectancy of 12 weeks * The presence of a solid, malignant tumour that is resistance to standard therapies or for which no standard therapies exist * In the expansion for the study patients must have a tumour at least 1cm in size that can be measure using a CT or MRI scan, and provide a tumour sample to the sponsor company for testing of FGFR1 and/or 2 amplification * Expansion, 5 groups of advanced cancer * Solid tumours,FGFR1 and/or FGFR2 gene amplified * Squamous NSCLC, FGFR1 gene low & high amplified * Gastric adenocarcinoma, including the lower oesophagus/gastro-oesophageal junction, FGFR2 gene low & high amplified * Aged at least 25 years
Exclusion criteria
* Treatment with any other chemotherapy, immunotherapy or anticancer agents within 3 weeks before the first dose of study * An inability to be able to take the study medication * A bad reaction to AZD4547 or any drugs similar to it in structure or class.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With at Least 1 Causally Related SAE | SAEs are continually monitored from screening to end of 30 FU period | To investigate the safety and tolerability of AZD4547: SAEs are assessed and deemed as causally related or not to AZD4547 |
| Number of Patients Who Experienced at Least 1 AE | AEs are monitored from screenng through to 30 day follow up period | To investigate the safety and tolerability of AZD4547. System organ class (SOC), preferred term (PT), duration and severity all recorded. |
| Number of Participants Who Experienced at Least 1 Causally Related AE. | AEs are continually assessed from screening up to 30 day FU period | To investigate the safety and tolerability of AZD4547. A causally related AE is an AE deemed to be causally related to AZD4547. |
| Number of Participants With at Least 1 AE of CTCAE >=G3 | Ongoing up to discontinuation up to 30 day FU. | To investigate the safety and tolerability of AZD4547 |
| Number of Participants With at Least 1 Causally Related AE of CTCAE >=G3 | Ongoing up to discontinuation up to 30 day FU. | To investigate the safety and tolerability of AZD4547 |
| Number of Participants Who Experienced at Least One SAE | Serious Adverse Events (SAEs) are continually assessed from Screening up to the end of the 30 day FU period. | To investigate the safety and tolerability of AZD4547. A SAE (Serious Adverse Event) is and AE (adverse Event) which fulfills one of the following criteria that the PI assesses closely such as results in death, immediately life-threatening, requires hospitalisation or prolongation of, results in significant disability, results in birth defect, may jepardise the patient or require intervention to prevent any of the previous outcomes. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tumour Response (Best Objective Response) - Number of Patients With a Confirmed Response of Partial Response (PR) or Confirmed Response (CR) | Baseline assessment, then assessment every 6 weeks after start of treatment until objective disease progression. | To obtain a preliminary assessment of the anti tumour activity of AZD4547 by evaluation of tumour response using Response Evaluation Criteria in Solid Tumours (RECIST) criteria version 1.1. Objective response = CR + PR; CR=disappearance of all target lesions and PR is \>=30% reduction in sum of longest diameter of target lesions |
| Cmax (ng/mL) | PK samples out to 96 hours 0-96 hours post dose after single dose (in parts A & B only). Steady state PK profile 3 weeks after the start of BD dosing. | To characterise the pharmacokinetics (PK) of AZD4547 following a single administration and at steady state after dosing when given orally. |
| Css,Max (ng/mL) | PK samples out to 96 hours 0-96 hours post-dose after single dose (in parts A & B only). Steady state PK profile 3 weeks after the start of BD dosing. | To characterise the pharmacokinetics (PK) of AZD4547 following a single administration and at steady state after dosing when given orally. |
| AUC,ss(0-infinity) | PK samples out to 96 hours 0-96 hours post dose after single dose (in parts A & B only). Steady state PK profile 3 weeks after the start of BD dosing. | To characterise the pharmacokinetics (PK) of AZD4547 following a single administration and at steady state after dosing when given orally. |
| AUC(0-infinity) | PK samples out to 96 hours 0 to 96 hours post-dose after single dose (in parts A & B only). Steady state PK profile 3 weeks after the start of BD dosing. | To characterise the pharmacokinetics (PK) of AZD4547 following a single administration and at steady state after dosing when given orally. |
Countries
France, Germany, Italy, Netherlands, Spain, United Kingdom, United States
Participant flow
Recruitment details
First patient enrolled: 21 October 2009 and last patient enrolled: 13 December 2013. This was a multicentre study conducted at a total of 29 centres in 7 countries.
Pre-assignment details
In Parts A and B, a single dose was followed by a Washout Period of 5 to 10 days before multiple dosing commenced.
Participants by arm
| Arm | Count |
|---|---|
| Part B Dose expansion phase (80mg bd tablet) | 6 |
| Part C (FISH Ratio >= 2) Dose expansion in patients with FGFR gene-amplified tumours | 33 |
| Part C (FISH Ratio < 2 ) Dose expansion in patients with FGFR gene-amplified tumours | 12 |
| Part A Dose escalation | 43 |
| Total | 94 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 2 |
| Overall Study | Death | 4 | 0 | 26 |
| Overall Study | Disease progression | 18 | 2 | 5 |
| Overall Study | Lost to Follow-up | 2 | 2 | 0 |
| Overall Study | Other | 8 | 1 | 5 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 2 |
Baseline characteristics
| Characteristic | Part B | Part C (FISH Ratio >= 2) | Part C (FISH Ratio < 2 ) | Part A | Total |
|---|---|---|---|---|---|
| Age, Continuous | 58.7 Years STANDARD_DEVIATION 8.1 | 59.5 Years STANDARD_DEVIATION 10.82 | 58.2 Years STANDARD_DEVIATION 11.77 | 55.8 Years STANDARD_DEVIATION 10.1 | 57.59 Years STANDARD_DEVIATION 10.57 |
| Sex: Female, Male Female | 3 Participants | 16 Participants | 3 Participants | 18 Participants | 40 Participants |
| Sex: Female, Male Male | 3 Participants | 17 Participants | 9 Participants | 25 Participants | 54 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 33 / 33 | 12 / 12 | 43 / 43 |
| serious Total, serious adverse events | 1 / 6 | 10 / 33 | 3 / 12 | 11 / 43 |
Outcome results
Primary
Number of Participants Who Experienced at Least 1 Causally Related AE.
To investigate the safety and tolerability of AZD4547. A causally related AE is an AE deemed to be causally related to AZD4547.
Time frame: AEs are continually assessed from screening up to 30 day FU period
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part B | Number of Participants Who Experienced at Least 1 Causally Related AE. | 6 Participants |
| Part C (FISH Ratio >= 2) | Number of Participants Who Experienced at Least 1 Causally Related AE. | 31 Participants |
| Part C (FISH Ratio < 2) | Number of Participants Who Experienced at Least 1 Causally Related AE. | 10 Participants |
| Part A | Number of Participants Who Experienced at Least 1 Causally Related AE. | 42 Participants |
Primary
Number of Participants Who Experienced at Least One SAE
To investigate the safety and tolerability of AZD4547. A SAE (Serious Adverse Event) is and AE (adverse Event) which fulfills one of the following criteria that the PI assesses closely such as results in death, immediately life-threatening, requires hospitalisation or prolongation of, results in significant disability, results in birth defect, may jepardise the patient or require intervention to prevent any of the previous outcomes.
Time frame: Serious Adverse Events (SAEs) are continually assessed from Screening up to the end of the 30 day FU period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part B | Number of Participants Who Experienced at Least One SAE | 1 Number of participants |
| Part C (FISH Ratio >= 2) | Number of Participants Who Experienced at Least One SAE | 10 Number of participants |
| Part C (FISH Ratio < 2) | Number of Participants Who Experienced at Least One SAE | 3 Number of participants |
| Part A | Number of Participants Who Experienced at Least One SAE | 11 Number of participants |
Primary
Number of Participants With at Least 1 AE of CTCAE >=G3
To investigate the safety and tolerability of AZD4547
Time frame: Ongoing up to discontinuation up to 30 day FU.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part B | Number of Participants With at Least 1 AE of CTCAE >=G3 | 1 Participants |
| Part C (FISH Ratio >= 2) | Number of Participants With at Least 1 AE of CTCAE >=G3 | 16 Participants |
| Part C (FISH Ratio < 2) | Number of Participants With at Least 1 AE of CTCAE >=G3 | 5 Participants |
| Part A | Number of Participants With at Least 1 AE of CTCAE >=G3 | 17 Participants |
Primary
Number of Participants With at Least 1 Causally Related AE of CTCAE >=G3
To investigate the safety and tolerability of AZD4547
Time frame: Ongoing up to discontinuation up to 30 day FU.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part B | Number of Participants With at Least 1 Causally Related AE of CTCAE >=G3 | 0 Participants |
| Part C (FISH Ratio >= 2) | Number of Participants With at Least 1 Causally Related AE of CTCAE >=G3 | 8 Participants |
| Part C (FISH Ratio < 2) | Number of Participants With at Least 1 Causally Related AE of CTCAE >=G3 | 3 Participants |
| Part A | Number of Participants With at Least 1 Causally Related AE of CTCAE >=G3 | 12 Participants |
Primary
Number of Participants With at Least 1 Causally Related SAE
To investigate the safety and tolerability of AZD4547: SAEs are assessed and deemed as causally related or not to AZD4547
Time frame: SAEs are continually monitored from screening to end of 30 FU period
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part B | Number of Participants With at Least 1 Causally Related SAE | 1 Number of participants |
| Part C (FISH Ratio >= 2) | Number of Participants With at Least 1 Causally Related SAE | 5 Number of participants |
| Part C (FISH Ratio < 2) | Number of Participants With at Least 1 Causally Related SAE | 0 Number of participants |
| Part A | Number of Participants With at Least 1 Causally Related SAE | 5 Number of participants |
Primary
Number of Patients Who Experienced at Least 1 AE
To investigate the safety and tolerability of AZD4547. System organ class (SOC), preferred term (PT), duration and severity all recorded.
Time frame: AEs are monitored from screenng through to 30 day follow up period
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part B | Number of Patients Who Experienced at Least 1 AE | 6 Participants |
| Part C (FISH Ratio >= 2) | Number of Patients Who Experienced at Least 1 AE | 33 Participants |
| Part C (FISH Ratio < 2) | Number of Patients Who Experienced at Least 1 AE | 12 Participants |
| Part A | Number of Patients Who Experienced at Least 1 AE | 43 Participants |
Secondary
AUC(0-infinity)
To characterise the pharmacokinetics (PK) of AZD4547 following a single administration and at steady state after dosing when given orally.
Time frame: PK samples out to 96 hours 0 to 96 hours post-dose after single dose (in parts A & B only). Steady state PK profile 3 weeks after the start of BD dosing.
Population: PK
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part B | AUC(0-infinity) | 1818 ng*h/mL | Geometric Coefficient of Variation 59.43 |
| Part A | AUC(0-infinity) | 2697 ng*h/mL | Geometric Coefficient of Variation 110.8 |
Secondary
AUC,ss(0-infinity)
To characterise the pharmacokinetics (PK) of AZD4547 following a single administration and at steady state after dosing when given orally.
Time frame: PK samples out to 96 hours 0-96 hours post dose after single dose (in parts A & B only). Steady state PK profile 3 weeks after the start of BD dosing.
Population: PK
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part B | AUC,ss(0-infinity) | 2606 ng*h/mL | Geometric Coefficient of Variation 41.32 |
| Part A | AUC,ss(0-infinity) | 2337 ng*h/mL | Geometric Coefficient of Variation 125.2 |
Secondary
Cmax (ng/mL)
To characterise the pharmacokinetics (PK) of AZD4547 following a single administration and at steady state after dosing when given orally.
Time frame: PK samples out to 96 hours 0-96 hours post dose after single dose (in parts A & B only). Steady state PK profile 3 weeks after the start of BD dosing.
Population: PK
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part B | Cmax (ng/mL) | 112.0 ng/mL | Geometric Coefficient of Variation 81.47 |
| Part C (FISH Ratio < 2) | Cmax (ng/mL) | 167.4 ng/mL | Geometric Coefficient of Variation 112.1 |
Secondary
Css,Max (ng/mL)
To characterise the pharmacokinetics (PK) of AZD4547 following a single administration and at steady state after dosing when given orally.
Time frame: PK samples out to 96 hours 0-96 hours post-dose after single dose (in parts A & B only). Steady state PK profile 3 weeks after the start of BD dosing.
Population: PK
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part B | Css,Max (ng/mL) | 289.3 ng/mL | Geometric Coefficient of Variation 45.98 |
| Part C (FISH Ratio < 2) | Css,Max (ng/mL) | 297.1 ng/mL | Geometric Coefficient of Variation 123.5 |
Secondary
Tumour Response (Best Objective Response) - Number of Patients With a Confirmed Response of Partial Response (PR) or Confirmed Response (CR)
To obtain a preliminary assessment of the anti tumour activity of AZD4547 by evaluation of tumour response using Response Evaluation Criteria in Solid Tumours (RECIST) criteria version 1.1. Objective response = CR + PR; CR=disappearance of all target lesions and PR is \>=30% reduction in sum of longest diameter of target lesions
Time frame: Baseline assessment, then assessment every 6 weeks after start of treatment until objective disease progression.
Population: Efficacy/Tumour response: All dosed patients meeting the final FISH 6 score criteria with a baseline tumour assessment and had a FGFR1 FISH ratio ≥2 if the patient was from Part C
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part B | Tumour Response (Best Objective Response) - Number of Patients With a Confirmed Response of Partial Response (PR) or Confirmed Response (CR) | 0 Patients |
| Part C (FISH Ratio >= 2) | Tumour Response (Best Objective Response) - Number of Patients With a Confirmed Response of Partial Response (PR) or Confirmed Response (CR) | 1 Patients |
| Part C (FISH Ratio < 2) | Tumour Response (Best Objective Response) - Number of Patients With a Confirmed Response of Partial Response (PR) or Confirmed Response (CR) | 0 Patients |
| Part A | Tumour Response (Best Objective Response) - Number of Patients With a Confirmed Response of Partial Response (PR) or Confirmed Response (CR) | 0 Patients |