Stage 1 - Patients with advanced solid tumours. Stage 2 - Histologically proven adenocarcinoma or undifferentiated carcinoma of the oesophagus, gastro-oesophageal junction, or stomach. MedDRA version: 16.0 Level: LLT Classification code 10065147 Term: Malignant solid tumor System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 16.0 Level: LLT Classification code 10030139 Term: Oesophageal adenocarcinoma NOS System Organ Class: 100291
Conditions
Interventions
Product Name: AZD4547
Product Code: AZD4547
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: AZD4547
CAS Number: Not availabl
Current Sponsor code: AZD4547
Other descriptive name: AZD4547
Sponsors
Greater Glasgow Health Board
University of Glasgow
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Inclusion Criteria (Stage 1 and Stage 2) 1. Male/Female and over 25 years of age. 2. ECOG performance status 0, or 1 (Appendix 1). 3. Written Informed Consent. 4. No chemotherapy, hormonal therapy, immunotherapy, targeted systemic cancer therapy, or investigational therapy within 4 weeks of study entry (6 weeks for mitomycin C and nitrosureas) 5. No radiotherapy within 4 weeks of study entry. 6. Adequate haematological function, as follows: - Haemoglobin > 10g/dl - Neutrophils > 1.5 x 109/l - Platelets > 100 x 109/l 7. Adequate biochemical function, as follows: - Bilirubin 60 mls/min. If the creatinine clearance / glomerular filtration rate is less than 60 mls/min as calculated by the Cockroft-Gault formula, then the creatinine clearance / glomerular filtration rate should be measured by either a radio-isotope technique or by 24-hour urine collection. 9. Life expectancy >12 weeks 10. Able to reliably tolerate and comply with oral medication Additional Dose-finding Inclusion Criteria: 1. Histologically or cytologically proven advanced solid tumour that is refractory to standard therapies, or for whom no standard therapies exist, or for whom cisplatin and capecitabine is an acceptable treatment option. 2. No concomitant use of another anti-cancer therapy with the exception of patients with prostate cancer who are on a LHRH analogue who can continue this during the study. 3. Disease which is either measurable (RECIST 1.1) or evaluable. Additional randomised component Inclusion Criteria: 1. Histologically or cytologically proven adenocarcinoma or undifferentiated carcinoma of the oesophagus, gastro-oesophageal junction, or stomach. 2. Locally advanced (inoperable) disease (that is not suitable for a combined chemo-radiation approach for tumours confined to the lower oesophagus) or metastatic disease. 3. Tumours with FGFR2 polysomy or amplification (FISH 4/5 or FISH 6) 4. No prior neo-adjuvant or adjuvant chemotherapy, and no prior chemotherapy for advanced disease. 5. No concomitant use of another anti-cancer therapy during the study. 6. At least one bi-dimensional measurable lesion as defined by RECIST 1.1 Are the trial subjects under 18? no Number of subjects for this age range: 0 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 0 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 0
Exclusion criteria
Exclusion criteria: Exclusion Criteria (Stage 1 and Stage 2) 1. History of physical or psychiatric disorder that would prevent informed consent and compliance 2. Pregnant or lactating women. 3. Fertile woman of childbearing potential not willing to use adequate contraception (oral contraceptives, intrauterine device or barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) for the study duration and at least six months afterwards. Fertile men who are not willing to use a barrier method of contraception (condoms with spermicidal jelly). Fertile men should also refrain from donating sperm from the start of dosing until 16 weeks after discontinuing study treatment. Male patients wishing to subsequently father children should attend for freezing of sperm samples prior to dosing. It is not known whether AZD4547 can induce hepatic enzymes. If oral contraception is used, it is recommended that this is used in combination with a barrier method as well. 4. Evidence of uncontrolled infection (defined as infection that cannot be resolved readily with antibiotics prior to patient entry into the trial) 5. Major surgery within 28 days prior to study entry or anticipated to occur while on study 6. Prolonged QTc (corrected) interval of > 470ms on ECG or a family history of long QT syndrome 7. History of active or treated brain metastases (with the exception of patients with resected brain metastases and no evidence of recurrence on CT or MRI of the brain) 8. CNS disease (uncontrolled seizures or cerebrovascular accident/transient ischaemic attack /subarachnoid haemorrhage within 6 months) 9. Any unresolved toxicity > CTC Grade 1 from previous systemic anti-cancer therapy except alopecia 10. Pre-existing sensory or motor neuropathy > grade 1 11. Known hypersensitivity to cisplatin 12. Known DPD deficiency or hypersensitivity to capecitabine 13. Known hypersensitivity to AZD4547 14. History of significant cardiac disease including myocardial infarction within the previous 6 months, uncontrolled ischaemic heart disease, second or third degree heart block, any other persistent or intermittent cardiac arrhythmia requiring medication, congestive cardiac failure > NYHA Grade 2, or left ventricular ejection fraction of < 50% 15. Patients with a lack of physical integrity of the GI tract leading to a malabsorption syndrome or intestinal obstruction 16. Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contra-indicates the use of an investigational drug or puts the patient at high risk for treatment-related complications 17. Patients with significant hearing loss such that Cisplatin is contra-indicated 18. Patients taking CYP3A4 and CYP2D6 inducers or inhibitors 19. Current evidence or previous history of retinal pigmented epithelial detachment (RPED) 20. Previous laser treatment or intra-ocular injection for treatment of macular degeneration 21. Current evidence or previous history of dry or wet age-related macular degeneration 22. Current evidence or previous history of retinal vein occlusion (RVO) 23.Current evidence or previous history of retinal degenerative diseases (e.g. hereditary) 24.Current evidence or previous history of any other clinically relevant chorioretinal defect THERE IS NO ADDITIONAL STAGE 1 EXCLUSION CRITERIA Additional Stage 2 Exclusion Criteria: History of prior malignancy within the last
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: (Stage 1) To identify a recommended dose of AZD4547 when administered in combination with Cisplatin and Capecitabine (CX). (Stage 2) To determine the effect of AZD4547 in combination with Cisplatin and Capecitabine (AZD4547-CX) compared with Cisplatin and Capecitabine (CX) and placebo on progression-free survival (PFS) when administered to patients with locally advanced or metastatic gastro-oesophageal adenocarcinoma and with FGFR2 polysomy or amplification (FISH > 4);Secondary Objective: Stage 1: •To identify the DLT (Dose-Limiting Toxicity) of AZD4547 when administered in combination with Cisplatin and Capecitabine •To explore the safety and tolerability of AZD4547 when administered in combination with Cisplatin and Capecitabine •To determine the pharmacokinetic profile of AZD4547 when administered in combination with Cisplatin and Capecitabine Stage 2: •To compare the mean change in tumour size assessments from baseline after 9 weeks of treatment between the study arms •To compare objective overall (complete and partial) response rates in these patients treated with either AZD4547-CX or CX-placebo •To compare overall survival in these patients treated with either AZD4547-CX or CX-placebo •To compare PFS in the FISH 6 and FISH 4/5 sub-groups •To compare the effect of AZD4547 between the FISH 6 and the FISH 4/5 sub-groups •To further describe the safety and toxicity profiles of AZD4547-CX and CX-placebo in this patient population ;Primary end point(s): The primary endpoint of the dose-finding component of the study will be the optimal dose of AZD4547 to be used in combination with Cisplatin and Capecitabine (CX) based on clinical and laboratory toxicity (NCI-CTC version 4.02), and the primary endpoint of the randomised component of the study will be the progression-free survival of patients with advanced gastro-oesophageal adenocarcinoma treated with AZD4547-CX or with placebo-CX. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary Objectives - Stage 1: •To identify the DLT (Dose-Limiting Toxicity) of AZD4547 when administered in combination with Cisplatin and Capecitabine •To explore the safety and tolerability of AZD4547 when administered in combination with Cisplatin and Capecitabine •To determine the pharmacokinetic profile of AZD4547 when administered in combination with Cisplatin and Capecitabine Secondary Objectives - Stage 2: •To compare the mean change in tumour size assessments from baseline after 9 weeks of treatment between the study arms •To compare objective overall (complete and partial) response rates in these patients treated with either AZD4547-CX or CX-placebo •To compare overall survival in these patients treated with either AZD4547-CX or CX-placebo •To compare PFS in the FISH 6 and FISH 4/5 sub-groups •To compare the effect of AZD4547 between the FISH 6 and the FISH 4/5 sub-groups •To further describe the safety and toxicity profiles of AZD4547-CX and CX-placebo in this patient population ;Timepoint(s) of evaluation of this end point: •Ongoing evaluation throughout each treatment cycle •Formal assessment every 9 weeks •During follow up | — |
Countries
United Kingdom
Outcome results
None listed