A Phase I/IIa Study of AZD4547 in combination with cisplatin and capecitabine

• Conditions: 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: 16.0Level: LLTClassification code 10065147Term: Malignant solid tumorSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 16.0Level: LLTClassification code 10030139Term: Oesophageal adenocarcinoma NOSSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 16.0Level: PTClassification code 10060139Term: Antineutrophil cytoplasmic antibody decreasedSystem Organ Class: 10022891 - Investigations; MedDRA version: 16.0Level: PTClassification code 10001150Term: Adenocarcinoma gastricSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2011-000642-37-GB
• Lead Sponsor: Greater Glasgow Health Board

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2011-09-09
• Last Update Posted: 4 August 2015

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 158

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 < 1.5 x ULN (Upper Limit of Normal)
- ALT or AST < 2.5 x ULN
- Alkaline Phosphatase < 2.5 x ULN
- Serum Phosphate < ULN
- Serum Calcium < ULN
- Serum Magnesium < ULN
8. Adequate renal function with creatinine clearance / glomerular filtration rate > 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 (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

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified