A Phase I/IIa trial of AZD4547 in combination with Cisplatin and Capecitabine (CX)

INTERVENTION: 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 Concentration unit: mg milligram(s) Concentration type: range Concentration number: 20‐80 Pharmaceutical form of the placebo: Film‐coated tablet Route of administration of the placebo: Oral use Product Name: Cisplatin Product Code: Not applicable Pharmaceutical Form: Sterile concentrate INN or Proposed INN: Cisplatin CAS Number: 15663‐27‐1 Current Sponsor code: Not applicable Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 1‐ Product Name: Capecitabine Product Code: Not applicable Pharmaceutical Form: Film‐coated tablet INN or Proposed INN: Capecitabine CAS Number: 154361‐50‐9 Current Sponsor code: Not applicable Concentration unit: mg milligram(s) Concentration type: up to Concentration number: 500‐ CONDITION: 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: 10029104 ‐ Neoplasms benign, malignant and unspecified (incl cysts and polyps) ; MedDRA version: 16.0 Level: PT Classification code 10060139 Term: Antineutrophil cytoplasmic antibody decreased System Organ Class: 10022891 ‐ Investigations ; MedDRA version: 16.0 Level: PT Classification code 10001150 Term: Adenocarcinoma gastric System Organ Class: 10029104 ‐ Neoplasms benign, malignant and unspecified (incl cysts and polyps) Therapeutic area: Diseases [C] ‐ Cancer [C04] PRIMARY OUTCOME: 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) 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 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; SECONDARY OUTCOME: 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 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