A Phase I Trial of Vandetanib (AZD6474) and Selumetinib (AZD6244) for Solid Tumours Including Non Small Cell Lung Cancer (VanSel-1)

Inclusion Criteria

• (Dose escalation cohorts) Histologically or cytologically proven solid tumour for which no conventional therapy exists or is declined by the patient
• (Expansion cohort only) Histologically or cytologically confirmed NSCLC patients only, for which no conventional therapy exists or is declined by the patient.
• If only cytologically confirmed, baseline biopsy is mandatory for a patient to be eligible.
• For NSCLC patients to be eligible for the expansion cohort they must have received:
• One prior line of chemotherapy and/or
• Previous platinum based chemotherapy and/or
• At least one previous EGFR inhibitor
• (Expansion cohort only) Measurable disease according to RECIST criteria Version 1.1 in final version of the protocol
• Life expectancy of at least 12 weeks
• World Health Organisation (WHO) performance status of 0-1
• Baseline LVEF > 50%
• Haematological and biochemical indices within the ranges shown below. These measurements must be performed within one week (Day -7 to Day -1) before the patient goes on study.

Laboratory Test Value required

Haemoglobin (Hb) ≥ 9.0 g/dL

Absolute neutrophil count ≥ 1.5 x 10^9/L

Platelet count ≥ 100 x 10^9 /L

Normal serum calcium (adjusted)* 2.15-2.55 mmol/L

Normal serum magnesium* 0.60-1.0 mmol/L

Normal serum potassium >4.0 mmol/L

Either: Serum bilirubin ≥1.5 x upper limit of normal (ULN) This does not apply to patients with Gilbert's disease.

Alanine amino-transferase (ALT) or aspartate amino-transferase (AST) and alkaline phosphatase (ALP) ≤ 2.5 x ULN unless raised due to liver metastases in which case up to 5 x ULN is permissible

Either: Calculated creatinine clearance (using the Wright or C&G formula) > 50 mL/min

Or: Isotope clearance measurement** ≥ 50 mL/min (uncorrected)

INR or aPTT 3 months post RT treatment) or spinal cord compression.

• Patients with interstitial lung disease.
• Pregnant or lactating women are excluded. Female patients with the ability to become pregnant who have a negative serum or urine pregnancy test before enrollment and agree to use two of the following three highly effective forms of combined contraception (oral, injected or implanted hormonal contraception and condom, have a intra-uterine device and condom, diaphragm with spermicidal gel and condom) for four weeks before entering the trial, during the trial and for six months afterwards are considered eligible.
• Male patients with partners of child-bearing potential (unless they agree to take measures not to father children by using one form of highly effective contraception [condom plus spermicide] during the trial and for six months afterwards). Men with pregnant or lactating partners should be advised to use barrier method contraception (e.g. condom plus spermicidal gel) to prevent exposure to the foetus or neonate.
• Major surgery from which the patient has not yet recovered.
• At high medical risk because of non-malignant systemic disease including active uncontrolled infection.
• Known to be serologically positive for Hepatitis B, Hepatitis C or Human Immunodeficiency Virus (HIV).
• Cardiac conditions as follows:
• Clinically significant cardiovascular event within 3 months prior to entry to include:
• Myocardial infarction
• Angina requiring use of nitrates more than once weekly
• Superior vena cava syndrome
• Class II/III/IV cardiac disease (New York Heart Association [NYHA])
• Presence of cardiac disease that in the opinion of the Investigator increases the risk of ventricular arrhythmia.
• History of arrhythmia which is symptomatic or requires treatment (CTCAE V4.02), symptomatic or uncontrolled atrial fibrillation despite treatment or asymptomatic sustained ventricular tachycardia. Patients with atrial fibrillation controlled by medication are permitted.
• Uncontrolled hypertension (BP > 160/100 despite optimal therapy)
• Prior or current cardiomyopathy
• Atrial fibrillation with heart rate > 100 bpm
• QTcB > or equal to 450 msec on scree