A Phase I Trial of Vandetanib (AZD6474) and Selumetinib (AZD6244) for Solid Tumours Including Non Small Cell Lung Cancer (VanSel-1)
Condition: Cancer; Non Small Cell Lung Cancer
MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
Intervention: Vandetanib, Selumetinib; Vandetanib, Selumetinib; Vandetanib, Selumetinib; Vandetanib, Selumetinib; Vandetanib, Selumetinib; Vandetanib, Selumetinib; Vandetanib, Selumetinib; Vandetanib, Selumetinib
Intervention description: Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). Cycle 1 is 42 days long.
Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long.
Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.; Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long.
Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long.
Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.; Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). Cycle 1 is 42 days long.
Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long.
Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.; Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). Cycle 1 is 42 days long.
Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long.
Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.; Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). Cycle 1 is 42 days long.
Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long.
Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.; Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 200 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long.
Cycle 2 onwards: Vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long.
Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.; Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 2) followed by vandetanib steady state dose of 300 mg OD (Days 3 to 14) followed by vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long.
Cycle 2 onwards: Vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long.
Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.; Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 200 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long.
Cycle 2 onwards: Vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long.
Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 61.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Phase I; Drug evaluation; Oncology; Vandetanib; Selumetinib; Dose escalation; Clinical trial; Vascular Endothelial Growth Factor (VEGFR) inhibitor; Epidermal Growth Factor Receptor (EGFR) inhibitor; Mitogen Activated Kinase (MEK) inhibitor; Non small cell lung cancer

Summary:

      The purpose of this study is to determine whether using two drugs together called vandetanib
      and selumetinib is effective in the treatment of cancer. The first part of this study will
      include patients with any solid tumour and the second part of this study will include only
      patients with non small cell lung cancer. The four main aims of this clinical study are to
      find out:

        -  If the two drugs can be given safely to patients when given together.

        -  The maximum dose that can be given safely to patients.

        -  More about the potential side effects of the drugs and how they can be managed.

        -  What happens to vandetanib and selumetinib inside the body.
    

Eligibility criteria:

        Inclusion Criteria:

          1. (Dose escalation cohorts) Histologically or cytologically proven solid tumour for
             which no conventional therapy exists or is declined by the patient

          2. (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

          3. (Expansion cohort only) Measurable disease according to RECIST criteria Version 1.1 in
             final version of the protocol

          4. Life expectancy of at least 12 weeks

          5. World Health Organisation (WHO) performance status of 0-1

          6. Baseline LVEF > 50%

          7. 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 < 1.5 x ULN

             *or normal range according to the local laboratory

             ** Isotope clearance result to be used to confirm eligibility if calculated C&G/Wright
             method results in GFR of = 50 mL/min.

             *** Therapeutic INR values (2.0-3.0) are acceptable to confirm eligibility for
             patients who are taking concomitant warfarin.

          8. 18 years or over

          9. Ability to swallow and retain oral medications.

         10. Written (signed and dated) informed consent and be capable of co-operating with
             treatment, and follow-up

        Exclusion Criteria:

          1. Radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy or
             chemotherapy during the previous 4 weeks (6 weeks for investigational medicinal
             products) before treatment.

          2. Patients who have been withdrawn from treatment with agents that target EGFR because
             of unacceptable toxicity (prior treatment with these agents is allowed) and those
             patients who have had EGFR dose reductions by 50% or more.

          3. Expansion cohort only: Prior treatment with any agent that targets MEK or VEGFR

          4. Any prior exposure to RAS or RAF inhibitors

          5. Ongoing toxic manifestations of previous treatments. Exceptions to this are alopecia
             or certain Grade 2 toxicities, which in the opinion of the Investigator and the Centre
             for Drug Development (CDD) should not exclude the patient.

          6. Symptomatic brain metastases (patients must be stable for >3 months post RT treatment)
             or spinal cord compression.

          7. Patients with interstitial lung disease.

          8. 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.

          9. 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.

         10. Major surgery from which the patient has not yet recovered.

         11. At high medical risk because of non-malignant systemic disease including active
             uncontrolled infection.

         12. Known to be serologically positive for Hepatitis B, Hepatitis C or Human
             Immunodeficiency Virus (HIV).

         13. 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 screening ECG (Note: If a patient has a QTcB
                  interval > or equal to 450 msec on screening ECG, the screen ECG may be repeated
                  twice [at least 24 hours apart]. The average QTcB from the three screening ECGs
                  must be < 450 msec in order for the subject to be eligible for the study.)

               -  History of congenital long QT syndrome

               -  History of Torsade de Pointes (or any concurrent medication with a known risk of
                  inducing Torsades de Pointes.)

         14. Concomitant medications that are potent inducers of CYP3A4 function i.e. rifampicin,
             rifabutin, phenytoin, carbamazepine, Phenobarbital and St John"s Wort.

         15. Any other condition which in the Investigator"s opinion would not make the patient a
             good candidate for the clinical trial (e.g. evidence of severe or uncontrolled
             systemic disease or concurrent condition or that may affect ability to absorb oral
             agents).

         16. Current malignancies of other types, with the exception of adequately treated
             cone-biopsied in situ carcinoma of the cervix uteri and basal or squamous cell
             carcinoma of the skin. Cancer survivors, who have undergone potentially curative
             therapy for a prior malignancy, have no evidence of that disease for five years or
             more and are deemed at negligible risk for recurrence, are eligible for the trial.

         17. If a participant plans to participate in another interventional clinical study, whilst
             taking part in this Phase I study. Participation in an observational study would be
             acceptable.

         18. Ophthalmological conditions as follows:

               1. Current or past history of retinal pigment epithelial detachment (RPED)/central
                  serous retinopathy (CSR) or retinal vein occlusion.

               2. Intraocular pressure (IOP) > 21 mmHg or uncontrolled glaucoma (irrespective of
                  IOP).