A Phase I Trial of Vandetanib (ZD6474) and Selumetinib (AZD6244)for Solid Tumours Including Non Small Cell Lung Cancer (VanSel-1)

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2013 by Cancer Research UK
Sponsor:
Information provided by (Responsible Party):
Cancer Research UK
ClinicalTrials.gov Identifier:
NCT01586624
First received: April 25, 2012
Last updated: November 27, 2013
Last verified: November 2013
  Purpose

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.

Condition Intervention Phase
Cancer
Non Small Cell Lung Cancer
Drug: Vandetanib, Selumetinib
Drug: Vandetanib, Selumetinib
Phase 1

Study Type: Interventional
Study Design: Masking: Open Label
Primary Purpose: Treatment
Official Title: A Cancer Research UK Phase I Dose Escalation Trial of Oral VEGFR and EGFR Inhibitor, Vandetanib in Combination With the Oral MEK Inhibitor, Selumetinib (VanSel-1) in Solid Tumours (Dose Escalation) and NSCLC (Expansion Cohort).

Resource links provided by NLM:


Further study details as provided by Cancer Research UK:

Primary Outcome Measures:
  • Determining causality of each adverse event to vandetanib or selumetinib and grading severity according to NCI CTCAE Version 4.02 [ Designated as safety issue: Yes ]
  • Determining the MTD of the combination of vandetanib and selumetinib [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • During the dose escalation phase: plasma PK profiles [ Designated as safety issue: No ]
    Determine the plasma PK profiles of vandetanib and selumetinib and their metabolites.

  • During the expansion cohort: PFS [ Designated as safety issue: No ]
    Determine the PFS at 12 weeks by RECIST criteria.

  • During the expansion cohort:1 year survival rate [ Designated as safety issue: No ]
    Determine the 1 year survival rate.

  • During the expansion cohort: tumour metabolism [ Designated as safety issue: No ]
    Assess tumour metabolism using FDG-PET-CT imaging.


Estimated Enrollment: 48
Study Start Date: December 2011
Estimated Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Vandetanib, Selumetinib

    Dose escalation phase

    This phase consists of three cohorts, each investigating an increasing dose level of selumetinib. The dose levels are 25mg bd, 50mg bd and 75mg bd. Administration of vandetanib remains the same throughout the cohorts.

    All patients in this phase will take the study treatment as follows:

    Cycle 1

    • Vandetanib 300mg once daily(4 days) followed by vandetanib 100mg once daily (10 days) followed by vandetanib 100mg once daily in combination with selumetinib twice daily (28 days).
    • Selumetinib dose is defined according to which cohort the patient is recruited to.
    • Cycle 1 is 42 days in length.
    Drug: Vandetanib, Selumetinib

    Cycle 2 onwards

    • Vandetanib 100mg once daily in combination with selumetinib twice daily(28 days).
    • Selumetinib dose is defined according to which cohort the patient is recruited to.
    • Cycle 2 and subsequent cycles are 28 days in length.

    From this phase, we will establish what the maximum tolerated dose (MTD) of the combination treatment is, which can safely be given to patients.

    Drug: Vandetanib, Selumetinib

    Expansion cohort (patients with non small cell lung cancer).

    All patients will receive the same dose of combination treatment (the MTD established during dose escalation phase). As follows:

    All patients in the expansion cohort will take the study treatment in the same way as follows:

    Cycle 1

    • Vandetanib 300mg once daily(4 days) followed by vandetanib 100mg once daily (10 days) followed by vandetanib 100mg once daily in combination with selumetinib twice daily (28 days).
    • Selumetinib dose is defined in the dose escalation phase.
    • Cycle 1 is 42 days in length.
    Drug: Vandetanib, Selumetinib

    Cycle 2 onwards

    • Vandetanib 100mg once daily in combination with selumetinib twice daily (28 days).
    • Selumetinib dose is defined in the dose escalation phase.
    • Cycle 2 and subsequent cycles are 28 days in length.

    Number of cycles: Patients will be allowed to receive 6 cycles of study treatment. If the patient is still benefiting clinically and experiencing no unacceptable toxicity, then the Investigator can make a request to the Sponsor for continuation of treatment.

Detailed Description:

The purpose of this Phase I study is to establish a safety and toxicity profile of combining two study drugs; vandetanib, a VEGFR (Vascular Endothelial Growth Factor Receptor) and EGFR (Epidermal Growth Factor Receptor) inhibitor, with selumetinib a MEK (Mitogen Activated Kinase)inhibitor.

This is the first time the drugs have been used together. These types of drugs have shown an effect in non small cell lung cancer (NSCLC) therefore the aim is to see if combining these drugs has an increased anti-tumour effect for this group of patients for which treatment options are limited.

The study is in two parts; the dose escalation phase and the expansion cohort.

In the dose escalation phase, 9-18 patients will receive vandetanib and increasing doses of selumetinib to establish a safe dose to recommend for the next stage of the study. Patients with any solid tumour will be eligible.

In the expansion cohort, approximately 30 patients will receive the dose recommended in the previous phase. Only patients with NSCLC will be eligible for this part of the study.

The expansion cohort will look at further evaluating the safety of the drug combination and the anti-tumour activity. Patients in this cohort will be requested to also consent to have additional imaging assessments and optional tumour biopsies.

Study treatment is administered orally; vandetanib tablets once daily and selumetinib capsules twice daily. Cycle 1 is 42 days long. Subsequent cycles are 28 days in length. Patients will receive a total of 6 cycles of the combination treatment. If the patient has not progressed after six cycles, they may be treated for further cycles following approval from the sponsor.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
      • Previous platinum based chemotherapy
    • Also eligible are those patients who:

      • are erlotinib resistant
      • are untreated with erlotinib
      • have been treated with docetaxel
  3. (Expansion cohort only) Measurable disease according to RECIST criteria Version 1.0
  4. Life expectancy of at least 12 weeks
  5. World Health Organisation (WHO) performance status of 0-1 (Appendix 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 109/L

    Platelet count ≥ 100 x 109/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.

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

  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.
  3. 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 1 toxicities, which in the opinion of the Investigator and the Drug Development Office (DDO) 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]) (Appendix 4)
      • 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 3), 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. See Appendix 16.8)
  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. (Expansion cohort only) If the patient is unsuitable for administration of DCE-MRI contrast material because of hypersensitivity or impaired renal function.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01586624

Locations
United Kingdom
Cambridge Cancer Trials Centre (S4), Box 279, Addenbrooke's Hospital Recruiting
Hills Road, Cambridge, United Kingdom, CB2 0QQ
Contact: Simon Pacey, Dr    01223 768435    simonpacey@medschl.cam.ac.uk   
Principal Investigator: Simon Pacey, Dr         
The Christie NHS Foundation Trust Recruiting
Withington, Manchester, United Kingdom, M20 4BX
Contact: Fiona Blackhall, Dr    0161 446 3745    fiona.blackhall@christie.nhs.uk   
Principal Investigator: Fiona Blackhall, Dr         
Churchill Hospital Recruiting
Headington, Oxford, United Kingdom, OX3 7LJ
Contact: Denis Talbot, Dr    01865 235 315    denis.talbot@oncology.ox.ac.uk   
Principal Investigator: Denis Talbot, Dr         
Sponsors and Collaborators
Cancer Research UK
  More Information

Additional Information:
No publications provided

Responsible Party: Cancer Research UK
ClinicalTrials.gov Identifier: NCT01586624     History of Changes
Other Study ID Numbers: CRUKD/11/001
Study First Received: April 25, 2012
Last Updated: November 27, 2013
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency
United Kingdom: Research Ethics Committee

Keywords provided by Cancer Research UK:
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

Additional relevant MeSH terms:
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms

ClinicalTrials.gov processed this record on October 01, 2014