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Phase I Trial of Vandetanib Combined With 131I-mIBG to Treat Patients With Advanced Phaeochromocytoma and Paraganglioma (VIBRaNT)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01941849
Recruitment Status : Withdrawn (Poor patient accrual)
First Posted : September 13, 2013
Last Update Posted : December 21, 2015
Cancer Research UK
Information provided by (Responsible Party):
University College, London

Brief Summary:
The phase I trial aims to determine the recommended phase II dose (RP2D) of vandetanib in combination with standard radiation therapy, 131I-mIBG, in patients with advanced phaeochromocytoma (phaeo) and paraganglioma (PG) by assessing the safety and tolerability of the combination treatment.

Condition or disease Intervention/treatment Phase
Phaeochromocytoma Paraganglioma Drug: Vandetanib Radiation: 131I-mIBG Phase 1

Detailed Description:

VIBRaNT is a registered phase I trial in patients with locally advanced or metastatic phaeochromocytoma or paraganglioma, not amenable to surgical resection.

Patients will receive vandetanib (an inhibitor of VEGF, EGFR and RET tyrosine kinase) in combination with standard radiation therapy Iodine-131 labelled Meta-iodobenzylguanidine (131I-mIBG).

Vandetanib and 131I-mIBG will be given in 12-weekly cycles: 131I-miBG will be given on day 1 of each cycle and vandetanib will started on day 1 of each cycle and continue to be taken once every day. The phase I trial aims to determine with recommended phase II dose of vandetanib (either 100, 200 or 300 mg once daily) - the dose of vandetanib that patients will receive will depend on the dose under investigation at the time of patient registration.

The vandetanib dose will be determined by the Modified Continual Reassessment Method (mCRM) - a toxicity model which described the probability of a toxicity occurring at each dose level, which is based on clinical judgement and any available toxicity data.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Trial of Vandetanib Combined With 131I-mIBG Radiotherapy in Patients With Neuroendocrine Tumours, Advanced Phaeochromocytoma and Paraganglioma
Study Start Date : October 2014
Actual Primary Completion Date : December 2015
Actual Study Completion Date : December 2015

Arm Intervention/treatment
Experimental: Vandetanib + 131I-mIBG

Vandetanib (100, 200 or 300 mg once daily) in combination with 131I-mIBG radiation therapy (activity to be prescribed to deliver whole body absorbed dose of 0.5 Gy) on day 1 of each 12-weekly cycle.

Patients will receive up to 4 cycles of vandetanib in combination with 131I-mIBG.

Drug: Vandetanib
100 mg, 200 mg or 300 mg taken once a day during each 12-weekly cycle
Other Name: Caprelsa

Radiation: 131I-mIBG
Activity will be prescribed to deliver whole body absorbed dose of 0.5 Gy (+/-10%)
Other Name: Iodine-131 labelled Meta-iodobenzylguanine

Primary Outcome Measures :
  1. Occurrence of Dose Limiting Toxicity [ Time Frame: From start of cycle 1 to end of cycle 1 (each cycle = 12 weeks) ]
    Detailed adverse event monitoring will be conducted according to CTCAE v4.03. Dose Limiting Toxicity (DLT) is defined as any adverse event or laboratory abnormality detailed in the trial protocol, that is considered to be highly probable or probable trial treatment related and commencing anytime during the DLT evaluation period (from start of cycle 1 to cycle 1 week 12). Adverse Events include: Haematological, Clinical Chemistry, Cardiovascular, Gastrointestinal, Skin.

Secondary Outcome Measures :
  1. Objective response [ Time Frame: Determined using imaging scans performed at baseline (registration), then every 3 months after start of treatment until disease progression up to 3 years from date of registration ]
    Response will be assessed according to RECIST v1.1. Confirmation of complete or partial response is not required. Stable disease will be considered the best response only is a second assessment has been carried out which confirmed stable disease at least 4 weeks after trial entry. Assessment will be determined using CT scans and 123I-mIBG scans performed at baseline, then every 3 months after start of treatment until disease progression (up to 3 years from registration)

  2. Occurrence and Severity of Adverse Events [ Time Frame: From date of registration until 30 days after completion of trial treatment (vandetanib and/or 131I-mIBG) ]
    Will include all grade 1-5 adverse events.

  3. Progression Free Survival [ Time Frame: From date of registration to date of documented disease progression or death from any cause, whichever comes first, assessed up to 3 years from date of registration ]
    Progression-free survival will be calculated from the date of trial entry to the date of documented disease progression, or death from any cause. Where progression is suspected and subsequently confirmed by scans, the date of documented suspected progression will be used.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Histopathological/cytological diagnosis of advanced phaeo/PG defined as patients with local or metastatic disease not amenable to surgical resection, or R1 resection post original surgical debulking
  2. Positive 123I-mIBG diagnostic scan
  3. Stable blood pressure (<140/90mmHg), if appropriate, on anti-hypertensive therapy
  4. No previous systemic chemotherapy within 3 months prior to registration
  5. No previous mIBG therapy within 12 months prior to registration (previous cumulative activity must not exceed 15 GBq)
  6. Measurable disease (RECIST v1.1)
  7. WHO performance status 0 or 1
  8. Age ≥ 18
  9. Estimated life expectancy > 3 months.
  10. Adequate bone marrow function: Haemoglobin ≥ 100 g/L, White Blood Cell ≥ 3.0 x 10^9/L, Absolute neutrophil ≥ 1.5 x 10^9/L, Platelet ≥ 100 x 10^9/L
  11. Adequate liver function: Total bilirubin ≤1.5 x Upper Limit of Normal (ULN); ALT/AST and ALP≤ 2.5 x ULN or ≤ 5 x ULN if related to liver metastases
  12. Adequate renal function: Serum urea and creatinine < 1.5x ULN AND Calculated creatinine clearance (GFR) ≥50 mL/min. If the calculated GFR is below 50, isotope clearance test is required to confirm GFR ≥50 mL/min
  13. Electrolytes: Potassium ≥ 4.0 mmol/L and ≤ 5.5 mmol/L, Magnesium ≥ Lower Limit of Normal and ≤ 1.23 mmol/L, Corrected calcium within institution normal range
  14. Negative pregnancy test for women of child-bearing potential AND be using adequate barrier contraception, which must be continued for 12 months after completion of treatment (male patients must also agree to use barrier contraception during the trial and for 12 months after completion of treatment)
  15. Able to swallow oral medication
  16. Capable of giving written informed consent

Exclusion Criteria:

  1. Patients undergoing current treatment with curative intent
  2. Previous or current malignancies of other histological types within the last 5 years (exceptions listed in the trial protocol)
  3. Any prior exposure to VEGF, EGFR or RET inhibitors or history of hypersensitivity to vandetanib or any excipient agents
  4. Evidence of severe or uncontrolled systemic diseases or laboratory finding that in the view of the investigator makes it undesirable for the patient to participate in the trial
  5. Evidence of active uncontrolled infection (patients on antibiotics are eligible)
  6. Chronic gastrointestinal disease (e.g. Inflammatory Bowel Disease) or significant bowel resection that would preclude adequate absorption
  7. Cardiovascular exclusion criteria (complete list provided in the trial protocol):

    • Significant cardiac event (myocardial infarction), New York Heart Association Class II or above, within 12 weeks before registration, or presence of cardiac disease that in the opinion of the investigator increased the risk of ventricular arrhythmia
    • Prior or current cardiomyopathy
    • Baseline LVEF < 40% as measured by ECHO/MUGA
    • Atrial fibrillation with heart rate >100 bpm
    • Unstable ischaemic heart disease (myocardial infarction within 6 months prior to starting treatment, or angina requiring use of nitrates more than once weekly)
    • History of arrhythmia that was symptomatic or required treatment
    • QTcB prolongation >480 ms at baseline
    • QT prolongation with other medications that required discontinuation of that medication
  8. Any psychiatric or other disorder likely to impact on informed consent or ability to manage isolation
  9. Major surgery within 28 days prior to registration
  10. Brain metastases or spinal cord compression, unless treated at least four weeks before the first dose and stable without steroid treatment for 10 days
  11. Any concomitant medications that may affect QTc, induce or inhibit CYP3A4 function (with the exception of somatostatin or somatostatin analogue) and/or prohibited medications
  12. Women who are pregnant or lactating

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01941849

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United Kingdom
Guy's and St Thomas' NHS Foundation Trust
London, United Kingdom
The Christie NHS Foundation Trust
London, United Kingdom
University College London Hospitals NHS Foundation Trust
London, United Kingdom
Sponsors and Collaborators
University College, London
Cancer Research UK
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Principal Investigator: Christina Thirlwell University College London (UCL) Cancer Institute

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Responsible Party: University College, London Identifier: NCT01941849    
Other Study ID Numbers: UCL/12/0499
First Posted: September 13, 2013    Key Record Dates
Last Update Posted: December 21, 2015
Last Verified: December 2015
Keywords provided by University College, London:
Neuroendocrine Tumour
Radionucleotide Therapy
Vascular Endothelial Growth Factor (VEGF)
Epidermal Growth Factor Receptor (EGFR)
Tyrosine Kinase
Additional relevant MeSH terms:
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Carotid Body Tumor
Paraganglioma, Extra-Adrenal
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors