A Phase I Trial of Vandetanib Combined With 131I-mIBG Radiotherapy in Patients With Neuroendocrine Tumours, Advanced Phaeochromocytoma and Paraganglioma
Overview
- Phase
- Phase 1
- Intervention
- Vandetanib
- Conditions
- Phaeochromocytoma
- Sponsor
- University College, London
- Locations
- 3
- Primary Endpoint
- Occurrence of Dose Limiting Toxicity
- Status
- Withdrawn
- Last Updated
- 10 years ago
Overview
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.
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •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
- •Positive 123I-mIBG diagnostic scan
- •Stable blood pressure (\<140/90mmHg), if appropriate, on anti-hypertensive therapy
- •No previous systemic chemotherapy within 3 months prior to registration
- •No previous mIBG therapy within 12 months prior to registration (previous cumulative activity must not exceed 15 GBq)
- •Measurable disease (RECIST v1.1)
- •WHO performance status 0 or 1
- •Estimated life expectancy \> 3 months.
- •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
- •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
Exclusion Criteria
- •Patients undergoing current treatment with curative intent
- •Previous or current malignancies of other histological types within the last 5 years (exceptions listed in the trial protocol)
- •Any prior exposure to VEGF, EGFR or RET inhibitors or history of hypersensitivity to vandetanib or any excipient agents
- •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
- •Evidence of active uncontrolled infection (patients on antibiotics are eligible)
- •Chronic gastrointestinal disease (e.g. Inflammatory Bowel Disease) or significant bowel resection that would preclude adequate absorption
- •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
Arms & Interventions
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.
Intervention: Vandetanib
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.
Intervention: 131I-mIBG
Outcomes
Primary Outcomes
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 Outcomes
- Objective response(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)
- Occurrence and Severity of Adverse Events(From date of registration until 30 days after completion of trial treatment (vandetanib and/or 131I-mIBG))
- Progression Free Survival(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)