Phaeochromocytoma, Paraganglioma
Conditions
Keywords
Phaeochromocytoma, Paraganglioma, Neuroendocrine Tumour, Vandetanib, 131I-mIBG, Radionucleotide Therapy, Vascular Endothelial Growth Factor (VEGF), Epidermal Growth Factor Receptor (EGFR), RET, Tyrosine Kinase
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.
Interventions
DRUGVandetanib
100 mg, 200 mg or 300 mg taken once a day during each 12-weekly cycle
RADIATION131I-mIBG
Activity will be prescribed to deliver whole body absorbed dose of 0.5 Gy (+/-10%)
Sponsors
Cancer Research UK
AstraZeneca
University College, London
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Occurrence of Dose Limiting Toxicity | 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
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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) |
| Occurrence and Severity of Adverse Events | 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. |
| 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 | 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. |
Countries
United Kingdom
Outcome results
None listed