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Clinical trial

Study title: First International randomized study placebo in malignant progressive pheochromocytoma and paraganglioma (PPGL)

This clinical trial was promoted by the Gustave Roussy
(114, rue Edouard Vaillant - 94 805 - VILLEJUIF - France)
under the aegis of "European Network for the Study of Adrenal Tumours (ENS@T)"

Clinical trial

Study title: First International randomized study placebo in malignant progressive pheochromocytoma and paraganglioma (PPGL)


This clinical trial was promoted by the Gustave Roussy
(114, rue Edouard Vaillant - 94 805 - VILLEJUIF - France)
under the aegis of "European Network for the Study of Adrenal Tumours (ENS@T)"

Summary

Malignant pheochromocytomas and paragangliomas (PPGLs) arise from the chromaffin cells of the adrenal medulla and sympathetic or parasympathetic nervous system respectively, respectively.
They are defined by the presence of metastases at sites where chromaffin cells are normally absent (i.e., liver, lungs, bones, lymph nodes).
Among PPGLs, malignant tumours have a frequency of about 14%, in particular in patient with SDHB mutation.
PPGLs are characterized by :

  • 1/ production of catecholamines, usually associated with hypertension mainly in case of abdomen primaries.
  • 2/ up to 30% of inherited forms (NF1, VHL, RET, MEN2, SDHA, SDHB, SDHC, SDHD, SDHAF2)
  • 3/ frequent bone metastases. The diagnosis of malignant PPGL is done by the both conventional (CT scan and MRI) and functioning imaging (123I-metaiodobenzylguanidine–MIBG-scintigraphy, somatostatin receptor scintography and/or positron emission tomography using 18F-fluorodeoxyglucise).

The treatment has two main goals:

  • a) to control of hormone-related symptoms
  • b) to reduce or stabilize the tumor mass.

Surgery currently remains the single curative option in these patients when the tumor remains localized. Five-year survival at the metastatic stage, is 50% but is mainly characterized by heterogeneity.
Up to now, only one phase II study using MIBG therapy in metastatic patients has been published. Chemotherapy based on the Cyclophospamide-Vincristine-Dacarbazine (CVD) regimen has been the most frequently used and only 2 publications were reported in more than 20 years.
Due to the absence of randomized trial, the survival impact of MIBG therapy or chemotherapy in malignant PPGLs is unknown.
Therefore, up to now, there is no recognized standard therapy validated in this pathology.
The prognostic role of the SDHB mutation, recently demonstrated, suggests that the molecular alterations associated to this mutation, as the increased expression of hypoxia-angiogenic pathway components (HIF/VEGF/PDGF), is an attractive therapeutic goal.
These results have been confirmed by our preclinical data and the objective response in 3 patients with malignant PPGLs treated with Sunitinib.
Sunitinib is an inhibitor of the tyrosine kinase receptor, with anti-angiogenic and anti-tumoral activities, targeting VEGF and PDGF receptors and KIT, FLT3.
Based on the preliminary results described above, a multidisplinary international board deemed a randomized double blind phase II trial assessing Sunitinib efficacy with a control group receiving placebo was the most intersting and feasible therapeutic option in this rare disease.
A randomised phase II study is proposed in order to evaluate the efficacy of Sunitinib.
In this study, the patients with progressive PPGLs (estimated prevalence of <=1 per million) will be included. A randomisation on the basis of 1:1 is scheduled:
1) arm treatment: Sunitinib 37.5 mg /day.
2) arm control: Placebo.

The primary objective is to evaluate the progressive-free survival (PFS) at 12 months.
The PFS is assessed according to RECIST 1.1 criteria, analyzed every 3 months.
A centralized imaging review is scheduled.
The secondary objectives are the evaluation of the objective responses (ORR), the delay of the response, the overall progression free survival, the time to progression, the overall survival, the toxicity and the cardiovascular tolerance, evaluated by a dedicated follow-up.
The exploratory objectives (translation research) are the identification of predictor factors of response and surrogate markers of response and survival.
Additional fundings will be applied for but storage of samples will be put in place in this trial.
On the basis of two-step Simon model, we plan to include 74 patients taking into account a PFS improvement at 12 months from 20% to 40%.
On the basis of the estimate prevalence of this disease and the hypothesis of 1.1 patient included for each center during 4 years, we plan to open at least 8 French centers from the French Network for adrenal cancers (INCA-COMETE) and the neuroendocrine tumors (GTE-RENATEN) and 16 European centers from the European Network for the Study of Adrenal Tumors (ENSAT).
This randomised phase II trial will be the first randomised trial in the field of malignant PPGLs.

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