567O_PR – FIrst International Randomized STudy in MAlignant Progressive Pheochromocytoma and Paraganliomas (FIRSTMAPPP): an academic double-blind trial investigating Sunitinib
E. Baudin1, B. Goichot2, A. Berruti3, J. Hadoux4, S. MOALLA5, S. Laboureau6, S. Noelting7, C. de la Fouchardière8, T. Kienitz9, T. Deutschbein10, S. Zovato11, L. Amar12, A. Tabarin13, H.J. Timmers14, P. Niccoli15, A. Faggiano16, F. Beuschlein17, M. Attard18, M. Texier19, M. Fassnacht20
1Endocrine Oncology, Gustave Roussy – Cancer Campus, Villejuif, France, 2Internal Medicine And Endocrinology, Hopital de Hautepierre – Hopitaux Universitaires de Strasbourg, Strasbourg, France, 3Department Of Medical And Surgical Specialties, Radiological Sciences, And Publi, Azienda Ospedaliera Spedali Civili di Brescia, Brescia, Italy, 4Endocrine Oncology, Institut Gustave Roussy, Villejuif, France, 5Imaging Departement, Institut Gustave Roussy, Villejuif, France, 6Endocrinology, Hopitaux Universitaire d’Angers, Angers, France, 7Medizinische Klinik Und Poliklinik Iv, MediziKlinikum der Universität München, Munchen, Germany, 8Department Of Medical Oncology, Léon Bérard Center, Lyon – EORTC Endocrine Tumours Group, France, 9Department Of Endocrinology And Metabolism, Charité Universitätsmedizin Berlin, Berlin, Germany, 10Department Internal Medicine I, Division Of Endocrinology And Diabetes, University Hospital Würzburg, Würzburg, Germany, 11Hereditary Tumors Unit-oncological Endocrinology, Istituto Oncologico Veneto-IRCCS, Padova, Italy, 12Paris, HEGP – Hopital Europeen Georges-Pompidou – AP-HP, Paris, France, 13Department Of Endocrinology, University of Bordeaux, Bordeaux, France, 14Internal Medicine, Radboud University Medical Center, Nijmegen, Nijmegen, Netherlands, 15Oncology, Institut Paoli Calmette, Marseille, France, 16Department Of Clinical And Molecular Medicine, Sapienza University of Rome, Rome, Italy, 17Endocrine Research, LMU Klinikum der Universität München, Munich, Germany, 18Ile De France, Gustave Roussy – Cancer Campus, Villejuif, France, 19Head And Neck Cancer, Institut Gustave Roussy, Villejuif, France, 20Department Of Internal Medicine I – Division Of Endocrinology, University Hospital Würzburg, Würzburg, Germany
Background: Malignant pheochromocytoma and paraganglioma (MPP) is a very rare cancer (annual incidence < 1 per million). Here, we report the first academic randomized double-blind phase II study results assessing Sunitinib efficacy compared to placebo (FIRSTMAPPP trial: NCT01371201).
Methods: Patients with progressive MPP with 1.5year according to (RECIST) were randomized 1/1 for Sunitinib therapy 37.5 mg/d or Placebo and stratified for SDHB status and line of treatment. Primary endpoint: progression-free survival (PFS) at 12 months according to real-time central review (RECIST 1.1), analyzed every 3 months (ITT). Key secondary endpoints: ORR, response (delay, duration), overall PFS, overall survival, safety (NCI CTCAE v.4). On the basis of a two-step Simon model (alpha 10%, power 90%), we aimed for 74 patients, assuming a PFS improvement at 12 months from 20 to 40%. 11 or more patients out of 37 with no progression at 12 months were expected to conclude that Sunitinib is effective. The placebo group served as an internal control to validate the hypothesis of the Simon design with a 12-m PFS equal to 20%. An IDMC was set up to review the accrual, toxicity, and interim analysis.
Results: 78 patients were enrolled (median age, 53 yrs; 59% men). Main characteristics: adrenal/PGL primaries, each 50%; 32% SDHx inherited, 71% secreting, distant lymph node/bone/lung/liver mets, 73%/65%/51%/49%; 60% prior therapy. 39 patients were randomized in each arm. The primary endpoint was met: PFS at 12 months was 35.9% (Sunitinib) vs. 18.9% (Placebo; within the 90%CI confirming the Simon design conclusion). Median PFS was 8.9 (95CI: 5.5-12.7) vs. 3.6 months (3.1-6.1). Reasons for drug discontinuation were AE/tumor progression in 14%/64% (Sunitinib) and 0%/86% (Placebo). 54% patients with Sunitinib vs. 49% with Placebo experienced SAE; most frequent grade 3-4 were asthenia/fatigue (18% vs. 3%) and hypertension (10% vs. 6%).One death occurred in each arm.
Conclusions: After 8 years of enrolment, this first randomized study in the field of MPP provides the highest level of evidence ever reached in this very rare cancer. Sunitinib becomes the first-line option in patients with progressive MPP.
Clinical trial identification: NCT01371201
Legal entity responsible for the study: Gustave Roussy
Funding: Foundation or academic group WITH funding from a pharma, biotech, or other commercial company- Pfizer (provided sunitinib and placebo for the study)
Disclosure: E. Baudin: Financial Interests, Personal and Institutional, Advisory Board, research grant and principal investigator: Novartis; Financial Interests, Personal and Institutional, Advisory Board, and research grant: HRA; Financial Interests, Personal and Institutional, Project Lead, Principal investigation: Ipsen; Financial Interests, Personal and Institutional, Advisory Board, research grant (drug supply for trial): AAA; Financial Interests, Personal and Institutional, Research Grant, drug supply for trial: Pfizer; Financial Interests, Personal and Institutional, Advisory Board: Hutchinson Pharma.
All other authors have declared no conflicts of interest.