title: ELYPSE-7: a randomized placebo-controlled phase IIa trial with CYT107 exploring the restoration of CD4+ lymphocyte count in lymphopenic metastatic breast cancer patients.
abstract: BACKGROUND
  Lymphopenia is a predictive factor for hematological toxicity, progression and early death in advanced cancers including metastatic breast cancer (MBC). CYT107 is a recombinant interleukin 7 (IL-7) (Cytheris, now Revimmune), well tolerated and able to expand lymphocyte pool in humans. The aims of this study were to determine the optimal schedule to deliver CYT107 and to assess its effect on clinical end points.
  
  
  METHODS
  This placebo-controlled, double blind, phase IIa was conducted in MBC patients with <1500/µl lymphocytes treated with capecitabine. Using a 2-by-2 factorial design, 20 patients were randomly allocated to four arms to receive (i) before chemotherapy: CYT107 or placebo; then (ii) during chemotherapy: CYT107 or placebo. The primary end point was CD4+ count changes before and during chemotherapy. Secondary end points were hematological toxicity, safety, overall response, progression-free survival (PFS) and overall survival (OS). Quantification and functional competence of circulating immune cells were also assessed.
  
  
  RESULTS
  When administered before chemotherapy, CYT107 induced a significant increase of CD4+ [+148.1% in CYT107 versus +9.9% in placebo groups, (Wilcoxon, P = 0.002)] and CD8+ T-cell counts, including both naïve and memory subsets. When CYT107 was administered during chemotherapy, the magnitude of CD4+ and CD8+ increase was less important. No modulation of immune cell functional competence was observed. CYT107 was well tolerated with no related ≥grade 3 adverse events except 1 fatal suspected unexpected serious adverse reaction (SUSAR) of uncertain relationship. Of the 12 cases evaluable for response, 6 of 7 patients (86%) receiving CYT107 before chemotherapy achieved a response or stabilization, whereas two of five patients (40%) receiving placebo achieved the same result. No significant difference was observed for PFS or OS.
  
  
  CONCLUSIONS
  In lymphopenic MBC, CYT107 increases CD4+ and other T-cell subset counts without altering their function. A larger clinical trial to demonstrate its impact on clinical outcome is warranted.
  
  
  BACKGROUND
  NCT01362107.
authors: Department of Medical Oncology, Leon Berard Cancer Center, Lyon Lyon University, Lyon ISPB, Lyon 1 University, Lyon CNRS UMR5286, Cancer Research Center of Lyon, Lyon.
authors: O
authors: O
authors: Trédan
authors: Lyon University, Lyon ISPB, Lyon 1 University, Lyon CNRS UMR5286, Cancer Research Center of Lyon, Lyon Innovation in Immuno-monitoring and Immunotherapy Platform (P3I), Leon Berard Cancer Center Team 11, INSERM U1052, Cancer Research Center of Lyon, Lyon.
authors: C
authors: C
authors: Ménétrier-Caux
authors: Department of Medical Oncology, Leon Berard Cancer Center, Lyon Lyon University, Lyon ISPB, Lyon 1 University, Lyon CNRS UMR5286, Cancer Research Center of Lyon, Lyon isabelle.ray-coquard@lyon.unicancer.fr.
authors: I
authors: I
authors: Ray-Coquard
authors: Clinical Research Platform (DRCI), Leon Berard Cancer Center, Lyon.
authors: G
authors: G
authors: Garin
authors: Clinical Research Platform (DRCI), Leon Berard Cancer Center, Lyon.
authors: C
authors: C
authors: Cropet
authors: Innovation in Immuno-monitoring and Immunotherapy Platform (P3I), Leon Berard Cancer Center.
authors: E
authors: E
authors: Verronèse
authors: Department of Medical Oncology, Leon Berard Cancer Center, Lyon.
authors: T
authors: T
authors: Bachelot
authors: Department of Medical Oncology, Leon Berard Cancer Center, Lyon.
authors: P
authors: P
authors: Rebattu
authors: Department of Medical Oncology, Leon Berard Cancer Center, Lyon.
authors: P E
authors: PE
authors: Heudel
authors: Department of Medical Oncology, Leon Berard Cancer Center, Lyon.
authors: P
authors: P
authors: Cassier
authors: Clinical Research Platform (DRCI), Leon Berard Cancer Center, Lyon.
authors: S
authors: S
authors: Chabaud
authors: Cytheris SA, Issy-Les-Moulineaux.
authors: T
authors: T
authors: Croughs
authors: Clinical Research Platform (DRCI), Leon Berard Cancer Center, Lyon.
authors: P
authors: P
authors: Dupont
authors: Clinical Research Platform (DRCI), Leon Berard Cancer Center, Lyon.
authors: A C
authors: AC
authors: Cadore
authors: Biological Sample Management Platform (BB-0033-00050).
authors: G
authors: G
authors: Clapisson
authors: Innovation in Immuno-monitoring and Immunotherapy Platform (P3I), Leon Berard Cancer Center.
authors: A
authors: A
authors: Delgado
authors: Innovation in Immuno-monitoring and Immunotherapy Platform (P3I), Leon Berard Cancer Center.
authors: C
authors: C
authors: Bardin-dit-Courageot
authors: Innovation in Immuno-monitoring and Immunotherapy Platform (P3I), Leon Berard Cancer Center.
authors: C
authors: C
authors: Rigal
authors: Innovation in Immuno-monitoring and Immunotherapy Platform (P3I), Leon Berard Cancer Center.
authors: A
authors: A
authors: N'Kodia
authors: Pharmacy, Leon Berard Cancer Center, Lyon.
authors: L
authors: L
authors: Gilles-Afchain
authors: Revimmune, Paris, France.
authors: M
authors: M
authors: Morre
authors: Clinical Research Platform (DRCI), Leon Berard Cancer Center, Lyon.
authors: D
authors: D
authors: Pérol
authors: Department of Medical Oncology, Leon Berard Cancer Center, Lyon Lyon University, Lyon ISPB, Lyon 1 University, Lyon CNRS UMR5286, Cancer Research Center of Lyon, Lyon Team 11, INSERM U1052, Cancer Research Center of Lyon, Lyon.
authors: J Y
authors: JY
authors: Blay
authors: Lyon University, Lyon ISPB, Lyon 1 University, Lyon CNRS UMR5286, Cancer Research Center of Lyon, Lyon Innovation in Immuno-monitoring and Immunotherapy Platform (P3I), Leon Berard Cancer Center Team 11, INSERM U1052, Cancer Research Center of Lyon, Lyon.
authors: C
authors: C
authors: Caux
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D018791:CD4 Lymphocyte Count; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D018275:Carcinoma, Lobular / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D015851:Interleukin-7 / Q000627:therapeutic use*; D008207:Lymphatic Metastasis; D008231:Lymphopenia / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D011994:Recombinant Proteins / Q000627:therapeutic use*; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D015851:Interleukin-7; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D011994:Recombinant Proteins; C508605:IL7 protein, human; C508053:ERBB2 protein, human
keywords: immune reconstitution; interleukin 7; lymphopenia; metastatic breast cancer