title: Phase I trial evaluating the antiviral agent Cidofovir in combination with chemoradiation in cervical cancer patients.
abstract: OBJECTIVE
  This phase I trial aimed to assess the safety and determine the recommended Phase II dose (RP2D) of Cidofovir combined with chemoradiotherapy in patients with stage IB2-IVA cervical cancer.
  
  
  METHODS
  Incremental doses (1, 2.5, 5 and 6.5 mg/kg) of IV Cidofovir were administered weekly for two weeks, and then every 2 weeks from the start of chemoradiotherapy to the initiation of utero-vaginal brachytherapy. Biological expression of HPV was analyzed during treatment and tumor response was assessed according to RECIST v1.0 criteria.
  
  
  RESULTS
  A total of 15 patients were treated with Cidofovir. Dose-limiting toxicities occurred in 2/6 patients at the 6.5 mg/kg dose level (G3 proteinuria, and G3 acute pyelonephritis with G3 febrile neutropenia). No toxicity occurred at the 5 mg/kg dose level, but only 3 patients received this dose due to trial interruption because of low accrual. The most frequent G3-4 adverse effects observed during the trial were: abdominal pain (n=3), infection (n=2), leuckoneutropenia (n=2), and others (n=6). No toxic death or major renal side effect occurred. The best response was that 8/9 evaluable patients achieved a complete response (89%). In the intention to treat population, the 2-year overall and progression-free survival rates were 93% and 76%, respectively. Biological monitoring of HPV-related markers (decreased p16 expression, and increased p53 and pRb levels) was possible on sequential tumor biopsy samples. The genomic alterations identified were PIK3CA (n=5; one also had a KRAS mutation), and HRAS (n=1) mutations.
  
  
  CONCLUSIONS
  Cidofovir at a dose of 5mg/kg combined with chemoradiotherapy appeared tolerable and yielded tumor regressions. Due to early trial interruption, the RP2D was not confirmed.
authors.affiliation: Department of Radiation Oncology, Gustave Roussy Cancer Campus, Paris-Sud University, Villejuif, France.|Drug Development Department (DITEP), Gustave Roussy Cancer Campus, Paris-Sud University, Villejuif, France.|Paris-Sud University, Kremlin-Bicêtre Medical University, DHU TORINO, SIRIC SOCRATES, LABEX LERMIT, Le Kremlin-Bicêtre, France.|INSERM U1030 Molecular Radiotherapy, Gustave Roussy Cancer Campus, Villejuif, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Deutsch
authors.affiliation: Department of Radiation Oncology, Gustave Roussy Cancer Campus, Paris-Sud University, Villejuif, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Haie-Meder
authors.affiliation: Biostatistics and Epidemiology Unit, Gustave Roussy Cancer Campus, Villejuif, France.
authors.forename: Mohamed Amine
authors.initials: MA
authors.lastname: Bayar
authors.affiliation: INSERM U1030 Molecular Radiotherapy, Gustave Roussy Cancer Campus, Villejuif, France.
authors.forename: Michele
authors.initials: M
authors.lastname: Mondini
authors.affiliation: Department of Medical Biology and Pathology, Translational Research Laboratory and Biobank (UMS3655 CNRS/US23 INSERM), INSERM Unit U981, Villejuif, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Laporte
authors.affiliation: Department of Radiation Oncology, Gustave Roussy Cancer Campus, Paris-Sud University, Villejuif, France.
authors.forename: Renaud
authors.initials: R
authors.lastname: Mazeron
authors.affiliation: Department of Medical Biology and Pathology, Translational Research Laboratory and Biobank (UMS3655 CNRS/US23 INSERM), INSERM Unit U981, Villejuif, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Adam
authors.affiliation: Drug Development Department (DITEP), Gustave Roussy Cancer Campus, Paris-Sud University, Villejuif, France.
authors.forename: Andrea
authors.initials: A
authors.lastname: Varga
authors.affiliation: Department of Clinical Research, Gustave Roussy Cancer Campus, Paris-Sud University, Villejuif, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Vassal
authors.affiliation: Department of Radiation Oncology, Institut de cancérologie de la Loire-Lucien Neuwirth, Saint-Priest en Jarez, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Magné
authors.affiliation: Department of Radiation Oncology, Gustave Roussy Cancer Campus, Paris-Sud University, Villejuif, France.|INSERM U1030 Molecular Radiotherapy, Gustave Roussy Cancer Campus, Villejuif, France.
authors.forename: Cyrus
authors.initials: C
authors.lastname: Chargari
authors.affiliation: Biostatistics and Epidemiology Unit, Gustave Roussy Cancer Campus, Villejuif, France.|Inserm U1018 Centre for Research in Epidemiology and Population Health, Paris-Sud University, Villejuif, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Lanoy
authors.affiliation: Drug Development Department (DITEP), Gustave Roussy Cancer Campus, Paris-Sud University, Villejuif, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Pautier
authors.affiliation: Department of Radiation Oncology, Gustave Roussy Cancer Campus, Paris-Sud University, Villejuif, France.|Drug Development Department (DITEP), Gustave Roussy Cancer Campus, Paris-Sud University, Villejuif, France.|INSERM U1030 Molecular Radiotherapy, Gustave Roussy Cancer Campus, Villejuif, France.
authors.forename: Antonin
authors.initials: A
authors.lastname: Levy
authors.affiliation: Drug Development Department (DITEP), Gustave Roussy Cancer Campus, Paris-Sud University, Villejuif, France.|Paris-Sud University, Kremlin-Bicêtre Medical University, DHU TORINO, SIRIC SOCRATES, LABEX LERMIT, Le Kremlin-Bicêtre, France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001918:Brachytherapy / Q000379:methods; D016190:Carboplatin / Q000008:administration & dosage; D059248:Chemoradiotherapy / Q000379:methods*; D000077404:Cidofovir; D003596:Cytosine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D005260:Female; D006801:Humans; D008875:Middle Aged; D063065:Organophosphonates / Q000008:administration & dosage* / Q000009:adverse effects; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000009:adverse effects; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy / Q000821:virology
chemical_list: D000998:Antiviral Agents; D063065:Organophosphonates; D011838:Radiation-Sensitizing Agents; D003596:Cytosine; D016190:Carboplatin; D000077404:Cidofovir
keywords: Cidofovir; HPV; cervix cancer; phase I; radiotherapy