Format

Send to

Choose Destination
Oncotarget. 2016 May 3;7(18):25549-57. doi: 10.18632/oncotarget.8224.

Phase I trial evaluating the antiviral agent Cidofovir in combination with chemoradiation in cervical cancer patients.

Author information

1
Department of Radiation Oncology, Gustave Roussy Cancer Campus, Paris-Sud University, Villejuif, France.
2
Drug Development Department (DITEP), Gustave Roussy Cancer Campus, Paris-Sud University, Villejuif, France.
3
Paris-Sud University, Kremlin-Bicêtre Medical University, DHU TORINO, SIRIC SOCRATES, LABEX LERMIT, Le Kremlin-Bicêtre, France.
4
INSERM U1030 Molecular Radiotherapy, Gustave Roussy Cancer Campus, Villejuif, France.
5
Biostatistics and Epidemiology Unit, Gustave Roussy Cancer Campus, Villejuif, France.
6
Department of Medical Biology and Pathology, Translational Research Laboratory and Biobank (UMS3655 CNRS/US23 INSERM), INSERM Unit U981, Villejuif, France.
7
Department of Clinical Research, Gustave Roussy Cancer Campus, Paris-Sud University, Villejuif, France.
8
Department of Radiation Oncology, Institut de cancérologie de la Loire-Lucien Neuwirth, Saint-Priest en Jarez, France.
9
Inserm U1018 Centre for Research in Epidemiology and Population Health, Paris-Sud University, Villejuif, France.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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.

KEYWORDS:

Cidofovir; HPV; cervix cancer; phase I; radiotherapy

PMID:
27016411
PMCID:
PMC5041925
DOI:
10.18632/oncotarget.8224
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Impact Journals, LLC Icon for PubMed Central
Loading ...
Support Center