Phase I/II study of oral etoposide plus GM-CSF as second-line chemotherapy in platinum-pretreated patients with advanced ovarian cancer

Abstract

The aim of this phase I/II study was to determine the maximum tolerated dose (MTD) and the dose-limiting toxicities of chronic oral etoposide given on days 1 -10 followed by rescue with subcutaneous (s.c.) granulocyte-macrophage colony-stimulating factor (GM-CSF) on days 12 -19 as second-line chemotherapy in platinum-pretreated patients (pts) with advanced ovarian carcinoma. Cohorts of three to six pts were treated with doses of oral etoposide from 750 mg m À2 cycle À1 escalated to 1250 mg m À2 cycle À1 over 10 days, every 3 weeks. Subcutanous GM-CSF, 400 mg once daily, days 12 -19, was added if dose-limiting granulocytopenia was encountered. In total, 18 pts with a median Karnofsky index of 80% (range, 70 -100%) and a median time elapsed since the last platinum dose of 10 months (range, 1 -24 months), 30% of whom showed visceral metastases, were treated at four dose levels (DLs) of oral etoposide on days 1 -10 of each cycle as follows: DL 1, 750 mg m À2 cycle À1 , without GM-CSF, three pts; DL 2, 1000 mg m À2 cycle À1 , without GM-CSF, three pts; DL 3, 1000 mg m À2 cycle À1 , with GM-CSF, six pts; and DL 4, 1250 mg m À2 cycle À1 , with GM-CSF, six pts. All pts were assessable for toxicity and 16 pts for response. Dose-limiting toxicity (DLT) was reached at DL 4 by three of six pts, showing World Health Organization (WHO) toxicity grade 4. One patient died from gram-negative sepsis associated with granulocytopenia grade 4. Two more pts developed uncomplicated granulocytopenia grade 4. Thus, we recommend that DL 3 can be used for further phase II evaluation (i.e. oral etoposide 1000 mg m À2 cycle À1 , days 1 -10, followed by s.c. GM-CSF 400 mg, days 12 -19). The clinical complete or partial responses in each patient cohort were: DL 1, one of three pts; DL 2, one of three pts; DL 3, three of five pts; and DL 4, two of five pts. In conclusion, in this phase I/II study, we defined the MTD and the dose recommended for the therapy with oral etoposide given over 10 days followed by s.c. GM-CSF in platinumpretreated patients with advanced ovarian cancer. Our data demonstrate encouraging activity of this regimen and strongly support its further investigation in a phase II study.

Immunotherapy with Chimeric NKG2D Receptors Leads to Long-Term Tumor-Free Survival and Development of Host Antitumor Immunity in Murine Ovarian Cancer

“…In addition, chNKG2D T cell-derived GM-CSF, a molecule involved in the recruitment and activation of APCs, also had a role in tumor reduction. Ongoing clinical trials in ovarian cancer include administering GM-CSF to patients, and some trials that have been completed showed efficacy when GM-CSF was provided alone or in combination with other treatments such as chemotherapy (34,35). Thus, both direct cytotoxicity and cytokine secretion by chNKG2D T cells are involved in complete antitumor efficacy.…”

Combined prophylactic and therapeutic cancer vaccine: Enhancing CTL responses to HPV16 E2 using a chimeric VLP in HLA‐A2 mice

“…[41][42][43] Therefore, they may be used for VLP vaccine to enhance the CTL response. Several studies reported the ability of GM-CSF to enhance the magnitude of CTL in vivo.…”

Local Applications of GM‐CSF Induce the Recruitment of Immune Cells in Cervical Low‐Grade Squamous Intraepithelial Lesions

“…Even if GM-CSF was already used in clinical trials [14][15][16] , we performed pre-clinical studies because GM-CSF was described to mildly stimulate the growth of HaCat keratinocyte cell line 22 . We confirmed previous results showing the stimulation of HaCat cell proliferation and a slight increased growth of normal keratinocytes, but no significant effect was detected with 4 different HPV + cell lines (Fig.…”

“…Manna et al 13 have also demonstrated a direct tumoricidal effect of DC on breast carcinoma cells. The safety of GM-CSF injected subcutaneously 14,15 or intradermally 16 to patients with cancer was previously evaluated, but to our knowledge, the tolerability of topical GM-CSF applications on a mucosal surface has never been assessed.…”