1 Department of Oncology, Albert Einstein Comprehensive Cancer Center and Montefiore Medical Center, New York, NY; 2 Albert Einstein College of Medicine, New York, NY; 3 New York University Comprehensive Cancer Center, New York, NY; 4 University of Pittsburgh Cancer Institute, Pittsburgh, PA; 5 National Cancer Institute, Bethesda, MD; 6 Sanofi-Synthelabo Inc., Malvern, PA; 7 Eli-Lilly, Indianapolis, IN, USA
Received 12 May 2003; accepted 7 August 2003
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Abstract |
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The aim of this study was to determine the maximum tolerated dose, recommended phase II dose (RPTD) and toxicities of the FOG regimen (infusional 5-fluorouracil, oxaliplatin, gemcitabine).
Patients and methods:
Patients with advanced solid tumors were treated in an accelerated titration scheme. 5-Fluorouracil was administered intravenously at 200 mg/m2/day for 14 days and repeated every 21 days (one cycle). Gemcitabine was administered on days 1 and 8 over 30 min at 450650 mg/m2. Oxaliplatin was administered on day 1 over 2 h at 85130 mg/m2. For cycles 1, 3 and beyond, gemcitabine followed oxaliplatin; for cycle 2, gemcitabine preceded oxaliplatin.
Results:
Forty-five and 39 patients were assessable for toxicity and response, respectively. Cycle 1 dose-limiting toxicities (DLT) included neutropenia, thrombocytopenia and diarrhea. No DLT was observed in cycle 1 at the first four dose levels (DL). At DL-5, two of four (50%) patients experienced DLT in cycle 1. Expanding DL-4, nine of 26 (35%) patients experienced DLT in cycle 1. Because recurrent grade 3 toxicities were observed in three of six (50%) patients at DL-3, DL-2 was considered the RPTD. At the RPTD, three patients had a partial response (response rate 23%).
Conclusions:
The RPTD for the 5-fluorouraciloxaliplatingemcitabine combination is 200/100/450 mg/m2. This novel regimen has demonstrated activity in advanced solid tumors and merits further investigation.
Key words: 5-fluorouracil, gemcitabine, oxaliplatin, phase I, solid tumors
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Introduction |
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Oxaliplatin (trans-L-1,2-diaminocyclohexane oxalatoplatinum; Eloxatin®; Sanofi-Synthelabo, Malvern, PA, USA) is a novel platinum derivative with a 1,2-diaminocyclohexane carrier ligand [9, 10]. Oxaliplatin exhibits synergic cytotoxicity in combination with 5-FU or gemcitabine in gastrointestinal tumor cell lines [11, 12], and interestingly, exhibits sequence dependence with gemcitabine [12]. Oxaliplatin in combination with infusional 5-FU has shown superior response and survival compared with bolus 5-FU and irinotecan (Camptosar®; Pharmacia and Upjohn) [13, 14]. Combination studies of oxaliplatin and gemcitabine have demonstrated feasibility and efficacy [1518].
To date, a triplet combination regimen comprising 5-FU, oxaliplatin and gemcitabine has not been investigated. The non-overlapping clinical toxicity for these drugs, and the synergic cytotoxicity observed in preclinical models using dual combinations, forms the rationale for such a trial [4, 8, 11, 12].
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Patients and methods |
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Drug treatment
Oxaliplatin was supplied by the Pharmaceutical Management Branch of the Cancer Therapy Evaluation Program, National Cancer Institute (NCI), as a freeze-dried powder for infusion in vials containing 50 or 100 mg. This was reconstituted, and subsequently diluted, in an infusion solution of 250500 ml of 5% glucose. Gemcitabine and 5-FU were obtained from commercial sources as 20 and 50 mg/ml vials, respectively, and were formulated as per the manufacturers recommendations [19, 20].
All patients were administered 5-FU at 200 mg/m2/day as a fixed daily intravenous infusion using a battery operated continuous ambulatory infusion pump (SIMS Deltec, Inc., St Paul, MN, USA) for seven consecutive days. The cassettes were changed every week for two consecutive weeks (14 days) followed by a 1 week rest period. Oxaliplatin was administered as a 2-h infusion on day 1 of each cycle at doses ranging from 85 to 130 mg/m2. Gemcitabine was administered as a 30-min infusion on days 1 and 8 of each cycle at doses ranging from 450 to 650 mg/m2. In cycles 1, 3 and beyond, gemcitabine was administered immediately after the completion of the oxaliplatin infusion. In cycle 2, gemcitabine preceded oxaliplatin.
Study design and dose escalation
This trial was an open-label, multicenter, non-randomized trial and used the NCI accelerated dose titration design without intrapatient dose escalation (design 4A) [21]. The starting doses of gemcitabine and oxaliplatin were 450 and 85 mg/m2/day, respectively. These doses were selected based on tolerable toxicities observed at 25% of the individual drug recommended phase II dose (RPTD) when combined with infusional 5-FU [8, 13]. There were five dose cohorts studied, each defining the effect of a single drug dose escalation. Twelve to 24 additional patients could be treated at the RPTD to gain further experience.
Study end points and definition of toxicities
The primary end point of the study was to define the maximum tolerated dose (MTD) and characterize toxicities associated with the FOG regimen (infusional 5-FU, oxaliplatin, gemcitabine). MTD was defined as that dose at which at least 33% of six patients experienced cycle 1 dose-limiting toxicity (DLT). RPTD was defined as one dose level below the MTD. DLT was defined using the NCI common toxicity criteria (CTC) (version 2.0) as any one or more of the following: grade 4 neutropenia or thrombocytopenia lasting 5 days; grade 4 neutropenia associated with grade
2 fever; grade
3 neuropathy that did not resolve prior to initiation of next cycle; grade
3 non-hematological toxicity related to study drugs; grade
3 nausea, vomiting or diarrhea that occurred despite maximal supportive therapy; or cycle 2 delay of >2 weeks due to toxicity.
Patient evaluation and follow-up
All patients underwent a complete medical history, physical examination, PS evaluation, complete blood count and chemistry profile within 2 weeks of study initiation and prior to the start of each cycle. Complete blood count and toxicity assessment was performed weekly. Imaging studies for tumor measurements were performed within 4 weeks of initiation of study drugs and after every two cycles.
The WHO criteria were used for response evaluation [22]. A complete response (CR) was defined as disappearance of all measurable lesions at two examinations at least 4 weeks apart. Partial response (PR), minimal response (MR), stable disease and progressive disease were defined, respectively, as 50% decrease,
25% and <50% decrease, <25% decrease or <25% increase, and
25% increase in the sum of bi-dimensional measurements of tumor burden. The appearance of any new lesion constituted disease progression. Response duration was the time from documentation of first response to the first date of objective progression of disease. After removal from study, all patients underwent follow-up examinations and toxicity assessments every 2 months until death.
Dose modifications
Dose modification of oxaliplatin was required for any persistent grade 2, or any grade 34 neurological toxicity. Doses of gemcitabine and 5-FU required modification for any grade 34 toxicity. Grade 4 neurological toxicity required removal of the patient from the protocol. Treatment was reinitiated only when the ANC was 1500/µl, platelets were
100 000/µl, and other toxicities had resolved to grade 01.
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Results |
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The incidence of grade 34 neutropenia was 8.3% across all cycles administered. The median nadir ANC appeared to correlate with dose level (data not shown). The mean ANC nadir beyond cycle 2 (n = 144, 1343/µl) was significantly lower than the cycle 1 ANC nadir of 1850/µl (P = 0.001). There was no episode of febrile neutropenia as defined by NCI CTC version 2.0. As with neutropenia, an apparent dose-dependent effect on median platelet nadir count was observed. The mean platelet nadir beyond cycle 1 (n = 183, 74 490/µl) was significantly lower than cycle 1 platelet nadir of 142 190/µl (P <0.001). Evaluating sequence effect of gemcitabine and oxaliplatin administration, there was no significant difference between the means of cycle 1 and cycle 2 ANC and platelet nadir (P = 0.066 and 0.578, respectively). At the RPTD, one patient experienced rectal bleeding associated with grade 3 thrombocytopenia requiring platelet transfusion support. Only one patient developed grade 3 anemia during cycle 1 and required blood transfusion.
Antitumor response
Although response evaluation was not the primary end point of this study, 39 patients were evaluable for objective response. One patient had a CR, five had a PR and two had a MR, with an overall response rate (CR + PR) of 15%. One patient with metastatic colon cancer had a CR after eight cycles of treatment and is alive and disease-free 24 months after discontinuation of the study drugs, without further antineoplastic therapy. Five patients with a primary diagnosis of mesothelioma (one), colorectal (one), pancreas (two) and gastric (one) cancer had a PR. At the RPTD, three patients had a PR (colon, pancreas and mesothelioma) and one patient had an MR (colon), giving a response rate of 23%.
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Discussion |
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Another unique aspect of our study is illustrated by the sequence of drug administration. Although a sequence-dependent cytotoxicity of oxaliplatin and gemcitabine has been observed in cell culture [12], there are no reports on animal studies. We looked for large differences in normal tissue toxicity while dosing patients in two drug sequences in cycles 1 and 2. The profile and character of toxic events, and the mean ANC and platelet nadir in cycles 1 and 2, was similar. This suggests that the development of clinically relevant toxicities does not depend on the sequence of administration of oxaliplatin and gemcitabine when given in combination with infusional 5-FU.
At the RPTD in this study, grade 34 neutropenia and thrombocytopenia were observed in 6% and 4% of the cycles administered, respectively. Grades 34 non-hematological toxicity included diarrhea, stomatitis, fatigue, vomiting and neuropathy. In studies that evaluated two-drug combinations, the incidence of grade 34 toxicities was similar [8, 13, 15, 16, 2325]. These data, comparing the FOG regimen with multiple doublet combinations, suggest that this triplet therapy may be tolerated equally well.
It was encouraging to observe antitumor activity at the RPTD. It is evident that this combination is feasible and tolerable. We propose that the FOG regimen warrants further phase II testing in advanced solid tumors such as mesothelioma [26], pancreatic and colorectal cancer.
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Acknowledgements |
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Footnotes |
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References |
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