Annals of Oncology 14:1682-1687, 2003
© 2003 European Society for Medical Oncology
Original Paper |
Phase I clinical study of infusional 5-fluorouracil with oxaliplatin and gemcitabine (FOG regimen) in patients with solid tumors
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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 Top Abstract IntroductionPatients and methodsResultsDiscussionReferences |
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Background:
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 450–650 mg/m2. Oxaliplatin was administered on day 1 over 2 h at 85–130 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-fluorouracil–oxaliplatin–gemcitabine 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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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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Gemcitabine (2'2'-difluorodeoxycytidine; Gemzar®; Eli Lilly, Indianapolis, IN, USA) is a pyrimidine nucleoside analog that is activated by intracellular phosphorylation to the active diphosphate and triphosphate forms. The triphosphate form induces DNA chain termination when incorporated during DNA replication [1], whereas the diphosphate form inhibits ribonucleotide reductase. 5-Fluorouracil (5-FU; Adrucil®; Pharmacia and Upjohn, Kalamazoo, MI, USA) is an antimetabolite the cytotoxicity of which is dependent on the relative concentrations of the pool of deoxynucleotides within the cell [2]. The inhibition of ribonucleotide reductase by gemcitabine results in the depletion of cellular deoxyuridine monophosphate (dUMP) pools and greater competitive inhibition of thymidylate synthase by the 5-fluoro-dUMP [3–5]. Preclinical models have demonstrated synergy between these two drugs [6, 7] and clinical trials have demonstrated feasibility [8].
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 [15–18].
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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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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Patient selection
Eligible patients were required to have histologically confirmed advanced solid malignancy, age
18 years, measurable or evaluable disease, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 
2, and adequate organ function as defined by absolute neutrophil count (ANC) 1500/µl, platelet count 100 000/µl, and bilirubin and creatinine within institutional normal limits. Patients were excluded if they had brain metastases, allergy to platinum compounds or clinical neuropathy, as were pregnant or nursing women. Patients of childbearing age were required to practice contraception. Patients were required to discontinue all previous chemotherapy and radiotherapy for at least 4 weeks prior to study initiation. All patients gave written informed consent approved by the Institutional Review Boards at participating institutions.
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 250–500 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 manufacturer’s 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 3–4 neurological toxicity. Doses of gemcitabine and 5-FU required modification for any grade 3–4 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 0–1.
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Results |
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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Patient characteristics
Forty-five patients with a median age of 62 years (range 29–85) and ECOG PS of 0–1 (96%) were enrolled (Table 1). Thirty-two patients (71%) had received prior chemotherapy and 21 (47%) had a primary diagnosis of colorectal cancer. Forty-five patients were assessable for toxicity and 39 for response.
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DLT and RPTD
In cycle 1, no DLT was observed in the first four dose cohorts (Table 2). At dose level 5, two of four (50%) patients experienced cycle 1 DLT. One patient developed grade 3 diarrhea despite maximal antidiarrheal therapy. A second patient developed grade 4 hyperglycemia and hypernatremia during week 3 of cycle 1. Since dose level 5 defined the MTD, dose level 4 was expanded to accrue 24 additional patients. At this dose, nine of 26 (35%) patients experienced cycle 1 DLT. No cycle 1 DLT was observed at dose level 3 (n = 1). However, among the six patients treated in cycle 2 and beyond (21 cycles) who underwent dose reduction to dose level 3, three (50%) experienced recurrent grade 3 thrombocytopenia. Therefore, dose level 2 was expanded to define the RPTD. At this dose level, two of 13 (15.4%) patients experienced cycle 1 DLT. One patient developed grade 3 diarrhea, dehydration and sepsis on day 15 of cycle 1. This patient died after 9 days in spite of antibiotic therapy. A second patient developed grade 4 neutropenia and grade 3 stomatitis in week 3 of cycle 1.
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Toxicities
Details of toxicities across all cycles are give in Table 3. Diarrhea was the most frequently observed non-hematological toxicity, occurring within the first 2 weeks of therapy and resolving before the next cycle. Mild nausea was a common toxicity across all dose levels. Vomiting was less frequent than nausea, and was the DLT in one patient treated at dose level 4. Fatigue was frequently reported.
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Neurotoxicity manifested predominantly as sensory neuropathy and paresthesias. Motor dysfunction and ataxia was observed in patients treated at the higher doses and with multiple infusions of oxaliplatin. Four patients experienced grade 3 neuropathy. One patient experienced suicidal ideation with the first cycle of chemotherapy at dose level 4. Although this patient had a history of depression, he had no prior suicidal episodes.
The incidence of grade 3–4 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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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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The present work constitutes the first human study to examine the combination of the triplet regimen of 5-FU, oxaliplatin and gemcitabine (FOG regimen). Although escalation proceeded to five dose levels, based on cumulative toxicities beyond cycle 1 the RPTD was defined at dose level 2. This illustrates the point of differentiating RPTD based on acute (cycle 1) versus chronic (cycle 2 and beyond) toxicities. With only one patient treated at each dose level, the NCI accelerated phase I design [21] possibly underestimates the true toxicity of a multidrug regimen. We therefore propose that a downfall of this design as applied to multidrug chemotherapy regimens is the lack of predictability of a safe dose for long-term repeated dosing. The statistically significant lower mean ANC and platelet nadir with repeated dosing suggests cumulative myelotoxicity.
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 3–4 neutropenia and thrombocytopenia were observed in 6% and 4% of the cycles administered, respectively. Grades 3–4 non-hematological toxicity included diarrhea, stomatitis, fatigue, vomiting and neuropathy. In studies that evaluated two-drug combinations, the incidence of grade 3–4 toxicities was similar [8, 13, 15, 16, 23–25]. 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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We would like to thank Elliott Nazario for his expert data assistance. This study was supported by National Institutes of Health grants CA 13330-30, U01 CA76642-01, R03 CA 86807, CA 39821 and GCRC M01 RR00096 (to F.M.). S.M. is supported by a clinical investigator award from the Damon Runyon Cancer Research Foundation (CI: 15-02) and an Institutional Research Grant from the American Cancer Society (ACS IRG 9824701). This study was subject to a final audit by the Clinical Data Update System (CDUS) of the National Cancer Institute (30 April 2003).
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Footnotes |
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+ Correspondence to: Dr S. Mani, Weiler Hospital, Department of Oncology, 1825 Eastchester Road, Bronx, NY 10461, USA. Tel: +1-718-904-2529; Fax: +1-718-904-2830; E-mail: smani{at}montefiore.org
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