Phase I–II and pharmacokinetic study of gemcitabine combined with oxaliplatin in patients with advanced non-small-cell lung cancer and ovarian carcinoma

S. Faivre1, T. Le Chevalier1, C. Monnerat1, F. Lokiec2, S. Novello1, J. Taieb1, P. Pautier1, C. Lhommé1, P. Ruffié1, L. Kayitalire3, J.-P. Armand1 and E. Raymond1,+

1 Department of Medicine, Institut Gustave-Roussy, Villejuif; 2 Pharmacokinetic Unit, Centre René-Huguenin, St-Cloud; 3 Lilly France, Saint-Cloud, France

Received 7 January 2002; accepted 14 January 2002


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

The aim of this study was to determine the toxicity profile, the recommended dose (RD) and the pharmacokinetic parameters, and to evaluate the antitumor activity of gemcitabine combined with oxaliplatin in patients with advanced non-small-cell lung cancer (NSCLC) and ovarian carcinoma (OC).

Methods:

Gemcitabine was administered as a 30-min infusion followed by a 2-h infusion of oxaliplatin, repeated every 2 weeks. Doses of gemcitabine and oxaliplatin ranged from 800 to 1500 and 70 to 100 mg/m2, respectively.

Results:

Forty-four patients (26 males, 18 females; median age 55 years) including 35 NSCLC (five platinum pretreated) and nine OC patients (all platinum pretreated) received a total of 355 cycles. All patients were evaluable for toxicity. No dose-limiting toxicity at any dose level occurred during the first two cycles; therefore, the highest dose-level of gemcitabine (1500 mg/m2) and oxaliplatin (85 mg/m2) was considered as the RD. Hematological toxicity was moderate amongst the 22 patients treated (167 cycles) at that dose level. Thirteen cycles were associated with grade 3–4 non-febrile neutropenia in six patients, and eight cycles with grade 3–4 thrombocytopenia in two patients. Other toxicities were mild to moderate, consisting of asthenia and peripheral neurotoxicity. Four of the 35 patients treated with oxaliplatin 85 mg/m2 experienced grade 3 neurotoxicity requiring treatment discontinuation at cycle 10. In the range of the doses used, gemcitabine and its main metabolite 2',2'-difluorodeoxyuridine appeared not to be affected by oxaliplatin 70–100 mg/m2. Of the 44 patients evaluable for activity, 12 NSCLC patients experienced objective responses (one complete and 11 partial responses) and three OC patients showed tumor stabilization lasting for 6 months with a 50% decrease of CA 125 level. Two partial responses (NSCLC) and one tumor stabilization (OC) occurred in platinum-resistant patients.

Conclusions:

The combination of gemcitabine and oxaliplatin could be safely administered on an out-patient schedule in patients with advanced NSCLC and OC. The RD was gemcitabine 1500 mg/m2 and oxaliplatin 85 mg/m2 every 2 weeks. Promising antitumor activity was reported in patients with NSCLC and platinum-pretreated OC, and thus, deserves further evaluation.

Key words: anti-metabolite, combination chemotherapy, diaminocyclohexane, neurotoxicity


    Introduction
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Gemcitabine (2',2'-difluoro-deoxycytidine) is structurally related to 1-ß-D-arabinofuranosylcytosine (ara-C). It inhibits cellular proliferation in S phase, and causes cells to accumulate in the G1–S phase of the cell cycle [1]. Gemcitabine showed a broad spectrum of activity against human tumor xenografts [2] and was registered for the treatment of patients with advanced pancreatic [3], non-small-cell lung (NSCLC) [4, 5] and bladder [6] cancers. Evidence of antitumor activity was also reported in ovarian carcinoma (OC) [7], with response rates ranging from 20% to 30%. Toxicity of gemcitabine was reported to be limited to mild myelosuppression, asthenia and nausea/vomiting, usually controlled using standard anti-emetic regimens. Over the last 6 years, gemcitabine has been combined with cisplatin, resulting in additive and synergistic effects in laboratory experiments using NSCLC and OC cell lines [8, 9]. Pre-clinical studies of gemcitabine–cisplatin combinations provided a rational for clinical studies, which yielded response rates ranging from 38% to 54% in advanced NSCLCs [5] and 53% to 69% in OCs [10, 11]. However, the use of this combination is hampered by dose-limiting thrombocytopenia, as well as renal, neurological and digestive toxicity [4, 5]. Therefore, new combinations that might display better toxicity profile and retain antitumor activity comparable to that of gemcitabine–cisplatin are urgently needed.

Oxaliplatin, a recent diaminocyclohexane platinum compound, acts through DNA damage [12] with partial or no cross-resistance with cisplatin in a wide range of human tumors in vitro and in vivo [13, 14]. Oxaliplatin shows potent in vitro cytotoxic activity against a large variety of human tumor specimens from patients using the human tumor cloning assay including colon, NSCLC and OC [15]. Several European phase II trials have reported encouraging activity and manageable toxicity in malignancies both sensitive and resistant to cisplatin, including colon cancer [16], OC [17, 18] and NSCLC [19]. Oxaliplatin is devoid of renal toxicity and is associated with lower hematological and digestive toxicity than cisplatin, making this compound easily manageable for out-patient combination chemotherapy. Cumulative peripheral neuropathy, consisting of cold-enhanced paresthesia, although reversible in the majority of patients, remains the main toxicity associated with oxaliplatin chemotherapy [20].

As mentioned above, gemcitabine and oxaliplatin are both active in a number of solid tumors, with no overlapping toxicity. In vitro, this combination has been demonstrated to be synergistic in several human cancer cell lines, with a sequence-dependency that favors the administration of gemcitabine followed by oxaliplatin [21]. The basic mechanisms of this synergistic interaction have not yet been elucidated, but it is likely to take place at the DNA level, as the incorporation of the anti-metabolite into DNA may increase platinum binding to DNA [21]. DNA mismatch repair (MMR) protein complexes (including hMLH1 and hMSH2) play a predominant role in genomic stability and are an important factor in cisplatin and carboplatin resistance. In contrast to those of cisplatin, adducts formed by oxaliplatin are not recognized by the MMR system, leading to similar toxicity in MMR-proficient and -deficient cell lines and xenografts [22]. Moreover, the loss of hMLH1 expression has been discussed in ovarian tumor cells that developed resistance to cisplatin [23]. Similarly, gemcitabine showed more potent cytotoxic effects in MMR-deficient than in MMR-proficient cells [24]. Therefore, the combination of gemcitabine with oxaliplatin may maintain antitumor activity in both MMR-proficient and MMR-deficient cancer cells that potentially express resistance to cisplatin.

Based on the above rationale, we designed a phase I–II dose escalation study in tumors that were thought to be sensitive to either gemcitabine or to oxaliplatin alone, such as advanced NSCLC and OC. The goal of this trial was to determine the recommended dose (RD) of this combination given on an every other week out-patient schedule. Based on the literature and clinical experience, the every other week schedule was selected in order to optimize synergistic interaction between gemcitabine and oxaliplatin, and to allow the maintenance of gemcitabine dose intensity. Secondary end points consisted of describing the toxicity profile, the pharmacokinetic parameters and the antitumor activity of this combination.


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient selection criteria
Patients with histologically or cytologically confirmed diagnosis of OC or NSCLC were considered for this study. Staging and pretreatment characteristics included: (i) patients with chemotherapy-naïve stage IIIB or IV NSCLC or with recurrent NSCLC who had received no more than two previous lines of chemotherapy; (ii) patients with FIGO (International Federation of Gynecology and Obstetrics) [25] stage III or IV ovarian carcinoma who had received no more than two previous chemotherapy regimens including cisplatin or carboplatin; (iii) measurable/evaluable lesions located outside irradiation fields or elevation of serum CA 125 level above the upper limit of normal (ULN); (iv) age >=18 years; (v) WHO performance status of 0–2; (vi) life expectancy of >=3 months; (vii) no chemotherapy within 4 weeks prior to entering the study (6 weeks for carboplatin or mitomycin C); (viii) adequate hematopoietic (granulocytes count >=2000/µl, platelet count of >=100 000/µl and hemoglobin level >=9 g/dl), hepatic [total serum bilirubin level of <=1.5 x ULN; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels <=3 x ULN or <=5 x ULN in the case of liver metastasis] and renal function (serum creatinin <=1.25 x ULN); and (ix) the use of reliable contraception for women of child-bearing age. Specific exclusion criteria included prior treatment with gemcitabine or oxaliplatin, and evidence of grade >=1 peripheral neuropathy. According to institutional and national guidelines, all patients gave written informed consent before receiving treatment.

Study design
This study was an open-label phase I–II dose escalation single center study. This study was performed according to the French national guidelines, conducted in compliance with the Helsinki declaration and following good clinical practice. The protocol was approved by the ethical review committee of the University of Kremlin-Bicêtre, France.

Pretreatment and follow-up examination
Baseline investigations before treatment included clinical history, physical exam, complete white blood cell count with differential, serum chemistry analysis (sodium, potassium, chloride, bicarbonate, calcium, phosphorus, magnesium, creatinine, urea, uric acid, bilirubin, AST, ALT, alkaline phosphatase, total protein and albumin), electrocardiogram and chest X-ray. Tumor measurement was assessed by clinical exam, ultrasound, computed tomography (CT) scan and/or MRI as appropriate. Baseline CA 125 assessment was performed for OC patients. Physical exam, evaluation of drug-related toxicity according to the WHO Common Toxicity Criteria (CTC) [26], blood hematology and biochemistry were repeated on a weekly basis. CA 125 was repeated each month. In patients with measurable disease, response evaluation was performed according to the WHO criteria [27] every four cycles (every 2 months of treatment). The occurrence of an objective response had to be confirmed by a second evaluation 1 month after the first documentation of the response. Survival was calculated using the Kaplan–Meier method and comparisons used the log rank test. Treatment was continued until evidence of disease progression or occurrence of an unacceptable toxicity.

Drug administration
Gemcitabine was supplied by Lilly France (St-Cloud, France) and oxaliplatin by Sanofi-Synthelabo (Gentilly, France). Gemcitabine was diluted with normal saline to obtain a final solution containing 10 mg/ml or less, and given as an intravenous infusion over 30 min, followed by oxaliplatin diluted in 5% glucose solution given intravenously over 2 h. Both drugs were administered every 2 weeks. In all patients, pre-medication consisted of 8 mg i.v. ondansetron combined with 80 mg i.v. methylprednisolone, administered 30 min before the start of gemcitabine infusion.

Dose-escalation procedures
The starting doses of gemcitabine (800 mg/m2 every 2 weeks) and oxaliplatin (70 mg/m2 every 2 weeks) were determined on the basis of literature and previous clinical data. Six dose levels (I–VI) were explored escalating gemcitabine/oxaliplatin doses as follows: 800/70, 1000/70, 1000/85, 1200/85, 1200/100 and 1500/85 mg/m2. No intra-patient dose escalation was allowed. In this study, dose-limiting toxicity (DLT) was defined, using the WHO CTC [26], as any of the following events occurring during the first two cycles of treatment (first month of treatment): (i) grade 4 neutropenia lasting >7 days and/or associated with fever >=38.5°C; (ii) grade 4 thrombocytopenia; (iii) grade 3 thrombocytopenia associated with hemorrhage; (iv) grade 3 non-hematological toxicity (excluding alopecia, nausea and vomiting); and (v) persistence of non-hematological toxicity (excluding alopecia) of CTC >2 at the scheduled retreatment. For oxaliplatin-induced neurotoxicity, the oxaliplatin-specific scale [28] was used. In the latter, grade 2 is described as permanent paresthesia between cycles, and grade 3 as permanent paresthesia associated with minor functional impairment. Grade 3 neuropathy was considered as a DLT. For each dose level, if one of the initial three patients showed a limiting toxicity, further evaluation was performed by treating three additional patients. The maximal tolerated dose (MTD) was defined as the dose level at which at least two of three, or three of six patients experienced DLT during the first two cycles. The RD was defined as the dose immediately below the MTD. If the MTD could not be reached at dose level VI, then the latter would be considered as the RD.

Pharmacokinetic study
Pharmacokinetic parameters of gemcitabine in plasma were analyzed at the first cycle (17 patients, starting at a dose level of 800 mg/m2). Peripheral blood (5 ml) from distant site of gemcitabine infusion was collected in heparinized tubes in the presence of tetrahydrouridine (Calbiochem, San Diego, CA, USA) immediately before drug administration, and 30 min, and 3, 4, 6, 8, 12 and 24 h from the start of the infusion (eight blood samples). After performing preliminary analysis in the first 10 patients, additional blood samples were drawn at 60 and 90 min, and 2 h from the start of the infusion for the dose level gemcitabine 1500 mg/m2 (11 blood samples in seven patients). Tetrahydrouridine was added to samples to inhibit the conversion of gemcitabine to its metabolite 2',2'-difluorodeoxyuridine (dFdU) by deoxycytidine deaminase. Whole blood samples were centrifuged immediately (3500 rpm for 10 min) and plasma was frozen at –20°C for subsequent analysis.

The levels of gemcitabine and its main deaminated metabolite dFdU were determined by the method described previously by Freeman et al. [29]. Separation and quantification of gemcitabine and dFdU in the plasma was achieved with an isocratic reverse-phase high-performance liquid chromatography (HPLC) system that consisted of a 515 Waters pump (Milford, MA, USA), a 484 Waters detector set at 272 nm and a 717+ Waters automatic injection system. The samples were injected onto a µBondapack C18 Waters column (particle size 10 µm) with a flow rate of 1 ml/min. Peak area were quantified using the data acquisition program Millenium, version 3.2 (Waters). Retention times of gemcitabine and dFdU were 4.8 and 6 min, respectively. The limit of quantification was 50 ng/ml for both gemcitabine and dFdU.

The area under the concentration–time curve (AUC) from t0 (start of infusion) to infinity t{infty} was calculated using the linear trapezoidal rule for non-compartmental analysis according to the Micropharm computer program (S. Urien, INSERM, St-Cloud, France). At doses ranging from 800 to 1200 mg/m2, available data allowed calculation of pharmacokinetic parameters Cmax, AUC and terminal half life only for dFdU. At the dose gemcitabine 1500 mg/m2, both gemcitabine and dFdU pharmacokinetic parameters could be calculated.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient characteristics
A total of 44 patients, whose characteristics are summarized in Table 1, were treated with gemcitabine and oxaliplatin through six dose levels and a total of 355 cycles (Table 2). Thirty-five patients had NSCLC, including 25 (71%) patients with stage IV and 10 (29%) patients with stage IIIB disease. Among these patients, five were platinum pretreated, and two patients had disease progression within the 6 months following a previous cisplatin-based line of therapy. Nine patients had OC, including four patients with stage IV disease. All patients with ovarian carcinoma were paclitaxel- and platinum-pretreated, and two patients were considered platinum resistant as defined by disease progression during or within 6 months after cisplatin- or carboplatin-based chemotherapy. The median number of metastatic sites was one (range one to three). The median number of cycles administered was eight (range two to 16). All the patients were evaluable for toxicity. Dose escalation proceeded initially as indicated in Table 2. The absence of acute toxicity during the first two cycles, and the occurrence of cumulative asthenia and neurological toxicity from cycles 6 to 10, prompted us to limit the dose escalation of oxaliplatin to 85 mg/m2 and to explore dose levels IV and VI in at least six patients for eight cycles to define the RD for future phase II trials.


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Table 1. Patient characteristics
 

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Table 2. Dose-escalation scheme
 
Hematological toxicity
Mild to moderate myelosuppression was associated with the gemcitabine–oxaliplatin administration in several patients. No hematological DLT was observed during the first two cycles. Hematological toxicity is summarized in Table 3. None of the grade 3–4 hematological toxicity occurring among repeated cycles was associated with sepsis or bleeding. Grade 3 neutropenia was observed in one patient treated at dose level I (at cycles 8, 9 and 10), in two patients treated at dose level IV (one patient at cycle 4 without recurrence during further cycles, and one patient at cycles 11 and 12), and in five patients treated at dose level VI (one patient at cycle 2 without recurrence during further cycles; one patient at cycles 4, 8 and 10; one patient at cycles 7 and 9; one patient at cycle 9; and one patient at cycles 7, 8, 9, 11 and 13). Only one non-febrile grade 4 neutropenia lasting <7 days was observed at cycle 2 in a patient treated at dose level VI, without recurrence at subsequent cycles. Grade 3 thrombocytopenia was observed at cycle 1 in one patient treated at dose level IV, without recurrence at subsequent cycles, and in one patient treated at dose level V at cycle 13. In two patients treated at dose level VI, grade 3–4 thrombocytopenia was observed, respectively, at cycles 8 and 10, and at cycles 3, 4, 5, 6, 9 and 10. These two episodes of grade 3–4 thrombocytopenia necessitated treatment delay. Overall, at dose level VI, grade 3–4 neutropenia occurred in 7.8% of cycles and grade 3–4 thrombocytopenia in 4.8% of cycles.


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Table 3. Worst hematological toxicities per patient
 
The duration of neutropenia and thrombocytopenia was usually <7 days, with recovery to normal in time for the subsequent planned infusion. Overall, sustained thrombocytopenia led to a total of 25 cycles being postponed, including 15 cycles at dose level VI. Grade 3–4 neutropenia and thrombocytopenia generally occurred between cycles 4 and 8, but did not appear to be more frequently observed after repeated cycles. Reversible grade 3 anemia was reported in one and two patients at dose levels IV and VI, respectively. No significant difference in terms of hematological toxicity was observed between previously treated and chemotherapy-naïve patients.

Non-hematological toxicity
Nausea/vomiting was mainly restricted to grade 2 and occurred in one, one, four, three and eight patients treated at dose levels I, II, IV, V and VI, respectively. Nausea/vomiting was satisfactorily treated and prevented by the addition of metoclopramide to the ondansetron/steroid cocktail for subsequent cycles.

No mucositis or alopecia was reported. Grade 1–2 asthenia was frequently observed (45% of patients, 18% of cycles) and appeared to increase with the number of cycles. Grade 3 asthenia was reported in a total of three patients treated, respectively, at dose levels I (one patient at cycle 7), IV (one patient at cycle 3 who recovered for further cycles) and VI (one patient at cycle 6). Sustained grade 3 asthenia caused treatment discontinuation in two patients, aged 57 and 78 years. One patient presented a gemcitabine-related grade 2 flu-like syndrome.

As expected with oxaliplatin, cold-enhanced paresthesia were reported in several patients receiving four or more cycles. Although not significant, an increasing severity trend was observed with higher doses (85 versus 70 mg/m2). Paresthesia were cumulative, grade 3 being observed after a median of 10 cycles (range 10–12). Figure 1 shows the probability of occurrence of the neurotoxicity as a function of time from the first oxaliplatin administration for all patients treated in this study. Grade 3 peripheral neurotoxicity was reported in four patients (9%), with minor functional impairment occurring at cycle 9–11 that prompted us to stop oxaliplatin. Among these four patients with NSCLC, three were chemotherapy-naïve and one had previously received a cumulative dose of cisplatin of 200 mg/m2. With a follow-up ranging from 6 to 12 months, all but one patient with grade 3 neurotoxicity recovered partially or completely. Table 4 summarizes worst non-hematological toxicity per patient according to dose level.



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Figure 1. Probability of neurotoxicity occurrence according to the time from the first oxaliplatin administration in all patients of the study. The grading refers to the oxaliplatin-specific scale [28]. Curves were similar for patients treated at oxaliplatin 85 mg/m2 and among all patients.

 

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Table 4. Worst non-hematological toxicities per patient
 
Determination of MTD and RD
As mentioned above, the absence of acute toxicity during the first two cycles and the occurrence of cumulative asthenia and peripheral neurotoxicity from cycles 6–10 prevented use of the classical definition of MTD. We decided that for safety reasons the RD for the combination should follow-up at least six patients for eight cycles, and should not go beyond the RDs for both oxaliplatin (85 mg/m2 every 2 weeks) and gemcitabine (3000 mg/m2 every 4 weeks). Therefore, dose level VI was expanded up to 22 patients and considered as the RD for phase II studies, since no acute toxicity and only three cumulative DLTs (grade 4 thrombocytopenia at cycle 5, grade 3 asthenia at cycle 6 and grade 3 neurotoxicity at cycle 10) occurred at this dose level. Among 167 cycles administrated at the recommended dose, only 15 cycles were delayed because of a sustained thrombocytopenia, allowing a median dose intensity of 99% (range 73% to 101%) for gemcitabine and 99% (range 78% to 101%) for oxaliplatin to be reached.

Pharmacokinetic study
Because of the short terminal half-life (t) of gemcitabine ranging from 10 to 20 min [30], only the end of infusion peak plasma levels of gemcitabine could be measured for dosage ranging from 800 to 1200 mg/m2. For gemcitabine, the pharmacokinetic profiles could only be obtained for the highest dosage (1500 mg/m2) due to the limit of quantification of the HPLC method (50 ng/ml). The calculated pharmacokinetic parameters were: Cmax 34.7 ± 19.1 µg/ml; AUC 21.3 ± 11.4 µg/ml·h; clearance 86.2 ± 37.9 l/h/m2; and t 0.39 ± 0.17 h.

Peak gemcitabine levels in the plasma showed important interpatient variability, with a median value of 34.7 µg/ml (range 18.6–59.8 µg/ml) at the recommended dose level of 1500 mg/m2.

Because of the longer persistence of the deaminated inactive product dFdU in plasma, a full pharmacokinetic profile could be evaluated (Figure 2). Peak dFdU concentrations were observed at the end of gemcitabine infusion and an increasing trend was observed with the dose. The AUC of dFdU in plasma showed inter-patient variability (Table 5). The AUC of dFdU was not correlated with the gemcitabine dose (r2 = 0.221). Although a limited number of patients underwent pharmacokinetics within dose levels I to V, it seemed that saturation occurred for gemcitabine metabolization into dFdU by deoxycytidine kinase (Figure 3). The elimination of dFdU followed a biphasic profile in all patients. In contrast to gemcitabine, the t of dFdU was delayed between 9.7 and 16 h, with a variation between patients ranging from 30% to 54%. Table 5 summarizes the pharmacokinetic results.



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Figure 2. Patients’ plasma concentration data for dFdU at the gemcitabine 1500 mg/m2 dose level (n = 6).

 

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Table 5. Plasma pharmacokinetic parameters of gemcitabine and the deaminated product dFdU
 


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Figure 3. Scatterplots showing the distribution of the AUC0–{infty} of dFdU as a function of gemcitabine dose. A trend, but not significant, towards increase of dFdU AUC for gemcitabine dose ranging from 800 to 1500 mg/m2 (r2 = 0.22).

 
Antitumor activity
Although antitumor activity was not the primary end point of this study, objective responses were observed both in chemotherapy-naïve and pretreated patients. Thirty-three patients were measurable and 11 were evaluable but not measurable for activity (one NSCLC patient with endobronchial localization and bone metastasis, another NSCLC patient with micronodular lung metastasis and bone metastasis, and nine patients with OC evaluable for activity based on the CA 125 level).

In patients with NSCLC, 11 of 33 patients with measurable diseases had objective response (1/3, 1/2, 1/1, 3/6, 1/3 and 4/20 for dose levels I, II, III, IV, V and VI, respectively). This included one patient with stage IIIB disease who experienced a complete response that lasted for 6 months with disappearance of primary tumor and mediastinal lymph nodes. Three partial responses were observed in platinum-pretreated patients (two responses occurred in patients who had disease progression within 6 months following cisplatin-based chemotherapy). In addition, one non-measurable patient experienced bone pain disappearance, significant regression of lung metastasis at CT scan and bone metastasis at bone scan that was considered as a partial response. Two patients with NSCLC experienced minor responses measured as a 46% tumor regression. Figure 4 represents the best tumor response observed per measurable patient.



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Figure 4. Best tumor response per measurable patient (n = 33).

 
In patients with OC, three of nine patients with non-measurable disease had 6-month tumor stabilization with symptom improvement and >=50% reduction of the baseline CA 125 values. None of these patients presented clinical evidence of ascitis at the baseline. Therefore, the decrease in CA 125 levels was considered likely to be related to antitumor activity of gemcitabine–oxaliplatin combination. Interestingly, one of these tumor stabilizations occurred in a platinum-resistant patient.

In this study, the overall median duration of response and time to progression were 8.1 months [95% confidence interval (CI) 3.9–10.7 months] and 4.8 months (95% CI 3.6–8.2 months), respectively (Figure 5). Time to progression and duration of response were not significantly different at the recommended dose and among all dose levels (P = 0.9 and 0.3, respectively).



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Figure 5. Kaplan–Meier analysis of (A) time to progression and (B) duration of response.

 

    Discussion
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Identification of new drug combinations represents a critical challenge to improve the antitumor activity and the toxicity profile of chemotherapy in patients with advanced tumors. Oxaliplatin has demonstrated potent antitumor activity, at least equivalent to cisplatin, against a broad spectrum of solid tumors, along with lower incidence of toxicity. The design of this trial was based on our previous pre-clinical data showing synergistic effects between gemcitabine and oxaliplatin [21]. At the cellular level, the optimal interaction is observed when gemcitabine is given before oxaliplatin. Therefore, in our clinical trial, gemcitabine was administrated before oxaliplatin, on the same day.

This regimen was remarkably well tolerated regarding hematological, digestive and renal toxicity. In this study, no DLT was observed during the first two cycles up to the highest dose level. Therefore, the RD for phase II studies was gemcitabine 1500 mg/m2 combined with oxaliplatin 85 mg/m2 every 2 weeks. The administration of this regimen every 2 weeks allowed the maintenance of the dose intensity. At the recommended dose, 99% of planned cycles were effectively received by the patients. The main cause of treatment delay was thrombocytopenia. Cumulative toxicities were asthenia and paresthesia, as previously reported with gemcitabine and oxaliplatin, respectively. At the RD, hematological toxicity was limited to infrequent episodes of grade 3–4 neutropenia and thrombocytopenia in 7.8% and 4.8% of cycles, respectively. Neither sepsis nor bleeding was observed, and no transfusion was required. Digestive toxicity was easily manageable with classical anti-emetics. None of the patients presented alopecia or mucositis. Since oxaliplatin has no renal toxicity, this allowed us to give treatment on an out-patient basis.

Two other phase I trials have reported preliminary data on gemcitabine–oxaliplatin combinations using different schedules. Mavroudis et al. [31] used gemcitabine 1000–1600 mg/m2 on days 1 and 8, combined with oxaliplatin 60–120 mg/m2 on day 8, every 21 days, in patients with advanced solid tumors. Early results indicate that the DLTs are grade 3–4 neutropenia, thrombocytopenia and asthenia. Overall, the incidence of grade 3–4 hematological toxicity was comparable to that for our study. Interestingly, in the Mavroudis et al. [31] study, the median age of patients was 65 years, and 42% of patients had been treated with two previous regimens. In this population, the combination was well tolerated up to gemcitabine 1600 mg/m2 on days 1 and 8, with oxaliplatin 120 mg/m2 on day 8, every 21 days, as no DLT was observed. These data are consistent with our results showing that the combination of gemcitabine with oxaliplatin can be well tolerated in both untreated and previously treated patients. The California Consortium trial has recently reported preliminary results for gemcitabine 700–1750 mg/m2 on days 1 and 8, plus a fixed dose of oxaliplatin 130 mg/m2 on day 1, every 21 days, in patients with advanced solid tumors [32, 33]. In this study, the DLTs occurring at the dose of gemcitabine 1250 mg/m2 were grade 4 thrombocytopenia and grade 3 confusion. This schedule appears to be associated with more severe grade 3–4 hematotoxic toxicity in about 30% to 33% of cycles. The authors are currently exploring doses of gemcitabine 1000 mg/m2 plus oxaliplatin 130 mg/m2 as an RD.

The pharmacokinetic parameters investigated in this study indicated a non-linear pharmacokinetic behavior of the gemcitabine main metabolite dFdU within the range of doses used. Although oxaliplatin pharmacokinetic evaluation has not been carried out in this study, gemcitabine and dFdU disposition appeared to be unaffected by oxaliplatin, since our data were consistent with those obtained in previous studies investigating the pharmacokinetic parameters of gemcitabine given as single agent and combinations [3437]. The limited occurrence of toxic events during the first two cycles did not permit us to explore pharmacodynamic interactions in this study.

In our study, gemcitabine combined with oxaliplatin achieved a number of objective responses. Activity was reported in chemotherapy-naïve and pretreated NSCLC and OC patients. Interestingly, responses were observed in two patients with NSCLC, and tumor stabilization in one patient with OC considered as resistant to classical platinum compounds. At the recommended dose, five of 20 patients with NSCLC showed objective responses and two of two patients with OC showed 6-month tumor stabilization. In this study, the duration of response reached a median of 8.1 months, and the time to progression a median of 4.8 months. Duration of response and time to progression appeared to be not significantly different at the RD and among all dose levels. The inclusion criteria in our study did not allow us to describe the activity of the combination in heavily pretreated patients. This was explored in another study, which found evidence of activity illustrated by a 13% response rate reported in patients having received one or two previous lines of chemotherapy [31].

Several studies have reported on the combination of gemcitabine with cisplatin. This regimen was recently acknowledged as one of the standard options for the treatment of patients with advanced NSCLC [3840]. The main toxicity of gemcitabine combined with cisplatin was grade 3–4 thrombocytopenia, occurring in 48% to 64% of patients and requiring platelets transfusion in 15% to 20% of cases [3840]. Grade 3–4 anemia also occurred in 29% to 65% of patients and required red blood cell transfusion in 38% of patients [3840]. Other toxicities were related to cisplatin. Grade 3–4 nausea and vomiting were reported in 18% to 37% and grade 3–4 renal toxicity in 1% to 9% of patients. Grade 3–4 neurotoxicity occurred in 2% to 16% of patients. Overall, treatment discontinuation caused by toxicity was as high as 28% in the randomized controlled Eastern Cooperative Oncology Group (ECOG) trial reported by Schiller et al. [40]. Although no comparison study is available, gemcitabine combined with oxaliplatin seems to be associated with a lower rate of nausea/vomiting, alopecia, hematological and renal toxicity. In contrast to cisplatin-induced neurotoxicity, most of the cases of oxaliplatin-induced neurotoxicity were reported as reversible in our study, as described previously [20].

In summary, this trial shows that gemcitabine combined with oxaliplatin on an every other week out-patient schedule has manageable toxicity. The recommended dose is gemcitabine 1500 mg/m2 combined with oxaliplatin 85 mg/m2 every 2 weeks. This combination shows promising antitumor activity and should be investigated in patients with NSCLC and OC. Other tumors currently treated with the gemcitabine–cisplatin regimen, such as pancreatic and bladder cancer, might also benefit from this regimen and could be evaluated. Phase II studies are underway in these tumor types.


    Acknowledgements
 
The authors wish to thank Esteban Cvitkovic for his suggestions and support. We also thank Joachim Vicente, Euloges Ganga, Nathalie Roux and Frédéric Mistretta for collecting data, as well as the nursing team of the Gard Unit, Department of Medicine, Institut Gustave-Roussy for performing pharmacokinetic sampling, and Joelle Santoni for contributing to pharmacokinetic analysis.


    Footnotes
 
+ Correspondence to: Dr E. Raymond, Department of Medicine, Institut Gustave-Roussy, 39 rue Camille-Desmoulins, 94805 Villejuif Cedex, France. Tel: +33-1-42-11-43-17; Fax: +33-1-42-11-52-17; E-mail: raymond@igr.fr Back


    References
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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