Phase I and pharmacological study of an oxaliplatin and carboplatin combination in advanced malignancies

C. Mita1,+, E. Chatelut1, M. Bekradda3, P. Soulié4, P. Canal1, J.-L. Misset2, E. Cvitkovic2,3 and R. Bugat1,§

1 Institut Claudius Regaud, and Université Paul Sabatier, Toulouse; 2 Department of Medical Oncology, Hôpital Paul Brousse, Villejuif; 3 CAC, Kremlin-Bicêtre; 4 Centre René Huguenin, Saint-Cloud, France

Received 2 April 2003; revised 5 June 2003; accepted 11 August 2003


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

Phase I and pharmacokinetic study to determine the maximal tolerated dose and the recommended dose, as well as the optimal sequence of a carboplatin/oxaliplatin combination delivered every 3 weeks.

Patients and methods:

Patients received either carboplatin [area under the curve (AUC)-based individually calculated dose (starting dose AUC 4 mg·min/ml), 1 h intravenous (i.v.) infusion] followed by oxaliplatin (110 mg/m2, 2 h i.v. infusion), every 3 weeks, or the reverse sequence.

Results:

Sixteen patients were included and only one dose level was assessed. In group A, 10 patients received 23 cycles of carboplatin followed by oxaliplatin. In group B, 6 patients received 20 cycles with the reverse sequence. Delayed recovery from hematological toxicities was treatment-limiting, with mainly moderate thrombocytopenia and neutropenia as dose-limiting toxicities for group A (5 of 10 patients for each) and thrombocytopenia for group B (3 of 6 patients). No febrile neutropenia or grade 3/4 non-hematological toxicity occurred. Pharmacokinetic analysis showed similar mean total platinum AUCs for the two groups: 37.2 ± 13.7 and 33.6 ± 9.9 mg·h/l, respectively. One complete response and two partial responses (World Health Organization–International Union Against Cancer criteria, response rate 18.8%) were seen in ovarian, Fallopian and neuroendocrine carcinomas, respectively.

Conclusions:

This platinum combination appears feasible and active at the dose of AUC 4 mg·min/ml for carboplatin (Chatelut formula) and oxaliplatin 110 mg/m2; however, it does not allow a significant increase in platinum dose-intensity delivery.

Key words: carboplatin, oxaliplatin, pharmacokinetics, phase I study


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Platinum salts are among the most active chemotherapeutic agents employed to improve disease control and survival in patients with solid tumors [1, 2]. Like many alkylating agents, they have concentration-dependent cytotoxicity in vitro. Levin and Hryniuk pointed out the importance of the cisplatin dose administered in a retrospective analysis of several clinical trials concerning ovarian cancer patients [3]. Increasing platinum doses is hindered by their inherent limiting toxicities which are exacerbated at high doses. For example, high-dose cisplatin is associated with renal function impairment and severe, cumulative neurotoxicity [4], while for carboplatin, severe thrombocytopenia is the limiting event [5, 6]. Thus, the combination of two different platinum compounds with different toxicity profiles may allow optimal dose intensity without intensifying toxicity. However, association of cisplatin and carboplatin delivered according to several schedules has failed to obtain the hoped-for results, mainly because of hematological toxicity [710]. Nevertheless, a randomized trial in previously untreated ovarian carcinoma patients comparing carboplatin/cisplatin/cyclophosphamide with cisplatin/cyclophosphamide, favored the triple combination not only in terms of response but also in time-related parameters [11].

Among the platinum compounds, oxaliplatin (trans-l-oxalato-diaminocyclohexane platinum), a third-generation diaminocyclohexane (DACH) platinum, has generated much interest. Its preclinical and clinical characteristics include a different spectrum of antitumor activity, absence of cross-resistance with cisplatin in experimental models and non-overlapping toxicity profiles [1214], suggesting that the DNA adducts formed by oxaliplatin and cisplatin have different molecular pathways of recognition and apoptotic triggering.

Oxaliplatin’s toxicity profile differs from that of cisplatin by its absence of nephrotoxicity and from that of carboplatin by its moderate hematological toxicity. It is characterized by peripheral neurological toxicity [15, 16] which is essentially sensory and proprioceptive [1719]. Its antitumor activity has mainly been demonstrated in colon and ovarian carcinoma patients [20].

The different toxicity spectrum of platinum compounds, their additive cytotoxic effect and absence of cross-resistance [21, 22] led to evaluation of platinum combinations. The feasibility and efficacy of the cisplatin/oxaliplatin combination has been evaluated in ovarian and testicular tumors [23, 24] and their combination with paclitaxel has also been reported [25]. Results observed in patients who have either relapsed or progressed after prior platinum treatment (both potentially sensitive and resistant/refractory to cisplatin and carboplatin) are encouraging. It is of note that some severe toxicities have been recorded, especially in patients with altered renal function, most of them cisplatin-related.

Unlike when it is combined with cisplatin, the absence of oxaliplatin nephrotoxicity may limit the pharmacokinetic interaction between carboplatin and oxaliplatin. A preliminary pilot experience of the feasibility of carboplatin (300–400 mg/m2) and oxaliplatin (100 mg/m2) in pretreated patients suggests that the combination is hematotoxic [26]. However, this may be explained by the fact that the patient cohort was heavily pretreated, mainly with cisplatin-based regimens. Thus we undertook a further assessment of this combination, in a less heavily pretreated patient cohort with individual optimization of the platinum dose.

We carried out a phase I study of the carboplatin/oxaliplatin combination using individualized area under the curve (AUC) dosing for determination of the carboplatin dose. The primary objective of this tricentric phase I trial was to determine the maximum tolerated dose and the recommended dose of the carboplatin/oxaliplatin combination administered every 3 weeks. An assessment of the toxicity profile of the combination, a pharmacokinetic investigation of potential interactions between the two platinum salts and a preliminary evaluation of antitumor activity will also be carried out. Initially carboplatin was administered first, followed by oxaliplatin. However, due to the toxicity reported with this administration schedule, the importance of sequence of administration of the two drugs was also assessed using the reverse sequence (i.e. oxaliplatin administered first).


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The study was conducted in three centers in France. The protocol was approved by the regional ethics committee. Written informed consent was obtained from all patients before study entry.

Patient selection
Eligible patients had a histologically proven solid tumor, at least one and no more than two previous treatment lines of platinum-containing chemotherapy, aged between 18 and 75 years, a World Health Organization (WHO) performance status of 0 to 2, life expectancy longer than 12 weeks, no chemotherapy or radiotherapy within 4 weeks of study entry, measurable and/or evaluable disease, neutrophil count >=2000/µl, platelet count >=150 000/µl, bilirubin level <1.5-fold upper limit of normal (ULN), AST, ALT, AP <2-fold ULN in the absence of liver metastases or <3-fold ULN in the presence of liver metastasis, creatinine clearance >=60 ml/min (calculated by the Cockcroft and Gault formula) [27].

Exclusion criteria included prior radiotherapy to >25% of bone marrow beaming, prior high-dose alkylants and/or carboplatin, bone-marrow invasion, symptomatic brain metastases, peripheral neuropathy >=grade 2 [National Cancer Institute Common Toxicity Criteria (NCI–CTC)], active infection, major organ failure and concurrent treatment with other experimental drugs.

Study design
Patients were to receive carboplatin followed by oxaliplatin (group A). As a result of unexpected hematological toxicity in the first six patients treated at the first dose level, and to explore pharmacodynamic and pharmacokinetic parameters, four additional patients were treated at the same dose level. As a result of these toxicities, the trial design was amended and six patients received the reverse administration sequence (i.e. oxaliplatin first; group B).

Carboplatin (Paraplatin®; Bristol-Myers Squibb) and oxaliplatin (Eloxatine®; Sanofi-Synthelabo) were diluted in 5% dextrose and administered as intravenous (i.v.) infusions over 1 and 2 h, respectively. In both groups, the second infusion started 2 h after completion of the first infusion. Antiemetic drugs including metoclopramide, anti-5HT3 and corticosteroids at standard doses were administered according to each center’s instructions. Further treatment cycles were administered every 21 days if patients had complete blood count recovery.

The carboplatin starting dose was calculated according to the formula: total carboplatin dose (mg) = carboplatin clearance (ml/min) x AUC, where AUC was set at 4 mg·min/ml. Carboplatin clearance was calculated at each cycle according to the Chatelut formula [28]. The oxaliplatin starting dose was 110 mg/m2.

Dose escalation of both drugs was to occur after at least three patients had been included at that dose level for a minimum of two cycles with 3 weeks follow-up for acute toxicity. If one out of the three patients developed a dose-limiting toxicity (DLT), three more patients were entered at the same dose level. DLTs were defined as prolonged (>7 days) grade 4 neutropenia, complicated (fever lasting >3 days) grade 3/4 neutropenia, grade 4 thrombocytopenia, grade >=1 platelet count or grade >=2 neutrophil count on day 28, grade >=2 neurotoxicity, grade 3/4 bleeding, infection, mucositis, diarrhea and skin toxicity; any other grade 3/4 toxicity excluding anemia. The maximum tolerated dose (MTD) was defined as the dose at which >=50% of patients developed the same DLT.

Dose reductions were implemented in the following cases: grade 2 thrombocytopenia and/or uncomplicated grade 3/4 neutropenia, oxaliplatin to 75% and carboplatin AUC = –1 mg·min/ml; grade 3 thrombocytopenia, oxaliplatin to 50% and carboplatin AUC = –2 mg·min/ml; grade 4 thrombocytopenia or prolonged (>5 days) or complicated grade 4 neutropenia, off-study; grade 3/4 diarrhea, oxaliplatin to 75%; grade 3 peripheral neuropathy, off-study. Doses reduced for toxicity were not re-escalated. Further treatment was delayed by one to no more than 2 weeks, with daily blood counts until recovery in the event of thrombocytopenia or grade >=2 neutropenia on day 21. If no recovery was observed within 2 weeks, the patient went off-study.

Patients received six treatment cycles except in the event of disease progression, unacceptable toxicity or patient refusal, in which case the patient went off-study. Patients were followed-up for 1 month after the last treatment infusion. Tumor evaluation was carried out for patients with objective response or stable disease up to disease relapse or progression.

Treatment assessments
Complete blood counts were performed on days 1, 8, 11, 14, 17 and 21 of each cycle and daily in the event of grade >=2 thrombocytopenia and/or grade >=3 neutropenia. Blood chemistries including electrolytes, urea, creatinine and 24-h proteinuria analysis were assessed on days 1 and 2 of each cycle. Serum creatinine was determined weekly and liver function tests and a physical examination were repeated before each treatment administration. Tumors were evaluated by CT scan every two cycles [World Health Organization–International Union Against Cancer (WHO–UICC) criteria]. Toxicity assessments were according to NCI criteria. Neurotoxicity was evaluated according to the oxaliplatin-specific scale [29].

Pharmacokinetic assessment
Platinum elimination from the plasma ultrafiltrate was investigated for the first three chemotherapy cycles. Blood samples (4 ml) were collected into heparinized tubes from an indwelling i.v. cannula placed in the arm not receiving chemotherapy. For group A, samples were collected prior to carboplatin administration, at 1 h (end of carboplatin infusion), 1.5, 2, 3, 5 (end of oxaliplatin infusion), 5.5, 6, 8, 12 and 24 h post-infusion. For group B, samples were collected prior to oxaliplatin administration, at 1, 2 h (end of oxaliplatin infusion), 2.5, 3, 4, 5 (end of carboplatin infusion), 6, 7, 9, 13 and 24 h post-infusion. Samples were immediately centrifuged at 4°C, 1500 g for 10 min. The plasma was ultrafiltered at 4°C for 20 min at 2000 g, and the ultrafiltrate was frozen until analysis. Platinum was measured with a 1100B Perkin–Elmer spectrophotometer equipped with a graphite furnace [30].

The total AUC of ultrafilterable platinum concentrations was calculated using the trapezoidal rule from time 0 to 24 h after the start of the first infusion. Oxaliplatin plasma ultrafiltrate concentrations were analyzed in group B only, the oxaliplatin contribution to platinum concentrations being too low when oxaliplatin followed carboplatin administration (Figure 1).



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Figure 1. Mean (±SD) ultrafilterable plasma concentration of platinum in groups A (A) and B (B).

 
The AUC of oxaliplatin ultrafiltrate platinum concentrations was calculated using the trapezoidal rule from time 0 to 4 h after the beginning of the oxaliplatin infusion. Extrapolation to infinity was performed using the rate constant of the terminal phase obtained by non-linear least-squares regression analysis using the SIPHAR software (Simed, Créteil, France). The carboplatin plasma ultrafiltrate concentration was analyzed for patients of both groups. In group A, only the concentrations obtained prior to oxaliplatin administration were used. In group B, residual platinum concentrations of oxaliplatin observed when carboplatin administration was started were negligible compared to those following carboplatin infusion (Figure 1).

A two-compartment open pharmacokinetic model with constant-rate i.v. infusion and first-order elimination was used to describe the pharmacokinetics of carboplatin. Data were analyzed by Bayesian approach using the program NONMEM [31] (version V, level 1.1, FOCE and POSTHOC options) and the PREDPP package (ADVAN 3, TRANS 4) [32]. Prior data was provided by a database (eight samples on average per patient, for 110 previously studied patients) [28]. Mean (and the coefficient of variation for interindividual variability) population parameters are: CL = 4.06 (57%) l/h, V1 (central volume) = 17.6 (28%) l, V2 (peripheral volume) = 9.32 (21%) l, Q (intercompartmental clearance) = 3.11 (41%) l/h. The pharmacokinetic parameters were estimated without any covariates. A proportional error model was used for the residual and interpatient variabilities. Carboplatin AUC was calculated according to the equation: AUC = dose/CL, where CL was the carboplatin clearance model-dependant obtained by Bayesian estimation.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient characteristics
Between January 1997 and December 1998, 16 patients were entered into this study (10 in group A and six in group B) and they received a total of 43 treatment cycles (23 and 20, respectively). All 16 treated patients were evaluable for safety and pharmacokinetics. The MTD was reached at the first level tested (oxaliplatin 110 mg/m2 and AUC 4 mg·min/ml for carboplatin), motivating administration of the reverse sequence which slightly modified the toxicity profile but still did not allow dose escalation beyond level 1.

Patient characteristics are shown in Table 1. The most frequent tumor type was malignant melanoma (six patients) and ovarian carcinoma (three patients). Other neoplastic diagnoses were pancreatic adenocarcinoma, non-small-cell lung cancer, Fallopian tube carcinoma, Ewing sarcoma, rhabdomyosarcoma, neuroendocrine tumor and adenocarcinoma of unknown primary (one of each). All patients had metastatic disease and tumor burden was relatively high, with 14 patients (88%) having two or more localization sites. Thirteen patients (81%) had received prior chemotherapy, 10 (63%) having platinum-containing regimens (median cisplatin and carboplatin cumulative dose of 480 and 2400 mg/m2, respectively).


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Table 1. Patient characteristics
 
Toxicity
No treatment-related deaths occurred. Four patients discontinued treatment due to treatment-related hematotoxicity (three had prolonged neutropenia, one had thrombocytopenia), two patients required treatment-related hospitalization for platelet transfusions and four for red blood cell transfusions. The median relative dose intensity of oxaliplatin was 0.86 (range 0.54–1.0). Median dose intensity was lower in group B (25.2 mg/m2/week) compared with group A (36.7 mg/m2/week). The median relative dose intensity for carboplatin was not assessed given that the carboplatin dose administered was calculated according to the Chatelut formula and not body surface area.

In group A, the DLTs were thrombocytopenia and neutropenia. In group B the only DLT was thrombocytopenia. The MTD was reached at dose level 1, with eight out of 16 treated patients experiencing either grade 4 thrombocytopenia or a platelet count grade >=1 at day 28. Five patients (31%), all in group A, did not recover from neutropenia.

The most common toxicities were hematological, being thrombocytopenia for 15 patients (94%) and neutropenia for 10 patients (63%). These toxicities were dose limiting and responsible for 16 out of 17 (94%) delayed cycles and four out of four (100%) dose reductions. It is of note that as a result of toxicity, only 10 of the 27 second or further cycles (37%) administered could be delivered every 3 weeks as per protocol, and that eight (30%) were delayed by more than 7 days. Severe (grade 3/4) hematotoxicities are presented in Tables 2 and 3. Severe thrombocytopenia was recorded in 75% of patients and 33% of cycles. Severe anemia was reported in 44% of patients in 21% of cycles. No febrile neutropenia occurred during the study. The median time to nadir neutrophil count was 21 days (range 17–26). The median duration of severe neutropenia was 10 days (range 4–17) and the median day of complete recovery was day 37 (range 23–63). The median time to nadir platelet count was 17 days (range 10–28) and the median day of complete recovery was day 29 (range 19–36).


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Table 2. Severe (grade 3/4) hematological toxicities, by patient
 

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Table 3. Severe (grade 3/4) hematological toxicities, by cycle
 
Non-hematological toxicities were generally mild, with only one severe treatment-related toxicity reported (grade 3 vomiting). All other toxicities, including diarrhea (five patients), mucositis (three patients), nausea/vomiting (11 patients), neurotoxicity (11 patients), asthenia (nine patients) and anorexia (five patients), were grade 1/2 and manageable.

Tumor response
Thirteen of the treated patients were evaluable for response. A total of three objective responses were reported, giving an objective response rate of 18.8% in the 16 treated patients with various advanced malignancies. One complete response was obtained in a previously treated ovarian carcinoma patient with a lymph node recurrence. Two partial responses were observed; one was in a patient with Fallopian tube carcinoma and one in a patient with a neuroendocrine tumor. Three other patients (18.8%) had stable disease. Median progression-free survival and overall survival were 1.8 (95% CI 0–4.3) and 7.4 months (95% CI 6.7–8.1), respectively.

Pharmacokinetic results
Figure 1 shows the mean (±SD) ultrafilterable plasma concentrations of platinum in the two groups. The mean total platinum AUC of ultrafilterable plasma concentrations is comparable in the two groups (37.2 ± 13.7 and 33.6 ± 9.9 mg·h/l for groups A and B, respectively). The pharmacokinetic parameters for carboplatin and oxaliplatin are shown in Tables 4 and 5, respectively. For carboplatin, there were no differences between values observed after cycle 1 in groups A and B.


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Table 4. Mean (±SD) pharmacokinetic parameters for carboplatin
 

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Table 5. Mean (±SD) pharmacokinetic parameters for oxaliplatin in group B
 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Cisplatin and carboplatin are important agents in the chemotherapeutic treatment of a variety of cancer types. Molecular biology studies and in vitro cytotoxic screening have shown that DACH platinum compounds such as oxaliplatin belong to a distinct cytotoxic family with specific intracellular targets, mechanisms of action and/or resistance (for review, see [22] and [33]). These unique intrinsic properties are likely to explain their different activities, toxicity profiles and interactions with other platinum salts.

In vitro combinations of carboplatin and/or cisplatin with oxaliplatin have cytotoxic and/or antitumor activity which is at least additive, if not synergistic [34]. This may be a result of the different, non-overlapping mechanisms of resistance of these compounds [21, 22]. Bulky oxaliplatin–DNA adducts do not appear to be well recognized by the mismatch repair (MMR) protein complex and could make replicative bypass difficult [21, 22, 35]. It may be that the MMR system is specific in its ability to discriminate between different types of closely related DNA adducts [36]. This could explain the selective activity of oxaliplatin in tumors recognized as either primary refractory/resistant to other platinum salts (e.g. colon) or secondary resistant (e.g. ovary), but with a low level of hMLM1 and hMSH2 expression.

The primary objective of this study was met, with the MTD being reached at dose level 1: oxaliplatin 110 mg/m2 and AUC 4 mg·min/ml for carboplatin, with 50% of treated patients experiencing grade 4 thrombocytopenia or grade >=1 platelets at day 28 as DLT, three of whom also experienced grade >=1 neutropenia at day 28. Although the toxicities observed were dose-limiting, they were relatively moderate and manageable, so no inferior dose levels were tested.

Patient accrual did not progress beyond the first dose level. Combination treatment resulted in prevalent hematological toxicity, characterized by both neutropenia and thrombocytopenia when carboplatin was administered first, and by thrombocytopenia only in the reverse sequence. The late nadir (after day 15), and more importantly the slow recovery from this toxicity led to establishment of dose level 1 as the MTD. Dose-limiting neutropenia was related to its delayed recovery (beyond day 28) rather than to its severity. There was no fever or infection related to neutropenia. Since administration of oxaliplatin at the recommended doses induces sporadic mild neutropenia and minor thrombocytopenia which is dose-related [15], this finding may signal a sequence-dependent pattern of hematological toxicity. Although these DLTs were more severe in previously platinum-treated patients, they were also encountered in poorly or previously untreated subjects. Thus, it appears that hematological toxicity is dose-limiting for all platinum dose escalation and irrespective of the platinum derivative used: cisplatin, high-dose carboplatin, cisplatin/carboplatin, oxaliplatin/cisplatin, oxaliplatin/carboplatin. These observations suggest that hematopoietic stem cells may be the site of primary toxicity, apparent above a certain threshold of total platinum adducts, even when combinations of theoretically less hematotoxic platinum compounds are used.

The relatively minimal contribution of oxaliplatin to ultrafilterable plasma platinum concentrations made the specific analysis of oxaliplatin pharmacokinetics when the drug was given after carboplatin impossible. However, when oxaliplatin was administered first, the residual platinum concentrations at the beginning of the carboplatin infusion represented one-fifth of the maximum concentrations. Both intra- and inter-individual pharmacokinetic variability were low.

The individual dosing with carboplatin was intended to reduce the inter-individual variability within each dose level of this phase I trial. This objective has been met since coefficients of variation for carboplatin AUC were close to 25%. However, there is a ratio of three between extreme values of carboplatin AUC. No difference was apparent in the carboplatin pharmacokinetic parameters with the alternative administration sequences.

The combination appears active, producing three objective responses (including one complete response) in diseases likely to be responsive to optimized platinum-based regimens (potentially platinum-sensitive). Alternative schedules (every 2 weeks or alternating) should also be considered when further exploring this combination.


    Acknowledgements
 
We thank Dr S. Mackenzie and Mrs C. Delamaire for help in editing the manuscript. This work was supported by a grant from Sanofi-Synthelabo, France.


    Footnotes
 
+ Correspondence to: Dr C. Mita, Institute for Drug Development, CTRC, 7979 Wurzbach Rd, Zeller Bdg, 4th Floor, San Antonio, TX 78229, USA. Tel: +1-210-949-5094; Fax: +1-210-692-7502; E-mail: amita{at}idd.org Back

§ Address reprint requests to: R. Bugat, Oncology Department, Institut Claudius Regaud, 20–24, Rue du Pont Saint-Pierre, 31052 Toulouse Cedex, France. Tel: +33-05-61-42-42-42; Fax: +33-05-61-42-42-44; E-mail: bugat{at}icr.fnclcc.fr Back


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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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