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Clinical Cancer Research 14, 3434, June 1, 2008. doi: 10.1158/1078-0432.CCR-07-4903
© 2008 American Association for Cancer Research
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Cancer Therapy: Clinical

A Phase I and Pharmacokinetic Study of Weekly Oxaliplatin Followed by Paclitaxel in Patients with Solid Tumors

Tanios S. Bekaii-Saab1,2, Jing Liu3, Kenneth K. Chan1,3, Stanley P. Balcerzak1, Percy S. Ivy4, Michael R. Grever1 and Eric H. Kraut1

Authors' Affiliations: 1 Division of Hematology and Oncology, Department of Medicine, 2 Department of Pharmacology, and 3 Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, Ohio; and 4 Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland

Requests for reprints: Eric H. Kraut, The Ohio State University, A434B Starling Loving Hall, 320 West 10th Avenue, Columbus, OH 43210. Phone: 614-293-3161; Fax: 614-293-7529; E-mail: Eric.Kraut{at}osumc.edu.


   Abstract
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 Abstract
Materials and Methods
 Results
 Discussion
 Disclosure of Potential...
 References
 
Purpose: Oxaliplatin and paclitaxel are widely used in treating solid tumors. We designed a phase I study with the purpose of determining the maximal tolerated dose and pharmacokinetic properties of weekly oxaliplatin followed by paclitaxel based on evidence suggesting that weekly administration of both drugs allows equivalent dose intensity with less neurotoxicity.

Experimental Design: Twenty-three patients with advanced solid tumors were treated. Starting doses were 35 mg/m2 oxaliplatin followed by 45 mg/m2 paclitaxel weekly for 4 weeks every 6 weeks. Dose was escalated as follows: 45 mg/m2 oxaliplatin and 45 mg/m2 paclitaxel, 60 mg/m2 oxaliplatin and 45 mg/m2 paclitaxel, and 60 mg/m2 oxaliplatin and 60 mg/m2 paclitaxel. Pharmacokinetic studies were evaluated during the first course of therapy for oxaliplatin using population kinetics approach.

Results: A total of 49 courses were administered. The dose-limiting toxicity was peripheral neuropathy with oxaliplatin and paclitaxel both at 60 mg/m2. There were three partial responses. There was evidence of pharmacokinetic interaction with a significant amount of total platinum (46.2-49.5%/24 h) eliminated in the urine in this group of patients, consistent with published data from others. The total body clearance values of plasma platinum and ultrafiltrable platinum were higher in this combination compared with corresponding values from our previous study with oxaliplatin only (P < 0.001).

Conclusions: The recommended phase II dose of this combination is 60 mg/m2 oxaliplatin followed by 45 mg/m2 paclitaxel. Evidence of antitumor activity and acceptable toxicity with this combination and schedule warrants further investigation. We have obtained more definitive pharmacokinetic properties of oxaliplatin and confirmed its drug interaction with paclitaxel in the current sequence.

Oxaliplatin (trans-l-1,2-diaminocyclohexane oxalatoplatinum) is a third-generation platinum derivative with a 1,2-diaminocyclohexane carrier ligand (1). Platinum compounds containing the 1,2-diaminocyclohexane ligand have antitumor activity in cell lines with acquired cisplatin resistance (2, 3) and lack the nephrotoxicity and significant myelosuppression associated with other platinum compounds (4, 5). Although its exact mechanism of action is not known, oxaliplatin like other platinum compounds forms DNA adducts (6). These 1,2-diaminocyclohexane-platinum adducts are more effective in inhibiting DNA synthesis and are more cytotoxic than those formed from cisplatin and carboplatin. Mechanisms thought to be important in resistance to cisplatin, such as alterations in mismatch repair activity and ability of the replication complex to synthesize DNA past the sites of DNA damage, do not affect oxaliplatin activity (1, 7).

In preclinical studies, oxaliplatin showed a wide spectrum of activity against a variety of murine and human tumor cell lines, including L1210 murine leukemia and human colon, ovarian, and breast cancers (2, 3, 6). Additive or synergistic activity was seen in vitro when oxaliplatin was combined with 5-fluorouracil, CPT-11, and paclitaxel (8–10).

Phase I trials with oxaliplatin as a single agent using i.v. bolus schedules given either weekly or every 3 weeks established that the major dose-limiting toxicity (DLT) was neurologic, manifested by a transient or persistent peripheral neuropathy enhanced by exposure to cold. The duration and intensity of the symptoms correlated with the cumulative dose of the drug administered, and was typically reversible (11).

Phase II studies of oxaliplatin as monotherapy have shown activity in both untreated and previously treated patients with metastatic colorectal cancer with response rates of 18% and 10%, respectively (5, 8). Oxaliplatin has also been successfully combined with other agents, such as 5-fluorouracil, gemcitabine, and paclitaxel, without marked increase in toxicity or loss of efficacy (12–18).

Paclitaxel is a diterpene plant product derived from the needles and bark of the western yew Taxus brevifolia. It is a unique mitotic spindle poison promoting assembly of microtubules and stabilizing them against depolymerization (9, 13). Cells treated with paclitaxel exhibit changes consistent with programmed cell death. Paclitaxel is highly active in numerous preclinical tumor models and has shown significant clinical activity in several human malignancies, including ovarian cancer, non–small cell lung cancer, and breast cancer (13, 14).

We initiated a phase I and pharmacokinetic study of the combination of weekly oxaliplatin and paclitaxel based on the following observations: (a) paclitaxel has been studied in vitro in combination and has shown synergism with platinum compounds including oxaliplatin (8–10) and (b) paclitaxel is used extensively in combination with the other platinums (cisplatin and carboplatin) in ovarian, non–small cell lung, germ cell, and thyroid cancers with evidence of clinical synergism (19–23).

The goal of this study was to attempt to deliver a more dose intense therapy by using a weekly dosing schedule in the hopes of improving efficacy without increasing toxicity.


   Materials and Methods
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Patients. Patients entered on this study had to have the following: histologically proven solid tumors for which no curative therapy was available; an age >18 y; life expectancy ≥12 wk; Eastern Cooperative Oncology Group performance status of 0 to 2; no concomitant chemotherapy, radiotherapy, or hormonal therapy; no prior treatment with oxaliplatin or paclitaxel; no more than two prior chemotherapy regimens; and no known brain metastases. Patients were required to have adequate organ function with absolute neutrophil count of ≥1,500/µL, platelets ≥100,000/µL, creatinine ≤1.4 mg/dL, aspartate aminotransferase and alanine aminotransferase ≤2.5 times the institutional normal, and a normal bilirubin. Patients were excluded from the study if they had evidence of peripheral neuropathy, history of allergy to platinum compounds, radiotherapy to >25% of the bone marrow, or documented HIV positivity.

Because of the potential toxicity from chemotherapy, pregnant women or women currently breast-feeding were also excluded.

All patients signed an informed consent. The human investigations were done after approval by our local institutional review board. The protocol and informed consent received approval from The Ohio State University Biomedical Review Board and the National Cancer Institute.

Drug administration. Patients were treated at the Ohio State University General Clinical Research Center according to the following guidelines and schedule. Oxaliplatin in 5% dextrose and water was administered as a 2-h infusion followed immediately by paclitaxel in 5% dextrose and water given over 1 h weekly for 4 wk with a 2-wk rest period (which defines one course of treatment). Oxaliplatin powder solution was reconstituted by adding 10 mL (for the 50 mg vials) or 20 mL (for the 100 mg vials) of water for injection or dextrose 5% in water, which yields a 5 mg/mL solution. The solution was then diluted in an infusion of 250 to 500 mL dextrose 5% in water. Patients received 16 mg ondansetron, 20 mg decadron i.v., 20 mg famotidine i.v., and 50 mg benadryl i.v. before medication to prevent hypersensitivity reactions to paclitaxel and reduce the risk of nausea and vomiting. Patients could receive weekly oxaliplatin and paclitaxel after their first week of treatment as long as their granulocyte count was ≥1,500/µL, platelets ≥125,000/µL, no significant mucositis persisted, and paresthesias or dysesthesias were grade ≤2.

Study design. This was a standard phase I dose escalation study (Table 1 ). At least three patients were planned to enter at each dose level with recruitment to the next dose level only when all patients had completed the first course and recovered from any toxicity. If one of three patients experienced a DLT at a level, an additional three patients were entered at that level. If one or more patients in this additional group had a DLT, then this level was considered too toxic and the prior level was then evaluated further with the addition of three patients. If no more than one of these six patients had a DLT, this level would be considered the maximal tolerated dose.


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  		Table 1. Dose levels

 
We defined DLT as follows: (a) neutropenia (polymorphonuclear <500/µL) and/or thrombocytopenia (platelets <25,000/µL), (b) irreversible grade 2 nonhematologic toxicity, (c) grade ≥3 nonhematologic toxicity including grade >3 nausea and/or vomiting occurring despite maximal antiemetic therapy and grade >3 diarrhea that occurs despite patient compliance with loperamide, (d) grade >3 neuropathy that does not resolve before the planned initiation of the next cycle of therapy, and (e) treatment delays of >3 wk. In addition, because of the potential for both drugs to induce neurotoxicity, patients were carefully evaluated before each treatment for neuropathy signs and symptoms by history and physical examination. The grading of specific toxicities was done using the National Cancer Institute Common Toxicity Criteria, except neuropathy grading was based on a scale developed specifically for oxaliplatin by Sanofi. Paresthesia/dysesthesias of short duration that resolve and do not interfere with function were grade 1, those interfering with function but not activities of daily living were considered grade 2, those with pain or with functional impairment that interfered with activities of daily living were grade 3, and persistent paresthesias/dyesthesias that were disabling or life threatening were grade 4.

Evaluation. We did a pretreatment evaluation consisting of a history and physical examination, including a thorough neurologic evaluation, complete blood count, liver enzymes, and chemistry profile. We also did radiographic evaluation of tumor measurements, including computed tomography scans before treatment and after every course. Response evaluation was done using the WHO (24) criteria for evaluation of solid tumors.

Correlative studies. We evaluated pharmacokinetic studies during the first course of therapy for oxaliplatin. Blood samples were collected at 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 7, 9, 13, 24, 27, 39, 51, and 74 h from the beginning of oxaliplatin infusion. Each blood sample was immediately centrifuged to separate plasma and plasma ultrafiltrate using the ultrafiltration method (25–27). Briefly, plasma sample was loaded onto an Amicon Centrifree Micropartition System (30,000 Da cutoff; Millipore Corp.), which was spun at 1,800 x g at 4°C for 10 min. Total platinum in plasma and plasma ultrafiltrate was measured by a validated inductively coupled plasma-mass spectrometry method (25). The pharmacokinetics of paclitaxel has been well studied in literature, and in our preclinical study (26), there was no indication that it was altered in the presence of oxaliplatin. Therefore, in the current study, paclitaxel levels were not measured.

We fitted platinum concentration-time data using a computer software NONMEM (version 5; GloboMax) and analyzed the data with population pharmacokinetics approach with mixed-effect modeling (28). Potential covariate effects (e.g., creatinine clearance, body weight, and paclitaxel) on the total platinum distribution and clearance were also evaluated. The 24-h urine following the first dose was collected from each patient. The total platinum in urine was also analyzed by the inductively coupled plasma-mass spectrometry method.


   Results
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A total of 23 patients were entered on this study. Their characteristics are shown in Table 2 . There were 12 females and 11 males included with a median age of 62 years (range, 34-76). Performance status with the majority of patients was 0 to 1 with three patients having a performance status of 2. Nineteen patients had at least one prior therapy. The group of patients included had a diversity of tumor types, with the majority (14) having colorectal cancer.


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  		Table 2. Patient characteristics (N = 23)

 
Toxicities. A total of 49 courses were given to the 23 patients with a median of 2 per patient (range, 1-10). The major DLT was persistent peripheral neuropathy seen in two patients at dose level 4 with oxaliplatin at 60 mg/m2 and paclitaxel at 60 mg/m2. The neuropathy was characterized by persistent pain and tingling in both upper and lower extremities exacerbated by exposure to cold. In one patient, the neuropathy clearly interfered with activities of daily living, although eventually resolving to a grade 1 after 2 months from stopping treatment. Patients were then treated at the next lower dose level (level 3: 60 mg/m2 oxaliplatin and 45 mg/m2 paclitaxel) and tolerated the treatment well with only transient cold-induced neuropathy that rapidly resolved when patients were in their 2-week rest period. Other toxicities observed were generally mild and included nausea, vomiting and/or diarrhea, as well as other predictable toxicities. Myelosuppression was minimal with this drug combination with only one patient having a treatment delay due to grade 2 neutropenia. There were no grade ≥3 hematologic toxicities observed (Tables 3 and 4 ).


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  		Table 3. All grade 3/4 toxicities (except neurotoxicity)

 

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  		Table 4. Neurotoxicity (all grades)

 
Responses. Twenty-one patients were evaluable for response. Two patients were nonevaluable: one patient withdrew consent and the other died from complications related to his malignancy before evaluation. There were three objective responses observed in the 12 patients treated at the two highest dose levels (3 and 4). One patient with metastatic colon cancer who was previously treated with two prior chemotherapy regimens, including irinotecan, 5-fluorouracil, and bevacizumab, followed by capecitabine had a partial response at level 3 that lasted for close to 20 months. Another patient with adenocarcinoma of unknown primary treated at dose level 3 achieved a partial response that lasted 9.5 months. His only prior therapy was chemoembolization. One other partial response lasted 6 months in a patient with recurrent rectal cancer at dose level 4. This patient received adjuvant 5-fluorouracil, leucovorin, and levamisole followed by radiation before her recurrence. There were also two other patients with colon and gastric cancer with one prior therapy that experienced prolonged stabilization of their disease.

Pharmacokinetics. The concentration-time profiles of total platinum in plasma and in plasma ultrafiltrate followed biexponential decays and were well described by a two-compartment model with a zero-order infusion to and first-order elimination from the central compartment (Fig. 1 ). The relevant pharmacokinetic variables as estimated are summarized in Table 5 . In the dose levels studied, the mean total plasma platinum concentrations at the end of oxaliplatin infusion (Cend) were 1.49 to 2.83 µg/mL and the mean ultrafiltrable platinum concentration were 0.694 to 1.29 µg/mL. The mean areas under the concentration-time curves (AUC) of total plasma platinum and ultrafiltrable platinum were 43.7 to 140.3 µg·h/mL and 4.65 to 10.1 µg·h/mL, respectively. The mean total body clearance (CL) of platinum was 0.694 L/h in plasma and 7.76 L/h in plasma ultrafiltrate, respectively. The mean steady-state volumes of distribution (Vss) of total plasma platinum and ultrafiltrable platinum were 45.5 and 134 L, respectively. The mean initial disposition half-lives (t1/2{alpha}) of total plasma platinum and ultrafiltrable platinum were 0.46 and 0.22 h, respectively, and the corresponding mean terminal disposition half-lives (t1/2β) were 39.4 and 18.5 h, respectively. The ultrafiltrable platinum (free drug) showed a shorter elimination half-life, a more rapid clearance, and a higher volume of distribution than the total drug in plasma because of the extensive irreversible plasma protein binding of total platinum derived from oxaliplatin. The substantial plasma protein binding of total platinum was also evidenced by the fact that the AUC of ultrafiltrable platinum was only 8.8% of that of total plasma platinum. The mean 24-h urinary elimination of total platinum was 46.2% to 49.5% in these groups of patients.


Figure 1
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  		Fig. 1. Concentration-time profiles of total platinum in plasma (A) and plasma ultrafiltrate (B) followed biexponential decays in patients receiving combination of oxaliplatin and paclitaxel at 35/45, 45/45, 60/45, and 60/60 mg/m2. Open symbols represent the observed data, and lines represent the model-predicted individual profiles using a two-compartment model.

 

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  		Table 5. Pharmacokinetic variables of total platinum in plasma, plasma ultrafiltrate, and 24-h urine elimination

 

   Discussion
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 Abstract
 Materials and Methods
 Results
 Discussion
Disclosure of Potential...
 References
 
We initiated this phase I study to evaluate the maximum tolerated dose and pharmacokinetic profile of the combination of oxaliplatin and paclitaxel given on a weekly basis. We chose this schedule due to the evidence that weekly administration of paclitaxel or oxaliplatin might allow equivalent dose intensity with less toxicity, specifically neurotoxicity (29–31), an overlapping toxicity of both agents that usually limits giving them in combination. We showed that this combination could be administered safely with dose intensity of oxaliplatin at 60 mg/m2 and paclitaxel at 45 mg/m2 weekly for 4 weeks every 6-week cycle with minimal hematologic and neurologic toxicity. In addition, we showed some interesting activity with the combination, especially in refractory metastatic colorectal cancer. The longest-lasting response was a partial response lasting for 20 months in one patient with refractory colorectal cancer, a disease traditionally resistant to paclitaxel and where oxaliplatin has minimal activity as a single agent in the refractory setting.

The relationship of neurologic toxicity to dose was especially interesting. At the established maximal tolerated dose, minimal neurologic complaints were seen, including one patient who received 10 courses with a cumulative dosage of 2,400 mg/m2. This is in contrast to the experience with oxaliplatin as a single agent, where cumulative doses of 1,200 mg/m2 produced significant functional impairment in 50% of patients (11). Increasing the dose of paclitaxel from 45 to 60 mg/m2 in the present regimen produced dose-limiting neurotoxicity in two patients when paclitaxel alone given at 70 to 80 mg/m2/wk typically produces grade 1 to 2 sensory neurotoxicity (13, 14).

Oxaliplatin, similar to other platinating agents, forms a variety of complexes with some active and some not (27, 32–36). It is generally accepted that protein-bound species are not important for activity (both antitumor activity and toxicity) but ultrafiltrable platinum species are. We used a sensitive and specific inductively coupled plasma-mass spectrometry method for measurement of the ultrafiltrable platinum species.

We did a population approach in the pharmacokinetic data analysis of oxaliplatin to examine any potential interactions when combined with paclitaxel. A similar approach has been used for studying the clinical pharmacokinetics of carboplatin (36). This approach has several advantages over the conventional approach of averaging individual pharmacokinetic variables: (a) it better defines the values of population pharmacokinetic variables, (b) it provides a better estimation of the interpatient variability of these variables, and (c) it defines a quantitative relationship between the covariate effect and pharmacokinetic variables (37). In this study, the intersubject variability was evaluated on CL (a dose-normalized value) and the central (V1) and peripheral (V2) volumes of distribution, and the values were less than 50% and 30% for plasma and ultrafiltrable platinum, respectively. Some of the variability was explained by the covariate effects. Covariate analysis indicated that individual's CL of ultrafiltrable platinum significantly correlated with their creatinine clearance, suggesting that glomerular filtration is a major pathway for ultrafiltrable platinum clearance. This is evidenced by the significant amount of total platinum (46.2-49.5% in 24 h) eliminated in the urine in this groups of patients. These data are consistent with the results from Takimoto et al. (27).

We analyzed the data obtained from this study with the platinum concentration data from a phase II study with oxaliplatin alone our group recently published (25). Although the AUC values reflect changes according to doses, their comparison from these two studies was not apparent. Covariate analysis showed that the CL values of plasma platinum and ultrafiltrable platinum were significantly higher (increased ~50%; P < 0.001) in this combination study compared with the corresponding values obtained from the study by oxaliplatin alone (4.81 ± 1.93 L/h; ref. 25). This increase in CL values confirms previous observation in a smaller population using a conventional pharmacokinetic analysis. More importantly, the current pharmacokinetic data herein provide a more statistically robust assessment of pharmacokinetic property of oxaliplatin when combined with paclitaxel. The objective functions, which are measurements of the statistical significance of covariate effects, also decreased in this population (data not shown). In a more recent study, we showed that the reverse sequence, with paclitaxel given first, could be more clinically favorable because it would prolong the residence of oxaliplatin in systemic circulation (26). This longer residence of oxaliplatin, as with the use of the platinum agent alone, may be due to a diminishing effect of Cremophor EL on oxaliplatin when a taxane is given earlier. Therefore, the alteration in the pharmacokinetics of oxaliplatin is thought to be due mainly to the formulation vehicle Cremophor EL.

In another rat model, administration of taxanes before platinums suggests further minimization of neurotoxicity when compared with the reverse sequence (38). It has been shown that administration of oxaliplatin alone, but not paclitaxel alone, induced both morphologic and nerve conduction changes in dorsal root ganglion (39). When paclitaxel is given before oxaliplatin, the morphologic and nerve conduction abnormalities were lessened compared with oxaliplatin alone. All these data justify considering the administration of a taxane before oxaliplatin, unlike what was done in our study.

In conclusion, the combination of oxaliplatin at 60 mg/m2 followed by paclitaxel at 45 mg/m2 given weekly for 4 weeks every 6 weeks merits further testing in the phase II testing. As shown, this combination has preliminary antitumor activity coupled with a relative low rate of toxicity at the maximal tolerated dose and eventual reversibility of most of the observed toxicities. We have obtained more definitive pharmacokinetic properties of oxaliplatin and confirmed its drug interaction with paclitaxel in the current sequence. We also think that, based on the preclinical data that have now become available to us, it would be interesting to look at other more novel taxanes, such as nanoparticles, or other effective congeners, such as docetaxel (all free of Cremophor EL), in combination with oxaliplatin and compare the different sequencing strategies in randomized clinical studies.


   Disclosure of Potential Conflicts of Interest
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 Results
 Discussion
 Disclosure of Potential...
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Tanios Bekaii-Saab has received a research grant from Sanofi-Aventis. He is also on the Speaker Bureau of Sanofi Aventis.


   Footnotes
 
Grant support: National Cancer Institute grant U01CA076576.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 11/15/07; revised 1/23/08; accepted 2/18/08.


   References
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