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Journal of Clinical Oncology, Vol 22, No 21 (November 1), 2004: pp. 4394-4400
© 2004 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2004.04.565
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Phase I and Pharmacokinetic Study of Thalidomide With Carboplatin in Children With Cancer

Murali Chintagumpala, Susan M. Blaney, Lisa R. Bomgaars, Aleksander Aleksic, John F. Kuttesch, Renee A. Klenke, Stacey L. Berg

From the Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine; and The University of Texas M.D. Anderson Cancer Center, Houston, TX

Address reprint requests to Stacey Berg, MD, Texas Children's Cancer Center, 6621 Fannin, MC 3-3320, Houston, TX 77030; e-mail: sberg{at}txccc.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
PURPOSE: Tumor growth and metastasis is believed to depend on the tumor's ability to induce neovascularization. Recent studies have indicated that thalidomide inhibits angiogenesis. We performed a phase I and pharmacokinetic study of thalidomide with carboplatin in children with refractory solid tumors.

PATIENTS AND METHODS: Carboplatin was administered as a single intravenous dose once every 21 days at a target area under the concentration-time curve of 6 mg/mL·min. Thalidomide was administered daily by mouth. The initial dose level was 100 mg/m2/d with intrapatient dose escalation to a maximum dose of 300 mg/m2/d. The next cohort of patients started at a dose of 300 mg/m2/d, with intrapatient dose escalation to a maximum dose of 500 mg/m2/d. Standard response and adverse event criteria were used. Serial blood samples for thalidomide pharmacokinetics studies were obtained after the first dose.

RESULTS: Twenty-two patients received 56 cycles of therapy. The maximum tolerated thalidomide dose was 400 mg/m2/d. The dose-limiting toxicity was somnolence. There were no objective responses. Thalidomide's apparent clearance was 55 ± 16 mL/min/m2 and the terminal half-life was 5.9 ± 2.8 hours. There was no evidence of dose-dependent pharmacokinetics in the narrow range studied.

CONCLUSION: Thalidomide at a dose of 400 mg/m2/d can be safely administered to children with solid tumors in combination with carboplatin. Somnolence is the major toxicity. In addition, we have characterized the pharmacokinetic behavior of thalidomide in children. This study can serve as the basis for future investigation of thalidomide as an anticancer agent in children.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
Tumor growth and metastasis is believed to depend on the tumor's ability to induce neovascularization.1 In vivo models demonstrate that tumor growth can be modulated by administration of angiogenesis promoters or inhibitors.2,3 Additionally, the presence of increased microvessels in a tumor may correlate with advanced stage or be otherwise indicative of a poor prognosis phenotype.4,5 Therefore, angiogenesis inhibitors may play a role either in prevention of tumor growth or in decreasing tumor propensity for metastasis.

Thalidomide was introduced in the 1950s as a nontoxic sedative, but was removed from the market because of its marked teratogenicity. Recent studies have demonstrated that the most likely etiology of the limb defects produced by fetal exposure to thalidomide is inhibition of blood vessel growth in the developing limb bud.6 This recognition of thalidomide's antiangiogenic activity, as well as other potential mechanisms of action such as immune modulation and tumor necrosis factor alpha inhibition,7 has led to renewed interest in its potential use as an anticancer agent. In addition, some anticancer activity was noted in adult studies combining thalidomide with platinum analogs.8 We performed a phase I and pharmacokinetic study of thalidomide in combination with carboplatin in children with refractory solid tumors, including brain tumors. The primary objective was to define the feasibility and safety of escalating doses of thalidomide administered daily in combination with carboplatin administered at a fixed exposure every 3 weeks. Other objectives were to determine the dose-limiting toxicity (DLT) and the incidence and severity of other toxicities of thalidomide administered in combination with carboplatin, to study the pharmacokinetics of thalidomide in children, and to obtain preliminary information about the antitumor activity of thalidomide administered in combination with carboplatin.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
Informed Consent
The protocol was reviewed and approved by institutional review boards of participating institutions. Informed consent was obtained according to federal and institutional guidelines.

Eligibility
Patients had to be between 1 and 21 years of age, with a cancer (other than leukemia) that was refractory to standard therapy, or for which there was no standard therapy or potential curative surgery. Patients must have recovered from the toxic effects of all prior therapy, have a life expectancy of at least 8 weeks, and have a Lansky or Karnofsky performance status ≥ 60. Adequate organ function (bilirubin ≤ 2.0 mg/dL, ALT < 5x normal, creatinine ≤ 1.5 mg/dL or glomerular filtration rate (GFR) ≥ 60 mL/min/m2, peripheral absolute granulocyte count of ≥ 1,500/mm3, hemoglobin ≥ 8.0 gm/dL and platelet count ≥ 100,000/mm3) was also required. Patients with histologic evidence of bone marrow involvement by tumor, or a history of either bone marrow transplantation or extensive radiotherapy, were eligible but not considered assessable for hematologic toxicity. Pregnant or lactating women, patients with uncontrolled infections, and patients with pre-existing neurocortical toxicity ≥ grade 2 (moderate somnolence, agitation) or ≥ grade 2 peripheral neurologic toxicity (mild or moderate objective sensory loss, mild or moderate objective weakness) were excluded.

Treatment
Carboplatin was obtained from commercial sources and administered as a single intravenous (IV) dose once every 21 days at a target area under the concentration-time curve (AUC) of 6 mg/mL·min. We chose to use a fixed AUC rather than a fixed dose in an attempt to decrease variability in carboplatin-related myelosuppression. The carboplatin dose for each patient was determined according to the formula9:

For patients assessable for hematologic toxicity, the absolute neutrophil count (ANC) had to be ≥ 1,000/mm3 and the platelet count ≥ 100,000/mm3 before the next cycle of carboplatin. For patients not assessable for hematologic toxicity, counts had to return to baseline or ANC had to be greater than 1,000/mm3, and platelet count ≥ 100,000/mm3, whichever was lower.

Thalidomide was supplied in capsule form by Celgene Inc (Warren, NJ) and was administered daily without planned interruption as a single bedtime dose, rounded to the nearest 50 mg. The initial dose level was 100 mg/m2/d. Intrapatient dose escalation was permitted as follows: if the patient tolerated the 100 mg/m2/d dose for 7 days without a nonhematologic toxicity of more than grade 2, then the dose was increased to 200 mg/m2/d. If the patient tolerated the 200-mg/m2/d dose for 7 days without a nonhematologic toxicity of more than grade 2, then the dose was increased to 300 mg/m2/d. No further dose escalation was permitted in this cohort of patients. At least three patients had to be followed for at least 21 days before the next cohort of patients could be enrolled. Patients were advised, but not required, to take stool softeners to prevent constipation.

If the maximum tolerated dose (MTD; see Definitions and Statistics) was not exceeded at the 300-mg/m2/d dose level, the next cohort of patients was to be enrolled starting at a dose of 300 mg/m2/d. If the patient tolerated the 300-mg/m2/d dose for 7 days without a nonhematologic toxicity of greater than grade 2, then the dose was increased to 400 mg/m2/d. If the patient tolerated the 400-mg/m2/d dose for 7 days without a nonhematologic toxicity of more than grade 2, then the dose was increased to 500 mg/m2/d. No further dose escalation was permitted in this cohort of patients. Because of dose-limiting toxicity reported in adults,10 we did not plan to raise doses beyond a dose of 500 mg/m2/d, rounded to the nearest 50 mg.

Patient Evaluation
A complete medical history, physical and neurologic examination, CBC, prothrombin time, partial thromboplastin time, ALT, bilirubin, electrolytes, creatinine, calcium, phosphate, uric acid, T4, and thyroid-stimulating hormone (TSH), and baseline assessment of sleep patterns were obtained in all patients within 7 days before the start of treatment. A negative serum pregnancy test within 24 hours prior to starting thalidomide was required in all female patients ≥ 8 years of age. Tumor extent with documentation of measurable disease by appropriate radiologic evaluation or bone marrow examination was obtained within 2 weeks before the start of therapy.

During treatment, a weekly complete physical and neurologic examination was performed during the first cycle and on day 1 of each subsequent cycle. CBC, serum electrolytes, creatinine, bilirubin, and ALT were obtained on day 1 of each cycle, then weekly. If the levels remained within normal limits during the first two cycles, they could be obtained every 2 weeks on subsequent cycles. Calcium, phosphate, and uric acid were obtained on day 1 of each cycle. T4 and TSH were obtained every two cycles. A GFR determined by technicium-99 DTPA scintigraphy for calculation of carboplatin dose was obtained before the first cycle and every two cycles thereafter except in patients who met the eligibility criteria for serum creatinine but had an abnormal GFR; these patients had a GFR for carboplatin dose calculation performed before each dose of carboplatin. Every 2 weeks, a serum pregnancy test was obtained in all female patients aged ≥ 8 years for the duration of thalidomide therapy. However, female patients with regular menstrual cycles could take pregnancy tests once a month after the first month. An assessment of the patient's sleep pattern was made on day 1 of each course, then weekly. Evaluation of disease status was performed after the first cycle, then every two cycles or as clinically indicated. Patients could remain on study as long as they had stable disease or better and did not have unacceptable toxicity, for up to a total duration of 1 year.

Definitions and Statistics
Responses were defined according to standard criteria (complete response = disappearance of all lesions; partial response = 50% reduction in the sum of the product of the two longest perpendicular diameters of all measurable tumors; progressive disease = increase in any previously measurable lesion by greater than 25% or appearance of new lesions; stable disease = not meeting criteria for progressive disease or response). The National Cancer Institute Common Toxicity Criteria Version 2 were used to define toxicity. Additionally, the Blaney somnolence scale11 was used to assess somnolence. Grade 1 indicates daytime drowsiness that does not impair the performance of daily activities or increased napping by less than 25% of baseline; grade 2, daytime drowsiness that interferes with the performance of daily activities and from which the patient is easily aroused, or that the patient experiences an increase in daytime napping (≥ 25% but < 50% increase from baseline); grade 3, daytime drowsiness from which the patient is difficult to arouse or more than 50% increase in daytime napping; and grade 4, equivalent to coma.

DLT of thalidomide was defined by any grade 3 or 4 nonhematologic toxicity. Hematologic DLT was always initially attributed to carboplatin and was defined as grade 4 neutropenia of more than 7 days duration, grade 4 anemia or thrombocytopenia that required transfusion therapy on more than two occasions in 7 days, or a delay of ≥ 14 days between treatment cycles. The MTD was the thalidomide dose level immediately below the dose level at which ≥ 2 patients (of a cohort of three to six patients) experienced a DLT.

In order to gain a reasonable overall experience with thalidomide in children for use in future studies, we planned to enroll additional patients at the MTD if necessary to bring the total number of assessable patients from 20 to 25.

Dose Modifications
Thalidomide administration was interrupted if there were any grade 3 or 4 nonhematologic toxicities. Thalidomide administration could be resumed at the dose the patient was receiving when the toxicity occurred if the toxicity reversed to ≤ grade 1 within 5 days of discontinuation of the drug. If the grade 3 or 4 nonhematologic toxicity recurred when thalidomide administration was resumed, then drug administration was again interrupted until the toxicity resolved to ≤ grade 1, at which time thalidomide could be resumed at one dose level (100 mg/m2/d) lower than that which the patient was receiving when the toxicity occurred. If grade 3 or 4 nonhematologic toxicity reversed to ≤ grade 1 within a 6 to 21-day period from the time drug administration was interrupted, thalidomide administration could be resumed at one dose level less than the dose that the patient was receiving when the toxicity occurred. Recurrence of thalidomide DLT after one dose reduction required removal of the patient from the study.

The carboplatin target AUC was reduced to 4.5 mg/mL·min if dose-limiting hematologic toxicity occurred at the AUC of 6 mg/mL·min. Patients experiencing a delay in carboplatin treatment due to delayed recovery of ANC or platelets could continue on thalidomide for up to 14 days during the delay.

Pharmacokinetics
Patients who were able to cooperate were asked to fast for 2 hours before and 2 hours after the thalidomide dose on the day of the pharmacokinetic sampling only (day 1, cycle 1). Before the dose was administered, and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours after the dose was administered, 3 mL of heparinized blood were drawn. All samples were placed immediately on wet ice, then centrifuged at 12,000 x g for 10 minutes to separate the plasma, which was frozen immediately at ≤ –20°C until analysis.

Pharmacokinetic Analysis
Thalidomide concentrations were measured using a validated modification of a previously published method.12 Plasma concentration-time data were fit to a model incorporating first-order absorption and first-order elimination implemented in ADAPT II (Biomedical Simulations Resource, Los Angeles, CA) using maximum likelihood estimation.13 In this model, ka and k10 are the rate constants for absorption and elimination, respectively, {tau} is the lag time, and Vc is the central volume of distribution. Patients' data were modeled with and without an absorption lag time ({tau}) and the best fit for each patient was determined using Akaike's Information Criterion.14 Apparent clearance (Cl) was determined from the equation

and half-lives for each phase were determined from the equation

where {lambda} is the disposition rate constant for the phase.15


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
Assessable Patients
Twenty-two patients were enrolled (Table 1); 56 cycles of therapy were administered. Two children withdrew in the first week of treatment because they had difficulty swallowing the thalidomide capsules; these patients were excluded from toxicity and response analyses. They did not have DLT or any serious adverse events. Twenty patients were assessable for response. Twenty patients were assessable for nonhematologic toxicity, and 15 were assessable for hematologic toxicity.


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  		Table 1. Patient Characteristics

 
Toxicity
Four patients were entered at the 100-mg/m2/d dose level and escalated 100 mg/m2/wk to a final dose of 300 mg/m2/d. No DLT occurred. The next cohort of patients therefore began with an initial dose of 300 mg/m2/d. Four of six patients tolerated weekly escalation by 100 mg/m2/wk to a final dose of 500 mg/m2/d without DLT. However, two patients had somnolence at the 400-mg/m2/d dose level that, while not dose-limiting by protocol definition, was judged to preclude escalation to 500 mg/m2/d. One of these patients also had dose-limiting ataxia at 400 mg/m2/d but tolerated a dose of 300 mg/m2/d. The protocol was therefore amended to treat all future patients at an initial dose of 300 mg/m2/d, with dose escalation in 1 week to 400 mg/m2/d. An additional 12 patients then entered the study. Ten of these 12 patients were assessable for toxicity; eight tolerated dose escalation to 400 mg/m2/d, and two patients had grade 3 somnolence and received a final dose of 300 mg/m2/d.

Non-dose-limiting somnolence was observed in 10 patients. Frequently the somnolence improved as patients continued to receive thalidomide. Other nonhematologic grade 3 to 4 toxicities that were considered possibly related to thalidomide are listed in Table 2. Additionally, two patients had asymptomatic (grade 1) bradycardia. No patients developed hypothyroidism on study. Table 3 lists all the grade 3/4 hematologic toxicities that were attributed to carboplatin.


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  		Table 2. Patients With Grade 3/4 Nonhematologic Adverse Events Possibly Related to Thalidomide

 

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  		Table 3. Patients With Grade 3/4 Hematologic Adverse Events Regardless of Attribution

 
Overall, constipation, rash, and peripheral neuropathy were not significant problems. No clinically evident venous thrombosis was noted. One patient had pancreatitis (grade 3 amylase, grade 4 lipase) that was considered possibly related to thalidomide.

Pharmacokinetics
Complete pharmacokinetic studies were performed on four patients at the 100-mg/m2/d dose level and 14 patients at the 300-mg/m2/d dose level (Fig 1). One patient's results (at the 300-mg/m2/d dose level) could not be modeled. Results are presented in Table 4. For 15 of 17 patients who could be modeled, the pharmacokinetic model incorporating a lag time in absorption provided the best fit. The lag time (median ± standard deviation) was 27 ± 20 minutes. The apparent clearance was 55 ± 16 mL/min/m2, and the terminal half-life was 5.9 ± 2.8 hours. (Two patients whose model-predicted terminal half-life was greater than the 24-hour sampling interval were excluded from the half-life statistics.) For the 100-mg/m2/d dose level, the peak concentration was 7.1 ± 2.0 µmol/L and the AUC was 104 ± 25 µmol/L·hr. For the 300-mg/m2/d dose level, the peak concentration was 22.9 ± 8.0 µmol/L, and the AUC was 381 ± 128 µmol/L·hr. There was no evidence of dose-dependent pharmacokinetics in the narrow dose range studied.



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  		Fig 1. Mean ± standard deviation of thalidomide concentrations measured after a 100 mg/m2 (n = 4, squares) or 300 mg/m2 (n = 14, circles) dose. Symbols represent measured concentrations and lines represent model-predicted concentrations.

 

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  		Table 4. Pharmacokinetic Parameters for 18 Patients

 
Response
There were no patients with complete or partial responses. The median number of cycles administered was one. Five patients who met the definition of stable disease received three or more cycles, including one patient with glioblastoma multiforme who received 13 cycles, one with anaplastic astrocytoma who received nine cycles, and one with medulloblastoma who received six cycles.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Authors' Disclosures of...
 REFERENCES
 
Previous studies in adults have shown that the major toxicity of thalidomide is reversible sedation, which is expected since the drug was developed as a sedative. Additional serious toxicities include peripheral neuropathy (including constipation), thrombosis, and rash.16-19 Thyroid dysfunction has also been reported.20-22 In a phase I study of thalidomide in adults with Kaposi's sarcoma, the MTD was 600 mg/d, with DLT of somnolence and rash.10 To our knowledge, no previous formal dose-escalation studies in children have been published. There have been several reports involving thalidomide use in children. In one report,23 five children were treated with 12 to 25 mg/kg/d (approximately 360 to 750 mg/m2/d) of thalidomide for graft-versus-host disease, with side effects reported as "minimal." In another study,24 two of 14 children receiving thalidomide for the treatment of graft-versus-host disease developed peripheral neuropathy, but the most common side effects were mild somnolence and constipation. Our study adds to these results and expands on their general findings.

We have demonstrated that it is feasible to administer thalidomide at a dose of 400 mg/m2/d in combination with carboplatin to children and adolescents. This dose is equivalent to a fixed dose of approximately 680 mg/d in an adult, a dose at the high end of those in common usage. The most significant toxicity was sedation. It seems that many patients experience tachyphylaxis to somnolence, though this is difficult to measure objectively. Some adolescents, while not meeting the strict criteria for dose-limiting somnolence, may complain that sleepiness interferes with their daily activities enough to warrant dose reduction. Other toxicities that have been reported in adults, such as constipation, rash, thrombosis, and peripheral neuropathy, were not prominent in this study. The concomitant use of carboplatin precludes direct assessment of hematologic toxicity from thalidomide. However, myelosuppression did not seem to exceed what we expected based on the carboplatin exposure we targeted, suggesting that thalidomide contributed little to the limited myelosuppression observed in this study.

This is the first report of the pharmacokinetics of thalidomide in children. The apparent Cl of 55 ± 16 mL/min/m2 and the terminal half-life of 5.9 ± 2.8 hours agree reasonably well with those seen in adult studies.25-29 We did not observe any correlation of pharmacokinetic parameters with patient age, but because patients had to be able to swallow capsules to participate, very young children or infants were not included in this trial. Thalidomide is metabolized by CYP2C19,30 an enzyme which is polymorphic and variable in activity but probably present in near-adult amounts in children older than 5 years.31,32 However, CYP2C19 activity is not fully developed in very young children,32 and thalidomide pharmacokinetics and tolerability should be studied carefully in this population.

Thalidomide has been used in the treatment of diverse diseases including graft-versus-host disease following bone marrow transplantation,24,33-35 leprosy,36 Behcet's disease,37 and wasting and oral ulceration associated with HIV infection.16,38 Although thalidomide has shown some anticancer activity against various solid tumors,39-44 its greatest current utility in adults seems to be in the treatment of multiple myeloma.45-50 The role of antiangiogenic agents in pediatric cancers is not yet well understood, though this is an area of intensive research. Our study provides the dosing and pharmacokinetic information necessary to pursue studies of thalidomide in this population.

In summary, we have identified a safe and tolerable dose of thalidomide that can be administered in combination with carboplatin, and characterized the pharmacokinetics of thalidomide in children. This study was not designed to test the single-agent activity of thalidomide in pediatric cancers. However, our observation of prolonged stable disease in a few patients suggests that there may be a role for thalidomide in combination with cytotoxic agents in pediatric cancers.


   Authors' Disclosures of Potential Conflicts of Interest
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
REFERENCES
 
The authors indicated no potential conflicts of interest.


   NOTES
 
Supported in part by the National Institutes of Health General Clinical Research Center grant M01 RR00188.

Authors' disclosures of potential conflicts of interest are found at the end of this article.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
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18. Minnema MC, Fijnheer R, De Groot PG, et al: Extremely high levels of von Willebrand factor antigen and of procoagulant factor VIII found in multiple myeloma patients are associated with activity status but not with thalidomide treatment. J Thromb Haemost 1:445-449, 2003[CrossRef][Medline]

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33. Lim S, McWhannell A, Vora A, et al: Successful treatment with thalidomide of acute graft-versus-host disease after bone marrow transplantation. Lancet 1:117, 1988

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35. Vogelsang G, Hess A, Gordon G, et al: Thalidomide induction of bone marrow transplantation tolerance. Transplant Proc 19:2658-2661, 1987[Medline]

36. Sheskin J: The treatment of lepra reaction in lepromatous leprosy: Fifteen years' experience with thalidomide. Int J Dermatol 19:318-322, 1980[Medline]

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Submitted April 14, 2004; accepted August 20, 2004.


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