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© 2000 American Society for Clinical Oncology Phase II Evaluation of Thalidomide in Patients With Metastatic Breast CancerFrom the Breast Cancer and Development Therapeutic Programs, Lombardi Cancer Center, Georgetown University Medical Center, Georgetown University, Washington, DC; Dana-Farber Cancer Institute, Boston, MA; University of Chicago Medical Center, Chicago, IL; Duke University Medical Center, Durham, NC; and Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD. Address reprint requests to Said Baidas, MD, Georgetown University Medical Center, Lombardi Cancer Center, 3800 Reservoir Rd, NW, Washington, DC 20007; email Baidass{at}gunet.georgetown.edu
PURPOSE: To determine the efficacy, safety, pharmacokinetics, and effect on serum angiogenic growth factors of two dose levels of thalidomide in patients with metastatic breast cancer. PATIENTS AND METHODS: Twenty-eight patients with progressive metastatic breast cancer were randomized to receive either daily 200 mg of thalidomide or 800 mg to be escalated to 1,200 mg. Fourteen heavily pretreated patients were assigned to each dose level. Each cycle consisted of 8 weeks of treatment. Pharmacokinetics and growth factor serum levels were evaluated. RESULTS: No patient had a true partial or complete response. On the 800-mg arm, 13 patients had progressive disease at or before 8 weeks of treatment and one refused to continue treatment. The dose was reduced because of somnolence to 600 mg for five patients and to 400 mg for two and was increased for one to 1,000 mg and for four to 1,200 mg. On the 200-mg arm, 12 patients had progressive disease at or before 8 weeks and two had stable disease at 8 weeks, of whom one was removed from study at week 11 because of grade 3 neuropathy and the other had progressive disease at week 16. Dose-limiting toxicities included somnolence and neuropathy. Adverse events that did not require dose or schedule modifications included constipation, fatigue, dry mouth, dizziness, nausea, anorexia, arrhythmia, headaches, skin rash, hypotension, and neutropenia. Evaluation of circulating angiogenic factors and pharmacokinetic studies failed to provide insight into the reason for the lack of efficacy. CONCLUSION: Single-agent thalidomide has little or no activity in patients with heavily pretreated breast cancer. Further studies that include different patient populations and/or combinations with other agents might be performed at the lower dose levels.
THALIDOMIDE, A derivative of glutamic acid, was introduced in Europe in 1954 as a sedative/hypnotic agent and was used to ameliorate nausea in pregnancy.1 Peripheral neuritis attributable to thalidomide was reported in patients after long-term use.2,3 Other reported side effects included somnolence, nausea, dry mouth and skin, constipation, urticaria, headaches, irregularities in menstrual cycles, hypothyroidism, and edema of lower extremities.4-8 Although thalidomide was well tolerated, with no apparent severe toxicities or addictive properties, a large increase in the incidence of limb malformations (amelia and phocomelia) in newborn children was observed as a result of thalidomide use during pregnancy.9,10 Thalidomide was withdrawn from the market in Europe by the end of 1961, and it was never marketed in the United States.
Despite these toxicities, clinical trials of thalidomide for other indications were performed. In 1998, thalidomide was approved by the Food and Drug Administration for the treatment of the cutaneous manifestations of moderate to severe erythema nodosum leprosum. Thalidomide also has activity in the treatment of cutaneous lupus erythematosus, recurrent erythema multiforme, recurrent aphthous ulcers (especially in patients with AIDS), and graft-versus-host disease after transplantation.5,11-15 Although the exact mechanism of this immune-modulating activity is unclear, it might be secondary to inhibition of lymphocyte proliferation or to modulation of integrin receptors on human WBCs.16,17 Thalidomide also inhibits tissue necrosis factor alpha (TNF- Soon after thalidomide was withdrawn from the market in 1961, reports of a disease response or stabilization in a patient with sarcoma treated with this agent prompted clinical studies in other patients with cancer.6 Thalidomide was administered to 21 patients with 14 types of cancer at doses ranging from 600 to 1,400 mg/d. No tumor regressions were noted, but subjective palliation was reported in seven patients. In two patients (with multiple myeloma and fibrosarcoma), the rapid progression of the disease seemed to be slowed.6 In another study, 71 patients with a wide spectrum of cancers were treated with thalidomide at variable doses ranging from 300 to 2,000 mg/d. In this trial, only one objective response was observed in a patient with renal cell cancer whose pulmonary lesion disappeared after treatment.7 However, in more recent studies, responses to thalidomide in patients with multiple myeloma and brain tumors have been reported.21,22 New blood vessel formation is an essential step in the establishment and growth of malignancies. Angiogenesis has acquired importance as an independent prognostic indicator in solid tumors.23-25 Importantly, tumor angiogenesis in invasive breast cancer correlates with the presence of local and distant metastasis.26-28 In addition to its immune-modulatory activities, thalidomide also inhibits angiogenesis. Indeed, one of the proposed mechanisms for the teratogenic activity of thalidomide is axial limb artery degeneration.29-31 For example, deformed tails from puppies treated with thalidomide seem to have been deprived of blood supply.30 Oral thalidomide inhibits angiogenesis induced by basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) in the rabbit corneal micropocket assay.32,33 This effect results from a direct inhibition of angiogenesis rather than from thalidomide immune-modulatory activity. Taken together, the direct antiangiogenic activity of thalidomide, its availability in a well-tolerated oral form, the availability of safe and effective birth control methods, and the apparent importance of angiogenesis in development, growth, and metastasis of malignant tumors prompted the initiation of thalidomide clinical trials in the treatment of cancer. We report the results of the first single-disease, prospective, phase II study of thalidomide in patients with metastatic breast cancer.
Patient Selection This prospective phase II clinical trial was conducted after obtaining protocol approval from the institutional review boards of the participating institutions. Eligible patients must have been 18 years or older and have had histologically confirmed metastatic breast cancer with documented progressive disease. Patients must have had assessable or bidimensionally measurable disease in at least one site. Patients with assessable bone-only disease were required to have a lytic lesion that had not been radiated previously. Ascites and pleural effusions were not considered as measurable or assessable disease. Patients may have had no more than three prior chemotherapy regimens. One adjuvant chemotherapy was permitted in addition to two regimens for metastatic disease. If no adjuvant chemotherapy was given, then as many as three chemotherapy regimens for metastatic disease were allowed. There were no limitations to previous hormonal or biologic therapies. Patients had to be ambulatory with Eastern Cooperative Oncology Group performance status of 0, 1, or 2. Patients had to have clinically adequate organ function as follows: WBC count  3,000 cells/µL; hemoglobin level 8 g/dL; platelet count 75,000 cells/µL; prothrombin time and partial thromboplastin time less than 1.25 times the upper limit of normal; bilirubin, AST, ALT, and alkaline phosphatase levels no greater than 1.5 times the upper limit of normal; magnesium level 1.8 mg/dL; and serum creatinine level no greater than 1.5 times the upper limit of normal. Patients must have recovered from the reversible side effects of any prior therapy. Negative serum pregnancy testing was required within 48 hours of the first dose and monthly thereafter for all women with childbearing potential. Exclusion criteria included the following: recent major surgery within 21 days from starting treatment on protocol; frequent vomiting and severe anorexia; chemotherapy, radiotherapy, or hormonal therapy within 4 weeks of study entry; presence of brain metastasis, carcinomatous meningitis, or cardiomyopathy; and grade 2 or greater peripheral neuropathy. Chemotherapy, radiation therapy, hormonal therapy, immune therapy, and investigational drug therapy were prohibited during treatment on protocol.
Study Design Patients were stratified according to the number of previous chemotherapy treatments, zero or one versus two or three, and then randomized to one of two thalidomide doses: low dose (200 mg/d) or high dose (800 mg/d). Escalation by 200 mg every 2 weeks at the 800-mg/d arm was permitted in patients with no toxicity to a maximum of 1,200 mg/d. Thalidomide was given at 9 PM. Patients were asked to start taking laxatives along with thalidomide and to taper off any sedative or hypnotics they were taking. Patients received thalidomide as long as there was no evidence of tumor progression and as long as there was no dose-limiting toxicity. In the absence of new symptoms, the first tumor assessment was performed at week 8 of therapy. Patients with progressive disease were taken off study. All others continued therapy if toxicity was acceptable. Tumor assessment thereafter was performed every 2 months. Complete response was considered as the disappearance of all clinical and laboratory signs and symptoms of the disease for at least 4 weeks. Partial response was defined as a minimum reduction of at least 50% in the sum of the products of the longest perpendicular diameters of all indicator lesions. Progressive disease was defined as the appearance of new lesions or an increase of at least 25% in the sum of the products of the longest perpendicular diameters of measurable lesions. Stable disease was considered failure of the patient to qualify for complete or partial response or progressive disease at 2 months or more. Patients were observed and evaluated for toxicity by history and physical examination every 2 weeks for the first 2 months and monthly thereafter. Thalidomide was withheld for grade 2 neurotoxicities, except drowsiness and somnolence, until resolution to less than or equal to grade 1 and then restarted at a 25% dose reduction of the original dose. For recurrent grade 2 neurotoxicity, either thalidomide was restarted at 50% of the original dose after toxicity resolution to less than or equal to grade 1 or the patient was removed from the study. If the patient developed intolerable drowsiness or somnolence at the starting dose of 200 mg/d, the dose was reduced to 100 mg/d. If the patient developed intolerable drowsiness and somnolence at the starting dose of 800 mg/d, the dose was reduced to 600 mg/d, and if she continued to be drowsy, to 400 mg/d, then to 200 mg/d, and finally to 100 mg/d. If the patient could not tolerate the 100 mg/d, then she was removed from the study. Patients were taken off study for grade 4 toxicities except hematologic toxicities. For hematologic toxicities, only grade 4 toxicity was considered dose limiting. For patients with grade 4 hematologic toxicities, the drug was withheld until resolution to grade 1 and then restarted at 75% of the original dose. Patients with recurrent grade 4 hematologic toxicities were removed from the study. For other dose-limiting toxicities, the drug was withheld until toxicity resolved to grade 1 and then restarted at 75% of the original dose. Re-evaluation occurred at weekly intervals. If it was not possible to resume therapy after 3 weeks of delay because of persistent treatment-related toxicities, the patient was removed from the study. For recurrent toxicities, the drug was withheld until toxicity resolved to grade 1 and then restarted at 50% the original dose. For recurrent toxicities while at a 50% dose reduction, patients were removed from the study.
Pharmacokinetics and Correlative Studies
Serum specimens for angiogenic factors were obtained on day 1 immediately before the first dose of thalidomide, every 2 weeks during the first 2 months, and then monthly. Circulating levels of bFGF, VEGF, and TNF- Levels of plasma MMP-2 and MMP-9 were measured using zymograms, as described previously.35 Briefly, patient plasma samples were diluted in 1 x zymogram loading buffer and run without boiling on 10% SDS Page gels (Sigma, St Louis, MO) that contained 0.1% gelatin. Conditioned media, treated with P-amino-phenyl-mercuric-acetate, from Hs578t and MDA-MB-231 cells were run on each gel to provide standards for the latent and active forms of MMP-2 and MMP-9. The gels were subsequently washed twice for 30 minutes in Tris-buffered saline that contained 2% Triton X-100 and then incubated overnight at 37°C in 50 mmol/L Tris pH 7, 5 mmol/L calcium chloride, and 1% Triton X-100 (Sigma) to allow gelatin degradation. Areas of digestion were then visualized by staining with Coomassie blue R250 (Sigma) in 10% acetic acid/20% methanol, followed by de-staining in 10% acetic acid/20% methanol. The gels were then dried, and the areas of clearing caused by the action of MMP-2 and MMP-9 were measured by image analysis of the appropriate portion of the gels.
Thalidomide Supply
Statistical Methods Serial circulating growth factor levels were determined for all but two patients. To evaluate whether relative changes in serial factor levels were significant, patients whose angiogenic factor levels never exceeded the cutoffs distinguished by 1 SD above the mean of a normal population were considered noninformative. Noninformative patients were excluded from these analyses because normal biologic changes may cause small absolute changes in marker levels within normal level range, and these small absolute changes may falsely represent large relative changes in serial levels. Furthermore, the standard curves for these assays are increasingly flatter toward the normal ranges. Therefore, small changes in the assay readout (for example, absorbance) are reflected as large relative changes in marker levels in this part of the curve. For example, if a normal cutoff is 2 U/mL, then 84% of the normal population are expected to have levels less than 2 U/mL. For both technical reasons (flat standard curve in this range) and biologic reasons (normal variation of 1 or 2 U/mL), a 50% change (from 1 to 2 U/mL) would not be considered likely to be a result of a therapeutic intervention. In contrast, the standard curves become quite linear and steep in ranges above the normal cutoff. Furthermore, normal biologic changes continue to account for serial changes of only 1 or 2 U/mL. Therefore, a 50% change (from 10 to 20 U/mL) is most likely to result from therapeutic intervention and not from biologic or technical causes. For these reasons, a relative change from baseline to a subsequent sample level was only considered informative if one, the other, or both sample levels exceeded the normal cutoff. To normalize the data, the natural logarithm of each marker level measurement at baseline and at time of removal from study (because of progression or toxicity) was taken. The log of the baseline level was subtracted from the log of the value at time of removal from study for each patient. Combining data from both dose levels, a paired t test was performed for each growth factor to test whether the mean difference from baseline to time of removal from study was statistically significant.
Patients Twenty-eight patients were accrued at the four centers between 1996 and 1998 (Table 1). Fourteen patients were accrued to each of the two dose levels. Patients’ ages varied from 30 to 85 years, with the largest number of patients between 41 and 60 years old (18 patients). Two patients on each arm had had zero or one chemotherapy regimens before enrollment, and twelve had had two or three prior chemotherapy regimens. Three patients on the low-dose arm and two on the high-dose arm had received high-dose chemotherapy with peripheral stem-cell support before enrollment onto the protocol. Patients on the two treatment arms were comparable with respect to age and the number of chemotherapy regimens.
Dose Modifications One patient at the 200-mg dose required dose reduction because of grade 3 peripheral neuropathy. At the 800-mg dose, five patients had to reduce doses to 600 mg and two patients to 400 mg, all because of neurotoxicity (somnolence). Two patients continued at the 800-mg dose with no changes. One patient’s dose was increased to 1,000 mg, and four had their dose escalated to 1,200 mg.
Efficacy As of August 26, 1998, all patients had been removed from the study, 26 because of progressive disease and two because of patient choice and/or unacceptable toxicity (Table 2). Of the two patients who did not progress, one was on the 200-mg arm and was removed from study at week 11 because of grade 3 peripheral neuropathy. The second patient was on the 800-mg arm and refused to continue treatment beyond week 4 because of drug-related somnolence. This patient refused dose reduction.
At the 200-mg level, one patient was taken off study at 2 weeks and a second patient at 4 weeks after starting treatment because of rapidly progressive disease. Ten patients were taken off at 8 weeks because of progressive disease detected by routine restaging. Two patients went beyond the first 8 weeks of staging. The first patient was removed from study at 11 weeks and the second at 16 weeks (Table 3).
At the 800-mg level, two patients were removed from the study at 4 weeks, one because of progressive disease and the second, who refused to continue treatment, because of somnolence. Four patients were taken off study at 6 weeks and eight patients at 8 weeks, all because of progressive disease. None of the patients at the 800-mg level continued beyond the first 8 weeks of treatment (Table 3).
Adverse Events
There were five serious adverse event reports during the study. Two patients on the 200-mg dose required hospital admissions for progressive shortness of breath. Both of these patients had progressive increase in pleural effusions that were not related to thalidomide. One patient on the 800-mg dose developed postural hypotension during the first treatment day. She became diaphoretic and light headed but improved rapidly after intravenous fluids were started, and she continued treatment on protocol without similar episodes. Another patient on the 200-mg dose developed dizziness and palpitation, and ECG showed sinus bradycardia with bigeminy that resolved spontaneously. Her echocardiogram was normal, and she continued treatment on the protocol with no similar episodes. The last patient, who was on the 800-mg dose, developed vomiting and headaches that required intravenous hydration at the end of her first day of treatment. She continued on the study with no similar episodes. Although the last three episodes were considered to be probably related to thalidomide, none recurred with continued treatment.
Correlative Studies
Circulating angiogenic factor levels.
Circulating baseline angiogenic growth factor levels were determined in all but one patient. Of 27 patients, five (18.5%), six (22.2%), and 13 (48.1%) had elevated levels (
Changes in serum bFGF, VEGF, and TNF-
Of interest, serial changes in circulating levels of bFGF and VEGF seemed random in the single patient who experienced a near-partial response. However, in contrast to all but two other patients, serial TNF-  levels from this patient decreased from baseline to each time point (2, 4, and 8 weeks). Plasma levels of MMP-2 and MMP-9 were determined by zymography. This method allows the simultaneous measurement of the latent and active forms of the enzyme. Plasma MMP-2 levels remained relatively unchanged over the period of the study. Comparison with the standards revealed that all of the enzyme was apparently in the inactive proform (data not shown). There was considerable variation in the plasma levels of MMP-9 over time, with no discernible, consistent pattern to these alterations (data not shown). Statistical analysis of MMP-9 levels before treatment and at any point during treatment by paired t test did not show any significant trend. Like MMP-2, all of the MMP-9 in patient plasma seemed to be in the inactive proform.
In this phase II study of thalidomide in patients with progressive metastatic breast cancer, we have observed little or no activity of thalidomide as a single agent in either the low- or high-dose arm. Two patients on the 200-mg dose level had stable disease at 8 weeks. One patient nearly had a partial response, with a 43% reduction in the size of mediastinal and hilar lymphadenopathy at 8 weeks, but this disease improvement was short lived. She suffered marked disease progression at week 16, manifested by possible lymphangitic spread, a 200% increase in the mediastinal and hilar lymph node size, and a new suprarenal mass and pleural effusions. The second patient had previously manifested slowly progressing disease over 20 months on no treatment before starting thalidomide. She had stable disease at week 8. She developed grade 3 peripheral neuropathy and was removed from study at week 11. In this case, the observed tumor stability at 8 weeks was more likely a result of a history of indolent disease rather than of thalidomide. Although the protocol stipulated the addition of another 11 patients if one or more patients had stable disease at 8 weeks of treatment in either arm, we elected not to proceed, because 25 of 28 patients had progressive disease at or before 8 weeks of treatment. Furthermore, the two patients who were treated beyond 8 weeks had either short-lived response with rapidly growing disease at week 16 or previously indolent disease. One patient refused to continue treatment beyond 4 weeks because of side effects and refused to have her dose reduced. Thalidomide was well tolerated at the 200-mg dose level, with only one grade 3 toxicity (peripheral neuropathy). In contrast, the 800-mg dose level was not as well tolerated. The main complaint was somnolence that required dose reduction in seven patients. Although the dose was increased to 1,000 mg in one patient and to 1,200 mg in four patients, those patients complained of early morning somnolence and dizziness that lasted for a few hours. Constipation, dry mouth, and fatigue were common. Nonetheless, at the two dose levels, apart from one patient with grade 3 neuropathy at the 200-mg dose and seven patients with moderate somnolence at the 800-mg dose level, no other symptom required dose modification.
In an effort to gain insight into the mechanism of thalidomide activity, we studied circulating markers of angiogenesis. No identifiable patterns were observed in bFGF and VEGF levels. However, circulating levels of TNF- Like bFGF and VEGF levels, serial MMP levels were inconsistent during thalidomide treatment. Determination of MMP levels by gelatin zymography of plasma is semiquantitative at best. Of interest, the identified MMP-2 and MMP-9 enzymes were all in the proform. This observation is in agreement with our previous results.35 The failure of thalidomide in this study was not a result of insufficient blood levels, because most patients achieved detectable plasma levels of thalidomide during treatment. Furthermore, although patients on the 800-mg dose achieved a higher plasma steady-state concentration of thalidomide, no antitumor activity was observed at this dose. The pharmacokinetics data in this study are consistent with the other published data on thalidomide clearance in a group of prostate cancer patients and in healthy normal volunteers.37,38 We conclude that thalidomide has little or no activity as a single agent in this population of patients with previously heavily treated progressive metastatic breast cancer. These results do not preclude activity of thalidomide in other settings, such as in patients with micrometastatic breast cancer or in patients with other types of malignancies. Moreover, they do not preclude possible activity of the drug in combination with other classically active agents, such as hormone therapy or chemotherapy. Likewise, thalidomide might be active with other biologic therapies, such as other inhibitors of angiogenesis or immunomodulators. If such studies are performed, our results suggest that thalidomide might be used at the lower dose levels. The lower dose was better tolerated, and the one near response that was observed was at this dose. Although a few patients tolerated thalidomide at higher doses, the side effects may preclude long-time administration at the dose of 800 mg or more.
Supported by Department of Defense Cancer Center grant no. DAMD17–96-C-6069 and by Fashion Footwear Association of New York, "Shoes on Sale."
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
), 200 mg/d.
