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© 2001 American Society for Clinical Oncology Phase I Clinical Trial of Alitretinoin and Tamoxifen in Breast Cancer Patients: Toxicity, Pharmacokinetic, and Biomarker EvaluationsFrom the Medicine Branch, Pediatric Oncology Branch, and Laboratory of Pathology, Division of Clinical Sciences, National Cancer Institute, and Diagnostic Radiology Department, Clinical Center, and National Eye Institute, National Institutes of Health, Bethesda, Maryland. Address reprint requests to JoAnne Zujewski, MD, Medicine Branch, National Cancer Institute, Building 10, 12N226, 9000 Rockville Pike, Bethesda, MD 20892.
PURPOSE: To determine the overall and dose-limiting toxicities (DLTs) of alitretinoin (9-cis-retinoic acid) in combination with tamoxifen and the pharmacokinetics of alitretinoin alone and when combined with tamoxifen in patients with metastatic breast cancer. The effect of tamoxifen and alitretinoin on MIB-1, a marker of proliferation, in unaffected breast tissue was explored. PATIENTS AND METHODS: Eligible patients had metastatic breast cancer. Previous tamoxifen therapy was allowed. Planned dose levels for alitretinoin ranged from 50 to 140 mg/m2/d with 20 mg/d tamoxifen in all patients after 4 weeks of alitretinoin as a single agent. Plasma concentrations of alitretinoin and retinol were measured at baseline and after 1, 2, and 3 months. Breast core biopsies were obtained at baseline and after 2 months of therapy. RESULTS: Twelve patients with metastatic breast cancer received a total of 86 cycles of therapy. At 90 mg/m2/d, three of five patients experienced a DLT: grade 3 headache, grade 3 hypercalcemia, and grade 3 noncardiogenic pulmonary edema. At 70 mg/m2/d, one of six patients experienced a DLT (headache), and this level was considered the maximal tolerated dose in this study. Three toxicities occurred that had not been reported previously with alitretinoin: an asymptomatic delay in dark adaptation, a marked decrease in high-density lipoprotein cholesterol, and the occurrence of enthesopathy. Two of the nine assessable patients had a durable clinical response: one partial response and stable disease for 18 months and one complete response in continuous remission for 48+ months. Both responding patients were estrogen receptor–positive and had had previous tamoxifen therapy. There was a high degree of interpatient variability of plasma alitretinoin concentrations, although a significant decline in alitretinoin plasma levels over time was observed. MIB-1 scores declined in four of the eight paired breast specimens obtained. CONCLUSION: The combination of tamoxifen and alitretinoin is well tolerated and has antitumor activity in metastatic breast cancer. The recommended phase II dose is 70 mg/m2/d with 20 mg/d tamoxifen.
BREAST CANCER accounts for 43,700 deaths in the United States annually. Of the 175,000 cases of invasive breast cancer diagnosed annually in the United States, 6% present with metastatic disease.1,2 In addition, 20% to 70% of patients will recur after adjuvant therapy within 10 years depending on stage at diagnosis.3-6 Therefore, the management of recurrent and metastatic breast cancer is a major public health concern. Management strategies have included hormone therapies, chemotherapy, chemohormone therapy, and biologics. Of patients with metastatic breast cancer, only 3% remain in continuous remission beyond 5 years.7 The response rates to initial hormone therapy for metastatic disease are 30% to 40% with expected durations of up to 2 years.8 The availability of additional therapies that are well tolerated for prolonged administration will have a significant impact on the quality of life for patients with recurrent and metastatic breast cancer. Retinoids have the potential to induce differentiation and inhibit proliferation of epithelial cells, and this holds promise for the treatment and prevention of cancer.9-11 In vitro and in vivo studies have suggested antitumor activity of the retinoids in breast cancer. In vitro studies have demonstrated an additive effect of tamoxifen and retinoids in growth inhibition assays of breast cancer cells, and antiestrogen-resistant cell lines retain their sensitivity to alitretinoin.12,13 In the N-methyl-N-nitrosurea animal model, the combination of alitretinoin and tamoxifen is more efficacious than either agent alone in the prevention of carcinogen-induced tumors.14,15 Bischoff et al16 reported that the retinoid X receptor (RXR) selective ligand (LGD1069) has antitumor activity in rodent models that fail to respond to tamoxifen. Alitretinoin has been reported to be a well-tolerated oral agent and may have pharmacologic advantages over other retinoids as it is not bound by cellular retinoic acid binding proteins and may not be susceptible to the progressive decline in plasma concentration as observed with all-trans-retinoic acid (ATRA).17-19
The cellular effects of retinoids are mediated in part through the intranuclear retinoic acid receptors (RARs), which include RAR We conducted a phase I, pharmacokinetic, and biomarker study of tamoxifen and alitretinoin in combination to determine the overall and dose-limiting toxicities (DLTs) and to recommend a dose for phase II testing in metastatic breast cancer patients. There are preclinical data to support the development of the combination of tamoxifen and alitretinoin for therapy as well as for the prevention of breast cancer. Developing agents for breast cancer prevention will require the identification of biomarkers of drug effect.27 Biomarkers that are modulated with a potential pharmacologic intervention may indicate agent efficacy and appropriate dose. Therefore, we obtained core biopsies of the contralateral unaffected breast to explore the effect of these agents on epithelial proliferation (MIB-1) as a potential biomarker.
Patient Selection All patients had metastatic breast cancer. Eligible patients had histologically confirmed diagnosis of breast cancer; age greater than 18 years; Zubrod performance status of 0, 1, or 2; absolute neutrophil count  1,500/mm3; platelet count 90,000/mm3; fasting triglycerides less than three times the upper limits of normal; serum creatinine  1.5 mg/dL or creatinine clearance 60 mL/min; and liver function tests (ALT, AST, and total bilirubin) two times the upper limit of normal. Patients with the following characteristics were excluded: cytotoxic chemotherapy within the previous 3 weeks, CNS metastasis, or a seizure disorder. There was no limit to the number of previous chemotherapy or hormone therapy regimens.
Treatment Plan The tamoxifen dose of 20 mg was held constant in all patients. Tamoxifen was purchased from commercial sources. Alitretinoin was supplied by Ligand Pharmaceuticals Inc (San Diego, CA) as 10-mg and 25-mg soft gelatin capsules; doses were rounded to the nearest 10 mg. Patients were instructed to ingest capsules with the morning meal because the absorption of retinoids is increased with the consumption of fat. On the day of pharmacokinetic monitoring after an overnight fast, alitretinoin was administered with 4 to 8 oz of Ensure (Abbott Laboratories, Columbus, OH) to standardize the intake of fat with drug administration. Patients with metastatic disease continued on therapy until disease progression.
On-Study Evaluations
Toxicity Evaluation
Patients who experienced a reversible grade 3 or 4 toxicity had alitretinoin held until the toxicity returned to
Patients who completed 3 months of therapy or 2 months of the combination underwent formal radiologic evaluation for response. A complete response (CR) was the total disappearance of all clinical evidence of disease for at least two measurements separated by periods of at least 4 weeks. A partial response (PR) was at least a 50% reduction in the size of all measurable tumor areas as measured by the sum of the products of the greatest length and maximum width. These parameters must have been present for at least two measurement periods by at least 4 weeks apart. Progressive disease is an increase of
Tissue Biopsies
Biomarker Assays MIB-1 staining on epithelial cells was evaluated independently by two investigators who were blinded to patient identity and time of biopsy. Total cell counts of up to 1,000 cells were counted per slide. The MIB-1 score was expressed as the number of positive nuclei per 1,000 epithelial cells. All assessable counts of the two investigators were combined. Discrepancies between the two investigators were resolved by an independent pathologist.
Ophthalmologic Evaluations
Pharmacokinetics Methods The plasma concentrations of alitretinoin and retinol were measured by a modification of a previously described high-performance liquid chromatography method.19 The area under the curve (AUC) from 0 to 8 hours was calculated by the trapezoidal method. Samples below the limit of detection (0.03 µmol/L) obtained immediately before the first detectable time point or immediately after the last detectable time point were set to 0.03 µmol/L. All other samples below the limit of detection were set equal to 0. Extrapolation of the AUC after the last time point was not performed because of the limited number of data points available to estimate accurately the terminal elimination in the majority of patients. In patients who had a minimum of three data points on the terminal portion of the plasma-concentration time curve, the terminal half-life was estimated by regression analysis.
Patient Characteristics Twelve patients with metastatic breast cancer were enrolled between March 19, 1996, and March 1, 1999. Patients were enrolled on two dose levels (70 and 90 mg/m2/d) and were treated over four dose levels (37.5, 50, 70, and 90 mg/m2/d) as a result of dose reductions to control chronic toxicities. Patient characteristics are described in Table 1.
Adverse Effects Five patients received a total of 12 cycles of 90 mg/m2/d, and three DLTs occurred. All three DLTs occurred within the first 4 weeks when alitretinoin was administered alone ( Table 2). One patient with breast cancer metastatic to bone developed symptomatic grade 3 hypercalcemia and asthenia with a normal parathyroid hormone and reverse parathyroid hormone levels. The hypercalcemia resolved after alitretinoin was stopped and pamidronate was administered. The patient did not require continued treatment for hypercalcemia after discontinuation of alitretinoin. A second patient had grade 3 headaches with secondary nausea and vomiting after 2 weeks of narcotic analgesia. The headaches persisted at dose reductions to 70 and 50 mg/m2/d, and she discontinued therapy for this toxicity. Complete neurologic examination and head magnetic resonance imaging scans were normal. It was believed that the headache was related to the alitretinoin. A third patient who received 90 mg/m2/d of alitretinoin developed grade 3 noncardiogenic pulmonary edema. She presented with dyspnea, peripheral edema, and confusion 15 days after starting alitretinoin. On chest x-ray, she had very small bilateral pleural effusions and increased interstitial markings. The diagnostic evaluation included an exclusion for myocardial infarction, an echocardiogram that revealed normal left ventricular function, and a bronchoscopic biopsy that was negative for malignancy. The alitretinoin was discontinued, and chemotherapy was initiated. The investigator considered this toxicity to be probably related to alitretinoin because of the temporal association with alitretinoin administration, rapid resolution after drug discontinuation, known reports of this adverse event with alitretinoin, and the absence of malignancy on bronchoscopic biopsy. Therefore, 90 mg/m2/d was considered to have exceeded the MTD.
Seven patients were enrolled at 70 mg/m2/d and received a total of 43 cycles. One patient withdrew voluntarily before completion of 8 weeks of therapy and was not assessable for the determination of DLT. Of six patients completing 8 weeks of therapy, one DLT was observed. The patient experienced a headache that did not abate with narcotics, and her dose was reduced to 50 mg/m2/d. The adverse event did not recur at the reduced dose. Therefore, 70 mg/m2/d was the MTD as defined in this study.
Twelve patients received a total of 86 cycles of therapy. Adverse events that were considered to be related possibly, probably, or definitively to drug administration are listed in Table 3. All patients were considered to be assessable for toxicity. Three patients had one or more dose reductions for alitretinoin toxicity. The reasons for dose reductions were grade 3 hypercholesterolemia, grade 3 headache, grade 3 hypercalcemia, and grade 2 bone pain with long-term use. Three patients received atorvastatin calcium (Lipitor; Parke-Davis, Morris Plains, NJ) for the management of hypercholesterolemia (two grade 3 and one grade 1). The most common clinical toxicity was mucocutaneous and included dry eyes, skin, and lips; skin pruritus; and rash. All of the mucocutaneous toxicities that occurred were of
Two patients who were treated for greater than 1 year required dose reductions for control of chronic toxicities. One patient began therapy with 90 mg/m2/d of alitretinoin and was dose reduced after five cycles for grade 3 hypercholesterolemia and decreased HDL (6 mg/dL). After 21 cycles on 70 mg/m2/d of alitretinoin, she developed grade 2 bone pain and asthenia and was found to have a new soft tissue calcification of her hip ( Fig 1). This clinical presentation was consistent with the enthesopathy reported with the prolonged administration of other retinoids. Pain persisted at a reduced dose and was relieved with a 2-week drug holiday. Because the toxicity was chronic, symptomatic, and potentially progressive, the dose of alitretinoin was reduced further to 37.5 mg/m2/d. She remains asymptomatic at the lower dose after 48+ cycles of therapy. The second patient was enrolled on 70 mg/m2/d of alitretinoin and experienced grade 3 hypercholesterolemia after three cycles, which did not resolve with dose reduction. Despite the addition of atorvastatin, the hypercholesterolemia was not controlled until the dose was reduced to 37.5 mg/m2/d. She remained on 37.5 mg/m2/d of alitretinoin until her disease progressed after 16 cycles of therapy.
Prolongation of adaptation to dark has been reported with other retinoids and is caused by a delay in the rod-cone break. Three of the nine assessable patients had a delay in their rod-cone break at the 3-month evaluation. The baseline mean rod-cone break of the assessable group was 5.94 minutes, and this was delayed 1.75 minutes in three patients. In the affected patients, dark adaptation was delayed 9 to 10 minutes, but no subjective loss was reported. A comparison of the dark adaptation at baseline and during alitretinoin administration demonstrated a mild delay of the rod-cone break (from 5.83 ± 0.86 minutes to 7.10 ± 2.03 minutes) and a minimal elevation of the cone-mediated threshold (from -2.32 ± 0.29 log cd/m2 to -2.17 ± 0.28 log cd/m2). In three of the nine patients in whom adaptometry was performed, the rod-cone break occurred beyond the upper normal limit (6.92 minutes).
Antitumor Response
Pharmacokinetic Results
Daily administration of alitretinoin resulted in a decrease in plasma retinol concentrations. Before treatment, the average (±SD) retinol concentration for all patients studied was 2.2 ± 09 µmol/L. After 28 days of alitretinoin, the predose retinol concentration was 1.7 ± 0.5 µmol/L ( Fig 3). The day 28 retinol concentration was no different in the patients with or without ocular toxicity (P = .16, Mann-Whitney U test).
Tissue Biomarker Results Core biopsies at baseline and at 2 and 5 months after therapy were obtained from the contralateral unaffected breast in eight patients to determine the effect of the agents on high-risk breast epithelium. Seven of the eight patients had tissue assessable at the baseline and the 2-month time points. One patient did not have adequate tissue at the 2-month time point, and a biopsy obtained at the 5-month time point was used for comparison. MIB-1 staining was evaluated over the entire slide. The MIB-1 scores at baseline ranged from 1.5 to 62 positively stained cells per 1,000 with a median of 16.5 ( Fig 4). The MIB-1 scores at follow-up ranged from 4 to 85 with a median of 14 per 1,000 cells counted. Four of the cases had a decline in the MIB-1 staining comparing the benign breast epithelium at baseline with the biopsy obtained after 2 months of therapy. The decline ranged from nine to 50 MIB-1 stained nuclei per 1,000 nuclei. The two patients who had had a clinical response to alitretinoin and tamoxifen had a decline in MIB-1 staining in their benign breast epithelium at the 2-month evaluation compared with baseline.
Histologic review of the core biopsies was performed in conjunction with MIB-1 staining. Of the four patients who had had a decline in MIB-1 staining at the 2-month time point, three had a consistent diagnosis of benign breast epithelium at both time points and the fourth had hyperplasia at baseline and sclerosing adenosis at the 2-month time point. The following histologies were found in the four patients who did not have a decrease in MIB-1 score: (1) benign breast epithelium at baseline and sclerosing adenosis with repair at the 2-month time point, (2) infiltrating breast cancer on both biopsies, (3) fibrofatty breast and fibroadenosis on both biopsies, and (4) benign breast epithelium at both time points.
We determined that the combination of tamoxifen and alitretinoin has acceptable tolerability when initially administered at the MTD of 70 mg/m2/d in patients with metastatic breast cancer. DLTs were headache, hypercalcemia, and noncardiogenic pulmonary edema. The most common non-DLTs were low-grade mucocutaneous effects and hyperlipidemia. However, given the toxicities observed with chronic dosing, a long-term dose of 37.5 to 50 mg/m2/d may be tolerated better. We initiated our dose escalation study based on the previously reported experience with alitretinoin alone. In two phase I studies of alitretinoin alone, doses of 100 and 140 mg/m2/d were reported as the MTD and recommended for further clinical trials.17,29 A total of 11 patients in the two single-agent phase I clinical trials received doses of 100 or 140 mg/m2/d without a grade 3 toxicity. However, in our study, 90 mg/m2/d exceeded the MTD and all DLTs occurred in the first 4 weeks, so the lower MTD observed cannot be attributed to the addition of tamoxifen. That increased doses of alitretinoin may not be tolerated in a substantial subset of patients has been suggested by other clinical trials. A more recently published phase I trial reported an MTD of 83 mg/m2/d.30 A phase I trial of alitretinoin in combination with tamoxifen reported grade 3 toxicities in two patients at 80 mg/m2/d of alitretinoin.31 Alitretinoin was administered to patients with previously treated multiple myeloma, and grade 3 or greater toxicities occurred in 14 of the 16 patients at the dose levels of 60 and 100 mg/m2/d.32 We report three new toxicities that have been associated with the class of retinoids but have not previously been reported for alitretinoin: a delay in dark adaptation, a decrease in HDL cholesterol, and the occurrence of enthesopathy. Such toxicities may have an impact on the potential for long-term administration of this agent. Reversible dark-adaptation changes and electroretinogram abnormalities have been reported with the retinoid fenretinide.28,33,34 The adverse effect of fenretinide and alitretinoin is similar to the retinal effects of vitamin A deficiency, suggesting an interference in retinal vitamin A metabolism.35 Three of the nine assessable patients who were receiving tamoxifen and alitretinoin had a delay in the rod-cone break. The dark-adaptation delay observed with fenretinide is associated with a decline in the plasma retinol levels.33 Retinol levels were assayed in the three patients with a delay in the rod-cone break on this study, and no difference at 28 days was noted. However, as patients were asymptomatic, the clinical significance is unknown and would not preclude further development of this combination. Future studies of this agent should incorporate formal evaluations of dark adaptation to define better this observation. Hypertriglyceridemia and hypercholesterolemia have been reported with alitretinoin; however, this is the first report of a significant decline in HDL cholesterol. Other synthetic retinoids and retinol have caused an increase in total cholesterol with a decline in HDL cholesterol.36-39 It has been suggested that retinoids may have long-term adverse effects on cardiovascular mortality as a result of alterations in cholesterol and lipoprotein levels from the Carotene and Retinol Efficacy Trial.40,41 Of particular interest in our trial was the occurrence of detrimental effects on lipid control with the coadministration of tamoxifen, because the latter typically has a favorable effect on serum lipids.42 Tamoxifen typically causes a decline in total and LDL cholesterol but, unlike estrogen, does not have the beneficial effect on HDL cholesterol levels.43-45 Interestingly, the combination of tamoxifen and fenretinide has been beneficial in raising HDL cholesterol.46,47 A negative impact of alitretinoin on lipoproteins and the association of those effects on cardiovascular mortality48-50 may affect the utility of the combination of alitretinoin and tamoxifen in breast cancer prevention. The effect on lipemic control may be less relevant to the further development of the regimen for metastatic breast cancer treatment, for which there is less concern for long-term cardiovascular morbidity. Skeletal toxicity with the long-term intake of retinoids (13-cis-retinoic acid) has been reported with the occurrence of an ossification disorder that resembles diffuse idiopathic skeletal hyperostosis presenting as arthralgias and stiffness.51 At drug cessation, the symptoms were relieved but the radiologic findings of ossifications at ligamentous insertions persisted. The clinical presentation of our patient who remained on the regimen for greater than 3 years is consistent with the presentation of the patients on 13-cis-retinoic acid. Other retinoid-induced calcification disorders have been reported, including extraspinal tendon and ligament calcification with the use of etretinate and axial hyperostotic changes with low-dose isotretinoin.52,53 Paradoxically, osteoporosis and a decrease in bone mineral density also have been reported with long-term retinoid intake.54,55 The skeletal effects of the retinoids are consistent with hypervitaminosis A toxicity and may be a direct effect on the vitamin D signaling pathway or by an effect on chondrocyte maturation.56,57 The pharmacokinetics of alitretinoin alone and when combined with tamoxifen were evaluated over time. After 28 days of daily alitretinoin administration, the average plasma AUC of alitretinoin was approximately 60% lower than that observed on the initial day of drug administration. This decrease, which likely represents autoinduction of metabolism, observed previously with alitretinoin administration,29,30 but the magnitude of the decrease does not seem to be as large as that observed with ATRA administration.58-60 The pharmacokinetics observed here are similar to those reported in other phase I trials of alitretinoin.29,30 Tamoxifen did not seem to have an impact on the pharmacokinetics of alitretinoin consistent with the effects of tamoxifen on ATRA.61 To facilitate further development of the combination of tamoxifen and alitretinoin for breast cancer prevention, we conducted an exploratory study of the effect of the combination on the expression of MIB-1 in high-risk breast epithelium. The expression of proliferation markers in breast tumors have been found to be related to prognosis and to be predictive of clinical response.62-64 However, little is known about their expression in high-risk breast epithelium and whether modulation of MIB-1 expression predicts response to the known chemopreventive agent tamoxifen. Our study examined the effect of 1 month of alitretinoin administration followed by 1 month of tamoxifen plus alitretinoin administration on the proliferative status of patients’ high-risk unaffected breast epithelium. No significant difference in MIB-1 staining before and after the combination treatment was found in the eight paired biopsies available for study. Difficulties with serial core biopsy studies include controlling for the effect of the biopsy procedure itself on tissue biomarkers and for the heterogeneity of the tissue being assayed. Of the four paired core biopsies that contained benign breast epithelium at both time points, three demonstrated a decline in MIB-1 staining. This exploratory study demonstrates the feasibility of studying the expression of MIB-1 in high-risk breast epithelium and the adequacy of obtaining samples. In the eight paired specimens, the total number of epithelial cells in the samples evaluated was greater than 1,000 in 87% of the cases and greater than 500 in 94% of the cases. It is possible to conduct biomarker studies of breast epithelia and stroma with the use of multiple core needle biopsies of mammographically dense tissue. Clinical activity for this combination was demonstrated in this phase I trial at alitretinoin doses of 37.5 to 70 mg/m2/d. The durable clinical responses of 18 and more than 48 months occurred in two patients with estrogen receptor–positive disease, both of whom had received previous tamoxifen and had a history of indolent disease. The preclinical data as well as the observations made in the current study suggest that tamoxifen in combination with alitretinoin is promising and that phase II trials in metastatic breast cancer are warranted. We recommend a phase II starting dose of 70 mg/m2/d but anticipate that patients may require dose reductions when treated chronically.
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ABSTRACT
INTRODUCTION
, RARß, and RAR
, and RXRs (RXR
, patients treated at 70 mg/m2/d; 
, patients treated at 90 mg/m2/d. Numbers represent individual patients. Decrease in plasma AUC was significant with 28 days of daily alitretinoin administration (P = .011, Wilcoxon signed rank test). The addition of tamoxifen did not seem to affect the plasma AUC of alitretinoin.
