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Clinical Trials |
Department of Medicine, Division of Hematology/Oncology, Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC 20007 [N. A. R., J. L. M., W. D., E. N., M. J. H.], and Ligand Pharmaceuticals Inc., San Diego, California 92121 [J. A. T., G. L., G. M. G., E. H. U., R. G., D. J.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Retinoids modulate normal, premalignant, and malignant cell phenotypes by changes in gene expression that are mediated through binding to two classes of nuclear hormone receptors, the RARs2
and the RXRs (6)
. There are six known retinoid IR subtypes, RAR (
, ß, 
) and RXR (, ß, ), which are members of the steroid receptor superfamily. These retinoid IRs form heterodimers that bind to specific DNA RA response elements and act as ligand-dependent transcriptional regulators for RA-responsive genes. The cytoplasmic RA binding proteins CRABPI and CRABPII exhibit specific patterns of expression and correspond to a second level of complexity in the retinoid signaling pathway (1)
. The RARs and RXRs coexist in most cells, and the effects of RA on cellular differentiation and death may reflect selective activation of RARs and/or RXRs (7
, 8)
. RAR, vitamin D receptor, TR, PPAR, and LXR (liver X receptors) preferentially bind to their hormone response elements in vitro as heterodimers complexed with RXR (9, 10, 11)
. Thus, RXRs seem to be essential pleiotropic regulators of several signaling pathways.
Naturally occurring and synthetic ligands have been described that have distinctive binding properties and transactivation effects on the various RAR and RXR subtypes, thereby allowing differential modulation of retinoid receptor gene expression. ATRA binds RAR with high affinity, but does not bind to RXR, whereas 9-cis-RA transactivates both RARs and RXRs (12) .
Using a series of RXR- and RAR-selective ligands, it has been shown that, in leukemic cells, activation of RAR pathways regulates cell proliferation and differentiation, whereas activation of RXR pathways leads to the induction of apoptosis (13) . LGD1069 (Targretin) has been identified as an RXR-selective ligand that does not have significant RAR binding and transactivation of RAR-responsive genes (14) . LGD1069 has been shown to have antiproliferative activity in preclinical in vitro and in vivo models, including human tumor xenografts of head and neck carcinomas.3 LGD1069 can reduce, in a dose-dependent manner, the volume of skin papillomas in the 7,12-dimethylbenz(a)anthracene-induced SENCAR mouse two-stage skin papilloma model.3 In the N-nitrosos-N-methylurea-induced rat mammary tumor model, LGD1069 showed a 90% reduction in tumor burden and tumor incidence compared with vehicle-treated rats (15) ; in this model, LGD1069 was very well tolerated without the classic signs of traditional retinoid toxicities. On the basis of these preclinical observations, this Phase I clinical trial of LGD1069 was conducted as a dose-finding study to determine the safety, toxicity, PKs, and metabolic profile of this agent in advanced cancer patients
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PATIENTS AND METHODS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Treatment Plan.
This study was an open-label, multiple-dose, dose escalation, safety evaluation study of oral LGD1069 in patients with advanced cancer. The drug was supplied by Ligand Pharmaceuticals, Inc. as 10-mg and 25-mg soft gelatin capsules, and doses were rounded to the nearest 5 mg. During the course of the study, a new micronized formulation that increased the surface area of LGD1069 from 0.37 m2/g to 5.3 m2/g became available and was introduced with an anticipated 6.8-fold enhancement of oral bioavailability based on evaluation in beagle dogs. The micronized formulation was substituted after the 75 mg/m2/day nonmicronized dose level and was initiated at a dose of 21 mg/m2/day. Patients were seen weekly for the first 4 weeks. In the absence of progressive disease, patients were allowed to continue on treatment in 4-week intervals. Dose escalation was not permitted within individual patients, and the starting dose was 5 mg/m2/day. Toxicity was assessed using the National Cancer Institute Common Toxicity Criteria (except for hypertriglyceridemia). If DLT was not observed in three patients, the dose was escalated to the next dose level. If DLT was observed in one of three patients, three additional patients were accrued at that dose level. The maximum tolerated dose was defined as the highest dose level that resulted in not more than one of six patients experiencing DLT during the first 4 weeks of study therapy. Standard laboratory tests, including complete blood counts, chemistry survey, coagulation tests, lipid profiles, thyroid tests, and urinalysis were followed during the study. Imaging studies to evaluate possible tumor response were performed as clinically indicated during the study.
PK Studies.
Patients underwent PK studies on days 1 and 15. After an overnight fast, LGD1069 was taken after ingestion of a liquid formula of defined lipid content (Ensure; 250 ml; Abbott Laboratories, Columbus, OH). Heparinized whole-blood samples were collected before dosing and at 0.5-, 1-, 2-, 4-, and 6-h time points. Plasma samples were obtained after centrifugation and stored at -20°C.
Analytical Methods.
Plasma samples were analyzed to determine LGD1069 drug substance concentrations using a validated gas chromatography-mass spectroscopy assay. In brief, internal standard (2H3-13C-LGD1069) was added to plasma, and samples were extracted with 1-chlorobutane. The upper organic layer was evaporated to dryness, and derivatization solution (5% acetyl chloride in methanol) was added. The residue was taken up in 25 µl of chloroform, and 3-µl aliquots were injected into the gas chromatography. Detection was by mass spectroscopy in the single ion mode. PK parameters were determined by noncompartmental methods using the PK analysis program Topfit, version 2.0 (16)
. Peak plasma LGD1069 concentrations (Cmax), trough concentrations (Cmin), and time to peak plasma concentration (tmax) values were recorded as observed. When determinable, apparent terminal elimination rate constants (
z) were determined as the slope of the terminal log-linear portion of the plasma concentration-time profile, and terminal elimination half-life (t1/2) values were determined as 0.693/z. AUC from time zero to 6 h (AUC0–6) was determined by linear trapezoidal approximation. AUC from time zero to infinite time (AUC0–
) was determined by summing AUC(0–6) and C(last)/z parameter values. Because (AUC0–) values were not determinable for all patients, AUC0–6 values were used for comparisons. Ratios of repeat-dose AUC0–6 divided by day 1 AUC0–6 were determined as an indicator of an autoinduction of clearance.
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RESULTS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. One patient in this study had non-Hodgkin’s lymphoma, and the remainder of the patients had a solid tumor, as described in Table 1
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Leukopenia occurred in 10 patients in this study, although it was mild (grade I/II) in 8 patients. Two patients experienced dose-limiting grade III leukopenia, and these cases occurred at 800 mg/m2/day. No infection-related complications resulted from LGD1069-related leukopenia.
Five of 60 patients experienced transaminitis with LGD1069 treatment, and none occurred below 650 mg/m2/day. Only one of five patients experienced grade III dose-limiting transaminitis, and this occurred at 1000 mg/m2/day. One patient experienced grade II hyperbilirubinemia at 800 mg/m2/day, and one patient experienced dose-limiting grade III hyperbilirubinemia at 1000 mg/m2/day. One patient experienced dose-limiting grade IV hyperbilirubinemia at 650 mg/m2/day, which occurred at day 71 of therapy.
Four patients experienced grade I PT prolongation at the 650–1000 mg/m2/day dose levels. One patient at 230 mg/m2/day developed a PT prolongation that rose to 40.1 by day 99 of therapy and was dose-limiting, but not considered a DLT because it occurred beyond the initial 4-week study period. It was not associated with clinical bleeding, and a coagulation evaluation including factors V, VII, VIII, and thrombin time was normal.
Asymptomatic metabolic alterations occurred in a dose-dependent manner with LGD1069 therapy. Hypertriglyceridemia was observed, to some degree, in the majority of patients treated with LGD1069. Hypertriglyceridemia typically occurred within 1 week of starting treatment and persisted while on LGD1069 therapy. The hypertriglyceridemia was most marked at the higher dose levels as is shown in Fig. 1
. Also observed was hypercholesterolemia with concomitant modest reductions in high-density lipoprotein and elevation in low-density protein levels (data not shown). No clinical sequelae were observed with these alterations in lipid profile. Treatment with a lipid-lowering agent (gemfibrozil) was attempted in two patients and was not found to be effective; however, hyperlipidemia was found to be reversible on discontinuation of treatment with LGD1069.
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and 3
. At higher dose levels, both TSH and free T4 levels decreased with continuous LGD1069 dosing and corrected to baseline values when LGD1069 was discontinued. This decline was not associated with clinical hypothyroidism. Patients did not have clinical evidence of fatigue, cold intolerance, or other clinical sequelae observed with hypothyroidism. Some patients at the higher dose levels of LGD1069 had subjective complaints of fatigue, however, it did not impair function and was not considered a toxicity by the National Cancer Institute Toxicity Criteria.
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PKs.
After the initial daily dose of the micronized LGD1069 formulation, the mean LGD1069 Cmax values increased from 183 (± 91) ng/ml to 6110 (± 1940) ng/ml as the dose increased from 21 mg/m2/day to 800 mg/m2/day. The mean day 1 Cmax value for the 1000 mg/m2/day dose group (2680 ± 1240 ng/ml) did not increase dose-proportionally, suggesting there may have been saturation of absorption mechanisms. The mean day 1 tmax values for the micronized formulation ranged from 1.4–3.6 h. Mean plasma AUC0–6 values increased from 491 (± 256) ng·h/ml to 23900 (± 8880) ng·h/ml as the dose increased from 21 mg/m2/day to 800 mg/m2/day (Fig. 4)
. As observed for Cmax, day 1 AUC0–6 for the 1000 mg/m2/day dose level (10300 ± 5260 ng·h/ml) was not significantly different from the 800 mg/m2/day dose group. For dose groups up to 500 mg/m2/day, terminal elimination half-live values generally ranged from 1–2 h and were independent of dose and study day. At the higher does levels, apparent t
values were longer, possibly due to prolonged or delayed absorption of the large doses. In many patients, particularly at the higher dose levels, the shape of the concentration-time profile suggested that absorption was still continuing at the time of the last sampling point (6 h). For this reason, it is likely that a large fraction of the AUC was not captured at the time of the last sample point, and, therefore, reported AUC values for the higher doses may be underestimates of the true AUC parameters (data not shown).
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. The inconsistency of repeat-dose AUC values may be due to intraindividual variability in LGD1069 PKs or interindividual patient differences in the effect of repeat-dose administration on LGD1069 PKs.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Skin reactions (cheilitis, xeroderma, skin peeling) occurred in up to 90% of patients treated with ATRA and 13-cis-RA, but were relatively infrequent and milder with LGD1069 (19 , 20) . Ocular toxicity (eye dryness, conjunctivitis) were seen in 25–40% of patients treated with ATRA or 13-cis-RA, but were relatively infrequent and milder with LGD1069 in this study. These mucocutaneous toxicities are a frequent complication of RAR-selective retinoids and pan-agonists, but were minimal with LGD1069 and observed only at the higher dose levels. This supports the theory that mucocutaneous toxicity is mediated by the RAR. Although LGD1069 is an RXR-selective ligand, weak RAR binding and transactivation does occur, particularly at higher doses, and may explain the mild cutaneous toxicity we observed. Similarly, headache was mild and infrequent in this study, and hypercalcemia was not observed; both have been frequently dose-limiting with RAR-selective and retinoid pan agonist.
In a Phase I study with LGD1069 conducted by Miller et al. (21) , patients were escalated to 500 mg/m2/day, with transaminitis being the most common DLT. Two of six patients experienced dose-limiting leukopenia and transaminitis at 400 mg/m2/day, such that the recommended Phase II dose in the study by Miller et al. (21) was 300 mg/m2/day. In a Phase I study (in progress) evaluating LGD1069 in combination with chemotherapy in the treatment of NSCLC, LGD1069 had been safely given in with vinorelbine and cisplatin at doses up to 400 mg/m2/day, and enrollment is continuing at the 600 mg/m2/day (22) . In this study, two of six patients experienced DLT at the 650 mg/m2/day dose level, however, one of the two patients did not experience a DLT until he had been on study for 71 days, such that dose escalation had already continued to 800 and 1000 mg/m2/day. Although this second DLT at 650 mg/m2/day occurred beyond the initial 4-week study period, this toxicity needs to be considered when defining a recommended phase II dose. Clearly, the toxicities overall increased considerably with the 500–650 mg/m2/day dose escalation, and our recommended phase II dose (RP2D) in this study is 500 mg/m2/day.
RXRs are unique in their ability to function as both homodimeric receptors and as obligate heterodimeric partners to receptors in multiple hormone-response pathways. The retinoid IRs form heterodimers that bind to specific DNA sequences (RA response elements) and act as ligand-dependent transcriptional regulators for RA-responsive genes. Depending on its partner, RXR might be either a silent or a ligand-responsive partner. RXR is a heterodimeric partner for PPAR that has been proven to be functionally involved in the peroxisome proliferator signaling pathway. It has been shown that cells transfected with RXR:PPAR respond to PPAR ligands (such as thiazolidinedione TZD). These heterodimers are also activated by RXR ligands, such as LG100268, a synthetic retinoid similar to LGD1069. On activation by fatty acids and drugs that affect lipid metabolism, PPARs control the expression of genes implicated in intracellular and extracellular lipid metabolism. Alterations in PPAR regulation may explain the dose-dependent hypercholesterolemia and hypertriglyceridemia observed with LGD1069 therapy. It has also been shown that retinoids increase the expression of apo C-III, an antagonist of plasma triglyceride catabolism. Cotransfection assays show that RXR activates apo C-III transcription through DR-1 response elements either as a homodimer or heterodimer with PPAR (23)
. There may also be other mechanisms responsible for the hypertriglyceridemia observed with LGD1069 therapy.
In contrast, RXR:TR and RXR:RAR do not show this dual-ligand responsiveness and are not activated with LG00268, but are activated by T3 and the RAR-selective ligand TTNPB (24)
. It has been shown that RXR is silent in RXR/TR heterodimers (25)
, but the dose-dependent reduction in thyroid function levels with LGD1069 therapy is unexplained. TRH is the principal positive regulator of TSH synthesis and secretion in man. T3 is able to control TRH synthesis through feedback inhibition at the transcriptional level, presumably by binding to its receptor which interacts with one or more negative thyroid hormone-response elements present within the TRH promoter. It has been shown that the specific negative thyroid hormone-response present within the human TRH promoter interact with TRs and the RXR (26)
; therefore, LGD1069 treatment may lead to central inhibition of thyroid function, although this explanation is not entirely satisfactory because RXR is a silent partner to TR, and this heterodimer is T3-responsive. However, RXR has also been identified in the anterior pituitary gland and found to be restricted to thyrotrope cells within the pituitary. There is data to suggest that retinoids can independently mediate suppression of TSHß promoter activity in TtT-97 thyrotropes and that the promoter region responsible for retinoid effect is distinct from the T3-responsive region (27)
. Further study of the effects of LGD1069 is required to increase our understanding of the complex interactions of hormones on regulation of gene expression.
Five of 60 patients experienced PT prolongation with LGD1069 therapy, however, the mechanism whereby PT prolongation occurs with LGD1069 therapy has not been defined. A recent study showed that in the hepatoma cell line HepG2, a ligand-dependent enhancement of the antithrombin gene expression is regulated by RXR, as well as TRß (28) . Antithrombin is a single chain 58.2-kDa glycoprotein that is a member of the serine protein inhibitor (serpin) superfamily that inhibits thrombin and several other activated coagulation factors (29) . It is unclear whether there is a relationship between antithrombin and PT elevation with LGD1069 therapy though, as the one patient with a grade IV elevation had a normal coagulation profile otherwise including a normal thrombin time.
ATRA has been shown to induce remission in patients with acute promyelocytic leukemia, but as a single agent did not maintain patients in remission (30) . Recent PK studies have demonstrated after 28 days of chronic oral dosing of ATRA, the AUC is up to 80% lower by day 28 than on day 1 of therapy (31 , 32) . At the molecular level, ATRA can increase CRABPII and cytochrome P450 gene transcription. This results in an increase of proteins that induce ATRA catabolism, which is proposed to lead to the reduced plasma levels observed during ATRA therapy (33) . LGD1069 catabolism may have occurred to a lesser degree in this Phase I study with LGD1069 AUC values decreasing an average of 44% of day 1 values by day 15. Similarly, in the study by Miller et al. (21) , at 400 mg/m2/day, LGD1069 AUC values decreased an average of 29% of day 1 values by day 28. In our study, the reductions on day 15 were inconsistent, possibly reflecting intraindividual variability in LGD1069 PKs or interindividual patient differences in the effect of repeat-dose administration on LGD1069 PKs. Despite the reduction in LGD1069 levels by catabolism, LGD1069 levels continue to be maintained in the range considered active in preclinical studies. In preclinical studies, induction of apoptosis with LGD1069 was studied in HL-60 cells; transglutaminase activity was measured as an indicator of apoptosis, and the EC50 value was 6 µM. The ability of LGD1069 to alter growth was also examined in cell lines, including a human head and neck squamous cell carcinoma cell line (1483) and a breast carcinoma cell line (MCF7). In all of these cell lines, LGD1069 inhibited cell growth with an IC50 value of 1–5 µM. This is consistent with values achieved clinically. In this study, the day 1 µM concentrations ranged from 0.9–17.5 µM, and the day 15 µM concentrations ranged from 0.54–5.9 µM, which remains in the active range based on preclinical studies.
Although no objective tumor responses were observed in this study, disease stabilization may have occurred with patients with a variety of tumor types remaining on study with stable disease for extended periods of time. The most impressive observations included: (a) one patient with a head and neck cancer who had persistent disease after surgery, radiation, and chemotherapy, who had resolution of clinical symptoms and remains without evidence of disease for more than 4.5 years on study; (b) five of 16 patients with NSCLC had stable disease on LGD1069 therapy for up to 394 days (mean, 132), however, 3 of 5 of these patients had not received prior chemotherapy, and this observation may reflect a more indolent group of patients with NSCLC. No patients with cutaneous T-cell lymphoma were treated in this study, however, in the study by Miller et al. (21) , two patients with cutaneous T-cell lymphoma had major responses. Also in the study by Miller et al., seven patients with advanced NSCLC remained on study for 3 months or more including one patient who remained on study for 8 months.
LGD1069 represents a novel RXR-selective retinoid with the potential for a more favorable therapeutic index than previous retinoids. The clinical observation that this agent can result in plasma concentrations up to 10-fold higher than previous retinoids without significant clinical toxicity is encouraging for its development as an anticancer and chemopreventive agent. Most of our present knowledge is derived from experiments performed in vitro or in transiently transfected cultured cells that overexpress receptors and recombinant reporter genes that are not in a natural chromatin environment. We do not know if interactions between receptors, ligands, regulatory proteins, and DNA observed under these conditions are also taking place in vivo. This Phase I study of LGD1069 gives a preliminary understanding of the clinical effects of an RXR-selective ligand. The biological activity of RXR ligands is so different from RAR ligands that it has been suggested that RXR activators should be considered a distinct class of pharmacological agents and referred to as "rexinoids," to distinguish their activity from "retinoids" (34) . This Phase I study of LGD1069 supports the uniqueness of this agent and further study of this agent and its biological effects is merited in the development of this rexinoid as an effective anticancer or chemopreventive agent.
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FOOTNOTES |
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1 To whom requests for reprints should be addressed, at Department of Medicine, Division of Hematology/Oncology, Lombardi Cancer Center, Georgetown University, Washington, DC 20007. Phone: (202) 687-2198; Fax: (202) 687-9861. 
2 The abbreviations used are: RAR, retinoic acid receptor; RA, retinoic acid; RXR, retinoid X receptor; IR, intracellular receptor; TR, thyroid hormone receptor; PPAR, peroxisome proliferator-activated receptor; ATRA, all-trans-RA; DLT, dose-limiting toxicity; PK, pharmacokinetic; AUC, area under the plasma concentration-time curve; TSH, thyroid-stimulating hormone; NSCLC, non-small cell lung cancer; T3, tri-iodothroxine; PT, prothrombin time; LGD1069, 4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphtalenyl) propenyl] benzoic acid; TRH, thyrotropin-releasing hormone; T4, thyroxine.
Received 6/ 8/98; revised 3/24/99; accepted 3/25/99.
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1 mediates 9-cis-retinoic acid suppression of thyrotropin-ß promoter activity. Mol Endocrinol., 11: 481-489, 1997. and thyroid hormone receptor ß. Biochem. J., 318: 263-271, 1996.
1-antitrypsin for structure and function of serpins. Biochemistry, 28: 8951-8966, 1989.[Medline]
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J. I. Song, M. N. Lango, J. D. Hwang, S. D. Drenning, Q. Zeng, W. W. Lamph, and J. R. Grandis Abrogation of Transforming Growth Factor-{alpha}/Epidermal Growth Factor Receptor Autocrine Signaling by an RXR-selective Retinoid (LGD1069, Targretin) in Head and Neck Cancer Cell Lines Cancer Res., August 1, 2001; 61(15): 5919 - 5925. [Abstract] [Full Text] [PDF]
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F. R. Khuri, J. R. Rigas, R. A. Figlin, R. J. Gralla, D. M. Shin, R. Munden, N. Fox, M. R. Huyghe, Y. Kean, S. D. Reich, et al. Multi-Institutional Phase I/II Trial of Oral Bexarotene in Combination With Cisplatin and Vinorelbine in Previously Untreated Patients With Advanced Non-Small-Cell Lung Cancer J. Clin. Oncol., May 15, 2001; 19(10): 2626 - 2637. [Abstract] [Full Text] [PDF]
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M. Duvic, K. Hymes, P. Heald, D. Breneman, A. G. Martin, P. Myskowski, C. Crowley, and R. C. Yocum Bexarotene Is Effective and Safe for Treatment of Refractory Advanced-Stage Cutaneous T-Cell Lymphoma: Multinational Phase II-III Trial Results J. Clin. Oncol., May 1, 2001; 19(9): 2456 - 2471. [Abstract] [Full Text] [PDF]
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M. Duvic, A. G. Martin, Y. Kim, E. Olsen, G. S. Wood, C. A. Crowley, R. C. Yocum, and for the Worldwide Bexarotene Study Group Phase 2 and 3 Clinical Trial of Oral Bexarotene (Targretin Capsules) |
