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Clinical Cancer Research Vol. 6, 1731-1735, May 2000
© 2000 American Association for Cancer Research

Clinical Trials

Initial Clinical Trial of a High-affinity Retinoic Acid Receptor Ligand (LGD1550)1

Steven L. Soignet2, Vincent A. Miller, David G. Pfister, Bryan J. Bienvenu, Raymond Ho, Barbara A. Parker, Shirley A. Amyotte, Allen Cato, III and Raymond P. Warrell, Jr.

Developmental Chemotherapy [S. L. S., B. J. B., R. H., R. P. W.], Thoracic Oncology [V. A. M.], and the Head and Neck/Genitourinary Oncology Services [D. G. P.], Department of Medicine, Memorial Sloan-Kettering Cancer Center, Cornell University Medical College, New York, New York 10021, and Ligand Pharmaceuticals, Inc., San Diego, California 92128 [B. A. P., S. A. A., A. C.]


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Retinoids mediate their biological response by binding to specific nuclear receptors, including retinoic acid receptors and/or retinoid X receptors. LGD1550 is a high-affinity ligand for all three retinoic acid receptors ({alpha}, ß, and {gamma} isoforms) and a potent inhibitor of AP-1, a protein that is closely linked with trophic responses and malignant transformation. We conducted a dose ranging study to evaluate the pharmacokinetics, safety, clinical tolerance, and potential efficacy of this drug in patients with advanced cancer. Twenty-seven patients received oral doses of LGD1550 once per day at doses ranging from 20–400 µg/m2. Skin toxicity was the dose-limiting reaction at the 400 µg/m2 daily dose level. Less prominent reactions included nausea and headache. No major antitumor effects were observed. Pharmacokinetic studies in 15 patients at five dose levels showed that the peak plasma concentration (Cmax) and areas under the plasma concentration-time curve on day 1 were dose-proportional and were similar to values obtained on days 15, 29, and 84. Unlike other retinoids, LGD1550 did not induce its own metabolism, and there was little evidence of drug accumulation. The t1/2 was approximately 5 h after both the initial and repeated doses. We conclude that once-daily doses of LGD1550 of up to 300 µg/m2 are relatively well tolerated. Additional clinical explorations are warranted, especially in patients with cancers of the prostate, thyroid, head and neck, and cervix.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Retinoids play a critical role in normal development and physiology by modulating cell growth, division, reproduction, differentiation, and immune function. These agents have various antitumor effects on tumor cell lines in vitro, including inhibition of cell growth and induction of differentiation and apoptosis (1, 2, 3) . Moreover, since the introduction of all-trans-RA3 as a routine therapy for patients with acute promyelocytic leukemia, the proportion of patients cured of this disease has more than doubled (4) .

Retinoids affect gene expression after binding to specific intracellular receptor families (5) : (a) the RARs (6) ; or (b) the RXRs (7) . Each of these families has three isoforms ({alpha}, ß, and {gamma} isoforms). The RXRs are also cofactors for RARs as well as receptors for vitamin D3, thyroid hormone, and peroxisome proliferation-activating receptors (8, 9, 10) .

LGD1550 [(2E,4E,6E)-3-methyl-7-(3,5-di-ter-butylphen-yl)octatrienoic acid; Fig. 1Citation ) binds all three RAR isoforms and is a potent activator of gene expression. However, the compound has a very low affinity for RXRs. RARs modulate cell proliferation in part through interaction with AP-1, a protein that is closely linked with trophic responses. LGD1550 is a potent inhibitor of AP-1, and in vitro studies have shown that the drug inhibited the growth of both hematological and epithelial tumor cell lines (11) . Both alone and in combination with other anticancer agents, LGD1550 exhibited striking growth inhibition in a head and neck squamous cell carcinoma xenograft model in vivo (12) .



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  		Fig. 1. LGD1550 (2E,4E,6E)-3-methyl-7-(3,5-di-ter-butylphenyl)octatrienoic acid).

 
In view of this preclinical activity, we conducted this dose ranging study to determine the toxicity, safety, and pharmacokinetics of LGD1550 in patients with advanced cancers.


   PATIENTS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients.
Adults who were at least 18 years old, had an Eastern Cooperative Oncology Group performance status of 0–2, and had histologically confirmed advanced cancer were eligible for entry. Other requirements included: (a) total leukocyte count >= 3,000/µl; (b) hemoglobin level >= 9 g/dl; (c) platelet count >= 100,000/µl; and (d) adequate coagulation, hepatic, and renal function. Patients were excluded if they had undergone major surgery or had received other anticancer or investigational therapy within the preceding 3–4 weeks. Exclusion criteria included: (a) hypercalcemia; (b) history of brain metastases or cardiomyopathy; (c) active choroidal or retinal inflammation; or (d) known allergy or hypersensitivity to retinoids. The clinical protocol was reviewed and approved in advance by the Memorial Sloan-Kettering Cancer Center institutional review board. Signed informed consent was obtained from all patients.

Treatment Plan.
LGD1550 was supplied in soft gelatin capsules containing either 5 or 50 µg of drug (Ligand Pharmaceuticals Inc., San Diego, CA). The drug was administered once daily p.o. with food. The initial starting dose was 20 µg/m2, and all doses were rounded to the nearest 5-µg equivalent. The intended treatment period was 4 weeks (or a minimum of 25 days). If no unacceptable toxicity was seen, patients could be retreated with additional monthly courses of therapy until their disease progressed.

Patients were evaluated weekly for the first 4 weeks, and then they were evaluated every 2 weeks until week 24 of treatment, and every 4 weeks thereafter. Dose escalation in an individual patient was not permitted. At least three patients were entered at each dose level. If any one of three patients experienced a DLT, accrual to that level was expanded to a total of six patients. The maximum-tolerated dose was defined as the highest dose that resulted in not more than one patient experiencing a DLT among at least six patients who completed 25 days of treatment at that dose level. DLT was defined by the National Cancer Institute Common Toxicity Criteria: grade 3 toxicity was considered to be dose-limiting in all categories, with the exception of cardiac and neurological toxicity, in which grade 2 toxicity was dose-limiting. Parameters monitored during the study included: (a) serial blood cell counts; (b) coagulation tests; (c) lipid profiles; (d) thyroid function tests; (e) urinalyses; (f) eye examinations; and (g) echocardiograms (or MUGA scans). The extent of disease was monitored as clinically indicated to evaluate possible antitumor effects.

Pharmacokinetic Studies.
LGD1550 was administered p.o. after at least an 8-h fast with 6 ounces of water or other fluid and was taken with food or a food supplement (Ensure). On the first day of dosing and on selected days thereafter (days 15, 29, and 84), blood samples were collected in tubes containing EDTA before dosing (0 h) and at 0.5, 1, 2, 4, 8, and 24 h after dosing, and the samples were placed immediately on ice. A predose blood sample was collected on day 8. Plasma samples were obtained after centrifugation and stored at -20°C until analysis. All samples were protected from direct light during collection, preparation, and storage.

Pharmacokinetic Analysis.
LGD1550 plasma concentrations were determined by a gas chromatography with mass spectrometric detection method with a lower limit of quantification of 0.020 ng/ml. Cmax and time to Cmax (Tmax) values were recorded as observed. Apparent terminal elimination rate constants ({lambda}z) were determined as the negative of the slope of the terminal log-linear portion of the plasma concentration-time profile. Terminal elimination half-life (t1/2) values were calculated as ln(2) /{lambda}z. The AUC from time 0 to the time of the last measurable concentration (AUC0–t) was determined by linear trapezoidal approximation, and the AUC from time 0 to infinite time (AUC0–{infty}) was determined by the summation of AUC0–t and Ct/{lambda}z, for which Ct was the last measurable concentration. Pharmacokinetic parameters were estimated by noncompartmental methods using nominal sample collection times.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics.
Twenty-seven patients were treated at seven dose levels. One patient was removed from the study after the first day of treatment due to dysphagia. Three other patients who had rapidly progressing disease discontinued therapy after 18, 19, and 21 days, respectively. Relevant patient characteristics are listed in Table 1Citation .


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  		Table 1

Pretreatment characteristics of patients treated with LGD1550

 
Adverse Effects.
Adverse effects potentially related to LGD1550 are listed in Table 2Citation . This agent was generally well tolerated. Skin toxicity was the most common reaction and was ultimately dose-limiting. Thirteen patients developed skin dryness and erythematous macular areas (grade 1) that were effectively treated with a water-based moisturizer. Two patients who were treated at the 400 µg/m2/day level developed a generalized nonpainful exfoliative dermatitis and hand-foot syndrome. After withholding therapy for approximately 3 weeks, one patient was subsequently treated at a lower dose. However, this patient required a second dose reduction due to recurrent exfoliation, which resolved on treatment with a lower dose. Subsequently, the second patient was determined to have progressive disease and never resumed treatment with the study drug.


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  		Table 2

Adverse reactions observed with LGD1550a

 
Antitumor Response.
Twenty-three of the 27 patients completed at least one cycle of therapy (25 days) and were evaluable for response. The median number of cycles administered was 2 (range, 1–24 cycles). No major antitumor response was observed. A minor objective response was observed in a patient with locally advanced cervix cancer who had an indurated thigh mass that decreased in size. Four of the six patients with thyroid cancer had stable disease ranging between 20 and 56 weeks. One of these patients had a transient decrease in serum thyroglobulin level; this individual completed a total of 348 days of therapy before being removed from study due to disease progression. The other three patients with thyroid cancer had relatively stable disease with slowly rising thyroglobulin levels. One patient with hormone-refractory prostate cancer had stable disease for 33 weeks.

Pharmacokinetics.
Blood samples from 15 patients at five different dose levels were assayed for pharmacokinetic analysis. After single-dose administration (see Fig. 1Citation ), mean plasma concentrations increased with increasing dose. Mean AUC0–{infty} ± SD ranged from 1.33 ± 0.89 ng·h/ml (n = 4) after a 20 µg/m2 dose to 11.22 ng·h/ml (n = 2) after a 180 µg/m2 dose, and mean plasma Cmax and AUC0–{infty} values were roughly dose-proportional after doses of 20–180 µg/m2. Mean ± SD Cmax values ranged from 0.20 ± 0.13 to 1.09 ± 0.25 ng/ml (0.59 ± 0.38 to 3.2 ± 0.73 nM), respectively. Tmax was variable, but it generally ranged from 3–5 h. The mean apparent terminal elimination half-life was typically approximately 5 h and was similar for all dose levels and after single or multiple doses.

After multiple doses of 20–180 µg/m2, the pharmacokinetics were similar to those observed after a single dose (Fig. 2)Citation . There was no evidence of autoinduced metabolism. There was minimal drug accumulation, and the predose concentrations were less than 5% of Cmax after repeated dosing.



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  		Fig. 2. Mean LGD1550 plasma concentration after a single (A) and multiple (B) dose(s).

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The objectives of this study were to determine the DLT, safety, pharmacokinetic profile, and potential antitumor activity of this novel retinoid. LGD1550 was generally well tolerated. Few adverse reactions that have frequently been observed with other retinoids were noted in this study. The characteristic skin dryness associated with retinoids was seen in about two-thirds of the patients. Most of these reactions were mild and self-limited at all dose levels up to the 400 mg/m2/day dose, which was associated with a generalized exfoliation that particularly involved the palms and soles. By comparison, skin reactions (especially cheilitis, xerosis, or peeling) were observed in approximately 90% of patients treated in a Phase I trial with all-trans-RA (13) , and these effects were dose-limiting in that study. A similar cutaneous toxicity profile was seen in clinical trials using 13-cis-RA. In a Phase I study of LGD1069 (a RXR-selective retinoid), we observed skin toxicity in approximately 40% of patients (14) . Retinoid skin toxicity may be a RAR-{gamma}-mediated effect (15 , 16) , which might account for the lower incidence of cutaneous reactions in that study. Thus, it is not surprising that skin toxicity was dose-limiting in this trial, considering the RAR selectivity of LGD1550.

Headache, which was dose-limiting in studies with 9-cis-RA (a RAR/RXR pan agonist; Ref. 14 ), was only of mild intensity and occurred in only five patients. LGD1550 had no effect on triglyceride concentrations, whereas hyperlipidemia is a common consequence of chronic therapy with all-trans-RA, 13-cis-RA, 9-cis-RA, and LGD1069 (13 , 17 , 18) .

In addition to having an improved safety profile, LGD1550 may also have a pharmacokinetic advantage relative to other retinoids. All-trans-RA, when given on a continuous oral dosing schedule, is associated with a progressive decline in plasma concentration (19) , which may contribute to relapse and retinoid resistance in patients with acute promyelocytic leukemia. Similarly, 9-cis-RA (in doses exceeding 140 mg/m2/day) also exhibited significant autoinduction of catabolism (14) . In contrast, LGD1550 plasma levels remained relatively stable over time at all dose levels (Fig. 3)Citation . There was minimal accumulation with repeat dosing. Moreover, plasma concentrations of LGD1550 exceeded those previously shown to induce growth-inhibitory effects in vitro, and the t1/2 (approximately 5 h) suggests that the agent can be effectively given on a once-daily schedule.



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  		Fig. 3. Mean LGD1550 plasma concentrations for the 40 (A), 65 (B), 108 (C), and 180 (D) µg/m2/day doses.

 
In conclusion, LGD1550 is a potent activator of RARs and a potent inhibitor of AP-1. Its unique pharmacokinetic/pharmacodynamic and safety profile suggests that Phase II studies can be safely conducted to examine its potential efficacy in selected indications using a dose of 300 µg/m2. In view of the preclinical effects, the modest activity we observed in cervical cancer, and the obvious cutaneous reactions, epidermoid cancers should be considered prime candidates for exploration in Phase II studies.


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

1 Supported in part by CA-77136 from the National Cancer Institute, and by grants from The Lymphoma Foundation and Ligand Pharmaceuticals Inc. Steven Soignet is a Mortimer J. Lacher Fellow. This work was presented in part at the annual meeting of the American Society of Clinical Oncology, Los Angeles,CA. Back

2 To whom requests for reprints should be addressed, at Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. Phone: (212) 639-8984; Fax: (212) 717-3272; E-mail: soignets{at}mskcc.org Back

3 The abbreviations used are: RA, retinoic acid; RAR, RA receptor; RXR, retinoid X receptor; AUC, area under the plasma concentration-time curve; Cmax, peak plasma concentration; DLT, dose-limiting toxicity. Back

Received 10/ 6/99; revised 2/17/00; accepted 2/18/00.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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