Phase 1/2 Pilot Study of Methotrexate-Laurocapram Topical Gel for the Treatment of Patients with Early-Stage Mycosis Fungoides

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STUDY Phase 1/2 Pilot Study of Methotrexate-Laurocapram Topical Gel for the Treatment of Patients With Early-Stage Mycosis Fungoides

Marie-France Demierre, MD, FRCPC; Luc Vachon, PhD; Vincent Ho, MD; Lynda Sutton, BS; Allen Cato, MD, PhD; Brian Leyland-Jones, MD, FRCPC

Objectives: To assess the safety and tolerability of a topi- cluded changes in lesion condition and severity cal gel formulation combining methotrexate and lauro- assessments, reduction in area of sample lesions, and the capram and to obtain preliminary information on the investigator’s global evaluation. therapeutic potential of methotrexate-laurocapram in patients with early-stage mycosis fungoides (stage IA or IB). Results: Adverse events consisted of skin reactions of mild severity. No clinically significant laboratory abnor- Design: An open-label, phase 1/2 pilot study. malities were observed. Based on the investigator’s global evaluation at the end of the treatment phase (week 24), Setting: Two academic referral centers. 7 (78%) of 9 patients demonstrated a slight-to- moderate response to treatment with methotrexate- Patients: Ten patients 18 years or older with histologi- laurocapram. Statistical significance (P=.049) was reached cally confirmed stage IA or IB mycosis fungoides. for induration and pruritus, a trend (P=.10) was observed for erythema, and no change was found for scal- Intervention: The gel formulation of methotrexate- ing (P=.37). laurocapram was applied to the total body surface, excluding genital, perianal areas, nipples, face, and skin un- Conclusions: These findings indicate that the topical ad- der the breasts, on an every-other-day basis for 24 ministration of methotrexate-laurocapram is safe and in consecutive weeks. general well tolerated. This treatment may represent a new therapeutic potential for patients with mycosis fun- Main Outcome Measures: The safety of methotrexate- goides. laurocapram was assessed in this study by reviewing adverse events and laboratory data. Efficacy outcomes in- Arch Dermatol. 2003;139:624-628

YCOSIS fungoides in treating erythrodermic MF,5 and oral (MF) is the most com- methotrexate has been used off-label for re- mon form of cutane- sistant patch or plaque MF and tumor stage ous T-cell lymphoma MF. However, its systemic toxicity poten- (CTCL).1 Mycosis fun- tial (gastrointestinal tract, bone marrow, goidesM is predominantly an indolent disease lungs, kidneys, liver, and immune system) with 5-year disease-specific survival rates has precluded its use in patients with early- of 100% and 80%, respectively, for individu- stage MF. No topical formulations of metho- als with either limited skin involvement or trexate are currently commercially avail- From the Skin Oncology 2 Program, Boston Medical skin tumors. To date, no therapies for MF able for clinical use. Topical therapy of early- 3,4 Center, Boston, Mass have demonstrated a survival advantage. stage MF with the existing oral or parenteral (Dr Demierre); Cato Research Thus, skin-directed therapies remain the formulations of methotrexate is ineffective Canada, St-Laurent, Quebec first line of therapy in patients with early- because of the inability of methotrexate to (Dr Vachon); Skin Care Center, stage MF (skin limited). Currently, these penetrate the stratum corneum from aque- Vancouver, British Columbia therapies include topical steroids, topical ous solutions.6 The development of a topi- (Dr Ho); Durham chemotherapy (topical carmustine and ni- cal formulation of methotrexate with en- Pharmaceuticals LLC, Durham, trogen mustard), topical retinoids, photo- hanced dermal penetration characteristics NC (Ms Sutton and Dr Cato); and McGill University, therapy, and local radiation. would hence provide an additional effec- St Mary’s Hospital, Montreal, Although oral or parenteral metho- tive therapy for patients with early-stage MF, Quebec (Dr Leyland-Jones). trexate is approved by the Food and Drug a population for whom oral or intravenous The authors have no relevant Administration for the treatment of ad- methotrexate is currently not indicated for financial interest in this article. vanced MF, this agent has shown efficacy treatment.

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 Methotrexate-laurocapram is a topical hydrophilic on an every-other-day basis for 24 consecutive weeks. Based gel formulation of methotrexate (1% wt/wt) with the pen- on the original design of this pilot study, the first patient, who etration enhancer laurocapram (Azone). Laurocapram is was enrolled at the University of British Columbia, Vancou- a lipophilic compound initially developed by Whitby Re- ver, also received daily topical administration of nitrogen mus- search (Richmond, Va) and now manufactured by tard on half the body, whereas the other half of the body was treated with 25 g/m2 of methotrexate-laurocapram; the results Durham Pharmaceuticals (Durham, NC) that has been obtained with nitrogen mustard in this particular patient will shown to enhance percutaneous absorption of a wide va- 7-13 be the subject of a separate report. To comply with interac- riety of pharmaceutical compounds. Results ob- tions with regulatory authorities, the protocol was then modi- tained in patients with psoriasis indicated that the topi- fied to include patients treated with methotrexate-laurocapram cal application of methotrexate-laurocapram was safe, was at Boston Medical Center only (Boston, Mass). well tolerated, and led to an improvement of the disease status in a significant proportion of patients.14-16 Prelimi- SAFETY ASSESSMENTS nary results from a pilot study in 4 patients with early- stage MF (stage IA or IB) indicated that methotrexate- The following safety assessments were conducted at screen- laurocapram was both safe and well tolerated,17 and 2 ing, baseline, and every 4 weeks during the study: routine labo- patients had a moderate response with a 50% to 99% dis- ratory evaluations (hematologic and clinical chemical analysis) and pregnancy test. Urinalysis was performed at screening, appearance of measurable and assessable disease. We pre- baseline, week 12, and week 26. Adverse reporting and a physi- sent the results of a phase 1/2 study in 10 patients with cal examination were conducted every 2 weeks during the first early-stage MF who were administered a topical formu- month of the study and every 4 weeks thereafter. lation of methotrexate-laurocapram every second day for 24 consecutive weeks. EFFICACY ASSESSMENTS

METHODS The evaluation of therapeutic response to treatment included the body surface area involvement of lesions and the assessment of The primary objective of this open-label, phase 1/2 study was severity in 3 test lesions selected before the initiation of treat- to evaluate the safety and tolerability of the topical adminis- ment; these outcomes were evaluated at baseline, weeks 12 and tration of methotrexate-laurocapram in patients with stages IA 24, and 2 weeks following the termination of treatment (week and IB plaque CTCL. The secondary objectives were to evalu- 26). Changes in severity outcomes (eg, induration, erythema, scal- ate the efficacy of topical methotrexate-laurocapram in this pa- ing, and pruritus) relative to baseline were graded as worsened tient population and to obtain preliminary information on the (Յ−2), no change (Ն−1 and Յ1), or improved (Ն2) for each systemic absorption of methotrexate following topical admin- test lesion and summed across the lesions for each patient. Pho- istration of methotrexate-laurocapram. tographic documentation was obtained at baseline, week 12, and week 24. Photographs were used to assess both the body sur- PATIENT POPULATION face area and severity (induration, erythema, scaling). Attempts were made to control both lighting and technical elements, but To be enrolled in the study, patients with histologically con- this was not possible for all patients. All photographs were evalu- firmed stage IA or IB CTCL18 had to be 18 years or older, be in ated by the site investigators (M.-F.D., V.H.) and were therefore good general health, and have liver transaminase levels less than not reviewed in a blinded fashion. At each enrolling site, the same twice the upper limit of the normal range, serum creatinine lev- investigator(s) scored the subjects throughout the study. Re- els less than 2.0 mg/dL (176.8 µmol/L), hemoglobin level greater sponses were defined as follows: progressive disease, defined as than 11 g/dL, a white blood cell count greater than 4000/µL, new lesions developing; no response, defined as stabilization of an absolute neutrophil count greater than 2000/µL, and plate- existing lesions with no new lesions developing; slight re- let counts greater than 130000/µL. Patients with stage II or sponse, defined as less than 50% disappearance of measurable higher CTCL, those with a history of intolerance to metho- and evaluable lesions; moderate response, defined as 50% to 74% trexate or related drugs, or those currently undergoing treat- disappearance of measurable and evaluable lesions; marked re- ment with sulfonamides and/or trimethoprim, phenytoin, sul- sponse, defined as 75% to 99% disappearance of measurable and fonylureas, phenylbutazone, or systemic steroids were excluded. evaluable lesions; and complete response, defined as disease that Also excluded were patients with active hepatitis or active cy- is 100% clinically cleared. tomegalovirus infection, systemic cutaneous bacterial infection or viral disease, or any other active malignant neoplastic METHOTREXATE SERUM LEVELS disorder. Pregnant or lactating women or individuals of child- bearing potential unwilling to practice adequate contracep- Blood samples were drawn at screening, baseline, and 24 to 48 tion were not eligible. A washout period was required before hours following the topical administration of methotrexate- study entry as follows: 6 weeks for topical mechlorethamine laurocapram every 4 weeks during the study and the posttreat- hydrochloride, topical steroids, topical carmustine, photo- ment follow-up visit (week 26). Samples were analyzed at the therapy, and oral methotrexate or 12 weeks for electron beam Department of Biochemistry of Maisonneuve-Rosemont Hos- therapy. The study protocol was approved by the local insti- pital, Montreal, Quebec, using the TDX Methotrexate system tutional review boards, and informed consent was obtained for (Abbott Laboratories Ltd, Diagnostics Division, Mississauga, all patients before the initiation of the study. Ontario). The lowest limit of detection for the methotrexate assay was 0.05 µmol/L. TREATMENT PLAN STATISTICAL ANALYSIS The gel formulation of methotrexate-laurocapram (provided in 2-oz jars containing 30 g of product) was applied at daily doses SAS statistical software for Windows (SAS Institute Inc, Cary, of either 12.5 or 25 g/m2 to the total body surface, excluding NC) was used to performed the ␹2 and Maxwell-Stuart homo- genital, perianal areas, nipples, face, and skin under the breasts, geneity tests.

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 RESULTS grade 1 or 2 according to the National Cancer Institute’s Common Toxicity Criteria and involved the following body Key demographic information on the study population is systems: skin and appendages (n=8), respiratory system summarized in Table 1. Seven of these patients had pre- (n=5), and hemic and lymphatic systems (n=2). Ten of viously received other treatment for MF, including topi- these adverse events, reported by 7 patients (70%), were cal therapies (steroids, carmustine, nitrogen mustard), pso- considered to be related to methotrexate-laurocapram ac- ralen–UV-A, oral methotrexate, and sunlight, with responses cording to the investigator (M.-F.D., V.H.). These adverse varying from progressive lesions to slight improvement. events included pruritus (n=6), rash (n=2), dry skin (n=1), Of 10 patients with early-stage CTCL (stage IA or and contact dermatitis (n=1). One patient who discontin- IB) who were enrolled in the study, 9 completed the study, ued treatment at week 10 had experienced moderate pru- and 1 discontinued participation at week 10 of the treat- ritus and a skin eruption consistent with contact derma- ment phase. Five patients were administered only the dose titis. Among the 5 patients who applied 12.5 g/m2 of of 12.5 g/m2, 2 applied both 12.5 g/m2 for 8 and 20 weeks, methotrexate-laurocapram, 3 interrupted the gel applica- respectively, and 25 g/m2, and 2 were treated only with tion (1 patient for 4 days, 1 patient for 9 days, and 2 pa- the dose of 25 g/m2 for the entire study. tients for 12 days) because of skin peeling and irritation, A total of 22 adverse events were reported in 9 of the personal reasons, and skin eruption, respectively. There- 10 patients enrolled in the study. These adverse events were after, 2 of these patients reapplied methotrexate- laurocapram on every third day instead of every second day. No clinically significant abnormalities in vital signs or urine Table 1. Demographic Information and Previous Therapies outcomes were observed during the study. Changes in clinical chemical and hematologic analysis results were re- Men Women ported in 9 and 8 patients, respectively. None of these Variable (n=7) (n=3) changes were reported by the investigators (M.-F.D., V.H.) Age, mean ± SD (range), y 48 ± 19 (22-78) 53 ± 18 (37-73) as being clinically significant in the context of the study. Ethnicity According to the investigator’s global evaluation that White 4 2 African American 1 1 was conducted at the end of the treatment phase (week Hispanic 2 0 24), 3 patients (33%) had a moderate response, 4 (44%) Previous therapies had a slight response, and 2 (22%) had no response to Topical steroids 3 3 treatment (Table 2), for a total of 7 (78%) who dis- Nitrogen mustard 0 2 played a slight-to-moderate response to treatment of the Topical carmustine 1 0 9 patients who completed the study. The Figure shows Psoralen−UV-A 1 1 Oral methotrexate 1 0 1 patient’s lesion at baseline and 24 weeks. Two weeks Sunlight 1 0 following treatment termination (week 26), 1 patient (11%) had a moderate response to treatment with

Table 2. Summary of Investigator’s Global Evaluation of Methotrexate-Laurocapram Therapy Relative to Baseline

Patient’s Response to Therapy, No. (%)

Visit Marked Moderate Slight None Progressive Disease Week 4 (n = 10) 0 (0) 4 (40) 3 (30) 3 (30) 0 (0) Week 12 (n = 8) 2 (25) 4 (50) 1 (13) 1 (13) 0 (0) Week 24 (n = 9) 0 (0) 3 (33) 4 (44) 2 (22) 0 (0) Week 26 (n = 9) 0 (0) 1 (11) 7 (78) 0 (0) 1 (11)

A B

Erythematous plaque of patient 9 at baseline visit (A) and week 24 (B).

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 Table 3. Summary of Collapse Changes in Methotrexate-Laurocapram–Treated Test Lesion Severity Outcomes Relative to Baseline Condition*

Lesion Severity Outcomes

Visit Degree of Severity Induration Erythema Scaling Pruritus Week 8 (n = 10) Deterioration 0 0 0 1 No change 5 4 5 6 Improvement 5 6 5 3 P value† .08 .06 .08 .06 Week 16 (n = 9) Deterioration 0 0 1 2 No change 6 5 5 6 Improvement 3 4 3 1 P value† .049 .10 .049 .10 P value‡ Ͼ.99 .22 Ͼ.99 .22 Week 24 (n = 9) Deterioration 0 0 1 1 No change 3 2 4 5 Improvement 6 7 4 3 P value† .049 .10 .37 .049 P value‡ .25 .14 .51 .37 Week 26 (n = 8) Deterioration 0 0 1 1 No change 3 2 6 6 Improvement 5 6 1 1 P value† .09 .09 .005 .09 P value‡ Ͼ.99 Ͼ.99 .22 Ͼ.99

*Data are number of patients unless otherwise indicated. †P value obtained using a ␹2 goodness-of-fit test. ‡P value obtained using a Maxwell-Stuart test. Comparison of a given proportion with the one obtained at the previous visit.

methotrexate-laurocapram, 7 (78%) had a slight re- laurocapram, was under the lowest limit of detection, sponse, and 1 (11%) had progressive disease, for a total ranging between 0.01 and 0.03 µmol/L in all samples ana- of 8 (89%) who had a slight-to-moderate response. lyzed, regardless of the dose received and the interval be- Table 3 outlines the changes in severity outcomes tween dosing and sample collection. of test lesions compared with baseline based on the col- lapsed categories derived from the sum of the lesion grad- COMMENT ing score. At the end of the treatment period, an improvement in induration, erythema, scaling, and pruritus was The results of this phase 1/2 pilot study, conducted in reported in 6, 7, 4, and 3 patients, respectively; these 10 patients with early-stage MF disease, indicate that the changes reached statistical significance for induration and topical application of 12.5 or 25 g/m2 of methotrexate- pruritus, whereas a trend (P=.10) was observed for ery- laurocapram once every other day for 24 consecutive thema. Two weeks following the completion of the treat- weeks led to minimal systemic exposure to methotrex- ment, the relative proportion of patients for whom an im- ate, was well-tolerated, did not generate changes in the provement was observed compared with baseline remained safety assessments indicative of the toxicity usually as- similar for both induration and erythema, whereas the num- sociated with methotrexate, and produced a slight-to- ber of patients for whom an improvement had been ob- moderate response in 7 (78%) of 9 patients, based on the served at week 24 decreased from 4 (44%) to 1 (13%) for investigator’s global evaluation. Except for unpublished scaling and from 3 (33%) to 1 (13%) for pruritus. data obtained in a pilot study of 4 patients,17 this is the The mean total surface area of the test lesions var- first published study to our knowledge demonstrating that ied from 5.6 to 165 cm2 among the individual patients topical methotrexate is safe and could potentially be ef- at baseline. On the whole, this outcome was not statis- ficacious in treating patients with early-stage CTCL. Since tically different at the end of the treatment (P=.38). At the improvement in the severity of the lesions was ac- the end of treatment, 5 patients displayed changes of less companied with positive changes in either the surface area than 25% compared with baseline, 3 had decreases of 26%, or body surface area involvement in some but not all pa- 33%, and 37%, respectively, and 1 had a 32% increase. tients, further investigation would be required to deter- Similarly, the total body surface area involvement, which mine the optimal drug concentration, frequency of ad- also varied substantially among the individual patients, ministration, and duration of treatment. was comparable at baseline (23%) and the end of the treat- Most patients had grade 1 toxic effects, and only 1 ment (18%). On an individual basis, changes of less than patient discontinued the study because of contact der- 25% were observed during the study in 6 patients, whereas matitis. Because this patient had also developed an al- decreases of 40% and 50% were observed in 2 patients lergic contact dermatitis to topical nitrogen mustard, the and an increase of 2% to 10% of BSA involvement was possibility that the patient had other topical allergies can- observed in 1 patient (data not shown). The serum con- not be excluded. centration of methotrexate, as measured 24 to 48 hours Skin-directed therapies have been the first-line treat- following the topical application of methotrexate- ments for early-stage disease. Current topical options in-

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 clude highly potent topical steroids, topical carmustine or Corresponding author and reprints: Marie-France De- nitrogen mustard, and topical retinoids (1% bexarotene ret- mierre, MD, FRCPC, Skin Oncology Program, Depart- inoid gel). High-potency steroids have been shown to be ment of Dermatology, Boston University School of Medi- effective, with a response rate of 94% in stage T1 disease cine, 720 Harrison Ave, Doctors Office Building, 801A, (complete response in 63%).19 Topical nitrogen mustard, Boston, MA 02118 (e-mail: [email protected]). which is the standard to which other therapies have been compared, displays response rates of approximately 88%, 20 with a 51% complete response in stage T1 disease. How- REFERENCES ever, its use has been limited by the frequency of allergic 21 contact dermatitis, which ranges from 30% to 80%. Topi- 1. 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The benefits of topical bexarotene (Tar- gretin) in patients with refractory or persistent early stage CTCL [abstract]. JIn- Accepted for publication September 17, 2002. vest Dermatol. 2000;114:860. This study was supported by grant FD-R-000843-02 25. Breneman D, Duvic M, Kuzel T, et al. Phase 1 and 2 trial of bexarotene gel for skin-directed treatment of patients with cutaneous T-cell lymphoma. Arch Der- from the Food and Drug Administration (Rockville, Md) Of- matol. 2002;138:325-332. fice of Orphan Products to Dr Leyland-Jones. 26. Fung MA, Murphy MJ, Hoss DM, Grant-Kels JM. Practical evaluation and man- We thank Marsha Stevens, RN, BSN, Jasmin Abd-el- agement of cutaneous lymphoma. J Am Acad Dermatol. 2002;46:325-357. 27. Zackheim HS, Amin S, Kashani-Sabet M, McMillan A. Prognosis in cutaneous Baki, MD, Atul Taneja, MD, and Frank Pietrantonio, PhD, T-cell lymphoma by skin stage: long-term survival in 489 patients. J Am Acad for their help with the study. 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