Phase I/II Trial of Formoterol Fumarate Combined with Megestrol Acetate in Cachectic Patients with Advanced Malignancy

Support Care Cancer DOI 10.1007/s00520-013-2081-3

ORIGINAL ARTICLE

Phase I/II trial of formoterol fumarate combined with megestrol acetate in cachectic patients with advanced malignancy

C. A. Greig & N. Johns & C. Gray & A. MacDonald & N. A. Stephens & R. J. E. Skipworth & M. Fallon & L. Wall & G. M. Fox & K. C. H. Fearon

Received: 1 July 2013 /Accepted: 26 November 2013 # Springer-Verlag Berlin Heidelberg 2014

Abstract response defined as an increase in muscle size ≥4%or Purpose The aim of this study was to test the safety, tolera- function ≥10 %. bility and efficacy of a novel combination of an anabolic β2- Results Six patients withdrew before 8 weeks, reflecting the agonist and an appetite stimulant in patients with cancer frail, comorbid population. In contrast, six out of seven (86 %) cachexia. patients completing the course achieved a major response for Methods Thirteen patients (M/F 5:8) with advanced malig- muscle size and/or function. In the six responders, mean nancy and involuntary weight loss received oral formoterol quadriceps volume increased significantly (left 0.99 vs. (80 μg/day) and megestrol acetate (480 mg/day) for up to 1.05 L, p =0.012; right 1.02 vs. 1.06 L, p =0.004). There 8 weeks. Quadriceps size (MRI), quadriceps and hand-grip was a trend towards an increase in quadriceps and handgrip strength, lower limb extensor power, physical activity and strength (p >0.05). The lack of appetite symptom score de- quality of life were measured at baseline and at 8 weeks. clined markedly (76.2 vs. 23.8; p =0.005), indicating im- Response criteria were specified pre-trial, with a major provement. Adverse reactions were few, the commonest being tremor (eight reports), peripheral oedema (three), tachycardia Electronic supplementary material The online version of this article (two) and dyspepsia (two). (doi:10.1007/s00520-013-2081-3) contains supplementary material, Conclusions In this frail cohort with advanced cancer cachex- which is available to authorized users. ia, an 8-week course of megestrol and formoterol in combi- : : : : nation was safe and well tolerated. Muscle mass and/or func- C. A. Greig N. Johns: A. MacDonald N. A. Stephens R. J. E. Skipworth K. C. H. Fearon tion were improved to a clinically significant extent in most School of Clinical Sciences and Community Health, patients completing the course. This combination regimen University of Edinburgh, Edinburgh EH16 4SB, UK warrants further investigation in larger, randomized trials. C. Gray Clinical Research Imaging Centre, University of Edinburgh, Keywords Adrenergic beta-2 receptor agonists . Megestrol . Edinburgh EH16 4SB, UK Neoplasms . Cachexia L. Wall Department Clinical Oncology, Western General Hospital, Edinburgh EH4 2XU, UK Introduction M. Fallon Centre for Molecular Medicine, University of Edinburgh, Cancer cachexia has recently been defined as a multifactorial Edinburgh EH4 2XU, UK syndrome characterized by an ongoing loss of skeletal muscle G. M. Fox mass (with or without loss of fat mass) [1]. Cancer patients Acacia Pharma Ltd., Harston Mill, Cambridge CB22 7GG, UK become cachectic as a result of reduced food intake (secondary to anorexia), abnormal metabolism or most commonly, a vari- * K. C. H. Fearon ( ) able combination of the two. In treating the anorexia compo- Department of Clinical Surgery, Royal Infirmary Edinburgh, 51 Little France Crescent, Edinburgh EH16 4SA, UK nent of cancer cachexia, it is possible to use nutritional e-mail: [email protected] counselling/supplements or a pharmacological approach. At Support Care Cancer present, two classes of drug are used off-label: progestins and Methods corticosteroids. Neither provides optimal control as they lead mainly to temporary increases in body fat and water, rather than Overview adding to the key component, muscle mass. Indeed, corticosteroids may induce muscle wasting. The progestin megestrol This was a single centre, uncontrolled, exploratory study, acetate is the most widely used drug but is approved only for assessing a fixed dose of formoterol fumarate and megestrol aids-related cachexia in the USA and cancer cachexia only in acetate given concomitantly to adult patients with advanced Italy and Spain. It is a potent appetite stimulant as well as cancer and cachexia. The protocol received research ethics enhancing physical performance and muscle force in tumour committee approval. Written informed consent was obtained bearing rats [2]. In a large meta-analysis, megestrol was shown from all patients. All procedures were in accordance with to improve appetite and weight but had no benefit in terms of International Conference on Harmonization guidelines on quality of life or survival [3].Thedoseof480mg/dayhasbeen Good Clinical Practise and the Helsinki Declaration. widely studied in cancer cachexia and is generally believed to be an appropriate dose, in terms of efficacy and safety [4, 5]. Objectives

In relation to key metabolic aspects of cachexia, β2-agonists offer strong potential to reverse muscle atrophy. The primary objective was to assess the efficacy of formoterol

Formoterol fumarate is a long-acting β2-agonist, widely used and megestrol in combination in cancer cachexia. The primary for more than 20 years as a therapy for asthma and chronic efficacy endpoint was muscle response (see below). obstructive pulmonary disease. Although formoterol has not Secondary efficacy endpoints included quantitative changes previously been studied clinically as a treatment for muscle in body weight, physical activity and quality of life. The wasting, there is evidence that other β2-agonists, such as secondary objective was assessment of the safety and tolera- albuterol (salbutamol) and clenbuterol, can arrest muscle at- bility of the combination therapy. rophy and increase muscle mass and strength in conditions such as Becker and Duchenne muscular dystrophies and after Protocol orthopaedic surgery [6, 7], as well as in healthy volunteers [8].

However, widespread clinical use of such β2-agonists has Patients were screened for eligibility (ESM 1) during the been limited due to relative lack of selectivity for skeletal over 14 days prior to trial entry. The diagnostic criterion for ca- cardiac muscle, leading to cardiovascular side effects. chexia was weight loss ≥2%inthepreceding2monthsor

Formoterol is a particularly promising β2-agonist due to a ≥5 % in the preceding 6 months compared with pre-illness high degree of selectivity for skeletal muscle β2-receptors, stable weight. Patients were admitted to the clinical research favourable efficacy/toxicity ratio and proven clinical tolera- facility on day 1 and discharged 6 h after the first dose of study bility by the oral route of administration. Formoterol, like drugs. Safety assessments included physical examination, other β2-agonists, has marked anti-catabolic and anabolic monitoring of vital signs, clinical laboratory tests and EKG. effects, mediated through at least two pathways: inhibition Patients were contacted at home by telephone after 24 h to of the ATP-dependent ubiquitin-proteasome pathway, leading assess any emergent toxicity. Further safety assessments were to reduced proteolysis, and inhibition of caspase-mediated conducted at 2, 4, 6, 8 and 12 weeks. Measurements of muscle apoptosis. Formoterol also appears to stimulate satellite cells size, strength and power output, total body weight, quality of directly to regenerate muscle fibres [9]. β2-agonists have also life and physical activity were conducted at baseline and at been shown to reduce production of TNFα and IFNγ in 8weeks. experimental systems [10, 11]. Formoterol has shown prom- Patients were requested to take formoterol 1×40 μgand ising influence on muscle mass in animal models, of cancer megestrol 2×160 mg tablets each morning and formoterol 1× cachexia. Using the rat Yoshida AH-130 ascites hepatoma and 40 μg and megestrol 1×160 mg tablet each evening, for a mouse Lewis lung tumour models, formoterol at 2 mg/kg period of 8 weeks. Patients surviving beyond 8 weeks were intra-peritoneally resulted in highly significant increases in offered the combination when requested on compassionate the mass of skeletal muscles such as gastrocnemius and sole- grounds. Self-reported tablet intake and a tablet count on us, as well as adipose tissues, compared with vehicle-treated return of medications were used to determine patient animals [12]. In normal rats, doses of formoterol as low as compliance. 1 mg/kg/day elicited significant muscle hypertrophy with minimal cardiac hypertrophy [13]. Adverse events This single-arm pilot study examined the safety and toler- ability of megestrol combined with formoterol in cachectic Intensity of AEs was graded in accordance with the National cancer patients and to evaluate the potential of the combina- Cancer Institute Common Terminology Criteria for Adverse tion to halt or reverse the muscle wasting seen in cachexia. Events version 3.0 (http://safetyprofiler-ctep.nci.nih.gov/ Support Care Cancer

CTC/CTC.aspx) and the relationship to study drug was also derived muscle mid-femur CSA was combined with the func- assessed. tional measurements to give a measure of muscle mechanical quality (muscle quality=IKES ÷ CSA (in Newton per square Physical activity Sample size calculation millimetre)). : This was monitored directly for at least three consecutive days at the beginning and again at the A sample size of 13 patients was sufficient to give an 80 % end of treatment using accelerometry (PAL Technologies Ltd., power of rejecting a reference proportion of muscle re- Glasgow, UK). Activity was quantified as average daily step Quality of life and performance scores sponders of 10 % with an exact 5 % one-sided test when the count (steps/24 h). : true proportion of muscle responders would be at the clinically Karnofsky performance score was assessed in each patient by relevant value of 40 %. If the lower bound of the 90 % one observer. The EORTC QLQ C-30 questionnaire was com- confidence interval of the proportion of muscle responders pleted by each patient and results analyzed according to the were wholly above the reference proportion, then the null scoring manual (version 3). hypothesis (that the true proportion of muscle responders is equal to or less than 10 %) would be rejected at a one-sided Statistics significance level of 5 %. This would be the case if four or more patients were muscle responders. All analyses were performed with SPSS (version 11.5). Descriptive statistics were used for demographic, baseline, Muscle response safety and efficacy variables. Arithmetic means of efficacy variables at baseline and 8 weeks were compared using Protocol-defined response criteria are given in Table 1.An Student’s t test. overall major response was documented if achieved in either domain of muscle size or muscle function (quadriceps strength and power), for either the left or right side of the body. Results

Physical assessments Thirteen patients received the combination regimen. Patient baseline characteristics and flow through the study are sum- Anthropometry: Body weight was measured using a beam marized in ESM 2 and Fig. 1, respectively. Patients were scale (Seca, Birmingham, UK) and height using a standard heavily pre-treated with surgery, chemotherapy and/or radio- wall mounted measure. Muscle function: Maximum voluntary therapy and all had end-stage, advanced disease (stage 4). isometric knee extensor strength (IKES), lower limb extensor Median age was 67 years and mean BMI was 22.3. Mean power (LLEP) and maximum handgrip strength (HGS) were prior weight loss was 11 %, generally documented over the measured using dynamometry. Muscle cross-sectional area prior 5-7 months, though in some cases much more recently. (CSA) and volume: These outcomes of muscle size were Of the 13 patients enrolled, 9 completed at least 4 weeks and 7 measured using magnetic resonance imaging (MRI). T1- completed the full 8-week course. Adherence to therapy was weighted axial images (Philips Gyroscan 1.5-T) were pre- close to 100 %; out of 2,196 doses which could have been scribed from the proximal border of the patella to the anterior taken, only 24 were missed. iliac spine using a previously described protocol [14]. The Six patients discontinued study treatment prior to complet- cross-sectional area (in square millimetres) of the quadriceps ing 8 weeks. In two cases, this was clearly due to their muscle in each image was quantified off-line using underlying malignancy. In the other four, although the event ANALYZE 8.0 (Mayo Clinic, Rochester, USA). CSA for each precipitating withdrawal may have been caused by the study slice area was multiplied by slice thickness and slice volumes treatment, there was in each case a co-morbidity or malignant summed to give quadriceps volume. Muscle Quality:MRI- progression which was a more probable cause or at least a

Table 1 Protocol-defined response criteria. An overall Muscle size (quadriceps Muscle function (quadriceps response was considered major if volume or CSA) strength or power) occurring in either domain Change compared with Change compared with baseline baseline

Response Non-response Any decline Any decline Minor response 0–2% 0–5% Moderate response >2 and <4 % >5 and <10 % Major response ≥4% ≥10 % Support Care Cancer

increases in mean IKES and LLEP were 17 and 12 %, respectively, for the left limb (p =0.078, 0.531) and 8 % for the right limb (p =0.389, 0.588). The increase in mean HGS was 16 % for the left limb (p =0.010) and 10 % for the right limb (p = 0.159). Lower limb muscle quality improved by 11 % for the left limb (p =0.250) and 5 % for the right limb (p =0.527). The mean total body weight of the seven patients who completed treatment increased by 2.6 % from 58.7 kg at baseline to 60.2 kg at 8 weeks (p =0.379). Five of the seven patients increased their total body weight, from 1.8 to 14.2 %. Fig. 1 Consort diagram showing patient flow through the study Average physical activity increased >1,000 steps per day between baseline and the end of treatment in 3/6 major responders. Average daily step count declined in the other three major contributing factor (i.e., mood alteration in a patient major responders, each of whom was, during the end-of- who developed brain metastases, hyperglycaemia in a patient treatment assessment period, suffering from an intercurrent with pre-existing type 2 diabetes mellitus, supraventricular illness/morbidity which adversely affected their activity, one tachycardia (SVT) in a patient with a prior undisclosed history with a DVT, one with worsening ankle oedema and one with of SVT and ankle oedema in a patient who developed malig- influenza. Global health status measured using the QLQ-C30 nant duodenal obstruction and associated malnutrition). questionnaire was unchanged from baseline to end of treat- Of the seven patients who reached 8 weeks, six had a major ment while the functional domains all showed a small but non- response to treatment (Table 2). Major responders showed a significant increase in mean score. For most of the symptom high degree of consistency in magnitude of strength improve- scales, mean scores fell slightly between baseline and week 8, ment between lower limb (knee extension) and upper limb indicating a trend towards symptomatic improvement. For (hand grip) and between left and right limbs. Increases in lack of appetite, the improvement was marked (76.2 vs. strength were highly concordant with increases in muscle size 23.8; p =0.005). (ESM 3). Due to the small sample size, few increases reached Few adverse events were considered probably or possibly statistical significance. The increase in mean quadriceps vol- related to study medication (ESM 4) the commonest being ume between baseline and 8 weeks was 6 % for the left limb tremor (eight reports in seven patients), peripheral oedema (p =0.012) and 4 % for the right limb (p =0.004). The (three), tachycardia (two) and dyspepsia (two). For the

Table 2 Muscle size and function data for patients completing 8w treatment period

Patient Muscle function Muscle size Overall response IKES (Newtons) LEP (Watts) Function HGS (kg) Volume (litres) CSA (mm2)Size response response %change RESP %change RESP % change % change RESP % change RESP

5R−14.6 % NON −9.1 % NON NON −3.0 % +1.9 % MIN +2.1 % MOD MOD MAJ L −3.0 % NON −5.0 % NON NON +6.7 % +9.3 % MAJ +13.4 % MAJ MAJ 6 R +1.7 % MIN +10.2 % MAJ MAJ +8.7 % +1.6 % MIN −0.6 % NON MIN MAJ L+0.3%MIN−7.1 % NON MIN +9.5 % −0.1 % NON −4.9 % NON NON 8 R +6.8 % MOD +9.6 % MOD MOD 0 % +10.9 % MAJ +8.4 % MAJ MAJ MAJ L+7.5%MOD−14.0 % NON MOD +17.6 % +11.4 % MAJ +8.6 % MAJ MAJ 9 R +35.7 % MAJ −15.9 % NON MAJ +20.0 % +5.5 % MAJ +3.5 % MOD MAJ MAJ L +34.5 % MAJ +23.5 % MAJ MAJ +30.0 % +3.9 % MOD +2.4 % MOD MOD 11 R +13.3 % MAJ +43.5 % MAJ MAJ +22.6 % +3.3 % MOD +1.5 % MIN MOD MAJ L +30.2 % MAJ +29.2 % MAJ MAJ +10.7 % +8.5 % MAJ +9.4 % MAJ MAJ 13 R +3.0 % MIN −17.9 % NON MIN −7.7 % −11.9 % NON −13.6 % NON NON MIN L −26.4 % NON −9.8 % NON NON −3.0 % −15.5 % NON −11.5 % NON NON 14 Ra +3.9 % MOD −1.5 % NON MOD MAJ L +25.0 % MAJ +44.0 % MAJ MAJ +26.7 % +5.6 % MAJ −0.3 % NON MAJ

IKES isometric knee extensor strength, LEP leg extensor power, HGS hand-grip strength, CSA cross-sectional area, NON non-response, MIN minor response, MOD moderate response, MAJ major response a Right-sided function for subject 14 not measurable due to pain Support Care Cancer patients who developed a tremor, this was mild (six patients) dose of formoterol would avoid these adverse effects while or moderate (one patient) and either resolved within the first retaining adequate efficacy. 2 weeks (three patients) or persisted intermittently (four pa- Themeanchangeinmusclevolumeforthepatientswitha tients). One patient developed a supraventricular tachycardia major response at 8 weeks was 6 and 4 % for left and right 14 days after treatment (grade 3 adverse event) that was quadriceps, respectively, which is consistent with increases possibly drug related and resulted in withdrawal from the seen in both young and older healthy volunteers undergoing study. The patient had an undisclosed history of similar epi- resistance exercise training over a similar period of time [17, sodes prior to study entry. Fifteen SAEs were reported during 18]. Thus, the mean change observed in the major responders the study, all judged unrelated to study medication, and in in the present study is physiologically significant. For those almost all cases due to progression of the underlying with a major response in this study, the proportional changes malignancy. in muscle volume were generally matched or exceeded in percentage terms by increases in muscle strength. Such improvements in muscle function could result from increased

muscle mass or may be related to the known effects of β2- Discussion agonists on muscle fibre type [19]. Clearly, one of the limita- tions of using MRI is that it does not measure muscle protein The present study has demonstrated that the combination of content. formoterol fumarate and megestrol acetate is safe and well It was not possible to determine whether the apparent gain tolerated in frail patients with advanced cancer and cachexia. in muscle mass in the ‘muscle responders’ was due to the For those patients who reached evaluation at 8 weeks (7/13), a formoterol alone or due to the combination with megestrol pre-defined overall major ‘muscle response’ was observed in acetate. In a study of healthy elderly men given megestrol 6/7. Thus, although there was the expected attrition of patients acetate alone (800 mg/day), thigh muscle cross-sectional area during the trial, the majority of those remaining on study had a actually decreased by 4.5 % over a period of 3 months [20]. major response for muscle mass and/or function. In this study, The induction of muscle atrophy by progestational agents has the experimental therapy was not randomized against an ac- been ascribed to the suppression of circulating testosterone tive or placebo control arm, thus interpretation of the changes levels [21]. However, about 70 % of male patients with observed in muscle mass or function can only be speculative. advanced cancer are already hypogonadal [22] and previous However, clinical experience and published data suggest that studies of progestational agents in cachectic cancer patients muscle loss in advanced cancer patients with cachexia is have suggested that lean body mass remains stable [23]. relentless, especially in the final year of life [15] and there is One of the key physiological stimuli for protein synthesis little evidence of spontaneous recovery. in skeletal muscle is dietary protein intake. Anorexia and The 40 % attrition of patients by 8 weeks is comparable reduced protein and energy intake are key components of with previous studies in similar groups of frail patients with the cachexia syndrome [24], and at baseline, this study popu- advanced disease and cachexia, in whom disease progression lation demonstrated marked lack of appetite. Progestational and co-morbidities are very common [16]. Even in this frail agents are powerful appetite stimulants and are known to population, adverse drug reactions played little part in those increase food intake in weight-losing cancer patients [25]. discontinuations which did occur. The selectivity of We did not measure food intake but patient-reported lack of formoterol for skeletal over heart muscle [13] may have appetite improved significantly. The anabolic action of β2- helped in this regard. The oral use of less selective β2-agonists adrenoreceptor agonists is maintained when substrate avail- such as clenbuterol has been limited principally by cardiovas- ability is reduced by food restriction in animal models [26]. cular side effects, a significant concern in an advanced cancer Thus, in circumstances where megestrol is unable to restore population, in around a quarter of whom significant cardio- normal food intake to normal, there may still be the potential vascular co-morbidity can be expected. In this study, there for benefit from formoterol. were only two episodes of tachycardia, one of which resolved Improvements in both muscle mass and muscle function without leading to patient discontinuation. The other episode, are likely to be a requirement for the regulatory approval of a in a patient with a prior undisclosed history of SVT, also new drug therapy for cancer cachexia. In addition, a clear resolved but the patient was withdrawn from the study as a improvement in clinical outcome, in terms of survival or precaution. Another adverse effect associated with β2-ago- quality of life, may also be required. Physical activity is one nists, tremor, occurred frequently in this study but was gener- of the key domains of quality of life that may be altered by the ally mild, often relatively short-lived and did not directly successful treatment of cachexia. Previous large randomized cause any discontinuations. The dose of formoterol chosen trials in cancer cachexia have failed to show any clear benefit for the study was the usual starting dose of formoterol for its from progestational agents on quality of life in general and respiratory indications. It remains to be seen whether a lower physical function in particular [25]. In this study, the average Support Care Cancer daily step count increased by over 1,000 steps per day in 3/6 7. 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