Phase II, double blind, placebo controlled, multi-site study to evaluate the safety, feasibility and desirability of conducting a phase III study of anamorelin for anorexia in people with small cell lung cancer: A study protocol (LUANA trial)

PLOS ONE · 20 authors, 16 centres

AI SUMMARY

FIDELITY 100%

POPULATIONAdults (≥18 years) with small cell lung cancer (newly diagnosed with planned systemic therapy OR first recurrence after ≥6-month disease-free interval) and anorexia (≤37 points on the 12-item FAACT A/CS scale).

INTERVENTIONAnamorelin HCl 100 mg orally once daily for 12 weeks (with optional blinded extension to 24 weeks).

COMPARISONMatched placebo orally once daily for 12 weeks (with optional blinded extension to 24 weeks).

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AGENT 01 · STRUCTURED SUMMARY

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TL;DR

This protocol describes a phase II, double-blind, placebo-controlled trial (LUANA trial) testing anamorelin 100 mg daily for anorexia in 50 adults with small cell lung cancer (SCLC). The primary aim is to assess safety, feasibility, and desirability of conducting a future phase III trial, with secondary outcomes including body weight, nutritional intake, quality of life, and chemotherapy completion rates. If successful, this study will provide the necessary data to design a fully powered phase III effectiveness trial for anamorelin in cancer-related anorexia.

Full summary

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**Background:** Cancer-related anorexia (appetite loss) affects over 50% of people at cancer diagnosis and is an independent negative prognostic factor for survival. It reduces chemotherapy effectiveness, physical capacity, and quality of life. Lung cancer represents over 12% of the global cancer burden, and approximately two-thirds of people with advanced small cell lung cancer (SCLC) experience anorexia. Current therapies are limited with marginal benefits. Anamorelin, a ghrelin receptor agonist, stimulates appetite by increasing growth hormone, IGF-1, and IGFBP-3. Two phase III trials (ROMANA 1 and ROMANA 2) in NSCLC showed anamorelin safely reversed muscle loss, augmented body weight, and improved appetite, but failed to meet functional co-primary endpoints (hand-grip strength). Anamorelin is approved in Japan for cancer cachexia in NSCLC, gastric, pancreatic, and colorectal cancers but not by the FDA or EMA. This phase II trial focuses on anorexia (not cachexia) and chemotherapy tolerance in SCLC.

**Methods:** This is a phase II, double-blind, placebo-controlled, parallel-arm, fixed-dose, multi-site study conducted at six Australian hospitals. Fifty participants (25 per arm) will be randomised 1:1 to receive anamorelin HCl 100 mg or matched placebo orally once daily for 12 weeks, with an optional blinded extension to 24 weeks. Block randomisation (size 4 or 8) is stratified by disease extent (limited vs. extensive) and baseline FAACT A/CS anorexia symptom score (≤10 vs. >10). Eligibility includes adults ≥18 years with confirmed SCLC (newly diagnosed with planned systemic therapy OR first recurrence after ≥6-month disease-free interval), anorexia (≤37 points on the 12-item FAACT A/CS scale), Australia-modified Karnofsky Performance Status ≥50, adequate hepatic and renal function, and English-speaking. Key exclusions include pregnancy, conditions impeding food intake (e.g., grade 3-4 oral mucositis or GI disorders), recent major surgery, concurrent appetite-stimulating medications (except short-term chemotherapy-related use), uncontrolled cardiovascular disease, poorly controlled diabetes (HbA1c >7% or fasting glucose >7 mmol/L or random glucose >11 mmol/L), and cognitive impairment (Short Blessed Test score ≥10). All participants receive standard physical activity and dietary advice leaflets at baseline. Primary outcomes are feasibility (recruitment rate of one participant per site every six weeks; ≥70% complete primary endpoint data; ≥70% medication adherence; ≥40% adherence to physical activity and dietary advice) assessed via a traffic light system (green/amber/red), and desirability (sufficient efficacy signal). Secondary outcomes include change in FAACT A/CS anorexia symptom domain score from baseline to week 12, rates of on-time/on-dose chemotherapy/radiotherapy completion, body weight, lean body mass (DEXA, BIA, CT at T4 level), functional status (AKPS, TUG test, step count), nutritional intake (3-day food diary), biochemistry (pre-albumin, CRP, IL-6), survival, quality of life (EQ-5D-5L, ICECAP-A), fatigue (FACIT-F), harms (NCI-CTCAE v5.0), and health economic outcomes. Safety assessments include clinical parameters, 12-lead ECGs, adverse events, and laboratory tests. Statistical analysis uses descriptive statistics for feasibility; efficacy outcomes will be analysed by t-test or Wilcoxon test and linear mixed models. Missing values will not be imputed.

**Key Results:** This is a study protocol; no results are reported. The proposed sample size of 50 participants (25 per arm) is based on feasibility study recommendations (range 24-55). The study is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12622000129785) and approved by the South Western Sydney Local Health District Human Research Ethics Committee (2021/ETH11339).

**Clinical Implications:** This phase II trial addresses the unmet need for safe and effective treatments for cancer-related anorexia in SCLC. By focusing on feasibility and desirability endpoints, the study will inform the design of a future phase III effectiveness trial. If successful, anamorelin could improve appetite, nutritional status, chemotherapy tolerance, and quality of life in people with SCLC. The 100 mg dose was well-tolerated in prior phase III NSCLC trials (ROMANA 1/2) with no new safety signals in longer dosing (ROMANA 3 extension). Common drug-related harms from prior trials included diabetes and hyperglycemia (<1% of patients), transient ECG changes (PR and QRS prolongation at supra-therapeutic doses of 300-400 mg, but no meaningful effect on ventricular repolarization at 100 mg), nausea, diarrhea, peripheral edema, and fatigue. This study specifically monitors cardiac dysfunction, symptomatic hyperglycemia, drug interactions, constipation, nausea, and vomiting using NCI-CTCAE gradings.

PICO

PPOPULATION

Adults (≥18 years) with small cell lung cancer (newly diagnosed with planned systemic therapy OR first recurrence after ≥6-month disease-free interval) and anorexia (≤37 points on the 12-item FAACT A/CS scale).

IINTERVENTION

Anamorelin HCl 100 mg orally once daily for 12 weeks (with optional blinded extension to 24 weeks).

OOUTCOME

Primary: safety, feasibility (recruitment rate, adherence, completion of study tools), and desirability (sufficient efficacy signal). Secondary: change in anorexia symptoms (FAACT A/CS), body weight/composition, functional status, nutritional intake, fatigue, quality of life, survival, harms, and health economic outcomes.

STUDY TYPE

other

SPECIALTY

oncology

SUMMARISED BY

AI pipeline

FIDELITY CHECK

100% · A

ORIGINAL PAPER

PMC10191352

Phase II, double blind, placebo controlled, multi-site study to evaluate the safety, feasibility and desirability of conducting a phase III study of anamorelin for anorexia in people with small cell lung cancer: A study protocol (LUANA trial)

PLOS ONE

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ABSTRACT

Abstract Anorexia is experienced by most people with lung cancer during the course of their disease and treatment. Anorexia reduces response to chemotherapy and the ability of patients to cope with, and complete their treatment leading to greater morbidity, poorer prognosis and outcomes. Despite the significant importance of cancer-related anorexia, current therapies are limited, have marginal benefits and unwarranted side effects. In this multi-site, randomised, double blind, placebo controlled, phase II trial, participants will be randomly assigned (1:1) to receive once-daily oral dosing of 100mg of anamorelin HCl or matched placebo for 12 weeks. Participants can then opt into an extension phase to receive blinded intervention for another 12 weeks (weeks 13–24) at the same dose and frequency. Adults (≥18 years) with small cell lung cancer (SCLC); newly diagnosed with planned systemic therapy OR with first recurrence of disease following a documented disease-free interval ≥6 months, AND with anorexia (i.e., ≤ 37 points on the 12-item Functional Assessment of Anorexia Cachexia Treatment (FAACT A/CS) scale) will be invited to participate. Primary outcomes are safety, desirability and feasibility outcomes related to participant recruitment, adherence to interventions, and completion of study tools to inform the design of a robust Phase III effectiveness trial. Secondary outcomes are the effects of study interventions on body weight and composition, functional status, nutritional intake, biochemistry, fatigue, harms, survival and quality of life. Primary and secondary efficacy analysis will be conducted at 12 weeks. Additional exploratory efficacy and safety analyses will also be conducted at 24 weeks to collect data over longer treatment duration. The feasibility of economic evaluations in Phase III trial will be assessed, including the indicative costs and benefits of anamorelin for SCLC to the healthcare system and society, the choice of methods for data collection and the future evaluation design. Trial registration. The trial has been registered with the Australian New Zealand Clinical Trials Registry [ACTRN12622000129785] and approved by the South Western Sydney Local Health District Human Research Ethics Committee [2021/ ETH11339 ]. https://clin.larvol.com/trial-detail/ACTRN12622000129785 .

CITATION EXPORT

Mariana S Sousa, Peter Martin, Miriam J Johnson et al.. Phase II, double blind, placebo controlled, multi-site study to evaluate the safety, feasibility and desirability of conducting a phase III study of anamorelin for anorexia in people with small cell lung cancer: A study protocol (LUANA trial). PLOS ONE. (2023). https://doi.org/10.1371/journal.pone.0285850

AUTHORS

20 · 16 CENTRES

Mariana S Sousa, Peter Martin, Miriam J Johnson, Michael Lind, Matthew Maddocks, Alex Bullock, Meera Agar, Sungwon Chang, Slavica Kochovska, Irina Kinchin, Deidre Morgan, Belinda Fazekas, Valentina Razmovski-Naumovski, Jessica T Lee, Malinda Itchins, Victoria Bray, David C Currow, Alexandra Schaefer, Junichi Matsubara, Junichi Matsubara

1Faculty of Health, Improving Palliative, Aged and Chronic Care through Clinical Research and Translation (IMPACCT), University of Technology Sydney, Ultimo, New South Wales, Australia
2School of Nursing and Midwifery, Western Sydney University, Penrith, New South Wales, Australia
3School of Medicine, Deakin University, Geelong, Victoria, Australia
4Palliative Care, Barwon Health, Geelong, Victoria, Australia
5Wolfson Palliative Care Research Centre, Hull York Medical School, University of Hull, Hull, England
6Cicely Saunders Institute of Palliative Care, Policy and Rehabilitation, King’s College London, Denmark Hill, London, United Kingdom
7Department of Medical Oncology, Liverpool Hospital, Liverpool, New South Wales, Australia
8South West Sydney Clinical Campuses, University of New South Wales Sydney, Kensington, Australia
9Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, New South Wales, Australia
10Trinity College Dublin, The University of Dublin, Dublin, Ireland
11RePaDD, Flinders University, Adelaide, South Australia, Australia
12Concord Centre for Palliative Care, Concord Repatriation General Hospital, Concord West, New South Wales, Australia
13Concord Clinical school, University of Sydney, Camperdown, New South Wales, Australia
14Royal North Shore Hospital, St Leonards, New South Wales, Australia
15Faculty of Medicine and Health, University of Sydney, Camperdown, New South Wales, Australia
16Kyoto University Graduate School of Medicine Faculty of Medicine: Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu, JAPAN