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Phase 2 study of the efficacy and safety of ponsegromab in patients with cancer cachexia: PROACC-1 study design.

Publication ,  Journal Article
Groarke, JD; Crawford, J; Collins, SM; Lubaczewski, SL; Breen, DM; Harrington, MA; Jacobs, I; Qiu, R; Revkin, J; Rossulek, MI; Saxena, AR
Published in: J Cachexia Sarcopenia Muscle
June 2024

BACKGROUND: Cancer cachexia is a multifactorial metabolic wasting syndrome characterized by anorexia, unintentional loss of weight involving both skeletal muscle and adipose tissues, progressive functional impairment and reduced survival. Therapeutic strategies for this serious condition are very limited. Growth differentiation factor 15 (GDF-15) is a cytokine that is implicated in cancer cachexia and may represent both a biomarker of cancer cachexia and a potential therapeutic target. Ponsegromab is a potent and selective humanized monoclonal antibody that inhibits GDF-15-mediated signalling. Preclinical and preliminary phase 1 data suggest that ponsegromab-mediated inactivation of circulating GDF-15 may lead to improvement in key characteristics of cachexia. The primary objective of this phase 2 study is to assess the effect of ponsegromab on body weight in patients with cancer, cachexia and elevated GDF-15 concentrations. Secondary objectives include assessing physical activity, physical function, actigraphy, appetite, nausea and vomiting, fatigue and safety. Exploratory objectives include evaluating pharmacokinetics, pharmacodynamics, immunogenicity, lumbar skeletal muscle index and Response Evaluation Criteria in Solid Tumors. METHODS: Approximately 168 adults with non-small-cell lung, pancreatic or colorectal cancers who have cachexia and elevated GDF-15 concentrations will be randomized in a double-blind, placebo-controlled study (NCT05546476). Participants meeting eligibility criteria will be randomized 1:1:1:1 to one of three dose groups of ponsegromab (100, 200 or 400 mg) or matching placebo administered subcutaneously every 4 weeks for an initial 12-week treatment period. This is followed by optional open-label treatment with ponsegromab of 400 mg administered every 4 weeks for up to 1 year. The primary endpoint is mean change from baseline in body weight at Week 12. A mixed model for repeated measures followed by a Bayesian Emax model will be used for the primary analysis. Secondary endpoints include physical activity, physical function and actigraphy measured by remote digital sensors; patient-reported appetite-related symptoms assessed by Functional Assessment of Anorexia-Cachexia Therapy subscale scores; anorexia/appetite, nausea and vomiting, and fatigue evaluated according to questions from the Cancer-Related Cachexia Symptom Diary; and incidence of adverse events, safety laboratory tests, vital signs and electrocardiogram abnormalities. PERSPECTIVE: Cancer-related cachexia is an area of significant unmet medical need. This study will support the clinical development of ponsegromab as a novel inhibitor of GDF-15, which may ameliorate key pathologies of cancer cachexia to improve patient symptoms, functionality and quality of life. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT05546476.

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Published In

J Cachexia Sarcopenia Muscle

DOI

EISSN

2190-6009

Publication Date

June 2024

Volume

15

Issue

3

Start / End Page

1054 / 1061

Location

Germany

Related Subject Headings

  • Neoplasms
  • Male
  • Humans
  • Growth Differentiation Factor 15
  • Female
  • Cachexia
  • Antibodies, Monoclonal, Humanized
  • Adult
  • 4207 Sports science and exercise
  • 4201 Allied health and rehabilitation science
 

Citation

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Groarke, J. D., Crawford, J., Collins, S. M., Lubaczewski, S. L., Breen, D. M., Harrington, M. A., … Saxena, A. R. (2024). Phase 2 study of the efficacy and safety of ponsegromab in patients with cancer cachexia: PROACC-1 study design. J Cachexia Sarcopenia Muscle, 15(3), 1054–1061. https://doi.org/10.1002/jcsm.13435
Groarke, John D., Jeffrey Crawford, Susie M. Collins, Shannon L. Lubaczewski, Danna M. Breen, Magdalena A. Harrington, Ira Jacobs, et al. “Phase 2 study of the efficacy and safety of ponsegromab in patients with cancer cachexia: PROACC-1 study design.J Cachexia Sarcopenia Muscle 15, no. 3 (June 2024): 1054–61. https://doi.org/10.1002/jcsm.13435.
Groarke JD, Crawford J, Collins SM, Lubaczewski SL, Breen DM, Harrington MA, et al. Phase 2 study of the efficacy and safety of ponsegromab in patients with cancer cachexia: PROACC-1 study design. J Cachexia Sarcopenia Muscle. 2024 Jun;15(3):1054–61.
Groarke, John D., et al. “Phase 2 study of the efficacy and safety of ponsegromab in patients with cancer cachexia: PROACC-1 study design.J Cachexia Sarcopenia Muscle, vol. 15, no. 3, June 2024, pp. 1054–61. Pubmed, doi:10.1002/jcsm.13435.
Groarke JD, Crawford J, Collins SM, Lubaczewski SL, Breen DM, Harrington MA, Jacobs I, Qiu R, Revkin J, Rossulek MI, Saxena AR. Phase 2 study of the efficacy and safety of ponsegromab in patients with cancer cachexia: PROACC-1 study design. J Cachexia Sarcopenia Muscle. 2024 Jun;15(3):1054–1061.
Journal cover image

Published In

J Cachexia Sarcopenia Muscle

DOI

EISSN

2190-6009

Publication Date

June 2024

Volume

15

Issue

3

Start / End Page

1054 / 1061

Location

Germany

Related Subject Headings

  • Neoplasms
  • Male
  • Humans
  • Growth Differentiation Factor 15
  • Female
  • Cachexia
  • Antibodies, Monoclonal, Humanized
  • Adult
  • 4207 Sports science and exercise
  • 4201 Allied health and rehabilitation science