Study of Ruxolitinib in the Treatment of Cachexia in Patients With Tumor-Associated Chronic Wasting Diseases.
Information source: Kantonsspital Aarau
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Cancer Cachexia
Intervention: Ruxolitinib (Drug)
Phase: Phase 2
Status: Recruiting
Sponsored by: Kantonsspital Aarau Official(s) and/or principal investigator(s): Nathan Cantoni, MD, Study Chair, Affiliation: Division of Hematology/Oncology, University Clinic of Medicine, Kantonsspital Aarau AG, CH-5001 Aarau, Switzerland Mario Bargetzi, MD, Study Chair, Affiliation: Division of Hematology/Oncology, University Clinic of Medicine, Kantonsspital Aarau AG, CH-5001 Aarau, Switzerland
Overall contact: Stefanie Hetzenecker, PhD, Phone: +41 62 838 60 58, Email: stefanie.hetzenecker@ksa.ch
Summary
The aim of this study is to investigate the effects and safety of Ruxolitinib, a Janus
kinase 1 (JAK1) and Janus kinase 2 (JAK2) inhibitor for the treatment of tumor-associated
cachexia in chronic wasting diseases.
Clinical Details
Official title: The RUXexia Trial: An Open-label Phase II Trial of Ruxolitinib in the Treatment of Cachexia in Patients With Tumor-Associated Chronic Wasting Diseases.
Study design: Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: Body weight
Secondary outcome: Body weightLean Body (muscle) Mass (LBM) Resting energy expenditure (REE) Activity Energy Expenditure (AEE) Body mass index (BMI) Tumor assessment Grip Strength Quality of Life Nutritional history Number of adverse events Stair climbing test
Detailed description:
Cachexia is a multifactorial syndrome characterized by tissue wasting, loss of body weight,
particularly of lean body (muscle) mass (LBM) and to a lesser extent adipose tissue,
metabolic alterations, fatigue, reduced performance status, and very often accompanied by
anorexia leading to a reduced food intake. Cachexia accompanies the end stage of many
chronic diseases and especially cancer and therefore is also termed "cancer-related
anorexia/cachexia syndrome" (CACS). Clinically, cachexia is defined as an unintentional 5%
resp. 10% loss of body weight over a 6-month resp. 12-month period that is directly
associated with an underlying disease. The progressive loss of adipose tissue and skeletal
muscle despite adequate feeding results in weakness, reduced ambulation, diminished quality
of life, poor response to therapy, and often death due to respiratory failure or infection.
At the time of cancer diagnosis, 80% of patients with upper gastrointestinal cancers and 60%
of patients with lung cancer have already had substantial weight loss. Currently, there are
no approved effective treatments for the treatment of cachexia. Understanding the molecular
mechanisms responsible for muscle wasting is necessary to develop targeted therapies that
play a central role in signal transduction initiated by cytokines (e. g., interleukin and
interferon signaling), growth factors, and hormones for these most vulnerable patients. Key
features of CACS are increased resting energy expenditure (REE), increased levels of
circulating factors produced by the host immune system in response to the tumor, such as
proinflammatory cytokines, or by the tumor itself, such as proteolysis-inducing factor.
Inflammation is a unifying mechanism for the entire cluster of sickness behaviours
(asthenia, increased slow-wave sleep, mood alteration, lethargy, depression, anorexia,
fever, anhedonia, cognitive impairment, hyperalgesia and decreased social interaction),
including lipolysis and muscle proteolysis. Inflammation is generated in the brain, by the
tumor, by tissues in the locale of the tumor and by a diversity of host cells including
skeletal muscle, adipose tissue, cells of the immune system, and liver. The specific
identity of the inflammation mediators participating in cancer cachexia is emerging. Both
host and tumor-derived factors have been shown experimentally to contribute to muscle
wasting. There is evidence that a chronic, low-grade, tumor-induced activation of the host
immune system, which shares numerous characteristics with the "acute-phase response" found
after major traumatic events, septic shock or chronic inflammatory diseases with an
excessive production of proinflammatory cytokines, is involved in CACS. Proinflammatory
cytokines interleukin (IL)-1, IL-6, and tumor necrosis factor-alfa (TNF-a) play a central
role in the pathophysiology of CACS, although the mechanisms by which they might induce
muscle wasting are unknown. A goal of anorexia-cachexia therapy is to interfere with these
responses to inflammation and so to restore positive energy balance and to promote the gain
of skeletal muscle mass. Understanding the specific management of the initiating
inflammatory pathways is crucial to that end. Recently a study reported that a "Signal
Transducers and Activators of Transcription (STAT)" protein (STAT3) activation is a common
feature of muscle wasting, activated in muscle by IL-6 in vivo and in vitro, by different
types of cancer, and by sterile sepsis. Moreover, STAT3 activation is necessary and
sufficient for causing muscle wasting. Conversely, the same authors showed that inhibiting
STAT3 pharmacologically with Janus kinase (JAK) or STAT3 inhibitors or genetically reduced
muscle atrophy downstream of IL-6 or cancer. Epidemiological studies suggest that as many as
25% of all cancers may be due to chronic inflammation. The connection between inflammation
and cancer consists of an extrinsic pathway, driven by inflammatory conditions that increase
cancer risk, and an intrinsic pathway, driven by oncogenic alterations that result in
creation of an inflammatory microenvironment that resolves in neoplasias. Immune cells play
key roles in connecting inflammation and cancer by producing various growth or angiogenic
factors, proteinases, chemokines, and cytokines that create a pro-inflammatory tumor
microenvironment. This milieu stimulates cell migration, proliferation, survival,
angiogenesis, and metastasis, and facilitates the subversion of adaptive immunity, thus
favoring cancer progression.
These theoretical considerations as well as pharmacological results and data from animal
models indicated that the JAK/STAT pathway is a primary mediator of muscle wasting in cancer
cachexia and other conditions of high IL-6 family signaling. Thus JAK/STAT pathway could
represent a novel therapeutic target for the preservation of skeletal muscle in cachexia. On
the basis of this rationale, we want to carry out an open label phase II study with the aim
of testing the efficacy and safety of a treatment based on a pharmacologic inhibition of the
JAK/STAT3 pathway with Ruxolitinib in patients with CACS. Ruxolitinib represents a novel
orally bioavailable, potent, and selective inhibitor of JAK1 and JAK2 developed primarily
for the treatment of Myeloproliferative Neoplasms (MPNs). A key feature of MPNs is the
dysregulation of JAK/STAT signaling.
Eligibility
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
Criteria:
Inclusion Criteria:
- Definition of cachexia (see Section 11. 1) fulfilled
- Age ≥ 18 years
- Confirmed tumor of any site
- Life expectancy of ≥3 months
- Subject must be willing to receive transfusion of blood products
- Patient must give written informed consent
- Females of childbearing potential (FCBP) must undergo pregnancy testing (serum) and
pregnancy result must be negative.*
- Reliable contraception should be maintained throughout the study and for 28 days
after study treatment discontinuation
- Unless practicing complete abstinence from heterosexual intercourse, sexually active
FCBP must agree to use adequate contraceptive methods
- Males (including those who have had a vasectomy) must use barrier contraception
(condoms) when engaging in sexual activity with FCBP. Males must agree not to donate
semen or sperm
Exclusion Criteria:
- Pregnant or breast feeding females
- Lack of written informed consent
- No consent for registration, storage and processing of the individual
disease-characteristics and course as well as information of the family physician
about study participation.
- No consent for "Translational Research" and "Biobanking" (see separate documents
"Aufbewahrung und Weiterverwendung von biologischem Material und von Daten für die
biomedizinische Forschung" und "Biobankreglement" for the RUXexia Trial).
- Thrombocytopenia < 50 x 10e9/l
- Peroral intake not possible, in particular by stenosis of the esophagus
- New started treatment of the tumor (first 3 months of a new treatment). Patients with
a new treatment of the cancer disease should delay screening/enrollment until 3
months after start of this treatment.
- Presence of any medical/psychiatric condition or laboratory abnormalities which may
limit full compliance with the study, increase the risk associated with study
participation or study drug administration, or may interfere with the interpretation
of study results and, in the judgment of the Investigator, would make the patient
inappropriate for entry into this study
- Patients with a Myeloproliferative Neoplasm
- Patients receiving any "Prohibited Medications" (see protocol) within 7 days prior to
the first dose of study drug
- Patients with clinically significant bacterial, fungal, parasitic or viral infection
which require therapy. Patients with acute bacterial infections requiring antibiotic
use should delay screening/enrollment until the course of antibiotic therapy has been
completed.
Locations and Contacts
Stefanie Hetzenecker, PhD, Phone: +41 62 838 60 58, Email: stefanie.hetzenecker@ksa.ch
Division of Hematology/Oncolgy, University Clinic of Medicine, Kantonsspital Aarau AG, Aarau, AG 5001, Switzerland; Recruiting Stefanie Hetzenecker, PhD, Phone: +41 62 838 60 58, Email: stefanie.hetzenecker@ksa.ch Therese Gurtner, CRA, Phone: +41 62 838 60 58, Email: therese.gurtner@ksa.ch Nathan Cantoni, MD, Principal Investigator
Division of Hematology/Oncology, Kantonsspital Olten, Olten, SO 4600, Switzerland; Not yet recruiting Stefanie Hetzenecker, PhD, Phone: +41 62 838 60 58, Email: stefanie.hetzenecker@ksa.ch Therese Gurtner, CRA, Phone: +41 62 838 60 58, Email: therese.gurtner@ksa.ch Walter Mingrone, MD, Principal Investigator
Additional Information
Starting date: April 2014
Last updated: March 30, 2015
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