Study of Ruxolitinib in the Treatment of Cachexia in Patients With Tumor-Associated Chronic Wasting Diseases.
Study of Ruxolitinib in the Treatment of Cachexia in Patients With Tumor-Associated Chronic Wasting Diseases.
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.
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.
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.