Individual Dose-escalated Bi-daily Subcutaneously (sc) Ghrelin in Cancer Cachexia: a Phase I/II Study
Individual Dose-escalated Bi-daily Subcutaneously (sc) Ghrelin in Cancer Cachexia: a Phase I/II Study
Cachexia, a condition of severe malnutrition, negative nitrogen balance, muscle wasting,
 weight loss, and anorexia, is a frequent affecting more than 80% of patients in advanced
 cancer disease causing a high burden on patients and their families. Nutritional,
 pharmacological, and behavioural interventions for cancer-related ACS and associated symptoms
 have, despite the importance for cancer care, limited effect on only a minority of patients.
 New strategies are required.

 Ghrelin, a 28 amino acid peptide discovered in 1999, is predominantly secreted by gastric
 endocrine cells and is an endogenous ligand for the growth hormone secretagogue (GHS)
 receptor. When administered peripherally it stimulates growth hormone secretion, food intake,
 triggers a positive energy balance, produces weight gain through a central mechanism
 involving hypothalamic neuropeptides and has anti-inflammatory effects. A recently completed
 trial on intravenous ghrelin in advanced cancer patients with ACS reports good tolerability
 and safety of single intravenous application of 2 and 8μg/kg Ghrelin.

 Given the facts that ACS is a major burden in patients suffering advanced cancer disease and
 ghrelin is a major signal for stimulating food intake, promoting positive energy balance and
 weight gain and may have anti-inflammatory effect it remains to be determined whether the
 administration of ghrelin will have a positive clinical effect on cancer anorexia/ cachexia
 syndrome ACS. The next logical clinical development step is a proper dose-finding study of
 twice daily subcutaneous administration and proof-of-concept of main outcomes.
Inclusion:

 -  Age: Patients must be older than 18 years of age

 -  Tumour situation: Patients with any type of advanced (defined as locally recurrent or
 metastatic), incurable solid tumour.

 -  Cachexia: defined as involuntary loss of weight of ≥2% in 2 months or ≥5% in 6 months,
 and ongoing in the last 4 weeks

 -  No simple starvation: Patients must be able to eat, defined as no severe structural
 barriers in the upper gastrointestinal tract and no bowel obstruction.

 -  No late cachexia: Patient must have an expected life expectancy > 3 months

 -  No anti-cachexia or appetite-stimulating medications: Patients are not allowed to have
 corticosteroids unless for maximum 2 days for chemotherapy, no progestin therapy
 within the last 2 weeks, no anabolic drugs within the last month. Prokinetic
 medication, NSAR (paracetamol and novamin sulphate are allowed, if given in a fixed
 dose for two weeks before visit 1, and expected to be given during the whole trial
 period.

 -  Laboratory test results within these ranges: Absolute neutrophil count ≥ 1.5 x 109/L,
 platelet count ≥ 100 x 109/L, serum creatinine ≤ 2.0 mg/dL (177 μmol/L), creatinine
 clearance ClCr ≥ 50ml/min, total bilirubin ≤1.5 mg/dL (25μmol/L), and AST (SGOT)/ ALT
 (SGPT) ≤2 x ULN or if hepatic metastases are present ≤ 5 x ULN.

 -  No other trial: Patient is not or was not participating in any other clinical trial
 within 28 before visit 2.

 -  Women of childbearing potential: A negative pregnancy test & effective contraception
 are mandatory in child-bearing age.

 -  Men agree not to father a child (i.e. use adequate birth control if sexually active)
 during participation in the trial.

 -  Cognition: Presence of a normal level of consciousness (mandatory is a normal
 abbreviated screening mini-mental test or a common mini-mental ≥ 27/30; in elderly
 patients age ≥ 65 years or patients with low education a mini mental status of ≥25/30
 points will be considered adequate).

 -  Consent: The patient has voluntarily signed and dated an independent Ethics Committee
 (IEC) approved consent prior to any study-specific procedures.

 -  Gastrectomy: Patients with history of gastrectomy are eligible.

 Exclusion:

 -  Questionnaires: Any psychiatric disorder, alcohol and illicit drug abuser language
 problem that would prevent the patient from filling in the questionnaires adequately.

 -  Patient with a history of psychiatric diagnosis of depression or clinical diagnosis of
 depression as determined by the treating physician or Hospital Anxiety Depression
 Scale total score of 13 or greater.

 -  History of alcohol abuse as determined by the CAGE questionnaire (≥2/4) or history of
 illicit drug abuse within last 12 months.

 -  Parenteral nutrition

 -  Diabetes mellitus with secondary organ dysfunction: coronary heart disease, previous
 stroke, renal insufficiency

 -  Patients with cerebral metastases or prophylactic whole brain irradiation for possible
 cerebral metastases.

 -  Known hypersensitivity to ghrelin.

 -  Known infection with HIV or a viral hepatitis

 -  Patients with known myeloid malignancy or tumours having bone marrow involvement

 -  Any condition, including the presence of laboratory abnormalities, which places the
 subject at unacceptable risk if he/she were to participate in the study or confounds
 the ability to interpret data from the study.

 -  Any serious medical condition, laboratory abnormality, or psychiatric illness that
 would prevent the subject from signing the informed consent form.