A Clinical Study With MT-102 in Subjects With Cancer Cachexia

Cachexia is a wasting disease, associated with significant morbidity and mortality, accompanying a wide range of serious illnesses, for which there are currently no widely approved therapeutic agents. Cachexia is defined as weight loss, associated with a chronic underlying disease, of at least 5% in 12 months or less. It is associated with fatigue, loss of muscle strength, a low fat free index and neurohormonal and biochemical abnormalities.

Cancer cachexia occurs in about a third of all patients with cancer and has been estimated to be the direct cause of death in up to 20% of all cancer related deaths. As with other solid tumours, colorectal cancer (CRC) and non-small cell lung cancer (NSCLC) have relatively high incidences of cachexia, approximately 28% and 34% respectively.Through its combined pharmacological actions, MT-102 has a multi-functional effect upon three potential pharmacological targets, each of which is relevant for cancer cachexia

Inclusion criteria

• 1. Adult patients aged between 25 to 80 years of age and with a life expectancy of greater than 3 months as judged by the treating physician.

• Confirmed diagnosis of one of:

a. Non-curative stage III or stage IV Colorectal Cancer (CRC) not suitable for surgery, or b. Non-curative stage III or stage IV Non-small Cell Lung Cancer (NSCLC) not suitable for surgery;

• Patients who are receiving or who have already received a course of chemotherapy, with or without radiotherapy or surgery, with one of the following regimes:

a. For non-small cell lung cancer, a platinum based regimen b. For colorectal cancer, a 5FU or Irinotecan based regimen

• Cachexia with ongoing weight loss that in the opinion of the investigator is due to the underlying cancer.

• Evidence of cachexia as judged by one of:

a. ≥5% documented weight loss in the previous 12 months; or b. A subjective report of weight loss in the previous 12 months and a recorded body mass index (BMI) less than 20.0 kg/m2 c. Ongoing documented weight loss of at least 1kg in the week prior to day 0; or 1.25kg in the 2 weeks prior to day 0, or 1.5kg in the 3 to 6 weeks prior to day 0; provided that BMI is not more than 25.

• At least two of the following:

a. Subjective report of decreased muscle strength b. Subjective report of fatigue c. Subjective report of anorexia d. Abnormal biochemistry with one or more of the following: i. CRP > ULN (as per Central Lab normal value) ii. Anemia (< 12 g/dl) iii. Low serum albumin (< 3.2 g/dl) 7. Patients of childbearing potential must use an effective method of avoiding pregnancy (including oral, transdermal, or implanted contraceptives; an intrauterine device; male or female condoms; diaphragm or cervical cap with spermicide; or abstinence) prior to randomisation and must agree to continue using such precautions until the end of the 140 day safety follow up; 8. Willing and able to comply with the protocol and to complete the study period; 9. Willing to forego other forms of experimental treatment during the study; 10. Signed and dated informed consent, prior to receipt of any study medication or any study related procedures.

• ECOG performance status 0, 1 or 2 12. Able to complete the performance tests (SCP, SMWT, SPPB, HGS) at the screening visit and with two consecutive pre-randomisation SMWT results that differ by no more than 30% from each other 13. At least 80% compliant during the placebo run in period

Exclusion criteria

• 1. Pregnancy or lactation at screen or baseline visit;
• ≥20% weight loss in the previous 3 months or a BMI of less than 16 kg/m2
• Age greater than 80 or less than 25 at baseline visit;
• Scheduled to start any new course of chemotherapy or to undergo a change in present chemotherapeutic regimen during the dose escalation phase of the study (the first three weeks after randomisation);
• Any surgical procedure within the past month or any planned surgical procedure;
• Any mechanical obstruction of the alimentary canal;
• Any history or evidence of intractable vomiting;
• A history or clinical evidence of any hyperthyroidism, cirrhosis, hepatic failure, HIV, renal failure (as determined by a serum creatinine > 250µmol/l or > 2.83 mg/dl at screen) or active tuberculosis (as confirmed by sputum or other microbiological methods, within the last five years);
• Any physical, medical, socioeconomic or other non-cancer related cause for simple starvation, muscle wasting or weight loss;
• Receiving enteral tube feeding or parenteral nutrition at screening or baseline visit;
• Any clinical evidence of ascites or significant oedema or significant pleural effusion at screening or baseline visit;
• Current or planned treatment with

• Any oral adrenal corticosteroids (inhaled or topical steroids and short-term use of dexamethasone around the time of chemotherapy are acceptable);
• Beta adrenergic blockers,
• Non-dihydropyridine calcium antagonists (e.g. Verapamil, diltiazem),
• Alpha adrenergic blockers,
• Ivabradine (Coralan, Procoralan),
• 5HT agonists or antagonists e.g. SSRI's, , (short-term use around the time of chemotherapy are acceptable)
• MAOI's,
• Beta agonists, (short term or on-and -off use of inhaled broncho-dilators are acceptable)
• Amiodarone,
• Megestrol, Anabolic Steroids or any other prescription medication intended to increase appetite or to treat unintentional weight loss.
• Treatment with any investigational drug therapy within 28 days prior to the screening visit;
• Previous history of administration of pindolol or s-pindolol;
• History of allergy or reaction to any component of the MT 102/study drug formulation;
• History or presence of congestive heart failure (with LVEF <45%) or uncontrolled hypertension (with BP >160/95 mm Hg);
• Use of a pacemaker, implantable defibrillator, or internalized metal stent;
• Resting pulse rate less than 68 beats per minute or high degree conduction defect on the electrocardiogram;
• A resting supine systolic blood pressure less than 100 mm Hg.
• A history of bronchospasm and bronchial asthma;
• History or diagnosis of brain metastases