Anamorelin Study for Advanced Pancreatic Cancer

Multicenter, double-blind, randomized, placebo-controlled study to evaluate the efficacy and safety of anamorelin HCl. Approximately 100 subjects with advanced PDAC and cachexia will be randomized 1:1 to anamorelin HCl 100 mg or placebo, taken orally once daily (QD) for a total of 25 weeks. Subjects will be instructed to take the study drug at least 1 hour before their first meal of the day

Anorexia and cachexia are common clinical sequelae of uncontrolled, metastatic cancer. These effects can impair physical function, reduce quality of life, impair tolerability of anticancer therapy, and reduce survival. Anorexia and cachexia are especially challenging problems in patients diagnosed with metastatic pancreatic cancer. With an annual incidence approaching 50,000 patients in the U.S. alone, pancreatic cancer has an annual mortality of approximately 40,000 patients with most individuals succumbing to their disease within two years. Between 70-80% of patients with metastatic pancreatic cancer experience cancer cachexia, which has been associated with reduced survival, increased risk of disease progression, and impaired chemotherapy tolerance.

Anamorelin HCl is an orally-active selective ghrelin receptor agonist which has shown anabolic and appetite-stimulating effects. Several randomized, double-blind, clinical trials in cancer patients have shown that anamorelin HCL is safe, efficacious and increases lean body mass, bodyweight, and appetite. Investigators propose to test anamorelin HCL administered with chemotherapy in the first-line treatment of locally advanced unresectable and metastatic pancreatic cancer.

The study is a randomized, placebo controlled multicenter, Phase II trial to evaluate the efficacy and safety of anamorelin HCl. Approximately 100 patients with be enrolled in a 1:1 randomization to anamorelin HCL 100mg per day given concurrently with first-line chemotherapy compared to chemotherapy alone. Patients randomized to anamorelin HCL will take it daily for 24 weeks starting one day prior to chemotherapy. All patients will undergo an assessment by a certified nutritionist at or prior to their first cycle of chemotherapy. Both body weight and appetite will be measured at enrollment as well as at the initiation of chemotherapy. Patients will be stratified by degree of weight loss in the six months prior to enrollment, choice of first-line chemotherapy, and by baseline score of 5-item Anorexia Symptom Scale.

Eligibility Criteria:
Inclusion Criteria:

1. Signed written informed consent
2. Female or male ≥18 years of age
3. Documented histologic or cytologic diagnosis of American Joint Committee on Cancer (AJCC) unresectable or metastatic pancreatic adenocarcinoma
4. Body mass index \< 20 kg/m2 with involuntary weight loss or \>5% within 6 months prior to screening
5. Ongoing problems with appetite/eating associated with the underlying cancer, as determined by having score of ≤ 17 points on the 5-item Anorexia Symptom Scale and ≤ 37 points on the 12-item FAACT A/CS
6. Subjects eligible to receive first line palliative chemotherapy
7. ECOG performance status 0 or 1 at screening
8. Acceptable hepatic function as defined by total bilirubin \< 1.6 mg/dl unless associated with Gilbert syndrome, then total bilirubin \< 2 x ULN. AST (SGOT) and ALT (SGPT) ≤ 2.5 x ULN or if hepatic metastases are present ≤ 5 x ULN
9. Appropriate treatment with pancreatic enzyme replacement prior to trial initiation
10. Female subjects shall be:

    1. of non-childbearing potential or
    2. of childbearing potential using reliable contraceptive measures and having a negative urine pregnancy test within 24 hours prior to first dose of investigational product.
11. The patient must be willing and able to comply with the protocol tests and procedures All inclusion criteria will be checked at screening visit (Visit 1).

Exclusion Criteria:

1. Patient with other forms of pancreatic cancer (e.g. neuroendocrine tumors)
2. Patient undergoing major surgery within 4 weeks of randomization or plans to undergo major surgery during study period.
3. Women who are pregnant or breastfeeding
4. Patient with alternative cause of cachexia as determined by the investigator including: a) severe COPD requiring O2, b) severe heart failure (NYHA Class III- IV), c) second malignancy
5. Reversible causes of reduced food intake as determined by the investigator including but not limited to: severe mucositis (\>=NCI CTCAE grade 3), mechanical obstruction, severe nausea, vomiting, or diarrhea (\>=NCI CTCAE grade 3)
6. Patient unable to swallow pills
7. Patient with history of bariatric surgery, gastrectomy, or malabsorption disorder (gastritis, esophagitis)
8. Patient with recent use of CYP3A4 inhibitors
9. Patient with current daily use of therapies that may increase the QRS interval durations
10. Patient currently taking medications/compounds intended to increase appetite or decrease weight loss (e.g. testosterone, megestrol acetate, cannabis products, methylphenidate, corticosteroids, olanzapine, mirtazapine (allowed if \>4 weeks of use as therapy for depression)
11. Patient with current use of tube feeding or parenteral feeding
12. Patient with pleural effusion requiring thoracentesis, pericardial effusion requiring drainage, edema or evidence of ascites
13. Patient with uncontrolled or significant cardiovascular disease, including:

    1. History of myocardial infarction within the past 3 months
    2. A-V block of second or third degree (may be eligible if currently have a pacemaker)
    3. Unstable angina
    4. Congestive heart failure within the past 3 months, if defined as NYHA class III-IV
    5. Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, Wolff-Parkinson-White (WPW) syndrome, or torsade de pointes)
    6. Uncontrolled hypertension (blood pressure \>150 mm Hg systolic and \>95 mm Hg diastolic)
    7. Heart rate \< 50 beats per minute on pre-entry electrocardiogram and patient is symptomatic
14. Patient with uncontrolled diabetes mellitus or unmonitored diabetes mellitus
15. Patient with uncontrolled pain.
16. Any condition, including the presence of laboratory abnormalities, which in the Investigator's opinion, 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
17. Enrollment in a previous study with anamorelin HCl
18. Enrollment in another clinical trial during the time of this trial.