Telotristat Ethyl to Promote Weight Stability in Patients With Advanced Stage Pancreatic Cancer

Study Overview
=================
Brief Summary
-----------------
This phase II trial studies how well telotristat ethyl works in promoting weight stability in patients with pancreatic adenocarcinoma that has come back and spread to other places in the body. Telotristat ethyl may decrease bowel movements which may make patients gain weight. Stabilizing weight may help patients tolerate chemotherapy better and improve longevity.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. Evaluate weight stability after 3 months of telotristat ethyl treatment in patients who have significant weight loss (documented to be more than or equal to 10%) prior to the start of treatment. (Group 1). II. Evaluate the change in serum and 24-hours (hr) urine 5-hydroxyindoleacetic acid (5-HIAA) in patients with locally advanced unresectable, recurrent or metastatic pancreatic adenocarcinoma (PDAC) receiving chemotherapy. (Group 2). SECONDARY OBJECTIVES: I. Evaluate the impact of weight stabilization/gain on patients in Group 1 on performance status, quality of life (QOL), mid arm circumference (MAC) and muscle mass on cross sectional imaging. II. Evaluate correlations between changes in serotonin/ 5HIAA levels on radiologic response, weight stability, mid arm circumference (MAC), and muscle mass on cross sectional imaging. III. Evaluate the relation of baseline serum and 24-hr urine 5-HIAA on weight loss in patients with advanced PDAC. IV. Safety and tolerability of telotristat ethyl with gemcitabine/nab-paclitaxel combination chemotherapy. V. Evaluate response rate (RR) assessed per Response Evaluation Criteria in Solid Tumors (RECIST), progression free survival and overall survival in patients receiving telotristat ethyl (Group 1). OUTLINE: Patients are randomized to 1 of 2 groups. GROUP 1: Patients receive gemcitabine/nab-paclitaxel combination chemotherapy on days 1, 8 and 15, and telotristat ethyl orally (PO) once daily (QD), twice daily (BID), or thrice daily (TID) on days 1 and 8. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. GROUP 2: Patients receive chemotherapy (at the discretion of the investigator) on days 1, 8 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days, then every 8 weeks thereafter.

Official Title
-----------------
Weight Loss in Patients With Advanced Stage Pancreatic Cancer: Role of Serotonin and Effects of Telotristat Ethyl

Conditions
-----------------
Recurrent Pancreatic Adenocarcinoma, Stage III Pancreatic Cancer AJCC v8, Stage IV Pancreatic Cancer AJCC v8, Locally Advanced Unresectable Pancreatic Adenocarcinoma, Metastatic Pancreatic Adenocarcinoma

Intervention / Treatment
-----------------
* Drug: Gemcitabine
* Drug: Nab-paclitaxel
* Drug: Telotristat Ethyl


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: GROUP 1 (Telotristat ethyl treatment group): Written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or obtained separately. GROUP 1 (Telotristat ethyl treatment group): Weight loss of 10% or more. GROUP 1 (Telotristat ethyl treatment group): Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 within 14 days prior to registration. GROUP 1 (Telotristat ethyl treatment group): Histologic or cytological diagnosis of recurrent or metastatic pancreas adenocarcinoma (PDAC) who present for first line chemotherapy treatment for metastatic disease. GROUP 1 (Telotristat ethyl treatment group): Advanced stage pancreas cancer (recurrent/metastatic). GROUP 1 (Telotristat ethyl treatment group): Measurable disease determined using guidelines of Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Baseline tumor assessment should be performed using high resolution computed tomography (CT) scans or magnetic resonance imaging (MRI). GROUP 1 (Telotristat ethyl treatment group): Prior systemic therapy (adjuvant or neoadjuvant setting are acceptable) if disease progressed or recurred within at least 3 months after treatment. GROUP 1 (Telotristat ethyl treatment group): Estimated life expectancy of > 12 weeks, as assessed by the site investigator. GROUP 1 (Telotristat ethyl treatment group): If sexually active, must be postmenopausal, surgically sterile, or using effective contraception (hormonal or barrier methods) due to unknown risk of teratogenicity. GROUP 1 (Telotristat ethyl treatment group): Hemoglobin ≥ 8 g/dL (obtained within 7 days prior to registration). GROUP 1 (Telotristat ethyl treatment group): Absolute Neutrophil Count (ANC) ≥ 1,500/mm³ (obtained within 7 days prior to registration). GROUP 1 (Telotristat ethyl treatment group): Platelet Count (PLT) ≥ 100,000/mm³ (obtained within 7 days prior to registration). GROUP 1 (Telotristat ethyl treatment group): Creatinine ≤ 1.5 mg/dL (obtained within 7 days prior to registration). GROUP 1 (Telotristat ethyl treatment group): Albumin ≥ 2 g/dL (obtained within 7 days prior to registration). GROUP 1 (Telotristat ethyl treatment group): Bilirubin ≤ 1.5 mg/dL (obtained within 7 days prior to registration). GROUP 1 (Telotristat ethyl treatment group): Aspartate aminotransferase (AST) ≤ 3 x upper limit of normal (ULN) or < 5 x ULN in the setting of liver metastases (obtained within 7 days prior to registration). GROUP 1 (Telotristat ethyl treatment group): Alanine aminotransferase (ALT) ≤ 3 x ULN or < 5 x ULN in the setting of liver metastases (obtained within 7 days prior to registration). GROUP 1 (Telotristat ethyl treatment group): Prior radiation is allowed if happened more than 2 weeks of enrollment. GROUP 2 (Non-Telotristat ethyl group): Written informed consent and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or obtained separately. GROUP 2 (Non-Telotristat ethyl group): Stable weight or loss of < 10% by history. GROUP 2 (Non-Telotristat ethyl group): ECOG Performance Status of 0-2 within 14 days prior to registration. GROUP 2 (Non-Telotristat ethyl group): Histologic or cytological diagnosis of locally advanced unresectable, recurrent/metastatic PDAC who present for first line chemotherapy treatment for metastatic disease. GROUP 2 (Non-Telotristat ethyl group): Advanced stage PDAC (locally advanced unresectable/recurrent/metastatic). GROUP 2 (Non-Telotristat ethyl group): Prior systemic therapy (adjuvant or neoadjuvant setting are acceptable) if disease progressed or recurred within at least 3 months after treatment. GROUP 2 (Non-Telotristat ethyl group): Estimated life expectancy of > 12 weeks, as assessed by the site investigator. GROUP 2 (Non-Telotristat ethyl group): Prior radiation is allowed if happened more than 2 weeks of enrollment. Exclusion Criteria: GROUP 1 (Telotristat ethyl treatment group): Subjects with histology other than adenocarcinoma. Examples include: neuroendocrine tumors, acinar cell cancer, sarcoma or lymphoma of the pancreas. GROUP 1 (Telotristat ethyl treatment group): Ongoing or active infection. GROUP 1 (Telotristat ethyl treatment group): Symptomatic congestive heart failure, unstable angina pectoris, symptomatic or poorly controlled cardiac arrhythmia. Symptomatic heart failure (New York Heart Association [NYHA] Class II-IV). GROUP 1 (Telotristat ethyl treatment group): Acute or sub-acute intestinal obstruction. GROUP 1 (Telotristat ethyl treatment group): Ascites. GROUP 1 (Telotristat ethyl treatment group): Documented and/or symptomatic or known brain or leptomeningeal metastases. GROUP 1 (Telotristat ethyl treatment group): Severely immune-compromised (other than being on steroids) including known human immunodeficiency virus (HIV) infection. GROUP 1 (Telotristat ethyl treatment group): Concurrent active malignancy, other than adequately treated non-melanoma skin cancer, other noninvasive carcinoma, or in situ neoplasm. A subject with previous history of malignancy is eligible if he/she has been disease-free for > 3 years. GROUP 1 (Telotristat ethyl treatment group): Breast-feeding or pregnant. Serum pregnancy test for women of child-bearing potential must be performed within 7 days prior to first dose of study treatment. GROUP 1 (Telotristat ethyl treatment group): Prior autologous or allogeneic organ or tissue transplantation. GROUP 1 (Telotristat ethyl treatment group): Known allergy to any of the treatment components. GROUP 1 (Telotristat ethyl treatment group): Have any condition that does not permit compliance with the study schedule including psychological, geographical, or medical. GROUP 1 (Telotristat ethyl treatment group): Not able to swallow. Inability to take oral medications. GROUP 1 (Telotristat ethyl treatment group): Patients with chronic constipation. GROUP 2 (Non-Telotristat ethyl group): Subjects with histology other than adenocarcinoma. Examples include: neuroendocrine tumors, acinar cell cancer, sarcoma or lymphoma of the pancreas. GROUP 2 (Non-Telotristat ethyl group): Ongoing or active infection. GROUP 2 (Non-Telotristat ethyl group): Symptomatic congestive heart failure, unstable angina or arrhythmia. Symptomatic heart failure (NYHA Class II-IV). GROUP 2 (Non-Telotristat ethyl group): Acute or sub-acute intestinal obstruction. GROUP 2 (Non-Telotristat ethyl group): Severely immune-compromised (other than being on steroids) including known HIV infection.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1 (gemcitabine/nab-paclitaxel and telotristat ethyl)<br>Patients receive gemcitabine/nab-paclitaxel combination chemotherapy on days 1, 8 and 15, and telotristat ethyl PO QD, BID, or TID on days 1 and 8. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: Gemcitabine<br>* Given gemcitabine/nab-paclitaxel combination therapy<br>* Other names: Difluorodeoxycytidine;Drug: Nab-paclitaxel<br>* Given gemcitabine/nab-paclitaxel combination therapy<br>* Other names: Nanoparticle Albumin-bound Paclitaxel;Drug: Telotristat Ethyl<br>* Given PO<br>* Other names: Xermelo;|
| Active Comparator: Group 2 (gemcitabine/nab-paclitaxel)<br>Patients receive gemcitabine/nab-paclitaxel chemotherapy (at the discretion of the investigator) on days 1, 8 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: Gemcitabine<br>* Given gemcitabine/nab-paclitaxel combination therapy<br>* Other names: Difluorodeoxycytidine;Drug: Nab-paclitaxel<br>* Given gemcitabine/nab-paclitaxel combination therapy<br>* Other names: Nanoparticle Albumin-bound Paclitaxel;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Weight stability | Weight stability will be documented as percent weight change at 3 months compared to baseline. | Baseline up to 3 months after study start | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in serum 5-hydroxyindoleacetic acid (5-HIAA) levels | The change will be summarized as mean and standard deviation. | Baseline up to 4 months after study start | 
| Change in 24-hr urine 5-hydroxyindoleacetic acid (5-HIAA) levels | The change will be summarized as mean and standard deviation. | Baseline up to 4 months after study start | 
| Mid arm circumference (MAC) measured in inches | Mid arm circumference (MAC) will be reviewed on cross sectional imaging and will be assessed with imaging guided measurements of the psoas and rectus abdominis muscle. | Up to 2 years after study start | 
| Quality of life (QOL) | Quality of life (QOL) will be assessed by the Obesity Related Quality of Life (OWL-QOL)-17 questionnaire. | Up to 2 years after study start | 
| Blood serotonin levels | Blood serotonin levels will be compared in the 2 groups. | Up to 2 years after study start | 
| Response rate (RR) | Response rate (RR) will be assessed per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1, in patients receiving telotristat ethyl (Group 1). | Up to 2 years after study start | 
| Median overall survival (MOS) | Median overall survival (MOS) will be measured using the Kaplan-Meier method. | Up to 2 years after study start | 
| Duration of response | Duration of response will be estimated from time of documentation of response to time of progression and will be evaluated by computed tomography/magnetic resonance imaging scans of the organ(s) with the target lesion(s) based on RECIST criteria. | Up to 2 years after study start |