A Study in Metastatic Cancer and Advanced or Metastatic Unresectable Pancreatic Cancer

Study Overview
=================
Brief Summary
-----------------
Phase 1b: To determine the safe and tolerable dose of galunisertib in combination with gemcitabine in patients with solid malignancy Phase 2a: To compare the overall survival (OS) of patients with Stage II to IV unresectable pancreatic cancer when treated with a combination of galunisertib and gemcitabine with that of gemcitabine plus placebo.

Official Title
-----------------
A Phase 1b/2 Study With Gemcitabine and LY2157299 for Patients With Metastatic Cancer (Phase 1b) and Advanced or Metastatic Unresectable Pancreatic Cancer (Phase 2)

Conditions
-----------------
Neoplasms, Neoplasm Metastasis, Pancreatic Cancer

Intervention / Treatment
-----------------
* Drug: Galunisertib
* Drug: Gemcitabine
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: For both Phase 1b and Phase 2 (unless specified in the following), patients are eligible to be included in the study only if they meet all of the following criteria: For Phase 1b: Have histological or cytological evidence of a diagnosis of cancer that is advanced and/or metastatic disease; that is refractory to standard therapy and/or therapies known to provide clinical benefit or for which no standard therapy exists; and/or in which gemcitabine therapy at the proposed doses and schedule would be considered appropriate treatment for the metastatic disease (eg, pancreatic cancer) Patients may have received prior chemotherapy, radiotherapy, cancer-related hormone therapy, or other investigational therapy as treatment. There is no limit in the number of previous lines of therapy. For Phase 1b and Phase 2: Have measurable disease or non-measurable disease, defined according to Response Evaluation Criteria In Solid Tumors (RECIST) Have given written informed consent prior to any study-specific procedures Have adequate organ function including: Hematologic: absolute neutrophil count (ANC) greater than or equal to 1.5 x 10^9/L, platelets greater than or equal to 100 x 10^9/L, and hemoglobin greater than or equal to 9 g/dL. Hepatic: bilirubin less than or equal to 1.5 times upper limit of normal (ULN), and alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT)less than or equal to 2.5 times ULN. If the liver has tumor involvement, AST less than or equal to 5 times ULN and ALT less than or equal to 5 times ULN are acceptable. Patients may have endoscopic or radiologic stenting to treat biliary obstructions. If so, then bilirubin must return to less than or equal to 1.5 times ULN and ALP, AST, and ALT to less than or equal to 5 times ULN prior to enrollment. Renal: serum creatinine within normal limits, less than or equal to 1.5 times ULN. Have a performance status of less than or equal to 2 on the Eastern Cooperative Oncology Group (ECOG) scale Patients must have recovered from any Grade 3/4 toxicities of previous therapies Are reliable and willing to make themselves available for the duration of the study and are willing to follow study procedures Prior radiation therapy for treatment of cancer is allowed to <25% of the bone marrow, and patients must have recovered from the acute toxic effects of their treatment prior to study enrollment. Prior radiation to the whole pelvis is not allowed. Prior radiotherapy must be completed at least 4 weeks before study entry. Male and female patients with reproductive potential must use an approved contraceptive method during and for 3 months after discontinuation of study treatment. Women of childbearing potential must have a negative beta-human chorionic gonadotropin (B-HCG) pregnancy test documented within 14 days prior to treatment. If condoms are used as a barrier contraceptive, a spermicidal agent should be added to ensure that pregnancy does not occur. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. For Phase 2: Have histological or cytological diagnosis of adenocarcinoma of the pancreas that is locally advanced (Stage II, III) or metastatic (Stage IV) and not amenable to resection with curative intent. Patients with previous radical surgery for pancreatic cancer are eligible after progression is documented. If they received adjuvant chemotherapy or chemoradiotherapy with gemcitabine, they can be enrolled if the treatment was completed 3 months before or longer Tumor tissue or unstained slides are available from original biopsy or resection or other tumor biopsies Patients may have received previous adjuvant treatment with gemcitabine with or without radiotherapy for pancreatic cancer. Adjuvant treatment must have finished at least 6 months before enrolling. Exclusion Criteria: Patients will be excluded from the study if they meet any of the following criteria: Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational product or unapproved use of a drug or device (other than the investigational product used in this study), or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study Have moderate or severe cardiac disease: Myocardial infarction within 6 months prior to study entry, unstable angina pectoris, New York Heart Association (NYHA) Class III/IV congestive heart failure, or uncontrolled hypertension Major abnormalities documented by echocardiography with Doppler (for example, moderate or severe heart valve function defect and/or left ventricular ejection fraction (LVEF) <50%, evaluation based on the institutional lower limit of normal) Predisposing conditions that are consistent with development of aneurysms of the ascending aorta or aortic stress (for example, family history of aneurysms, Marfan-Syndrome, bicuspid aortic valve, evidence of damage to the large vessels of the heart documented by CT scan or MRI with contrast) Are unable to swallow tablets or capsules Are pregnant or breastfeeding Have any significant medical illnesses that, in the investigator's opinion, cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate this therapy Have a history of any other cancer (except non-melanoma skin cancer or carcinoma in-situ), unless in complete remission and off of all therapy for that disease for a minimum of 3 years Have active infection that would interfere with the study objectives or influence study compliance Phase 2 only: Endocrine pancreatic tumors or ampullary cancer Patients with acute or chronic leukemia or with any other disease likely to have a significant bone marrow infiltration (screening not required) Have previously completed or withdrawn from this study or any other study investigating galunisertib or any other TGF-ß inhibitor Have known allergy to galunisertib or gemcitabine or any ingredient of galunisertib or gemcitabine formulations

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: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1b: 80 mg Galunisertib + Gemcitabine<br>Cohort 1: 40 mg Galunisertib was administered orally twice daily (BID) for 14 days followed by 14 days of rest (28 day cycle). Gemcitabine at a dose of 1000 mg/m^2 was administered intravenously once per week for 7 weeks followed by 1 week of rest and then once per week for 3 weeks of every 4 weeks. | Drug: Galunisertib<br>* Administered orally<br>* Other names: LY2157299;Drug: Gemcitabine<br>* Administered intravenously<br>* Other names: LY188011;|
| Experimental: Phase 1b: 160 mg Galunisertib + Gemcitabine<br>Cohort 2: 80 mg Galunisertib was administered orally twice daily for 14 days followed by 14 days of rest (28 day cycle). Gemcitabine at a dose of 1000 mg/m^2 was administered intravenously once per week for 7 weeks followed by 1 week of rest and then once per week for 3 weeks of every 4 weeks. | Drug: Galunisertib<br>* Administered orally<br>* Other names: LY2157299;Drug: Gemcitabine<br>* Administered intravenously<br>* Other names: LY188011;|
| Experimental: Phase 1b: 300 mg Galunisertib + Gemcitabine<br>Cohort 3: 150 mg Galunisertib was administered orally twice daily for 14 days followed by 14 days of rest (28 day cycle). Gemcitabine at a dose of 1000 mg/m^2 was administered intravenously once per week for 7 weeks followed by 1 week of rest and then once per week for 3 weeks of every 4 weeks. | Drug: Galunisertib<br>* Administered orally<br>* Other names: LY2157299;Drug: Gemcitabine<br>* Administered intravenously<br>* Other names: LY188011;|
| Experimental: Phase 2: Recommended dose of Galunisertib + Gemcitabine<br>Galunisertib recommended dose (300 mg) determined from phase 1, administered orally twice daily for 14 days followed by 14 days of rest (28 day cycle). Gemcitabine at a dose of 1000 mg/m^2 was administered intravenously once per week for 7 weeks followed by 1 week of rest and then once per week for 3 weeks of every 4 weeks. | Drug: Galunisertib<br>* Administered orally<br>* Other names: LY2157299;Drug: Gemcitabine<br>* Administered intravenously<br>* Other names: LY188011;|
| Experimental: Phase 2: Placebo + Gemcitabine<br>Placebo administered orally twice daily for 14 days followed 14 days of rest (28 day cycle). Gemcitabine at a dose of 1000 mg/m^2 was administered intravenously once per week for 7 weeks followed by 1 week of rest and then once per week for 3 weeks of every 4 weeks. | Drug: Gemcitabine<br>* Administered intravenously<br>* Other names: LY188011;Drug: Placebo<br>* Administered orally<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b: Recommended Phase 2 Dose | The recommended Phase 2 dose was the highest dose where less than 1/3 of participants experienced dose limiting toxicities (DLTs). The recommended dose was determined based on a review of overall toxicity, dose reductions, omissions, and pharmacokinetic information from Phase 1b. | Time of first phase 1b dose until time of last phase 1b dose (up to 1 year) | 
| Phase 2: Overall Survival (OS) | Overall survival is defined as the time from the date of randomization to the date of death from any cause. For each participant who is not known to have died as of the data-inclusion cut-off date for a particular analysis, overall survival duration was censored for that analysis at the date of last prior contact. | Baseline to date of death from any cause (up to 2 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b: Pharmacokinetics: Area Under the Concentration-Time Curve at Steady State From Time Zero to 24 Hours (AUC[0-24], ss) and Time Zero to Infinity (AUC[0-∞], ss) | AUC[0-24h] is a combined measure obtained from Day 14 at 0 hour (pre-dose), 0.5, 2,3, 6 hours post dose and morning doses from 24h and 48h to compute. AUC0-infinity will take 48h and extrapolation beyond this in addition to earlier time points to be calculated. All mentioned time points are used to calculate the two AUCs. | Cycle 1 Days 14 (predose; 0.5, 2, 3, and 6 hours post dose), 24h (Days 15) and 48h (Days 16) | 
| Phase 1b: Pharmacokinetics: Maximum Plasma Drug Concentration at Steady State (Cmax,ss) | Plasma samples for pharmacokinetic (PK) analysis were obtained on Day 14 at 0 hours (Pre-dose), 0.5, 2, 3, 6 hours post dose and morning doses from 24h and 48h. Cmax takes all time points post dose into account and one value is reported. | Cycle 1 Days 14 (predose; 0.5, 2, 3, and 6 hours post dose), 24h (Days 15) and 48h (Days 16) | 
| Phase 1b: Number of Participants With Tumor Response | Response was defined using RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1. Complete Response (CR) was defined as the disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 millimeter (mm) and normalization of tumor marker level of non-target lesions; Partial Response (PR) was defined as having at least a 30% decrease in sum of longest diameter of target lesions; Progressive Disease (PD) was defined as having at least 20% increase in sum of longest diameter of target lesions and minimum 5 mm increase above nadir; Stable Disease (SD) was defined as small changes that did not meet above criteria. | Baseline to end of Phase 1b (up to 1 year) | 
| Phase 2: Progression Free Survival (PFS) | PFS is defined as the date of randomization to the first date of progression of disease or of death from any cause. For each participant who is not known to have died or to have had a progression of disease as of the data-inclusion cut-off date for a particular analysis, PFS will be censored at the date of last prior contact. PFS will be calculated and analyzed twice: (1) including clinical progressions of disease not based on lesion measurements, and (2) excluding clinical progressions. Progression Disease (PD) was defined as having at least a 25% increase in the sum of the longest diameter of target lesions. | Baseline to first date of progressive disease or death due to any cause (up to 2 years) | 
| Phase 2: Percentage Change From Baseline in Tumor Size (CTS) | Change in tumor size is defined as the maximum percent change from baseline in the sum of target lesions. Change was assessed in each participant using radiographic imaging. | Baseline, end of Cycle 2 (up to 56 days) | 
| Phase 2: Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR) (Overall Response Rate[ORR]) | Overall response rate is the best response of complete response (CR) or partial response (PR) as classified by the independent central review according to the Response Evaluation Criteria In Solid Tumors (RECIST v1.1). CR is a disappearance of all target and non-target lesions and normalization of tumor marker level. PR is an at least 30% decrease in the sum of the diameters of target lesions (taking as reference the baseline sum diameter) without progression of non-target lesions or appearance of new lesions. Overall response rate is calculated as a total number of participants with CR or PR divided by the total number of participants with at least 1 measurable lesion, multiplied by 100. | Baseline to measured progressive disease (up to 2 years) | 
| Phase 2: Population Pharmacokinetics (PK): Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC[0-24]) | AUC[0-24] is a combined measure obtained from Day 14 at 0 hour (pre-dose), 0.5, 2,3, 6 hours post dose and morning doses from 24h and 48h to compute. | Cycle 1 Days 14 (predose; 0.5, 2, 3, and 6 hours post dose), 24h (Days 15) and 48h (Days 16) | 
| Phase 2: Population PK: Maximum Concentration (Cmax) of Galunisertib | Plasma samples for pharmacokinetic (PK) analysis were obtained on Day 14 at 0 hours (Pre-dose), 0.5, 2, 3, 6 hours post dose and morning doses from 24h and 48h. Cmax takes all time points post dose into account and one value is reported. | Cycle 1 Days 14 (predose; 0.5, 2, 3, and 6 hours post dose), 24h (Days 15) and 48h (Days 16) | 
| Phase 2: Change From Baseline in Brief Pain Inventory-short Form (BPI-sf) at Study Completion | The BPI-SF Pain Severity Subscale was a participant-rated questionnaire that measured the severity of pain. Severity scores could have ranged from 0 (no pain) to 10 (pain as bad as you can imagine) for questions that included assessing average pain in the past 24 hours. | Baseline, study treatment completion (up to 1 year) | 
| Phase 2: Change From Baseline in Carbohydrate Antigen 19.9 (CA19-9) Level at First Study Completion Follow-up | Carbohydrate antigen 19-9 (CA 19-9) is a modified Lewis(a) blood group antigen, and has been used as a tumor marker. The outcome measure is the median, minimum and maximum values from participants who had samples collected at baseline and at follow-up | Baseline, study treatment completion after first follow up visit (up to 1 year) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Neoplasms, Neoplasm Metastasis, Pancreatic Cancer