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

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01373164
• Collaborator: (none)
• Enrollment: 170
• Locations: 24
• Arms: 5
• Duration (Months): 66
• Patients Per Site: 7.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Neoplasms; Neoplasm Metastasis; Pancreatic Cancer	Drug: Galunisertib; Drug: Gemcitabine; Drug: Placebo	Phase 1/Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 170 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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)
• Study Start Date: Jun 1, 2011
• Actual Primary Completion Date: Nov 1, 2015
• Actual Study Completion Date: Dec 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase 1b: 80 mg Galunisertib + Gemcitabine 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; Administered orally; Other Names: LY2157299 ; Drug: Gemcitabine; Administered intravenously; Other Names: Gemzar LY188011
Experimental: Phase 1b: 160 mg Galunisertib + Gemcitabine 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; Administered orally; Other Names: LY2157299 ; Drug: Gemcitabine; Administered intravenously; Other Names: Gemzar LY188011
Experimental: Phase 1b: 300 mg Galunisertib + Gemcitabine 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; Administered orally; Other Names: LY2157299 ; Drug: Gemcitabine; Administered intravenously; Other Names: Gemzar LY188011
Experimental: Phase 2: Recommended dose of Galunisertib + Gemcitabine 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; Administered orally; Other Names: LY2157299 ; Drug: Gemcitabine; Administered intravenously; Other Names: Gemzar LY188011
Experimental: Phase 2: Placebo + Gemcitabine 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; Administered intravenously; Other Names: Gemzar LY188011 ; Drug: Placebo; Administered orally

Outcome Measures

Primary Outcome Measures

1. Phase 1b: Recommended Phase 2 Dose [Time of first phase 1b dose until time of last phase 1b dose (up to 1 year)]

   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.

2. Phase 2: Overall Survival (OS) [Baseline to date of death from any cause (up to 2 years)]

   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.

Secondary Outcome Measures

1. 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) [Cycle 1 Days 14 (predose; 0.5, 2, 3, and 6 hours post dose), 24h (Days 15) and 48h (Days 16)]

   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.

2. Phase 1b: Pharmacokinetics: Maximum Plasma Drug Concentration at Steady State (Cmax,ss) [Cycle 1 Days 14 (predose; 0.5, 2, 3, and 6 hours post dose), 24h (Days 15) and 48h (Days 16)]

   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.

3. Phase 1b: Number of Participants With Tumor Response [Baseline to end of Phase 1b (up to 1 year)]

   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.

4. Phase 2: Progression Free Survival (PFS) [Baseline to first date of progressive disease or death due to any cause (up to 2 years)]

   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.

5. Phase 2: Percentage Change From Baseline in Tumor Size (CTS) [Baseline, end of Cycle 2 (up to 56 days)]

   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.

6. Phase 2: Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR) (Overall Response Rate[ORR]) [Baseline to measured progressive disease (up to 2 years)]

   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.

7. Phase 2: Population Pharmacokinetics (PK): Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC[0-24]) [Cycle 1 Days 14 (predose; 0.5, 2, 3, and 6 hours post dose), 24h (Days 15) and 48h (Days 16)]

   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.

8. Phase 2: Population PK: Maximum Concentration (Cmax) of Galunisertib [Cycle 1 Days 14 (predose; 0.5, 2, 3, and 6 hours post dose), 24h (Days 15) and 48h (Days 16)]

   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.

9. Phase 2: Change From Baseline in Brief Pain Inventory-short Form (BPI-sf) at Study Completion [Baseline, study treatment completion (up to 1 year)]

   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.

10. Phase 2: Change From Baseline in Carbohydrate Antigen 19.9 (CA19-9) Level at First Study Completion Follow-up [Baseline, study treatment completion after first follow up visit (up to 1 year)]

    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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Florida Hospital Tampa HPG and Foregut Surgery	Tampa	Florida	United States	33613
2	Ingalls Memorial Hospital	Harvey	Illinois	United States	60426
3	Seattle Cancer Care Alliance	Seattle	Washington	United States	98109
4	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Brussel		Belgium	1000
5	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Liège		Belgium	4000
6	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Besancon		France	25030
7	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Clermont-Ferrand		France	63003
8	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Marseille		France	13273
9	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Montbéliard		France	25250
10	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Paris		France	75674
11	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Frankfurt		Germany	60596
12	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Friedrichshafen		Germany	88045
13	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Leipzig		Germany	04103
14	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Marburg		Germany	35043
15	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Munich		Germany	81925
16	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Mönchengladbach		Germany	41063
17	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Reutlingen		Germany	72764
18	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Bergamo		Italy	24128
19	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Bologna		Italy	40138
20	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Verona		Italy	37134
21	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Barcelona		Spain	08035
22	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Madrid		Spain	28033
23	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Pozuelo De Alarcon		Spain	28223
24	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Sevilla		Spain	41013

Sponsors and Collaborators

• Eli Lilly and Company

Investigators

• Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST), Eli Lilly and Company

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT01373164
• Other Study ID Numbers: 13663; H9H-MC-JBAJ
• First Posted: Jun 14, 2011
• Last Update Posted: May 16, 2018
• Last Verified: Jan 1, 2017

• Keywords provided by Eli Lilly and Company: Neoplasms; Neoplasm Metastasis; Pancreatic Cancer
• Additional relevant MeSH terms: Neoplasms; Neoplasm Metastasis; Pancreatic Neoplasms; Gemcitabine

Study Results

Participant Flow

Pre-assignment Detail	Completers included participants who died from any cause and participants who were alive and on study (either on study treatment or in long term follow-up) at study conclusion.

Arm/Group Title	Phase 1b: 80 mg (Milligrams) Galunisertib + Gemcitabine	Phase 1b: 160 mg Galunisertib + Gemcitabine	Phase 1b: 300 mg Galunisertib + Gemcitabine	Phase 2: 300 mg Galunisertib + Gemcitabine	Phase 2: Placebo + Gemcitabine
Arm/Group Description	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 (milligrams per square meter) 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.	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.	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.	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.	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.
Period Title: Overall Study
STARTED	5	4	5	104	52
Received at Least One Dose	5	4	5	103	52
COMPLETED	5	3	4	92	50
NOT COMPLETED	0	1	1	12	2

Baseline Characteristics

Arm/Group Title	Phase 1b: 80 mg Galunisertib + Gemcitabine	Phase 1b: 160 mg Galunisertib + Gemcitabine	Phase 1b: 300 mg Galunisertib + Gemcitabine	Phase 2: 300 mg Galunisertib + Gemcitabine	Phase 2: Placebo + Gemcitabine	Total
Arm/Group Description	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.	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.	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.	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.	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. participants may continue until disease progression, unacceptable toxicity, or another withdrawal criterion is met.	Total of all reporting groups
Overall Participants	5	4	5	103	52	169
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	63.2 (12.9)	63.8 (9.0)	56.6 (9.2)	67.3 (8.2)	66.3 (8.9)	63.5 (9.7)
Sex: Female, Male (Count of Participants)
Female	0 0%	3 75%	3 60%	46 44.7%	24 46.2%	76 45%
Male	5 100%	1 25%	2 40%	57 55.3%	28 53.8%	93 55%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	1 20%	0 0%	0 0%	1 0.6%
Not Hispanic or Latino	5 100%	4 100%	4 80%	37 35.9%	18 34.6%	68 40.2%
Unknown or Not Reported	0 0%	0 0%	0 0%	66 64.1%	34 65.4%	100 59.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	2 40%	0 0%	0 0%	0 0%	0 0%	2 1.2%
White	3 60%	4 100%	5 100%	95 92.2%	50 96.2%	157 92.9%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	8 7.8%	2 3.8%	10 5.9%
Region of Enrollment (Count of Participants)
Belgium	0 0%	0 0%	0 0%	4 3.9%	2 3.8%	6 3.6%
United States	5 100%	2 50%	1 20%	7 6.8%	4 7.7%	19 11.2%
Italy	0 0%	0 0%	0 0%	23 22.3%	10 19.2%	33 19.5%
France	0 0%	0 0%	0 0%	21 20.4%	9 17.3%	30 17.8%
Germany	0 0%	0 0%	0 0%	22 21.4%	14 26.9%	36 21.3%
Spain	0 0%	2 50%	4 80%	26 25.2%	13 25%	45 26.6%

Outcome Measures

1. Primary Outcome

Title	Phase 1b: Recommended Phase 2 Dose
Description	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 Frame	Time of first phase 1b dose until time of last phase 1b dose (up to 1 year)

Outcome Measure Data

Analysis Population Description

Phase 1b: All participants who received at least one dose of study drug.

Arm/Group Title	Phase 1b Participants
Arm/Group Description	Participants received galunisertib at a starting dose of 80 mg/day in combination with gemcitabine. Dose escalation proceeded in cohorts of between 3 to 6 evaluable participants until ≥2 participants experienced a dose limiting toxicity (DLT) or an galunisertib dose level of 300 mg/day was reached.
Measure Participants	14
Number [milligrams (mg)]	300

2. Primary Outcome

Title	Phase 2: Overall Survival (OS)
Description	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.
Time Frame	Baseline to date of death from any cause (up to 2 years)

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study drug and had baseline & at least one post baseline observation. Number of participants censored were Galunisertib + Gemcitabine = 20 and Placebo + Gemcitabine = 4.

Arm/Group Title	Phase 2: 300 mg Galunisertib + Gemcitabine	Phase 2: Placebo + Gemcitabine
Arm/Group Description	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.	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. Participant's may continue until disease progression, unacceptable toxicity, or another withdrawal criterion is met.
Measure Participants	104	52
Median (95% Confidence Interval) [Months]	8.9	7.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 1b Participants, Phase 2: Placebo + Gemcitabine
	Comments
	Type of Statistical Test	Superiority
	Comments	The planned primary analysis for this study utilized a Bayesian exponential-likelihood model, incorporating historical overall survival (OS) data from 2 studies (Oettle et al. 2005; Saif et al. 2009). The primary analysis was performed using strong borrowing from the historical data. The model was estimated to borrow approximately 37 events from the historical studies.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.794
	Confidence Interval	(2-Sided) 95%; 0.590 to 1.085
	Parameter Dispersion	Type: Value:
	Estimation Comments	This is a Credible Interval estimated from the Bayesian analysis.

3. Secondary Outcome

Title	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)
Description	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.
Time Frame	Cycle 1 Days 14 (predose; 0.5, 2, 3, and 6 hours post dose), 24h (Days 15) and 48h (Days 16)

Outcome Measure Data

Analysis Population Description

Phase 1b: All participants who received at least one dose of study drug and had evaluable PK (pharmacokinetics) data.

Arm/Group Title	Phase 1b: 80 mg Galunisertib + Gemcitabine	Phase 1b: 160 mg Galunisertib + Gemcitabine	Phase 1b: 300 mg Galunisertib + Gemcitabine
Arm/Group Description	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.	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.	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.
Measure Participants	3	2	3
AUC(0-24)	2530 (116)	NA (NA)	9090 (27)
AUC(0-∞)	2740 (117)	NA (NA)	10600 (10)

4. Secondary Outcome

Title	Phase 1b: Pharmacokinetics: Maximum Plasma Drug Concentration at Steady State (Cmax,ss)
Description	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.
Time Frame	Cycle 1 Days 14 (predose; 0.5, 2, 3, and 6 hours post dose), 24h (Days 15) and 48h (Days 16)

Outcome Measure Data

Analysis Population Description

Phase 1b: All participants who received at least one dose of study drug and had evaluable PK data.

Arm/Group Title	Phase 1b: 80 mg Galunisertib + Gemcitabine	Phase 1b: 160 mg Galunisertib + Gemcitabine	Phase 1b: 300 mg Galunisertib + Gemcitabine
Arm/Group Description	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.	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.	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.
Measure Participants	3	2	3
Geometric Mean (Geometric Coefficient of Variation) [nanogram per milliliter (ng/mL)]	385 (101)	NA (NA)	1050 (39)

5. Secondary Outcome

Title	Phase 1b: Number of Participants With Tumor Response
Description	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.
Time Frame	Baseline to end of Phase 1b (up to 1 year)

Outcome Measure Data

Analysis Population Description

Phase 1b: All participants who received at least one dose of study drug.

Arm/Group Title	Phase 1b: 80 mg Galunisertib + Gemcitabine	Phase 1b: 160 mg Galunisertib + Gemcitabine	Phase 1b: 300 mg Galunisertib + Gemcitabine
Arm/Group Description	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.	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.	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.
Measure Participants	5	4	5
Progressive Disease (PD)	3 60%	1 25%	2 40%
Stable Disease (SD)	1 20%	2 50%	2 40%
Partial Response (PR)	0 0%	1 25%	0 0%
Non-Complete Response/Non-Progressive Disease (NC)	0 0%	0 0%	1 20%
Not Assessed (NA)	1 20%	0 0%	0 0%

6. Secondary Outcome

Title	Phase 2: Progression Free Survival (PFS)
Description	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.
Time Frame	Baseline to first date of progressive disease or death due to any cause (up to 2 years)

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study drug and had baseline & at least one post baseline observation. Number of participants censored were Galunisertib + Gemcitabine = 21 and Placebo + Gemcitabine = 11.

Arm/Group Title	Phase 2: 300 mg Galunisertib + Gemcitabine	Phase 2: Placebo + Gemcitabine
Arm/Group Description	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.	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.
Measure Participants	104	52
Median (95% Confidence Interval) [Months]	4.11	2.86

7. Secondary Outcome

Title	Phase 2: Percentage Change From Baseline in Tumor Size (CTS)
Description	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.
Time Frame	Baseline, end of Cycle 2 (up to 56 days)

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study drug and had baseline and a post-baseline measurement for change in tumor size.

Arm/Group Title	Phase 2: 300 mg Galunisertib + Gemcitabine	Phase 2: Placebo + Gemcitabine
Arm/Group Description	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.	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.
Measure Participants	104	52
Independent Assessor 1	0.95	0.92
Independent Assessor 2	1.03	0.98

8. Secondary Outcome

Title	Phase 2: Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR) (Overall Response Rate[ORR])
Description	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.
Time Frame	Baseline to measured progressive disease (up to 2 years)

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study drug and had baseline and a post-baseline measurement for ORR.

Arm/Group Title	Phase 2: 300 mg Galunisertib + Gemcitabine	Phase 2: Placebo + Gemcitabine
Arm/Group Description	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.	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.
Measure Participants	104	52
Number (95% Confidence Interval) [Percentage of Participants]	10.6 212%	3.8 95%

9. Secondary Outcome

Title	Phase 2: Population Pharmacokinetics (PK): Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC[0-24])
Description	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.
Time Frame	Cycle 1 Days 14 (predose; 0.5, 2, 3, and 6 hours post dose), 24h (Days 15) and 48h (Days 16)

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study drug with evaluable PK data.

Arm/Group Title	Phase 2: 300 mg Galunisertib + Gemcitabine
Arm/Group Description	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.
Measure Participants	99
Mean (Inter-Quartile Range) [mg*h/L]	5.56

10. Secondary Outcome

Title	Phase 2: Population PK: Maximum Concentration (Cmax) of Galunisertib
Description	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.
Time Frame	Cycle 1 Days 14 (predose; 0.5, 2, 3, and 6 hours post dose), 24h (Days 15) and 48h (Days 16)

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study drug with evaluable PK data.

Arm/Group Title	Phase 2: 300 mg Galunisertib + Gemcitabine
Arm/Group Description	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.
Measure Participants	99
Mean (Inter-Quartile Range) [ng/mL]	904

11. Secondary Outcome

Title	Phase 2: Change From Baseline in Brief Pain Inventory-short Form (BPI-sf) at Study Completion
Description	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.
Time Frame	Baseline, study treatment completion (up to 1 year)

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study drug and had baseline and a post-baseline measurement for BPI-sf.

Arm/Group Title	Phase 2: 300 mg Galunisertib + Gemcitabine	Placebo+Gemcitabine
Arm/Group Description	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.	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.
Measure Participants	7	2
Mean (Standard Deviation) [Units on a scale]	2.54 (2.53)	1.50 (2.12)

12. Secondary Outcome

Title	Phase 2: Change From Baseline in Carbohydrate Antigen 19.9 (CA19-9) Level at First Study Completion Follow-up
Description	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
Time Frame	Baseline, study treatment completion after first follow up visit (up to 1 year)

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study drug and had baseline and a post-baseline measurement for CA19-9 level.

Arm/Group Title	Phase 2: 300 mg Galunisertib + Gemcitabine	Phase 2: Placebo + Gemcitabine
Arm/Group Description	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.	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.
Measure Participants	38	21
Median (Full Range) [Units/Milliliter (U/mL)]	32.7	-33.3

Adverse Events

Time Frame	Up to 30 days
Adverse Event Reporting Description	All participants who received at least one dose of study drug.
Arm/Group Title	Phase 1b: 80 mg Galunisertib + Gemcitabine		Phase 1b: 160 mg Galunisertib + Gemcitabine		Phase 1b: 300 mg Galunisertib + Gemcitabine		Phase 2: 300 mg Galunisertib + Gemcitabine		Phase 2: Placebo + Gemcitabine
Arm/Group Description	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.		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.		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.		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.		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.
All Cause Mortality
	Phase 1b: 80 mg Galunisertib + Gemcitabine		Phase 1b: 160 mg Galunisertib + Gemcitabine		Phase 1b: 300 mg Galunisertib + Gemcitabine		Phase 2: 300 mg Galunisertib + Gemcitabine		Phase 2: Placebo + Gemcitabine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Phase 1b: 80 mg Galunisertib + Gemcitabine		Phase 1b: 160 mg Galunisertib + Gemcitabine		Phase 1b: 300 mg Galunisertib + Gemcitabine		Phase 2: 300 mg Galunisertib + Gemcitabine		Phase 2: Placebo + Gemcitabine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/5 (20%)		1/4 (25%)		2/5 (40%)		56/103 (54.4%)		26/52 (50%)
Cardiac disorders
Angina pectoris	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Cardiac failure	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Cardiogenic shock	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Myocardial ischaemia	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Pericardial effusion	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Gastrointestinal disorders
Abdominal pain	0/5 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	5/103 (4.9%)	5	1/52 (1.9%)	2
Abdominal pain upper	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/103 (0%)	0	1/52 (1.9%)	1
Ascites	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	1/52 (1.9%)	1
Colitis ischaemic	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Constipation	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	1/52 (1.9%)	1
Diarrhoea	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Duodenal obstruction	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Duodenal stenosis	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/103 (0%)	0	1/52 (1.9%)	1
Femoral hernia incarcerated	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Gastric ulcer	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/103 (0%)	0	1/52 (1.9%)	1
Gastrointestinal haemorrhage	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	2	0/52 (0%)	0
Haematemesis	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/103 (0%)	0	1/52 (1.9%)	1
Ileus paralytic	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Intestinal obstruction	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	3/52 (5.8%)	3
Large intestinal obstruction	1/5 (20%)	1	0/4 (0%)	0	0/5 (0%)	0	0/103 (0%)	0	0/52 (0%)	0
Lower gastrointestinal haemorrhage	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Melaena	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Nausea	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	2/103 (1.9%)	2	2/52 (3.8%)	2
Obstruction gastric	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/103 (0%)	0	1/52 (1.9%)	1
Oesophagitis	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/103 (0%)	0	1/52 (1.9%)	1
Pancreatitis acute	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Small intestinal obstruction	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	2/103 (1.9%)	2	0/52 (0%)	0
Upper gastrointestinal haemorrhage	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Vomiting	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	4/103 (3.9%)	4	2/52 (3.8%)	2
General disorders
Asthenia	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Fatigue	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/103 (0%)	0	1/52 (1.9%)	1
General physical health deterioration	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	2/103 (1.9%)	2	1/52 (1.9%)	1
Multi-organ failure	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/103 (0%)	0	1/52 (1.9%)	1
Oedema peripheral	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Pain	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Pyrexia	0/5 (0%)	0	0/4 (0%)	0	1/5 (20%)	2	4/103 (3.9%)	4	3/52 (5.8%)	4
Hepatobiliary disorders
Bile duct obstruction	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/103 (0%)	0	1/52 (1.9%)	1
Bile duct stenosis	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	2/103 (1.9%)	3	1/52 (1.9%)	1
Cholangitis	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	4/103 (3.9%)	7	2/52 (3.8%)	2
Cholangitis acute	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Cholecystitis	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Cholecystitis acute	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Cholestasis	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	1/52 (1.9%)	1
Hepatic cirrhosis	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Hepatic failure	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Hepatocellular injury	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/103 (0%)	0	1/52 (1.9%)	1
Jaundice cholestatic	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	3/103 (2.9%)	3	0/52 (0%)	0
Infections and infestations
Biliary tract infection	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Bronchitis	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Catheter site infection	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/103 (0%)	0	1/52 (1.9%)	1
Cholecystitis infective	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Device related infection	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Endocarditis	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Infection	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/103 (0%)	0	1/52 (1.9%)	1
Liver abscess	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Lung infection	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	2/103 (1.9%)	2	1/52 (1.9%)	1
Peritonitis	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/103 (0%)	0	1/52 (1.9%)	1
Peritonitis bacterial	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Pneumonia	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	2	0/52 (0%)	0
Pyelonephritis	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Sepsis	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	2/103 (1.9%)	2	2/52 (3.8%)	2
Staphylococcal infection	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Urinary tract infection	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	1/52 (1.9%)	1
Urosepsis	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/103 (0%)	0	1/52 (1.9%)	1
Injury, poisoning and procedural complications
Fall	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Femur fracture	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/103 (0%)	0	1/52 (1.9%)	1
Gastrointestinal stoma complication	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Humerus fracture	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/103 (0%)	0	1/52 (1.9%)	1
Lower limb fracture	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Toxicity to various agents	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Investigations
Blood bilirubin increased	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Blood creatinine increased	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Metabolism and nutrition disorders
Diabetes mellitus	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Hyperglycaemia	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/103 (0%)	0	1/52 (1.9%)	1
Hyponatraemia	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Musculoskeletal and connective tissue disorders
Osteoarthritis	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/103 (0%)	0	1/52 (1.9%)	1
Rhabdomyolysis	0/5 (0%)	0	0/4 (0%)	0	1/5 (20%)	1	0/103 (0%)	0	0/52 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant ascites	1/5 (20%)	1	0/4 (0%)	0	0/5 (0%)	0	0/103 (0%)	0	0/52 (0%)	0
Tumour pain	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Nervous system disorders
Cerebral ischaemia	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Cerebrovascular accident	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	2	0/52 (0%)	0
Disturbance in attention	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/103 (0%)	0	1/52 (1.9%)	1
Hepatic encephalopathy	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Ischaemic stroke	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Presyncope	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/103 (0%)	0	1/52 (1.9%)	1
Syncope	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	1/52 (1.9%)	1
Product Issues
Device occlusion	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	3/103 (2.9%)	3	0/52 (0%)	0
Psychiatric disorders
Agitation	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/103 (0%)	0	1/52 (1.9%)	1
Confusional state	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Delirium	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/103 (0%)	0	1/52 (1.9%)	1
Renal and urinary disorders
Acute kidney injury	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/103 (0%)	0	1/52 (1.9%)	1
Renal failure	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Ureteric stenosis	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	2	0/52 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	2/103 (1.9%)	2	0/52 (0%)	0
Haemothorax	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Pleural effusion	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/103 (0%)	0	1/52 (1.9%)	1
Pneumonitis	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Pneumothorax	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	2	0/52 (0%)	0
Pulmonary embolism	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	5/103 (4.9%)	5	1/52 (1.9%)	1
Pulmonary hypertension	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/103 (0%)	0	1/52 (1.9%)	1
Respiratory distress	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Respiratory failure	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Surgical and medical procedures
Pancreatic pseudocyst drainage	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/103 (0%)	0	1/52 (1.9%)	1
Vascular disorders
Orthostatic hypotension	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/103 (0%)	0	1/52 (1.9%)	1
Shock haemorrhagic	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Other (Not Including Serious) Adverse Events
	Phase 1b: 80 mg Galunisertib + Gemcitabine		Phase 1b: 160 mg Galunisertib + Gemcitabine		Phase 1b: 300 mg Galunisertib + Gemcitabine		Phase 2: 300 mg Galunisertib + Gemcitabine		Phase 2: Placebo + Gemcitabine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/5 (100%)		4/4 (100%)		5/5 (100%)		100/103 (97.1%)		49/52 (94.2%)
Blood and lymphatic system disorders
Anaemia	3/5 (60%)	3	3/4 (75%)	3	3/5 (60%)	4	44/103 (42.7%)	95	28/52 (53.8%)	35
Febrile neutropenia	0/5 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	0/103 (0%)	0	0/52 (0%)	0
Leukopenia	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	4/103 (3.9%)	6	3/52 (5.8%)	8
Neutropenia	3/5 (60%)	3	2/4 (50%)	2	3/5 (60%)	3	34/103 (33%)	76	17/52 (32.7%)	42
Thrombocytopenia	4/5 (80%)	4	1/4 (25%)	5	1/5 (20%)	1	29/103 (28.2%)	83	13/52 (25%)	21
Cardiac disorders
Angina pectoris	0/5 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	0/103 (0%)	0	0/52 (0%)	0
Atrial fibrillation	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	3/52 (5.8%)	3
Gastrointestinal disorders
Abdominal pain	2/5 (40%)	2	1/4 (25%)	1	0/5 (0%)	0	26/103 (25.2%)	38	12/52 (23.1%)	16
Abdominal pain upper	0/5 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	12/103 (11.7%)	16	5/52 (9.6%)	6
Ascites	0/5 (0%)	0	1/4 (25%)	8	0/5 (0%)	0	13/103 (12.6%)	14	1/52 (1.9%)	1
Constipation	2/5 (40%)	2	2/4 (50%)	3	1/5 (20%)	1	30/103 (29.1%)	31	15/52 (28.8%)	22
Diarrhoea	2/5 (40%)	2	2/4 (50%)	2	2/5 (40%)	2	23/103 (22.3%)	56	12/52 (23.1%)	26
Dry mouth	0/5 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	3/103 (2.9%)	3	1/52 (1.9%)	1
Dyspepsia	1/5 (20%)	1	0/4 (0%)	0	0/5 (0%)	0	8/103 (7.8%)	8	3/52 (5.8%)	5
Gastrooesophageal reflux disease	0/5 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	2/103 (1.9%)	2	5/52 (9.6%)	5
Nausea	2/5 (40%)	2	4/4 (100%)	5	4/5 (80%)	9	39/103 (37.9%)	69	17/52 (32.7%)	30
Rectal haemorrhage	1/5 (20%)	2	0/4 (0%)	0	0/5 (0%)	0	0/103 (0%)	0	0/52 (0%)	0
Vomiting	3/5 (60%)	3	3/4 (75%)	4	3/5 (60%)	4	27/103 (26.2%)	57	19/52 (36.5%)	26
General disorders
Asthenia	0/5 (0%)	0	1/4 (25%)	1	3/5 (60%)	4	36/103 (35%)	72	17/52 (32.7%)	30
Chills	1/5 (20%)	4	0/4 (0%)	0	0/5 (0%)	0	10/103 (9.7%)	12	4/52 (7.7%)	6
Early satiety	0/5 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	0/103 (0%)	0	0/52 (0%)	0
Face oedema	0/5 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	0/103 (0%)	0	0/52 (0%)	0
Fatigue	2/5 (40%)	2	2/4 (50%)	4	1/5 (20%)	1	21/103 (20.4%)	28	9/52 (17.3%)	14
Localised oedema	0/5 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	0/103 (0%)	0	0/52 (0%)	0
Mucosal inflammation	0/5 (0%)	0	0/4 (0%)	0	2/5 (40%)	4	1/103 (1%)	1	4/52 (7.7%)	4
Oedema peripheral	1/5 (20%)	1	2/4 (50%)	2	1/5 (20%)	1	23/103 (22.3%)	33	12/52 (23.1%)	15
Pain	1/5 (20%)	1	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	2/52 (3.8%)	2
Peripheral swelling	0/5 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	0/103 (0%)	0	0/52 (0%)	0
Pyrexia	1/5 (20%)	3	3/4 (75%)	8	2/5 (40%)	4	38/103 (36.9%)	93	11/52 (21.2%)	17
Hepatobiliary disorders
Jaundice	0/5 (0%)	0	0/4 (0%)	0	1/5 (20%)	1	3/103 (2.9%)	3	1/52 (1.9%)	1
Infections and infestations
Folliculitis	1/5 (20%)	1	0/4 (0%)	0	0/5 (0%)	0	0/103 (0%)	0	0/52 (0%)	0
Nasopharyngitis	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	7/103 (6.8%)	9	1/52 (1.9%)	1
Pneumonia	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	4/52 (7.7%)	4
Urinary tract infection	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	6/103 (5.8%)	8	3/52 (5.8%)	4
Injury, poisoning and procedural complications
Ligament sprain	0/5 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	0/103 (0%)	0	0/52 (0%)	0
Investigations
Alanine aminotransferase increased	2/5 (40%)	2	1/4 (25%)	1	1/5 (20%)	1	10/103 (9.7%)	14	3/52 (5.8%)	6
Aspartate aminotransferase increased	2/5 (40%)	2	1/4 (25%)	1	1/5 (20%)	1	8/103 (7.8%)	14	2/52 (3.8%)	4
Blood alkaline phosphatase increased	2/5 (40%)	2	0/4 (0%)	0	0/5 (0%)	0	3/103 (2.9%)	3	1/52 (1.9%)	1
Blood bilirubin increased	0/5 (0%)	0	0/4 (0%)	0	1/5 (20%)	1	8/103 (7.8%)	8	0/52 (0%)	0
Blood calcium decreased	1/5 (20%)	1	0/4 (0%)	0	0/5 (0%)	0	0/103 (0%)	0	0/52 (0%)	0
Blood sodium decreased	1/5 (20%)	1	0/4 (0%)	0	0/5 (0%)	0	0/103 (0%)	0	0/52 (0%)	0
Brain natriuretic peptide increased	0/5 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	0/103 (0%)	0	0/52 (0%)	0
C-reactive protein increased	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	2/103 (1.9%)	2	3/52 (5.8%)	4
Ejection fraction decreased	0/5 (0%)	0	0/4 (0%)	0	1/5 (20%)	1	0/103 (0%)	0	0/52 (0%)	0
Neutrophil count decreased	0/5 (0%)	0	0/4 (0%)	0	1/5 (20%)	2	11/103 (10.7%)	31	5/52 (9.6%)	10
Platelet count decreased	0/5 (0%)	0	0/4 (0%)	0	1/5 (20%)	1	17/103 (16.5%)	38	8/52 (15.4%)	14
White blood cell count decreased	0/5 (0%)	0	0/4 (0%)	0	1/5 (20%)	2	9/103 (8.7%)	16	3/52 (5.8%)	3
Metabolism and nutrition disorders
Decreased appetite	1/5 (20%)	1	2/4 (50%)	2	2/5 (40%)	2	30/103 (29.1%)	42	13/52 (25%)	18
Dehydration	1/5 (20%)	1	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	2	3/52 (5.8%)	3
Hyperglycaemia	2/5 (40%)	2	0/4 (0%)	0	0/5 (0%)	0	8/103 (7.8%)	14	4/52 (7.7%)	5
Hypoalbuminaemia	3/5 (60%)	3	1/4 (25%)	1	1/5 (20%)	1	4/103 (3.9%)	4	1/52 (1.9%)	1
Hypocalcaemia	1/5 (20%)	1	0/4 (0%)	0	1/5 (20%)	1	6/103 (5.8%)	7	2/52 (3.8%)	2
Hypokalaemia	0/5 (0%)	0	0/4 (0%)	0	1/5 (20%)	1	13/103 (12.6%)	17	2/52 (3.8%)	2
Hypomagnesaemia	1/5 (20%)	2	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	2/52 (3.8%)	2
Hyponatraemia	0/5 (0%)	0	1/4 (25%)	1	1/5 (20%)	1	3/103 (2.9%)	3	2/52 (3.8%)	2
Musculoskeletal and connective tissue disorders
Arthralgia	0/5 (0%)	0	1/4 (25%)	5	0/5 (0%)	0	5/103 (4.9%)	6	0/52 (0%)	0
Arthritis	0/5 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	1/103 (1%)	1	0/52 (0%)	0
Back pain	0/5 (0%)	0	0/4 (0%)	0	1/5 (20%)	1	8/103 (7.8%)	9	4/52 (7.7%)	4
Bone pain	0/5 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	0/103 (0%)	0	1/52 (1.9%)	1
Muscle spasms	1/5 (20%)	1	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	2/52 (3.8%)	2
Musculoskeletal chest pain	0/5 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	0/103 (0%)	0	0/52 (0%)	0
Myalgia	0/5 (0%)	0	1/4 (25%)	1	2/5 (40%)	2	6/103 (5.8%)	7	0/52 (0%)	0
Pain in extremity	0/5 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	4/103 (3.9%)	6	1/52 (1.9%)	2
Nervous system disorders
Dizziness	0/5 (0%)	0	1/4 (25%)	1	1/5 (20%)	1	6/103 (5.8%)	7	4/52 (7.7%)	7
Dysgeusia	0/5 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	2/103 (1.9%)	2	0/52 (0%)	0
Headache	3/5 (60%)	3	1/4 (25%)	1	1/5 (20%)	1	6/103 (5.8%)	6	6/52 (11.5%)	8
Neurotoxicity	0/5 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	0/103 (0%)	0	0/52 (0%)	0
Paraesthesia	1/5 (20%)	1	0/4 (0%)	0	0/5 (0%)	0	4/103 (3.9%)	4	1/52 (1.9%)	1
Peripheral sensory neuropathy	0/5 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	1/103 (1%)	1	1/52 (1.9%)	1
Psychiatric disorders
Anxiety	0/5 (0%)	0	2/4 (50%)	2	0/5 (0%)	0	6/103 (5.8%)	6	4/52 (7.7%)	4
Depression	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/103 (1%)	1	4/52 (7.7%)	4
Insomnia	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	6/103 (5.8%)	6	3/52 (5.8%)	4
Renal and urinary disorders
Dysuria	0/5 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	4/103 (3.9%)	4	0/52 (0%)	0
Haematuria	2/5 (40%)	2	0/4 (0%)	0	0/5 (0%)	0	2/103 (1.9%)	2	0/52 (0%)	0
Pollakiuria	0/5 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	0/103 (0%)	0	1/52 (1.9%)	1
Urinary incontinence	0/5 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	0/103 (0%)	0	0/52 (0%)	0
Reproductive system and breast disorders
Pelvic pain	0/5 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	1/103 (1%)	1	1/52 (1.9%)	1
Respiratory, thoracic and mediastinal disorders
Cough	0/5 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	7/103 (6.8%)	10	2/52 (3.8%)	2
Dyspnoea	0/5 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	6/103 (5.8%)	7	4/52 (7.7%)	4
Epistaxis	0/5 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	2/103 (1.9%)	2	0/52 (0%)	0
Oropharyngeal pain	0/5 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	0/103 (0%)	0	0/52 (0%)	0
Skin and subcutaneous tissue disorders
Dry skin	0/5 (0%)	0	0/4 (0%)	0	1/5 (20%)	1	5/103 (4.9%)	6	2/52 (3.8%)	2
Erythema	0/5 (0%)	0	2/4 (50%)	2	0/5 (0%)	0	2/103 (1.9%)	2	2/52 (3.8%)	2
Night sweats	0/5 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	2/103 (1.9%)	2	2/52 (3.8%)	6
Pruritus	1/5 (20%)	1	0/4 (0%)	0	0/5 (0%)	0	5/103 (4.9%)	6	2/52 (3.8%)	2
Rash	0/5 (0%)	0	2/4 (50%)	2	1/5 (20%)	1	5/103 (4.9%)	7	5/52 (9.6%)	9

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.