A Study of BBI608 in Combination With Sorafenib, or BBI503 in Combination With Sorafenib in Adult Patients With Hepatocellular Carcinoma

• Sponsor: Sumitomo Pharma Oncology, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02279719
• Collaborator: (none)
• Enrollment: 97
• Locations: 29
• Arms: 3
• Duration (Months): 58
• Patients Per Site: 3.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is an open label, three-arm, phase 1 dose escalation study and phase 2 study of BBI608 in combination with sorafenib, or BBI503 in combination with sorafenib. The study population is adult patients with advanced hepatocellular carcinoma who have not received systemic chemotherapy.

Condition or Disease	Intervention/Treatment	Phase
Hepatocellular Carcinoma	Drug: BBI608; Drug: BBI503; Drug: Sorafenib	Phase 1/Phase 2

Detailed Description

This is an open label, three-arm, phase 1 dose escalation study and phase 2 study of BBI608 in combination with sorafenib, or BBI503 in combination with sorafenib. The study population is adult patients with advanced hepatocellular carcinoma (HCC) who have not received systemic chemotherapy.

The phase 1 portion will involve dose-escalation of BBI608 administered in combination with a fixed starting dose of sorafenib (Arm 1), and dose escalation of BBI503 administered in combination with a fixed starting dose of sorafenib (Arm 2). The fixed starting dose-level of sorafenib for both arms will be 400 mg twice daily (800 mg total daily dose). Eligible patients will be randomized to either Arm 1 or Arm 2.

The phase 2 portion will be an open-label, 3-arm, randomized trial of patients with advanced HCC who have not received prior systemic treatment. Patients will be randomized to receive either, Arm 1: sorafenib administered in combination with BBI608 (at the RP2D determined for BBI608 plus sorafenib during the phase 1 portion); Arm 2: sorafenib in combination with BBI503 (at the RP2D determined for BBI503 plus sorafenib during the phase 1 portion), or Arm 3: sorafenib alone at a starting dose of 400 mg twice daily. The starting dose for sorafenib is the same for all study arms.

Study Design

• Study Type: Interventional
• Actual Enrollment: 97 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase Ib/II Clinical Study of BBI608 in Combination With Sorafenib, or BBI503 in Combination With Sorafenib in Adult Patients With Hepatocellular Carcinoma
• Study Start Date: Dec 1, 2014
• Actual Primary Completion Date: Jul 1, 2019
• Actual Study Completion Date: Oct 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BBI608 and Sorafenib	Drug: BBI608; BBI608 will be administered in combination with sorafenib at the RP2D determined during the phase 1 dose-escalation portion of study.; Other Names: Napabucasin BBI-608 BB608 ; Drug: Sorafenib; Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose). Sorafenib should be taken on an empty stomach, one hour prior to or two hours after meals. Sorafenib should not be taken with study drug, and at least 2 hours should separate a dose of sorafenib from a dose of study drug.; Other Names: Nexavar
Experimental: BBI503 and Sorafenib	Drug: BBI503; BBI503 will be administered in combination with sorafenib at the RP2D determined during the phase 1 dose-escalation portion of study.; Other Names: Amcasertib BBI-503 BB503 ; Drug: Sorafenib; Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose). Sorafenib should be taken on an empty stomach, one hour prior to or two hours after meals. Sorafenib should not be taken with study drug, and at least 2 hours should separate a dose of sorafenib from a dose of study drug.; Other Names: Nexavar
Active Comparator: Sorafenib	Drug: Sorafenib; Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose). Sorafenib should be taken on an empty stomach, one hour prior to or two hours after meals. Sorafenib should not be taken with study drug, and at least 2 hours should separate a dose of sorafenib from a dose of study drug.; Other Names: Nexavar

Outcome Measures

Primary Outcome Measures

1. Assessment of the Dose Limiting Toxicities for the Napabucasin and Amcasertib Arm in Combination With Sorafenib for Phase IB [16 weeks including 2-week Sorafenib run-in period prior to initiation of combination therapy]

   To assess the dose limiting toxicities for phase IB

2. To Assess the Number of Patients Who Experienced Adverse Events for Phase IB. [Adverse events will be assessed at baseline, while the participant is taking drugs, and for 30 days after stopping therapy. It was expected that patients would receive between 4-24 weeks treatment.]

   Assessment of safety of either BBI608 or BBI503 given in combination with sorafenib to patients with hepatocellular carcinoma by reporting of adverse events and serious adverse events

3. Determination of the Recommended Phase II Dose for Napabucasin and Amcasertib Arm in Combination With Sorafenib [16 weeks including 2-week Sorafenib run-in period prior to initiation of combination therapy]

   To determine the recommended phase II dose for Napabucasin and Amcasertib arm in combination with sorafenib

4. Assessment of Objective Response Rate in the Intent to Treat Population - Phase II [Assessment of the preliminary anti-tumor activity by performing tumor assessments at baseline and every 8 weeks after the date of the first dose of protocol therapy]

   To evaluate the preliminary anti-tumor activity in patients with advanced hepatocellular carcinoma randomized to receive treatment with sorafenib in combination with Napabucasin or sorafenib in combination with Amcasertib, or sorafenib alone; Napabucasin and Amcasertib will be administered at their respective RP2D dose levels for combination administration with sorafenib, which were determined during the phase Ib portion of the study. The radiologic assessments will be evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and modified RECIST for patients with hepatocellular carcinoma. ORR was defined as the percentage of patients with a best overall response (BOR) of complete response (CR) or partial response (PR), using both RECIST and mRECIST assessment data.

5. Assessment of Disease Control Rate in the Intent to Treat Population- Phase II [Assessment of the preliminary anti-tumor activity by performing tumor assessments at baseline and every 8 weeks after the date of the first dose of protocol therapy]

   To evaluate the preliminary anti-tumor activity in patients with advanced hepatocellular carcinoma randomized to receive treatment with sorafenib in combination with Napabucasin, sorafenib in combination with Amcasertib*, or sorafenib alone; Napabucasin and Amcasertib will be administered at their respective RP2D dose levels for combination administration with sorafenib, which were determined during the phase Ib portion of the study. The radiologic assessments will be evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and modified RECIST for patients with hepatocellular carcinoma. Disease control rate (DCR), defined as the proportion of patients with best response of complete response (CR), Partial Response (PR), or stable disease (SD)

Secondary Outcome Measures

1. Assessment of the Pharmacokinetic Profile (Maximum Plasma Concentration and Area Under the Curve) of Either Napabucasin or Amcasertib. [On Day 15 of the first cycle and Day 15 of the second cycle, prior to dosing and every one hours to 11 hours and 24 hours after first dose]

   To determine the pharmacokinetic (PK) profile of napabucasin administered in combination with sorafenib and of amcasertib administered in combination with sorafenib.

2. Assessment of the Pharmacodynamic Studies as Well as the Concentration of Study Drug (Either Napabucasin or Amcasertib) in Tumors [On day 15 of the second cycle]

   To perform biomarker studies for napabucasin administered in combination with sorafenib and for amcasertib administered in combination with sorafenib.

Eligibility Criteria

Criteria

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

Inclusion Criteria

1. Signed written informed consent must be obtained and documented according to International Conference on Harmonisation (ICH) and local regulatory requirements

2. Histologically or cytologically confirmed hepatocellular carcinoma that is metastatic, unresectable, or recurrent.

3. Patients must not be candidates for curative resection

4. Patients who have recurrent disease after having had one or more prior resections may be eligible, provided that they are not candidates for further curative resection.

5. Patients who have recurrent hepatocellular carcinoma following hepatic transplantation are excluded unless the following criteria are met:

1. Transplantation was performed at least 6 months prior to the relapse of HCC. ii. Patients are on stable immune suppressive therapy with no clinical evidence of rejection.

1. Are receiving ≤ 2.5 mg everolimus daily. d. Patients with known HIV infection are excluded. e. Patients with Hepatitis B are eligible provided there is no active viral replication. Patients with Hepatitis C who are not on interferon are eligible.

1. Patients who have a diagnosis of hepatocellular carcinoma made through radiologic imaging may be eligible, provided they meet the criteria according to the American Association for the Study of Liver Disease, AASLD (Bruix and Sherman, 2005; Bruix and Sherman, 2011)

2. Patients must be candidates for sorafenib

3. Must have had no previous systemic anti-cancer treatment, though previous loco-regional therapy is allowed:

1. Prior treatment with any of the following is allowed: trans-arterial embolization, trans-arterial chemo-embolization, percutaneous ethanol injection, radio-embolization, radio-frequency ablation, or other ablation techniques.

1. Must be Child-Pugh class A

1. Patients with uncontrolled massive ascites or presence of hepatic encephalopathy are excluded

1. Must have total serum bilirubin ≤ 3 mg/dl

2. ≥ 18 years of age

3. Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1

4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

5. Male or female patients of child-producing potential must agree to use contraception or avoidance of pregnancy measures during the study and for 30 days after the last BBI608 or BBI503 dose

6. Females of childbearing potential must have a negative serum pregnancy test

7. Aspartate Aminotransferase (AST) and Alanine transaminase (ALT) < 5.0x the upper limit of normal (ULN)

8. Glomerular filtration rate (GFR) > 45 mL/min/1.73m^2 according to the Cockcroft-Gault estimation.

9. Hemoglobin ≥ 8.5 mg/dl 14. Absolute neutrophil count ≥ 1.5 x 10^{9/L 15. Platelets ≥ 75 x 10}9/L 16. Life expectancy ≥ 3 months

Exclusion Criteria

1. Previous treatment with sorafenib

2. Patients with known hypersensitivity to sorafenib or any other component of sorafenib.

3. Previous systemic anti-vascular endothelial growth factor (VEGF) or any prior systemic anti-cancer therapy, including prior treatment with systemic agents such as regorafenib, ramucirumab, pazopanib, or experimental agents such as brivanib.

4. Have had a surgical procedure requiring general anesthesia or inpatient hospitalization for recovery less than 4 weeks prior to beginning protocol therapy.

5. Have had a loco-regional procedure for the treatment of hepatocellular carcinoma (such as a percutaneous, trans-arterial, or radio-ablative procedure) less than 4 weeks prior to beginning protocol therapy. Protocol therapy may begin a minimum of 4 weeks after such a procedure provided the following criteria are met:

6. There is progression of disease documented by RECIST 1.1

7. All adverse events from the procedure have resolved or have been deemed irreversible and the patient meets inclusion criteria.

8. Any known symptomatic or untreated brain metastases requiring increase of steroid dose within 2 weeks prior to starting on study. Patients with treated brain metastases must be stable for 4 weeks after completion of that treatment. Patients must have no clinical symptoms from brain metastases and must be either off steroids or on a stable dose of steroids for at least 2 weeks prior to protocol enrollment. Patients with known leptomeningeal metastases are excluded, even if treated.

9. Pregnant or breastfeeding

10. Significant gastrointestinal disorder(s), (e.g., Crohn's disease, ulcerative colitis, extensive gastric and small intestine resection) such that, in the opinion of the treating investigator, absorption of oral medications may be impaired.

11. Unable or unwilling to swallow BBI608, BBI503, or sorafenib capsules or tablets

12. Uncontrolled inter-current illness including, but not limited to: ongoing or active infection, clinically significant non-healing or healing wounds, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, significant pulmonary disease (shortness of breath at rest or mild exertion), or uncontrolled infection or psychiatric illness/social situations that would limit compliance with study requirements (e.g. no reliable transportation).

13. Subjects with a history of another primary cancer, with the exception of: a) curatively resected non-melanoma skin cancer; b) curatively treated cervical carcinoma in situ; or c) other primary solid tumor with no known active disease present that, in the opinion of the investigator, will not affect patient outcome in the setting of current hepatocellular carcinoma diagnosis.

14. Abnormal ECGs which are clinically significant such as QT prolongation (QTc > 480 msec), clinically significant cardiac enlargement or hypertrophy, new bundle branch block, or signs of active ischemia. Patients with evidence of prior infarction who are New York Heart Association (NYHA) functional classes II, III, or IV are excluded, as are patients with marked arrhythmias such as Wolff Parkinson White pattern or complete atrioventricular (AV) dissociation.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Banner MD Anderson Cancer Center	Gilbert	Arizona	United States	85234
2	Mayo Clinic	Phoenix	Arizona	United States	85054
3	Southern California Research Center	Coronado	California	United States	92118
4	California Center Associates for Research and Excellence, Inc. (Ccare)	Encinitas	California	United States	92024
5	USC Norris Comprehensive Cancer Center	Los Angeles	California	United States	90033
6	USOR - Rocky Mountain Cancer Centers	Denver	Colorado	United States	80218
7	Baptist Health Medical Group Oncology, LLC	Miami	Florida	United States	33176
8	Piedmont Cancer Institute, P.C.	Atlanta	Georgia	United States	30318
9	Winship Cancer Institute of Emory University	Atlanta	Georgia	United States	30322
10	Norton Cancer Institute	Louisville	Kentucky	United States	40202
11	Karmanos Cancer Institute	Detroit	Michigan	United States	48201
12	Minnesota Oncology Hematology, P.A.	Minneapolis	Minnesota	United States	55404
13	Kansas City Research Institure	Kansas City	Missouri	United States	64131
14	USOR - Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada	United States	89169
15	The Valley Hospital Luckow Pavilion	Paramus	New Jersey	United States	07652
16	USOR - New York Oncology Hematology	Albany	New York	United States	12206
17	University of Rochester, Wilmot Cancer Institute	Rochester	New York	United States	14642
18	Carolinas Health Care System	Charlotte	North Carolina	United States	28204
19	Wake Forest Baptist Health	Winston-Salem	North Carolina	United States	27157
20	University of Cincinnati, Vontz Center	Cincinnati	Ohio	United States	45267
21	Drexel University	Philadelphia	Pennsylvania	United States	19102
22	USOR - Texas Oncology, Austin Midtown	Austin	Texas	United States	78705
23	Texas Oncology-Baylor Charles A. Sammons Cancer Center	Dallas	Texas	United States	75246
24	Texas Oncology - El Paso Cancer Treatment Center Joe Battle	El Paso	Texas	United States	79938
25	USOR - Texas Oncology, Fort Worth 12th Ave	Fort Worth	Texas	United States	76104
26	Oncology Consultants	Houston	Texas	United States	77030
27	Texas Oncology-McAllen South Second Street	McAllen	Texas	United States	78503
28	USOR - Texas Oncology, Tyler	Tyler	Texas	United States	75702
29	Oncology and Hematology Associates of Southwest Virginia, Inc., DBA Blue Ridge Cancer Care	Roanoke	Virginia	United States	24014

Sponsors and Collaborators

• Sumitomo Pharma Oncology, Inc.

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Apr 3, 2018
• Statistical Analysis Plan - Sep 10, 2020

More Information

Publications

None provided.

• Responsible Party: Sumitomo Pharma Oncology, Inc.
• ClinicalTrials.gov Identifier: NCT02279719
• Other Study ID Numbers: BBIHCC-103; BBI608-503-103HCC
• First Posted: Oct 31, 2014
• Last Update Posted: Apr 6, 2022
• Last Verified: Apr 1, 2022

• Additional relevant MeSH terms: Carcinoma; Carcinoma, Hepatocellular; Sorafenib

Study Results

Participant Flow

Arm/Group Title	Experimental Napabucasin+Sorafenib Phase IB Dose- Level 1	Experimental Napabucasin+Sorafenib Phase IB Dose-Level 2	Experimental Amcasertib +Sorafenib Phase IB Dose- Level 1	Experimental Amcasertib+Sorafenib Phase IB Dose-Level 2	Experimental Napabucasin+Sorafenib Phase II	Experimental Amcasertib+Sorafenib Phase II	Sorafenib Phase II
Arm/Group Description	Napabucasin will be administered orally twice daily in combination with sorafenib. The dose of Napabucasin will be 160 mg twice daily Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose). This dose of sorafenib will be the same for each arm and for each dose-level cohort. Sorafenib should be taken on an empty stomach, one hour prior to or two hours after meals. Sorafenib should not be taken with study drug, and at least 2 hours should separate a dose of sorafenib from a dose of study drug.	Napabucasin will be administered orally twice daily in combination with sorafenib. The dose of Napabucasin will be 240 mg twice daily Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose). This dose of sorafenib will be the same for each arm and for each dose-level cohort. Sorafenib should be taken on an empty stomach, one hour prior to or two hours after meals. Sorafenib should not be taken with study drug, and at least 2 hours should separate a dose of sorafenib from a dose of study drug.	Amcasertib will be administered orally daily in combination with sorafenib. The dose of Amcasertib to be administered will be 100mg once daily. Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose). This dose of sorafenib will be the same for each arm and for each dose-level cohort. Sorafenib should be taken on an empty stomach, one hour prior to or two hours after meals. Sorafenib should not be taken with study drug, and at least 2 hours should separate a dose of sorafenib from a dose of study drug.	Amcasertib will be administered orally daily in combination with sorafenib. The dose of Amcasertib to be administered will be 200mg once daily. Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose). This dose of sorafenib will be the same for each arm and for each dose-level cohort. Sorafenib should be taken on an empty stomach, one hour prior to or two hours after meals. Sorafenib should not be taken with study drug, and at least 2 hours should separate a dose of sorafenib from a dose of study drug.	Phase II Napabucasin will be administered in combination with sorafenib at the RP2D determined during the phase 1 dose-escalation portion of study. Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose). Sorafenib should be taken on an empty stomach, one hour prior to or two hours after meals. Sorafenib should not be taken with study drug, and at least 2 hours should separate a dose of sorafenib from a dose of study drug.	Phase II Amcasertib will be administered in combination with sorafenib at the RP2D determined during the phase 1 dose-escalation portion of study. Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose). Sorafenib should be taken on an empty stomach, one hour prior to or two hours after meals. Sorafenib should not be taken with study drug, and at least 2 hours should separate a dose of sorafenib from a dose of study drug.	Phase II Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose). Sorafenib should be taken on an empty stomach, one hour prior to or two hours after meals. Sorafenib should not be taken with study drug, and at least 2 hours should separate a dose of sorafenib from a dose of study drug.
Period Title: Overall Study
STARTED	5	10	4	9	28	10	31
COMPLETED	5	10	4	9	25	10	28
NOT COMPLETED	0	0	0	0	3	0	3

Baseline Characteristics

Arm/Group Title	Experimental Napabucasin +Sorafenib Phase IB- Dose Level 1	Experimental Napabucasin +Sorafenib Phase IB- Dose Level 2	Experimental Amcasertib +Sorafenib Phase IB- Dose Level 1	Experimental Amcasertib +Sorafenib Phase IB- Dose Level 2	Experimental Napabucasin +Sorafenib Phase II	Experimental Amcasertib +Sorafenib Phase II	Sorafenib Phase II	Total
Arm/Group Description	Napabucasin will be administered orally twice daily in combination with sorafenib. The dose of Napabucasin will be 160 mg twice daily Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose). This dose of sorafenib will be the same for each arm and for each dose-level cohort. Sorafenib should be taken on an empty stomach, one hour prior to or two hours after meals. Sorafenib should not be taken with study drug, and at least 2 hours should separate a dose of sorafenib from a dose of study drug.	Napabucasin will be administered orally twice daily in combination with sorafenib. The dose of Napabucasin will be 240 mg twice daily Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose). This dose of sorafenib will be the same for each arm and for each dose-level cohort. Sorafenib should be taken on an empty stomach, one hour prior to or two hours after meals. Sorafenib should not be taken with study drug, and at least 2 hours should separate a dose of sorafenib from a dose of study drug.	Amcasertib will be administered orally daily in combination with sorafenib. The dose of Amcasertib to be administered will be 100mg once daily. Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose). This dose of sorafenib will be the same for each arm and for each dose-level cohort. Sorafenib should be taken on an empty stomach, one hour prior to or two hours after meals. Sorafenib should not be taken with study drug, and at least 2 hours should separate a dose of sorafenib from a dose of study drug	Amcasertib will be administered orally daily in combination with sorafenib. The dose of Amcasertib to be administered will be 200mg once daily. Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose). This dose of sorafenib will be the same for each arm and for each dose-level cohort. Sorafenib should be taken on an empty stomach, one hour prior to or two hours after meals. Sorafenib should not be taken with study drug, and at least 2 hours should separate a dose of sorafenib from a dose of study drug.	Phase II Napabucasin will be administered in combination with sorafenib at the RP2D determined during the phase 1 dose-escalation portion of study. Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose). Sorafenib should be taken on an empty stomach, one hour prior to or two hours after meals. Sorafenib should not be taken with study drug, and at least 2 hours should separate a dose of sorafenib from a dose of study drug.	Phase II Amcasertib will be administered in combination with sorafenib at the RP2D determined during the phase 1 dose-escalation portion of study. Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose). Sorafenib should be taken on an empty stomach, one hour prior to or two hours after meals. Sorafenib should not be taken with study drug, and at least 2 hours should separate a dose of sorafenib from a dose of study drug.	Phase II Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose). Sorafenib should be taken on an empty stomach, one hour prior to or two hours after meals. Sorafenib should not be taken with study drug, and at least 2 hours should separate a dose of sorafenib from a dose of study drug.	Total of all reporting groups
Overall Participants	5	10	4	9	28	10	31	97
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65.4 (5.22)	70.8 (4.42)	55.0 (22.20)	60.6 (5.22)	64.1 (8.72)	68.4 (9.98)	67.7 (8.73)	65.7 (9.38)
Sex: Female, Male (Count of Participants)
Female	1 20%	1 10%	2 50%	3 33.3%	4 14.3%	3 30%	7 22.6%	21 21.6%
Male	4 80%	9 90%	2 50%	6 66.7%	24 85.7%	7 70%	24 77.4%	76 78.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	1 3.6%	0 0%	0 0%	1 1%
Asian	0 0%	1 10%	1 25%	2 22.2%	2 7.1%	1 10%	2 6.5%	9 9.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	1 3.6%	0 0%	0 0%	1 1%
Black or African American	0 0%	0 0%	1 25%	1 11.1%	2 7.1%	0 0%	9 29%	13 13.4%
White	5 100%	9 90%	2 50%	5 55.6%	18 64.3%	8 80%	19 61.3%	66 68%
More than one race	0 0%	0 0%	0 0%	1 11.1%	4 14.3%	1 10%	0 0%	6 6.2%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 3.2%	1 1%

Outcome Measures

1. Primary Outcome

Title	Assessment of the Dose Limiting Toxicities for the Napabucasin and Amcasertib Arm in Combination With Sorafenib for Phase IB
Description	To assess the dose limiting toxicities for phase IB
Time Frame	16 weeks including 2-week Sorafenib run-in period prior to initiation of combination therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Napabucasin+Sorafenib Phase IB- Dose Level 1	Napabucasin+Sorafenib Phase IB- Dose Level 2	Amcasertib+Sorafenib Phase IB- Dose Level 1	Amcasertib+ Sorafenib Phase IB Dose Level 2
Arm/Group Description	Napabucasin will be administered orally twice daily in combination with sorafenib. The dose of Napabucasin to be administered will be 160 mg twice daily. The patients are considered evaluable for the determination dose level toxicities and determination of dose escalation if they have been exposed to at least 28 days of continues daily administration of Napabucasin in combination with sorafenib at a compliance level of at least 80% Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose).	Napabucasin will be administered orally twice daily in combination with sorafenib. The dose of Napabucasin to be administered will be 240 mg twice daily. The patients are considered evaluable for the determination dose level toxicities and determination of dose escalation if they have been exposed to at least 28 days of continues daily administration of Napabucasin in combination with sorafenib at a compliance level of at least 80% Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose).	Amcasetib will be administered orally once daily in combination with sorafenib. The dose of Amcasertib to be administered will be 100mg once daily. The patients are considered evaluable for the determination dose level toxicities and determination of dose escalation if they have been exposed to at least 28 days of continues daily administration of Amcasertib in combination with sorafenib at a compliance level of at least 80% Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose).	Amcasertib will be administered orally once daily in combination with sorafenib. The dose of Amcasertib will be 200mg once daily. The patients are considered evaluable for the determination dose level toxicities and determination of dose escalation if they have been exposed to at least 28 days of continues daily administration of Amcasertib in combination with sorafenib at a compliance level of at least 80% Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose).
Measure Participants	5	10	4	9
Number [Dose limiting toxicities]	0	0	0	0

2. Primary Outcome

Title	To Assess the Number of Patients Who Experienced Adverse Events for Phase IB.
Description	Assessment of safety of either BBI608 or BBI503 given in combination with sorafenib to patients with hepatocellular carcinoma by reporting of adverse events and serious adverse events
Time Frame	Adverse events will be assessed at baseline, while the participant is taking drugs, and for 30 days after stopping therapy. It was expected that patients would receive between 4-24 weeks treatment.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Napabucasin+Sorafenib Phase IB- Dose Level 1	Napabucasin+Sorafenib Phase IB - Dose Level 2	Amcasertib +Sorafenib Phase IB- Dose Level 1	Amcasertib+ Sorafenib Phase IB- Dose Level 2
Arm/Group Description	Napabucasin will be administered orally twice daily in combination with sorafenib. The dose of Napabucasin to be administered will be 160mg twice daily. The patients are considered evaluable for the determination dose level toxicities and determination of dose escalation if they have been exposed to at least 28 days of continues daily administration of Napabucasin in combination with sorafenib at a compliance level of at least 80% Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose).	Napabucasin will be administered orally twice daily in combination with sorafenib. The dose of Napabucasin to be administered will be 240 mg twice daily. The patients are considered evaluable for the determination dose level toxicities and determination of dose escalation if they have been exposed to at least 28 days of continues daily administration of Napabucasin in combination with sorafenib at a compliance level of at least 80% Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose).	Amcasetib will be administered orally once daily in combination with sorafenib. The dose of Amcasertib to be administered will be 100mg once daily. The patients are considered evaluable for the determination dose level toxicities and determination of dose escalation if they have been exposed to at least 28 days of continues daily administration of Amcasertib in combination with sorafenib at a compliance level of at least 80% Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose).	Amcasetib will be administered orally once daily in combination with sorafenib. The dose of Amcasertib to be administered will be 200mg once daily. The patients are considered evaluable for the determination dose level toxicities and determination of dose escalation if they have been exposed to at least 28 days of continues daily administration of Amcasertib in combination with sorafenib at a compliance level of at least 80% Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose).
Measure Participants	5	10	4	9
Patients with TEAEs	5 100%	10 100%	4 100%	9 100%
Patients with TEAEs CTCAE ≥Grade 3 TEAEs	3 60%	8 80%	3 75%	5 55.6%
Patients with serious TEAEs	0 0%	3 30%	2 50%	5 55.6%
Patients with TEAEs leading to treatment discontinuation	0 0%	2 20%	2 50%	1 11.1%
Patients with TEAEs leading to Death	0 0%	0 0%	1 25%	1 11.1%
Patients with TEAEs leading to Napabucasin reduction	1 20%	3 30%	0 0%	0 0%
Patients with TEAEs leading to Amcasertib dose reduction	0 0%	0 0%	0 0%	0 0%
Patients with TEAEs leading to Napabucasin dose held	1 20%	7 70%	0 0%	0 0%
Patients with TEAEs leading to Amcasertib dose held	0 0%	0 0%	2 50%	6 66.7%

3. Primary Outcome

Title	Determination of the Recommended Phase II Dose for Napabucasin and Amcasertib Arm in Combination With Sorafenib
Description	To determine the recommended phase II dose for Napabucasin and Amcasertib arm in combination with sorafenib
Time Frame	16 weeks including 2-week Sorafenib run-in period prior to initiation of combination therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Napabucasin+Sorafenib Phase IB	Amcasertib+ Sorafenib Phase IB
Arm/Group Description	Napabucasin will be administered orally twice daily in combination with sorafenib. The dose of Napabucasin to be administered will depend on the assigned dose-level cohort. The patients are considered evaluable for the determination dose level toxicities and determination of dose escalation if they have been exposed to at least 28 days of continues daily administration of Napabucasin in combination with sorafenib at a compliance level of at least 80% Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose).	Amcasertib will be administered orally daily in combination with sorafenib. The dose of Amcasertib to be administered will depend on the assigned dose-level cohort. The patients are considered evaluable for the determination dose level toxicities and determination of dose escalation if they have been exposed to at least 28 days of continues daily administration of Amcasertib in combination with sorafenib at a compliance level of at least 80% Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose).
Measure Participants	15	13
Recommended Dose of Napabucasin for phase II	480	NA
Recommended dose of Amcasertib for Phase II	NA	100

4. Primary Outcome

Title	Assessment of Objective Response Rate in the Intent to Treat Population - Phase II
Description	To evaluate the preliminary anti-tumor activity in patients with advanced hepatocellular carcinoma randomized to receive treatment with sorafenib in combination with Napabucasin or sorafenib in combination with Amcasertib, or sorafenib alone; Napabucasin and Amcasertib will be administered at their respective RP2D dose levels for combination administration with sorafenib, which were determined during the phase Ib portion of the study. The radiologic assessments will be evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and modified RECIST for patients with hepatocellular carcinoma. ORR was defined as the percentage of patients with a best overall response (BOR) of complete response (CR) or partial response (PR), using both RECIST and mRECIST assessment data.
Time Frame	Assessment of the preliminary anti-tumor activity by performing tumor assessments at baseline and every 8 weeks after the date of the first dose of protocol therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Experimental Napabucasin +Sorafenib Phase II	Experimental Amcasertib+Sorafenib Phase II	Sorafenib Phase II
Arm/Group Description	Phase II Napabucasin will be administered in combination with sorafenib at the RP2D determined during the phase 1 dose-escalation portion of study. Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose). Sorafenib should be taken on an empty stomach, one hour prior to or two hours after meals. Sorafenib should not be taken with study drug, and at least 2 hours should separate a dose of sorafenib from a dose of study drug.	Phase II Amcasertib will be administered in combination with sorafenib at the RP2D determined during the phase 1 dose-escalation portion of study. Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose). Sorafenib should be taken on an empty stomach, one hour prior to or two hours after meals. Sorafenib should not be taken with study drug, and at least 2 hours should separate a dose of sorafenib from a dose of study drug	Phase II Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose). Sorafenib should be taken on an empty stomach, one hour prior to or two hours after meals. Sorafenib should not be taken with study drug, and at least 2 hours should separate a dose of sorafenib from a dose of study drug
Measure Participants	28	10	31
Assessment of Objective Response Rate based on RECIST 1.1 criteria	3.6 72%	0 0%	9.7 242.5%
Assessment of Objective Response Rate based on mRECIST 1.1 criteria	3.6 72%	0 0%	6.5 162.5%

5. Primary Outcome

Title	Assessment of Disease Control Rate in the Intent to Treat Population- Phase II
Description	To evaluate the preliminary anti-tumor activity in patients with advanced hepatocellular carcinoma randomized to receive treatment with sorafenib in combination with Napabucasin, sorafenib in combination with Amcasertib*, or sorafenib alone; Napabucasin and Amcasertib will be administered at their respective RP2D dose levels for combination administration with sorafenib, which were determined during the phase Ib portion of the study. The radiologic assessments will be evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and modified RECIST for patients with hepatocellular carcinoma. Disease control rate (DCR), defined as the proportion of patients with best response of complete response (CR), Partial Response (PR), or stable disease (SD)
Time Frame	Assessment of the preliminary anti-tumor activity by performing tumor assessments at baseline and every 8 weeks after the date of the first dose of protocol therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Experimental Napabucasin +Sorafenib Phase II	Experimental Amcasertib+Sorafenib Phase II	Sorafenib Phase II
Arm/Group Description	Phase II Napabucasin will be administered in combination with sorafenib at the RP2D determined during the phase 1 dose-escalation portion of study. Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose). Sorafenib should be taken on an empty stomach, one hour prior to or two hours after meals. Sorafenib should not be taken with study drug, and at least 2 hours should separate a dose of sorafenib from a dose of study drug.	Phase II Amcasertib will be administered in combination with sorafenib at the RP2D determined during the phase 1 dose-escalation portion of study. Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose). Sorafenib should be taken on an empty stomach, one hour prior to or two hours after meals. Sorafenib should not be taken with study drug, and at least 2 hours should separate a dose of sorafenib from a dose of study drug	Phase II Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose). Sorafenib should be taken on an empty stomach, one hour prior to or two hours after meals. Sorafenib should not be taken with study drug, and at least 2 hours should separate a dose of sorafenib from a dose of study drug
Measure Participants	28	10	31
Assessment of Objective Response Rate based on RECIST 1.1 criteria	35.7 714%	70.0 700%	48.4 1210%
Assessment of Objective Response Rate based on mRECIST 1.1 criteria	35.7 714%	50.0 500%	48.4 1210%

6. Secondary Outcome

Title	Assessment of the Pharmacokinetic Profile (Maximum Plasma Concentration and Area Under the Curve) of Either Napabucasin or Amcasertib.
Description	To determine the pharmacokinetic (PK) profile of napabucasin administered in combination with sorafenib and of amcasertib administered in combination with sorafenib.
Time Frame	On Day 15 of the first cycle and Day 15 of the second cycle, prior to dosing and every one hours to 11 hours and 24 hours after first dose

Outcome Measure Data

Analysis Population Description

PK parameters were not calculated for this study and are not available. The analyses were not performed as decisions were made to discontinue all clinical development of amcasertib, and of napabucasin for hepatocellular carcinoma.

Arm/Group Title	Experimental Napabucasin Plus Sorafenib Phase IB- Dose Level 1	Experimental Napabucasin Plus Sorafenib Phase IB- Dose Level 2	Experimental Amcsertib Plus Sorafenib Phase IB- Dose Level 1	Experimental Amcasetib Plus Sorafenib Phase IB- Dose Level 2	Experimental Napabucasin Plus Sorafenib Phase II	Experimental Amcasertib Plus Sorafenib Phase II	Sorafenib Phase II
Arm/Group Description	Napabucasin will be administered orally twice daily in combination with sorafenib. The dose of Napabucasin to be administered will be 160mg daily. Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose). This dose of sorafenib will be the same for each arm and for each dose-level cohort. Sorafenib should be taken on an empty stomach, one hour prior to or two hours after meals. Sorafenib should not be taken with study drug, and at least 2 hours should separate a dose of sorafenib from a dose of study drug	Napabucasin will be administered orally twice daily in combination with sorafenib. The dose of Napabucasin will be 240 mg twice daily Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose). This dose of sorafenib will be the same for each arm and for each dose-level cohort. Sorafenib should be taken on an empty stomach, one hour prior to or two hours after meals. Sorafenib should not be taken with study drug, and at least 2 hours should separate a dose of sorafenib from a dose of study drug.	Amcasertib will be administered orally daily in combination with sorafenib. The dose of Amcasertib to be administered will be 100mg once daily. Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose). This dose of sorafenib will be the same for each arm and for each dose-level cohort. Sorafenib should be taken on an empty stomach, one hour prior to or two hours after meals. Sorafenib should not be taken with study drug, and at least 2 hours should separate a dose of sorafenib from a dose of study drug.	Amcasertib will be administered orally daily in combination with sorafenib. The dose of Amcasertib to be administered will be 200mg once daily. Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose). This dose of sorafenib will be the same for each arm and for each dose-level cohort. Sorafenib should be taken on an empty stomach, one hour prior to or two hours after meals. Sorafenib should not be taken with study drug, and at least 2 hours should separate a dose of sorafenib from a dose of study drug.	Phase II Napabucasin will be administered in combination with sorafenib at the RP2D determined during the phase 1 dose-escalation portion of study. Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose). Sorafenib should be taken on an empty stomach, one hour prior to or two hours after meals. Sorafenib should not be taken with study drug, and at least 2 hours should separate a dose of sorafenib from a dose of study drug	Phase II Amcasertib will be administered in combination with sorafenib at the RP2D determined during the phase 1 dose-escalation portion of study. Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose). Sorafenib should be taken on an empty stomach, one hour prior to or two hours after meals. Sorafenib should not be taken with study drug, and at least 2 hours should separate a dose of sorafenib from a dose of study drug.	Phase II Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose). Sorafenib should be taken on an empty stomach, one hour prior to or two hours after meals. Sorafenib should not be taken with study drug, and at least 2 hours should separate a dose of sorafenib from a dose of study drug
Measure Participants	0	0	0	0	0	0	0

7. Secondary Outcome

Title	Assessment of the Pharmacodynamic Studies as Well as the Concentration of Study Drug (Either Napabucasin or Amcasertib) in Tumors
Description	To perform biomarker studies for napabucasin administered in combination with sorafenib and for amcasertib administered in combination with sorafenib.
Time Frame	On day 15 of the second cycle

Outcome Measure Data

Analysis Population Description

PD assessments were not performed for this study and are not available. Archival tissue, with raw staining scores, and no correlative analyses with clinical data were performed. Analyses were not performed as decisions were made to discontinue all clinical development of amcasertib, and also to discontinue development of napabucasin for hepatocellular carcinoma.

Arm/Group Title	Experimental Napabucasin Plus Sorafenib Phase IB- Dose Level 1	Experimental Napabucasin Plus Sorafenib Phase IB- Dose Level 2	Experimental Amcasertib Plus Sorafenib Phase IB- Dose Level 1	Experimental Amcasertib Plus Sorafenib Phase IB- Dose Level 2	Experimental Napabucasin Plus Sorafenib Phase II	Experimental Amcasertib Plus Sorafenib Phase II	Sorafenib Phase II
Arm/Group Description	Napabucasin will be administered orally twice daily in combination with sorafenib. The dose of Napabucasin to be administered will be 160mg twice daily. Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose). This dose of sorafenib will be the same for each arm and for each dose-level cohort. Sorafenib should be taken on an empty stomach, one hour prior to or two hours after meals. Sorafenib should not be taken with study drug, and at least 2 hours should separate a dose of sorafenib from a dose of study drug	Napabucasin will be administered orally twice daily in combination with sorafenib. The dose of Napabucasin will be 240 mg twice daily Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose). This dose of sorafenib will be the same for each arm and for each dose-level cohort. Sorafenib should be taken on an empty stomach, one hour prior to or two hours after meals. Sorafenib should not be taken with study drug, and at least 2 hours should separate a dose of sorafenib from a dose of study drug.	Amcasertib will be administered orally daily in combination with sorafenib. The dose of Amcasertib to be administered will be 100mg once daily. Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose). This dose of sorafenib will be the same for each arm and for each dose-level cohort. Sorafenib should be taken on an empty stomach, one hour prior to or two hours after meals. Sorafenib should not be taken with study drug, and at least 2 hours should separate a dose of sorafenib from a dose of study drug.	Amcasertib will be administered orally daily in combination with sorafenib. The dose of Amcasertib to be administered will be 200mg once daily. Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose). This dose of sorafenib will be the same for each arm and for each dose-level cohort. Sorafenib should be taken on an empty stomach, one hour prior to or two hours after meals. Sorafenib should not be taken with study drug, and at least 2 hours should separate a dose of sorafenib from a dose of study drug.	Phase II Napabucasin will be administered in combination with sorafenib at the RP2D determined during the phase 1 dose-escalation portion of study. Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose). Sorafenib should be taken on an empty stomach, one hour prior to or two hours after meals. Sorafenib should not be taken with study drug, and at least 2 hours should separate a dose of sorafenib from a dose of study drug.	Phase II Amcasertib will be administered in combination with sorafenib at the RP2D determined during the phase 1 dose-escalation portion of study. Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose). Sorafenib should be taken on an empty stomach, one hour prior to or two hours after meals. Sorafenib should not be taken with study drug, and at least 2 hours should separate a dose of sorafenib from a dose of study drug.	Phase II Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose). Sorafenib should be taken on an empty stomach, one hour prior to or two hours after meals. Sorafenib should not be taken with study drug, and at least 2 hours should separate a dose of sorafenib from a dose of study drug
Measure Participants	0	0	0	0	0	0	0

Adverse Events

Time Frame	From the date of the first treatment until 30 days of the last administration of the study drug for an average period of 28 weeks. The total period for both phase I and phase II of the study was 5 years.
Adverse Event Reporting Description	Napabucasin+Sorafenib Phase II:There were 25 who received at least 1 dose.5 discontinued during the Run-inperiod consisting of sorafenib only;total to receive both napabucasin + sorafenib was 20. Amcasertib+Sorafenib Phase II: There were 10 patients and 3 discontinued during the Run-inperiod consisting of sorafenib only;total to receive both amcasertib + sorafenib was 7.Sorafenib Phase II:Patients from napabucasin and amcasertib arms who only received sorafenib were analyzed with sorafenib arm.
Arm/Group Title	Experimental Napabucasin+Sorafenib Phase IB- Dose Level 1		Experimental Napabucasin +Sorafenib Phase IB- Dose Level 2		Experimental Amcasertib+Sorafenib Phase IB- Dose Level 1		Experimental Amcasertib+Sorafenib Phase IB- Dose Level 2		Experimental Napabucasin +Sorafenib Phase II		Experimental Amcasertib +Sorafenib Phase II		Sorafenib Phase II
Arm/Group Description	Patients who have received at least one dose of Napabucasin in combination with sorafenib during the phase 1 dose-escalation portion of study. Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose).		Patients who have received at least one dose of Napabucasin in combination with sorafenib during the phase 1 dose-escalation portion of study. Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose).		Patients who have received at least one dose of Amcasertib in combination with sorafenib during the phase 1 dose-escalation portion of study. Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose).		Patients who have received at least one dose of Amcasertib in combination with sorafenib during the phase 1 dose-escalation portion of study. Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose).		Phase II: Patients who have received at least one dose of Napabucasin (at the RP2D determined for napabucasin plus sorafenib during the Phase 1b portion) in combination with sorafenib. In the amcasertib + sorafenib arm, there were 10 patients randomized. Of these 10 patients, 3 discontinued during the Run-in period consisting of sorafenib monotherapy; therefore, the total to receive both amcasertib + sorafenib in Phase 2 was 7		Phase II: Patients who have received at least one dose of amcasertib (at the RP2D determined for amcasertib plus sorafenib during the Phase 1b portion) in combindation with sorafenib. There were 28 total randomized and 25 who received at least 1 dose of study treatment. Of these 25 patients, 5 discontinued during the Run-in period consisting of sorafenib monotherapy; therefore, the total number of patients to receive both napabucasin + sorafenib in Phase 2 was 20		Phase II: Patients who have received at least one dose of sorafenib
All Cause Mortality
	Experimental Napabucasin+Sorafenib Phase IB- Dose Level 1		Experimental Napabucasin +Sorafenib Phase IB- Dose Level 2		Experimental Amcasertib+Sorafenib Phase IB- Dose Level 1		Experimental Amcasertib+Sorafenib Phase IB- Dose Level 2		Experimental Napabucasin +Sorafenib Phase II		Experimental Amcasertib +Sorafenib Phase II		Sorafenib Phase II
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/5 (80%)		7/10 (70%)		4/4 (100%)		9/9 (100%)		15/20 (75%)		6/7 (85.7%)		23/36 (63.9%)
Serious Adverse Events
	Experimental Napabucasin+Sorafenib Phase IB- Dose Level 1		Experimental Napabucasin +Sorafenib Phase IB- Dose Level 2		Experimental Amcasertib+Sorafenib Phase IB- Dose Level 1		Experimental Amcasertib+Sorafenib Phase IB- Dose Level 2		Experimental Napabucasin +Sorafenib Phase II		Experimental Amcasertib +Sorafenib Phase II		Sorafenib Phase II
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		3/10 (30%)		2/4 (50%)		5/9 (55.6%)		10/20 (50%)		3/7 (42.9%)		16/36 (44.4%)
Cardiac disorders
Angina Pectoris	0/5 (0%)		1/10 (10%)		0/4 (0%)		0/9 (0%)		0/20 (0%)		0/7 (0%)		1/36 (2.8%)
Acute Myocardial Infarction	0/5 (0%)		0/10 (0%)		1/4 (25%)		0/9 (0%)		0/20 (0%)		0/7 (0%)		0/36 (0%)
Cardiac Arrest	0/5 (0%)		0/10 (0%)		0/4 (0%)		0/9 (0%)		1/20 (5%)		0/7 (0%)		1/36 (2.8%)
Gastrointestinal disorders
Abdominal Pain	0/5 (0%)		0/10 (0%)		0/4 (0%)		3/9 (33.3%)		2/20 (10%)		2/7 (28.6%)		3/36 (8.3%)
Gastric Hemorrhage	0/5 (0%)		1/10 (10%)		0/4 (0%)		0/9 (0%)		1/20 (5%)		0/7 (0%)		2/36 (5.6%)
Vomiting	0/5 (0%)		0/10 (0%)		0/4 (0%)		1/9 (11.1%)		0/20 (0%)		0/7 (0%)		0/36 (0%)
Esophageal varices	0/5 (0%)		0/10 (0%)		0/4 (0%)		1/9 (11.1%)		0/20 (0%)		0/7 (0%)		0/36 (0%)
Nausea	0/5 (0%)		0/10 (0%)		0/4 (0%)		0/9 (0%)		1/20 (5%)		0/7 (0%)		0/36 (0%)
Acute Focal Pancreatitis	0/5 (0%)		0/10 (0%)		0/4 (0%)		0/9 (0%)		1/20 (5%)		0/7 (0%)		2/36 (5.6%)
Gastointestinal Hemorrhage	0/5 (0%)		0/10 (0%)		0/4 (0%)		2/9 (22.2%)		0/20 (0%)		0/7 (0%)		0/36 (0%)
Ascites	0/5 (0%)		0/10 (0%)		0/4 (0%)		0/9 (0%)		1/20 (5%)		0/7 (0%)		1/36 (2.8%)
Large intestine perforation	0/5 (0%)		0/10 (0%)		0/4 (0%)		0/9 (0%)		1/20 (5%)		0/7 (0%)		0/36 (0%)
Constipation	0/5 (0%)		0/10 (0%)		0/4 (0%)		0/9 (0%)		1/20 (5%)		0/7 (0%)		0/36 (0%)
Small bowel obstruction	0/5 (0%)		0/10 (0%)		0/4 (0%)		0/9 (0%)		0/20 (0%)		0/7 (0%)		1/36 (2.8%)
Gastroparesis	0/5 (0%)		0/10 (0%)		0/4 (0%)		0/9 (0%)		0/20 (0%)		0/7 (0%)		1/36 (2.8%)
Hematemesis	0/5 (0%)		0/10 (0%)		0/4 (0%)		0/9 (0%)		0/20 (0%)		0/7 (0%)		1/36 (2.8%)
General disorders
Asthenia generalized	0/5 (0%)		1/10 (10%)		0/4 (0%)		0/9 (0%)		0/20 (0%)		0/7 (0%)		0/36 (0%)
Pyrexia	0/5 (0%)		0/10 (0%)		0/4 (0%)		0/9 (0%)		1/20 (5%)		0/7 (0%)		1/36 (2.8%)
Hepatobiliary disorders
Portal Vein Thrombosis	0/5 (0%)		0/10 (0%)		1/4 (25%)		0/9 (0%)		0/20 (0%)		0/7 (0%)		0/36 (0%)
Hepatic Cirrhosis	0/5 (0%)		0/10 (0%)		0/4 (0%)		0/9 (0%)		1/20 (5%)		0/7 (0%)		0/36 (0%)
Acute Cholecystitis	0/5 (0%)		0/10 (0%)		0/4 (0%)		0/9 (0%)		1/20 (5%)		0/7 (0%)		0/36 (0%)
Hepatic Failure	0/5 (0%)		0/10 (0%)		0/4 (0%)		0/9 (0%)		0/20 (0%)		0/7 (0%)		1/36 (2.8%)
Hepatitis	0/5 (0%)		0/10 (0%)		0/4 (0%)		0/9 (0%)		0/20 (0%)		0/7 (0%)		1/36 (2.8%)
Infections and infestations
Meningitis	0/5 (0%)		1/10 (10%)		0/4 (0%)		0/9 (0%)		0/20 (0%)		0/7 (0%)		0/36 (0%)
Sepsis	0/5 (0%)		0/10 (0%)		0/4 (0%)		0/9 (0%)		1/20 (5%)		0/7 (0%)		0/36 (0%)
Enterocolitis infectious	0/5 (0%)		0/10 (0%)		0/4 (0%)		0/9 (0%)		1/20 (5%)		0/7 (0%)		0/36 (0%)
Pneumonia	0/5 (0%)		0/10 (0%)		0/4 (0%)		0/9 (0%)		1/20 (5%)		0/7 (0%)		1/36 (2.8%)
Appendicitis	0/5 (0%)		0/10 (0%)		0/4 (0%)		0/9 (0%)		0/20 (0%)		0/7 (0%)		1/36 (2.8%)
Septic Shock	0/5 (0%)		0/10 (0%)		0/4 (0%)		0/9 (0%)		0/20 (0%)		0/7 (0%)		1/36 (2.8%)
Urinary Track infection	0/5 (0%)		0/10 (0%)		0/4 (0%)		0/9 (0%)		0/20 (0%)		0/7 (0%)		1/36 (2.8%)
Injury, poisoning and procedural complications
spinal fracture	0/5 (0%)		0/10 (0%)		0/4 (0%)		0/9 (0%)		1/20 (5%)		0/7 (0%)		1/36 (2.8%)
Hypoxia	0/5 (0%)		0/10 (0%)		0/4 (0%)		0/9 (0%)		0/20 (0%)		0/7 (0%)		1/36 (2.8%)
Metabolism and nutrition disorders
Dehydration	0/5 (0%)		0/10 (0%)		1/4 (25%)		0/9 (0%)		3/20 (15%)		0/7 (0%)		0/36 (0%)
Hyponatremia	0/5 (0%)		0/10 (0%)		0/4 (0%)		0/9 (0%)		1/20 (5%)		0/7 (0%)		1/36 (2.8%)
Metabolic acidosis	0/5 (0%)		0/10 (0%)		0/4 (0%)		0/9 (0%)		0/20 (0%)		0/7 (0%)		1/36 (2.8%)
Anorexia	0/5 (0%)		0/10 (0%)		0/4 (0%)		0/9 (0%)		0/20 (0%)		0/7 (0%)		1/36 (2.8%)
Musculoskeletal and connective tissue disorders
Myositis	0/5 (0%)		0/10 (0%)		0/4 (0%)		0/9 (0%)		1/20 (5%)		0/7 (0%)		0/36 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Mature B-Cell Lymphoma	0/5 (0%)		0/10 (0%)		0/4 (0%)		0/9 (0%)		0/20 (0%)		0/7 (0%)		1/36 (2.8%)
Nervous system disorders
Spinal cord compression	0/5 (0%)		0/10 (0%)		0/4 (0%)		0/9 (0%)		1/20 (5%)		0/7 (0%)		0/36 (0%)
Metabolic encephalopathy	0/5 (0%)		0/10 (0%)		0/4 (0%)		0/9 (0%)		0/20 (0%)		0/7 (0%)		1/36 (2.8%)
Product Issues
Biliary tube displaced	0/5 (0%)		0/10 (0%)		0/4 (0%)		0/9 (0%)		1/20 (5%)		0/7 (0%)		0/36 (0%)
Bile Sten Occlusion	0/5 (0%)		0/10 (0%)		0/4 (0%)		0/9 (0%)		1/20 (5%)		0/7 (0%)		0/36 (0%)
Psychiatric disorders
Delirium	0/5 (0%)		1/10 (10%)		0/4 (0%)		0/9 (0%)		0/20 (0%)		0/7 (0%)		0/36 (0%)
Altered mental status	0/5 (0%)		0/10 (0%)		0/4 (0%)		1/9 (11.1%)		0/20 (0%)		0/7 (0%)		0/36 (0%)
Renal and urinary disorders
Acute Kidney Injury	0/5 (0%)		0/10 (0%)		0/4 (0%)		0/9 (0%)		2/20 (10%)		0/7 (0%)		0/36 (0%)
Hematuria	0/5 (0%)		0/10 (0%)		0/4 (0%)		0/9 (0%)		0/20 (0%)		1/7 (14.3%)		1/36 (2.8%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	0/5 (0%)		0/10 (0%)		0/4 (0%)		0/9 (0%)		1/20 (5%)		0/7 (0%)		0/36 (0%)
Acute Respiratory Failure	0/5 (0%)		0/10 (0%)		0/4 (0%)		0/9 (0%)		0/20 (0%)		0/7 (0%)		2/36 (5.6%)
Pulmonary edema	0/5 (0%)		0/10 (0%)		0/4 (0%)		0/9 (0%)		0/20 (0%)		0/7 (0%)		1/36 (2.8%)
Other (Not Including Serious) Adverse Events
	Experimental Napabucasin+Sorafenib Phase IB- Dose Level 1		Experimental Napabucasin +Sorafenib Phase IB- Dose Level 2		Experimental Amcasertib+Sorafenib Phase IB- Dose Level 1		Experimental Amcasertib+Sorafenib Phase IB- Dose Level 2		Experimental Napabucasin +Sorafenib Phase II		Experimental Amcasertib +Sorafenib Phase II		Sorafenib Phase II
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/5 (100%)		10/10 (100%)		4/4 (100%)		9/9 (100%)		20/20 (100%)		7/7 (100%)		35/36 (97.2%)
Gastrointestinal disorders
Diarrhea	4/5 (80%)		7/10 (70%)		3/4 (75%)		7/9 (77.8%)		17/20 (85%)		6/7 (85.7%)		18/36 (50%)
Nausea	3/5 (60%)		5/10 (50%)		2/4 (50%)		5/9 (55.6%)		9/20 (45%)		3/7 (42.9%)		17/36 (47.2%)
Abdominal pain	3/5 (60%)		3/10 (30%)		0/4 (0%)		3/9 (33.3%)		10/20 (50%)		3/7 (42.9%)		7/36 (19.4%)
Constipation	1/5 (20%)		2/10 (20%)		1/4 (25%)		2/9 (22.2%)		5/20 (25%)		4/7 (57.1%)		9/36 (25%)
Dyspepsia	1/5 (20%)		2/10 (20%)		0/4 (0%)		4/9 (44.4%)		0/20 (0%)		0/7 (0%)		0/36 (0%)
Vomiting	0/5 (0%)		0/10 (0%)		0/4 (0%)		0/9 (0%)		4/20 (20%)		2/7 (28.6%)		8/36 (22.2%)
Stomatitis	0/5 (0%)		2/10 (20%)		1/4 (25%)		2/9 (22.2%)		0/20 (0%)		0/7 (0%)		0/36 (0%)
General disorders
Fatigue	4/5 (80%)		8/10 (80%)		1/4 (25%)		6/9 (66.7%)		15/20 (75%)		6/7 (85.7%)		22/36 (61.1%)
Asthenia	0/5 (0%)		5/10 (50%)		0/4 (0%)		1/9 (11.1%)		0/20 (0%)		0/7 (0%)		0/36 (0%)
Pyrexia	1/5 (20%)		4/10 (40%)		0/4 (0%)		1/9 (11.1%)		0/20 (0%)		0/7 (0%)		0/36 (0%)
Chills	1/5 (20%)		2/10 (20%)		0/4 (0%)		1/9 (11.1%)		0/20 (0%)		0/7 (0%)		0/36 (0%)
Hepatobiliary disorders
Hyperbilirubinaemia	3/5 (60%)		0/10 (0%)		0/4 (0%)		1/9 (11.1%)		0/20 (0%)		0/7 (0%)		0/36 (0%)
Investigations
Aspartate aminotrasnferase increased	1/5 (20%)		3/10 (30%)		0/4 (0%)		0/9 (0%)		5/20 (25%)		2/7 (28.6%)		6/36 (16.7%)
Weight Decreased	2/5 (40%)		2/10 (20%)		1/4 (25%)		3/9 (33.3%)		4/20 (20%)		3/7 (42.9%)		14/36 (38.9%)
Blood bilirubin increased	0/5 (0%)		3/10 (30%)		0/4 (0%)		1/9 (11.1%)		0/20 (0%)		0/7 (0%)		0/36 (0%)
Metabolism and nutrition disorders
Decreased appetite	1/5 (20%)		4/10 (40%)		2/4 (50%)		5/9 (55.6%)		8/20 (40%)		3/7 (42.9%)		16/36 (44.4%)
Dehydration	0/5 (0%)		1/10 (10%)		1/4 (25%)		2/9 (22.2%)		0/20 (0%)		0/7 (0%)		0/36 (0%)
Hypoalbuminaemia	0/5 (0%)		3/10 (30%)		0/4 (0%)		1/9 (11.1%)		0/20 (0%)		0/7 (0%)		0/36 (0%)
Hyponatraemia	2/5 (40%)		1/10 (10%)		0/4 (0%)		1/9 (11.1%)		0/20 (0%)		0/7 (0%)		0/36 (0%)
Musculoskeletal and connective tissue disorders
Pain in extremity	1/5 (20%)		2/10 (20%)		1/4 (25%)		0/9 (0%)		0/20 (0%)		0/7 (0%)		0/36 (0%)
Psychiatric disorders
Insomnia	1/5 (20%)		3/10 (30%)		0/4 (0%)		0/9 (0%)		0/20 (0%)		0/7 (0%)		0/36 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	0/5 (0%)		0/10 (0%)		0/4 (0%)		0/9 (0%)		4/20 (20%)		3/7 (42.9%)		7/36 (19.4%)
Skin and subcutaneous tissue disorders
Dry Skin	2/5 (40%)		2/10 (20%)		0/4 (0%)		1/9 (11.1%)		0/20 (0%)		0/7 (0%)		0/36 (0%)
Palmar-plantar erythrosaesthesia syndrome	2/5 (40%)		2/10 (20%)		2/4 (50%)		2/9 (22.2%)		3/20 (15%)		3/7 (42.9%)		9/36 (25%)
Rash	0/5 (0%)		2/10 (20%)		2/4 (50%)		1/9 (11.1%)		0/20 (0%)		0/7 (0%)		0/36 (0%)
Vascular disorders
Hypertension	0/5 (0%)		3/10 (30%)		1/4 (25%)		2/9 (22.2%)		5/20 (25%)		1/7 (14.3%)		8/36 (22.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

A copy of any proposed publication or disclosure of the results of the Study will be given to Sponsor for review at least thirty (30) days prior to the date of submission for publication ( including abstracts) or of public disclosure ( the review period).