A Study of BBI608 in Combination With Sorafenib, or BBI50... | NCT02279719

ID	Type	Description	Link
BBI608-503-103HCC	Other Identifier	Boston Biomedical, Inc.

Description Module

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.

Label	Type	Intervention Names
BBI608 and Sorafenib	Experimental	Drug: BBI608 Drug: Sorafenib
BBI503 and Sorafenib	Experimental	Drug: BBI503 Drug: Sorafenib
Sorafenib	Active Comparator	Drug: Sorafenib

Name	Type	Description	Arm Group Labels	Other Names
BBI608	Drug	BBI608 will be administered in combination with sorafenib at the RP2D determined during the phase 1 dose-escalation portion of study.	BBI608 and Sorafenib

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Assessment of the Dose Limiting Toxicities for the Napabucasin and Amcasertib Arm in Combination With Sorafenib for Phase IB	To assess the dose limiting toxicities for phase IB	16 weeks including 2-week Sorafenib run-in period prior to initiation of combination therapy
To Assess the Number of Patients Who Experienced Adverse Events for Phase IB.	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	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.
Determination of the Recommended Phase II Dose for Napabucasin and Amcasertib Arm in Combination With Sorafenib	To determine 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
Assessment of Objective Response Rate in the Intent to Treat Population - Phase II	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.	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

Secondary Outcomes

Measure	Description	Time Frame
Assessment of the Pharmacokinetic Profile (Maximum Plasma Concentration and Area Under the Curve) of Either Napabucasin or Amcasertib.	To determine the pharmacokinetic (PK) profile of napabucasin administered in combination with sorafenib and of amcasertib administered in combination with sorafenib.	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

Eligibility Module

Eligibility Criteria

Inclusion Criteria

Signed written informed consent must be obtained and documented according to International Conference on Harmonisation (ICH) and local regulatory requirements
Histologically or cytologically confirmed hepatocellular carcinoma that is metastatic, unresectable, or recurrent.
1. Patients must not be candidates for curative resection
2. 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.
3. Patients who have recurrent hepatocellular carcinoma following hepatic transplantation are excluded unless the following criteria are met:
i. 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.

iii. 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.
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)
Patients must be candidates for sorafenib
Must have had no previous systemic anti-cancer treatment, though previous loco-regional therapy is allowed:

a. 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.
Must be Child-Pugh class A

a. Patients with uncontrolled massive ascites or presence of hepatic encephalopathy are excluded
Must have total serum bilirubin ≤ 3 mg/dl
≥ 18 years of age
Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
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
Females of childbearing potential must have a negative serum pregnancy test
Aspartate Aminotransferase (AST) and Alanine transaminase (ALT) < 5.0x the upper limit of normal (ULN)
Glomerular filtration rate (GFR) > 45 mL/min/1.73m^2 according to the Cockcroft-Gault estimation.

13. 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

Previous treatment with sorafenib
Patients with known hypersensitivity to sorafenib or any other component of sorafenib.
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.
Have had a surgical procedure requiring general anesthesia or inpatient hospitalization for recovery less than 4 weeks prior to beginning protocol therapy.
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:
1. There is progression of disease documented by RECIST 1.1
2. All adverse events from the procedure have resolved or have been deemed irreversible and the patient meets inclusion criteria.
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.
Pregnant or breastfeeding
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.
Unable or unwilling to swallow BBI608, BBI503, or sorafenib capsules or tablets
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).
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.
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.

Facility	Status	City	State	ZIP	Country	Contacts
Banner MD Anderson Cancer Center		Gilbert	Arizona	85234	United States
Mayo Clinic

ID	Title	Description
FG000	Experimental Napabucasin+Sorafenib Phase IB Dose- Level 1	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.

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Apr 3, 2018	Jun 3, 2021

Arm/Group Information

ID	Title	Description
BG000	Experimental Napabucasin +Sorafenib Phase IB- Dose Level 1	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.
BG001	Experimental Napabucasin +Sorafenib Phase IB- Dose Level 2	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.
BG002	Experimental Amcasertib +Sorafenib Phase IB- Dose Level 1	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
BG003	Experimental Amcasertib +Sorafenib Phase IB- Dose Level 2	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.
BG004	Experimental Napabucasin +Sorafenib Phase II	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.
BG005	Experimental Amcasertib +Sorafenib Phase II	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.
BG006	Sorafenib Phase II	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.
BG007	Total	Total of all reporting groups

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Reporting Status

Anticipated Posting Date

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Arm/Group Information

Denominators

Classes

Analyses

Primary

Assessment of the Dose Limiting Toxicities for the Napabucasin and Amcasertib Arm in Combination With Sorafenib for Phase IB

To assess the dose limiting toxicities for phase IB

Posted

Number

Dose limiting toxicities

16 weeks including 2-week Sorafenib run-in period prior to initiation of combination therapy

ID	Title	Description
OG000	Napabucasin+Sorafenib Phase IB- Dose Level 1	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).
OG001	Napabucasin+Sorafenib Phase IB- Dose Level 2	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).
OG002	Amcasertib+Sorafenib Phase IB- Dose Level 1	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).
OG003	Amcasertib+ Sorafenib Phase IB Dose Level 2	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).

Units	Counts
Participants	OG0005 OG00110 OG0024 OG003

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Title	Measurements
	OG0000 OG0010 OG0020 OG003

Primary

To Assess the Number of Patients Who Experienced Adverse Events for Phase IB.

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

Posted

Number

count of participants

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.

ID	Title	Description
OG000	Napabucasin+Sorafenib Phase IB- Dose Level 1	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).
OG001	Napabucasin+Sorafenib Phase IB - Dose Level 2	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).

Primary

Determination of the Recommended Phase II Dose for Napabucasin and Amcasertib Arm in Combination With Sorafenib

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

Posted

Number

16 weeks including 2-week Sorafenib run-in period prior to initiation of combination therapy

ID	Title	Description
OG000	Napabucasin+Sorafenib Phase IB	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).
OG001	Amcasertib+ Sorafenib Phase IB	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).

Primary

Assessment of Objective Response Rate in the Intent to Treat Population - Phase II

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.

Posted

Number

95% Confidence Interval

percentage of participants

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

ID	Title	Description
OG000	Experimental Napabucasin +Sorafenib Phase II	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.
OG001

Primary

Assessment of Disease Control Rate in the Intent to Treat Population- Phase II

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)

Posted

Number

95% Confidence Interval

percentage of participants

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

ID	Title	Description
OG000	Experimental Napabucasin +Sorafenib Phase II	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.
OG001

Secondary

Assessment of the Pharmacokinetic Profile (Maximum Plasma Concentration and Area Under the Curve) of Either Napabucasin or Amcasertib.

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

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.

Posted

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

ID	Title	Description
OG000	Experimental Napabucasin Plus Sorafenib Phase IB- Dose Level 1	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
OG001	Experimental Napabucasin Plus Sorafenib Phase IB- Dose Level 2	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.

Secondary

Assessment of the Pharmacodynamic Studies as Well as the Concentration of Study Drug (Either Napabucasin or Amcasertib) in Tumors

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

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.

Posted

On day 15 of the second cycle

ID	Title	Description
OG000	Experimental Napabucasin Plus Sorafenib Phase IB- Dose Level 1	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
OG001	Experimental Napabucasin Plus Sorafenib Phase IB- Dose Level 2	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.

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Experimental Napabucasin+Sorafenib Phase IB- Dose Level 1	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).	4	5	0	5	5	5
EG001	Experimental Napabucasin +Sorafenib Phase IB- Dose Level 2	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).	7	10	3	10	10	10
EG002	Experimental Amcasertib+Sorafenib Phase IB- Dose Level 1	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).	4	4	2	4	4	4
EG003	Experimental Amcasertib+Sorafenib Phase IB- Dose Level 2	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).	9	9	5	9	9	9
EG004	Experimental Napabucasin +Sorafenib Phase II	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	15	20	10	20	20	20
EG005	Experimental Amcasertib +Sorafenib Phase II	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	6	7	3	7	7	7
EG006	Sorafenib Phase II	Phase II: Patients who have received at least one dose of sorafenib	23	36	16	36	35	36

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Abdominal Pain	Gastrointestinal disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0020 affected4 at risk EG0033 affected9 at risk EG0042 affected20 at risk EG0052 affected7 at risk EG0063 affected36 at risk
Gastric Hemorrhage	Gastrointestinal disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0011 affected10 at risk EG0020 affected4 at risk EG003
Vomiting	Gastrointestinal disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0020 affected4 at risk EG003
Esophageal varices	Gastrointestinal disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0020 affected4 at risk EG003
Nausea	Gastrointestinal disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0020 affected4 at risk EG003
Acute Focal Pancreatitis	Gastrointestinal disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0020 affected4 at risk EG003
Gastointestinal Hemorrhage	Gastrointestinal disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0020 affected4 at risk EG003
Ascites	Gastrointestinal disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0020 affected4 at risk EG003
Large intestine perforation	Gastrointestinal disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0020 affected4 at risk EG003
Constipation	Gastrointestinal disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0020 affected4 at risk EG003
Small bowel obstruction	Gastrointestinal disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0020 affected4 at risk EG003
Gastroparesis	Gastrointestinal disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0020 affected4 at risk EG003
Hematemesis	Gastrointestinal disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0020 affected4 at risk EG003
Meningitis	Infections and infestations	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0011 affected10 at risk EG0020 affected4 at risk EG003
Sepsis	Infections and infestations	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0020 affected4 at risk EG003
Enterocolitis infectious	Infections and infestations	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0020 affected4 at risk EG003
Pneumonia	Infections and infestations	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0020 affected4 at risk EG003
Appendicitis	Infections and infestations	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0020 affected4 at risk EG003
Septic Shock	Infections and infestations	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0020 affected4 at risk EG003
Urinary Track infection	Infections and infestations	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0020 affected4 at risk EG003
Angina Pectoris	Cardiac disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0011 affected10 at risk EG0020 affected4 at risk EG003
Acute Myocardial Infarction	Cardiac disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0021 affected4 at risk EG003
Cardiac Arrest	Cardiac disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0020 affected4 at risk EG003
Delirium	Psychiatric disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0011 affected10 at risk EG0020 affected4 at risk EG003
Altered mental status	Psychiatric disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0020 affected4 at risk EG003
Asthenia generalized	General disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0011 affected10 at risk EG0020 affected4 at risk EG003
Pyrexia	General disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0020 affected4 at risk EG003
Dehydration	Metabolism and nutrition disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0021 affected4 at risk EG003
Hyponatremia	Metabolism and nutrition disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0020 affected4 at risk EG003
Metabolic acidosis	Metabolism and nutrition disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0020 affected4 at risk EG003
Anorexia	Metabolism and nutrition disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0020 affected4 at risk EG003
Portal Vein Thrombosis	Hepatobiliary disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0021 affected4 at risk EG003
Hepatic Cirrhosis	Hepatobiliary disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0020 affected4 at risk EG003
Acute Cholecystitis	Hepatobiliary disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0020 affected4 at risk EG003
Hepatic Failure	Hepatobiliary disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0020 affected4 at risk EG003
Hepatitis	Hepatobiliary disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0020 affected4 at risk EG003
Acute Kidney Injury	Renal and urinary disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0020 affected4 at risk EG003
Hematuria	Renal and urinary disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0020 affected4 at risk EG003
Myositis	Musculoskeletal and connective tissue disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0020 affected4 at risk EG003
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0020 affected4 at risk EG003
Acute Respiratory Failure	Respiratory, thoracic and mediastinal disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0020 affected4 at risk EG003
Pulmonary edema	Respiratory, thoracic and mediastinal disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0020 affected4 at risk EG003
spinal fracture	Injury, poisoning and procedural complications	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0020 affected4 at risk EG003
Hypoxia	Injury, poisoning and procedural complications	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0020 affected4 at risk EG003
Spinal cord compression	Nervous system disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0020 affected4 at risk EG003
Metabolic encephalopathy	Nervous system disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0020 affected4 at risk EG003
Biliary tube displaced	Product Issues	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0020 affected4 at risk EG003
Bile Sten Occlusion	Product Issues	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0020 affected4 at risk EG003
Mature B-Cell Lymphoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0020 affected4 at risk EG003

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Diarrhea	Gastrointestinal disorders	MedDRA 19.0	Systematic Assessment	EG0004 affected5 at risk EG0017 affected10 at risk EG0023 affected4 at risk EG0037 affected9 at risk EG00417 affected20 at risk EG0056 affected7 at risk EG00618 affected36 at risk
Nausea	Gastrointestinal disorders	MedDRA 19.0	Systematic Assessment	EG0003 affected5 at risk EG0015 affected10 at risk EG0022 affected4 at risk EG003
Abdominal pain	Gastrointestinal disorders	MedDRA 19.0	Systematic Assessment	EG0003 affected5 at risk EG0013 affected10 at risk EG0020 affected4 at risk EG003
Constipation	Gastrointestinal disorders	MedDRA 19.0	Systematic Assessment	EG0001 affected5 at risk EG0012 affected10 at risk EG0021 affected4 at risk EG003
Dyspepsia	Gastrointestinal disorders	MedDRA 19.0	Systematic Assessment	EG0001 affected5 at risk EG0012 affected10 at risk EG0020 affected4 at risk EG003
Vomiting	Gastrointestinal disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0020 affected4 at risk EG003
Stomatitis	Gastrointestinal disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0012 affected10 at risk EG0021 affected4 at risk EG003
Fatigue	General disorders	MedDRA 19.0	Systematic Assessment	EG0004 affected5 at risk EG0018 affected10 at risk EG0021 affected4 at risk EG003
Asthenia	General disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0015 affected10 at risk EG0020 affected4 at risk EG003
Pyrexia	General disorders	MedDRA 19.0	Systematic Assessment	EG0001 affected5 at risk EG0014 affected10 at risk EG0020 affected4 at risk EG003
Chills	General disorders	MedDRA 19.0	Systematic Assessment	EG0001 affected5 at risk EG0012 affected10 at risk EG0020 affected4 at risk EG003
Dry Skin	Skin and subcutaneous tissue disorders	MedDRA 19.0	Systematic Assessment	EG0002 affected5 at risk EG0012 affected10 at risk EG0020 affected4 at risk EG003
Palmar-plantar erythrosaesthesia syndrome	Skin and subcutaneous tissue disorders	MedDRA 19.0	Systematic Assessment	EG0002 affected5 at risk EG0012 affected10 at risk EG0022 affected4 at risk EG003
Rash	Skin and subcutaneous tissue disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0012 affected10 at risk EG0022 affected4 at risk EG003
Decreased appetite	Metabolism and nutrition disorders	MedDRA 19.0	Systematic Assessment	EG0001 affected5 at risk EG0014 affected10 at risk EG0022 affected4 at risk EG003
Dehydration	Metabolism and nutrition disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0011 affected10 at risk EG0021 affected4 at risk EG003
Hypoalbuminaemia	Metabolism and nutrition disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0013 affected10 at risk EG0020 affected4 at risk EG003
Hyponatraemia	Metabolism and nutrition disorders	MedDRA 19.0	Systematic Assessment	EG0002 affected5 at risk EG0011 affected10 at risk EG0020 affected4 at risk EG003
Aspartate aminotrasnferase increased	Investigations	MedDRA 19.0	Systematic Assessment	EG0001 affected5 at risk EG0013 affected10 at risk EG0020 affected4 at risk EG003
Weight Decreased	Investigations	MedDRA 19.0	Systematic Assessment	EG0002 affected5 at risk EG0012 affected10 at risk EG0021 affected4 at risk EG003
Blood bilirubin increased	Investigations	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0013 affected10 at risk EG0020 affected4 at risk EG003
Insomnia	Psychiatric disorders	MedDRA 19.0	Systematic Assessment	EG0001 affected5 at risk EG0013 affected10 at risk EG0020 affected4 at risk EG003
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA 19.0	Systematic Assessment	EG0001 affected5 at risk EG0012 affected10 at risk EG0021 affected4 at risk EG003
Hyperbilirubinaemia	Hepatobiliary disorders	MedDRA 19.0	Systematic Assessment	EG0003 affected5 at risk EG0010 affected10 at risk EG0020 affected4 at risk EG003
Hypertension	Vascular disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0013 affected10 at risk EG0021 affected4 at risk EG003
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected5 at risk EG0010 affected10 at risk EG0020 affected4 at risk EG003

ID	Term
D000230	Adenocarcinoma
D002277	Carcinoma
D009375	Neoplasms, Glandular and Epithelial
D009370	Neoplasms by Histologic Type
D009369	Neoplasms
D008113	Liver Neoplasms
D004067	Digestive System Neoplasms
D009371	Neoplasms by Site
D004066	Digestive System Diseases
D008107	Liver Diseases

ID	Term
D010671	Phenylurea Compounds
D014508	Urea
D000577	Amides
D009930	Organic Chemicals
D001555	Benzene Derivatives
D006841	Hydrocarbons, Aromatic
D006844	Hydrocarbons, Cyclic
D006838	Hydrocarbons
D009536	Niacinamide
D009539	Nicotinic Acids
D000147	Acids, Heterocyclic
D006571	Heterocyclic Compounds
D011725	Pyridines
D006573	Heterocyclic Compounds, 1-Ring