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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase Ib/II Clinical Study of BBI608 in Combination With Sorafenib, or BBI503 in Combination With Sorafenib in Adult Patients With Hepatocellular Carcinoma

Conditions
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Hepatocellular Carcinoma

Intervention / Treatment
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* Drug: BBI608
* Drug: BBI503
* Drug: Sorafenib


Participation Criteria
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Eligibility Criteria
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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. Patients must not be candidates for curative resection 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. 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: There is progression of disease documented by RECIST 1.1 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BBI608 and Sorafenib<br> | Drug: BBI608<br>* BBI608 will be administered in combination with sorafenib at the RP2D determined during the phase 1 dose-escalation portion of study.<br>* Other names: BB608;Drug: Sorafenib<br>* 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.<br>* Other names: Nexavar;|
| Experimental: BBI503 and Sorafenib<br> | Drug: BBI503<br>* BBI503 will be administered in combination with sorafenib at the RP2D determined during the phase 1 dose-escalation portion of study.<br>* Other names: BB503;Drug: Sorafenib<br>* 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.<br>* Other names: Nexavar;|
| Active Comparator: Sorafenib<br> | Drug: Sorafenib<br>* 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.<br>* Other names: Nexavar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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 | 
| 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) | 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 Outcome Measures

| Outcome Measure | 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 | 
| 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. | On day 15 of the second cycle |