Clinical trial NCT02279719: A Study of BBI608 in Combination With Sorafenib, or BBI503 in Combination With Sorafenib in Adult Patients With Hepatocellular Carcinoma
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Hepatocellular Carcinoma
Lead sponsor: Sumitomo Pharma America, Inc.
Sponsor class: INDUSTRY
First posted: 2014-10-31
Enrollment: 97
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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.

   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.
3. 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)
4. Patients must be candidates for sorafenib
5. 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.
6. Must be Child-Pugh class A

   a. Patients with uncontrolled massive ascites or presence of hepatic encephalopathy are excluded
7. Must have total serum bilirubin ≤ 3 mg/dl
8. ≥ 18 years of age
9. Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
10. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
11. 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
12. Females of childbearing potential must have a negative serum pregnancy test
13. Aspartate Aminotransferase (AST) and Alanine transaminase (ALT) \< 5.0x the upper limit of normal (ULN)
14. 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

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:

   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.
6. 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.
7. Pregnant or breastfeeding
8. 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.
9. Unable or unwilling to swallow BBI608, BBI503, or sorafenib capsules or tablets
10. 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).
11. 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.
12. 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.

Primary outcomes:
measure: Assessment of the Dose Limiting Toxicities for the Napabucasin and Amcasertib Arm in Combination With Sorafenib for Phase IB
timeFrame: 16 weeks including 2-week Sorafenib run-in period prior to initiation of combination therapy
measure: To Assess the Number of Patients Who Experienced Adverse Events for Phase IB.
timeFrame: 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.
measure: Determination of the Recommended Phase II Dose for Napabucasin and Amcasertib Arm in Combination With Sorafenib
timeFrame: 16 weeks including 2-week Sorafenib run-in period prior to initiation of combination therapy
measure: Assessment of Objective Response Rate in the Intent to Treat Population - Phase II
timeFrame: 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
measure: Assessment of Disease Control Rate in the Intent to Treat Population- Phase II
timeFrame: 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: Assessment of the Pharmacokinetic Profile (Maximum Plasma Concentration and Area Under the Curve) of Either Napabucasin or Amcasertib.
timeFrame: 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
measure: Assessment of the Pharmacodynamic Studies as Well as the Concentration of Study Drug (Either Napabucasin or Amcasertib) in Tumors
timeFrame: On day 15 of the second cycle
Other outcomes:
Locations:
city: Gilbert
country: United States
facility: Banner MD Anderson Cancer Center
state: Arizona
city: Phoenix
country: United States
facility: Mayo Clinic
state: Arizona
city: Coronado
country: United States
facility: Southern California Research Center
state: California
city: Encinitas
country: United States
facility: California Center Associates for Research and Excellence, Inc. (Ccare)
state: California
city: Los Angeles
country: United States
facility: USC Norris Comprehensive Cancer Center
state: California
city: Denver
country: United States
facility: USOR - Rocky Mountain Cancer Centers
state: Colorado
city: Miami
country: United States
facility: Baptist Health Medical Group Oncology, LLC
state: Florida
city: Atlanta
country: United States
facility: Piedmont Cancer Institute, P.C.
state: Georgia
city: Atlanta
country: United States
facility: Winship Cancer Institute of Emory University
state: Georgia
city: Louisville
country: United States
facility: Norton Cancer Institute
state: Kentucky
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
city: Minneapolis
country: United States
facility: Minnesota Oncology Hematology, P.A.
state: Minnesota
city: Kansas City
country: United States
facility: Kansas City Research Institure
state: Missouri
city: Las Vegas
country: United States
facility: USOR - Comprehensive Cancer Centers of Nevada
state: Nevada
city: Paramus
country: United States
facility: The Valley Hospital Luckow Pavilion
state: New Jersey
city: Albany
country: United States
facility: USOR - New York Oncology Hematology
state: New York
city: Rochester
country: United States
facility: University of Rochester, Wilmot Cancer Institute
state: New York
city: Charlotte
country: United States
facility: Carolinas Health Care System
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest Baptist Health
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati, Vontz Center
state: Ohio
city: Philadelphia
country: United States
facility: Drexel University
state: Pennsylvania
city: Austin
country: United States
facility: USOR - Texas Oncology, Austin Midtown
state: Texas
city: Dallas
country: United States
facility: Texas Oncology-Baylor Charles A. Sammons Cancer Center
state: Texas
city: El Paso
country: United States
facility: Texas Oncology - El Paso Cancer Treatment Center Joe Battle
state: Texas
city: Fort Worth
country: United States
facility: USOR - Texas Oncology, Fort Worth 12th Ave
state: Texas
city: Houston
country: United States
facility: Oncology Consultants
state: Texas
city: McAllen
country: United States
facility: Texas Oncology-McAllen South Second Street
state: Texas
city: Tyler
country: United States
facility: USOR - Texas Oncology, Tyler
state: Texas
city: Roanoke
country: United States
facility: Oncology and Hematology Associates of Southwest Virginia, Inc., DBA Blue Ridge Cancer Care
state: Virginia
Study officials:
References: