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

NCT02279719 | Completed Phase 1 Results

• 2 other identifiers: BBIHCC-103BBI608-503-103HCC
• Study Type: interventional
• Target: 97
• Locations: 1 country
• Sites: 29

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.

Conditions

Hepatocellular Carcinoma

Outcome Measures

Primary Outcomes (5)

• 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 Outcomes (2)

• 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

• 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

Study Arms (3)

BBI608 and Sorafenib

EXPERIMENTAL

Drug: BBI608; Drug: Sorafenib

BBI503 and Sorafenib

EXPERIMENTAL

Drug: BBI503; Drug: Sorafenib

Sorafenib

ACTIVE COMPARATOR

Drug: Sorafenib

Interventions

BBI608 DRUG

BBI608 will be administered in combination with sorafenib at the RP2D determined during the phase 1 dose-escalation portion of study.

Also known as: Napabucasin, BBI-608, BB608

BBI608 and Sorafenib

BBI503 DRUG

BBI503 will be administered in combination with sorafenib at the RP2D determined during the phase 1 dose-escalation portion of study.

Also known as: Amcasertib, BBI-503, BB503

BBI503 and Sorafenib

Sorafenib DRUG

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.

Also known as: Nexavar

BBI503 and Sorafenib; BBI608 and Sorafenib; Sorafenib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• 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.

Sponsors & Collaborators

• Sumitomo Pharma America, Inc.: lead

Study Sites (29)

Banner MD Anderson Cancer Center

Gilbert, Arizona, 85234, United States

Location

Mayo Clinic

Phoenix, Arizona, 85054, United States

Location

Southern California Research Center

Coronado, California, 92118, United States

Location

California Center Associates for Research and Excellence, Inc. (Ccare)

Encinitas, California, 92024, United States

Location

USC Norris Comprehensive Cancer Center

Los Angeles, California, 90033, United States

Location

USOR - Rocky Mountain Cancer Centers

Denver, Colorado, 80218, United States

Location

Baptist Health Medical Group Oncology, LLC

Miami, Florida, 33176, United States

Location

Piedmont Cancer Institute, P.C.

Atlanta, Georgia, 30318, United States

Location

Winship Cancer Institute of Emory University

Atlanta, Georgia, 30322, United States

Location

Norton Cancer Institute

Louisville, Kentucky, 40202, United States

Location

Karmanos Cancer Institute

Detroit, Michigan, 48201, United States

Location

Minnesota Oncology Hematology, P.A.

Minneapolis, Minnesota, 55404, United States

Location

Kansas City Research Institure

Kansas City, Missouri, 64131, United States

Location

USOR - Comprehensive Cancer Centers of Nevada

Las Vegas, Nevada, 89169, United States

Location

The Valley Hospital Luckow Pavilion

Paramus, New Jersey, 07652, United States

Location

USOR - New York Oncology Hematology

Albany, New York, 12206, United States

Location

University of Rochester, Wilmot Cancer Institute

Rochester, New York, 14642, United States

Location

Carolinas Health Care System

Charlotte, North Carolina, 28204, United States

Location

Wake Forest Baptist Health

Winston-Salem, North Carolina, 27157, United States

Location

University of Cincinnati, Vontz Center

Cincinnati, Ohio, 45267, United States

Location

Drexel University

Philadelphia, Pennsylvania, 19102, United States

Location

USOR - Texas Oncology, Austin Midtown

Austin, Texas, 78705, United States

Location

Texas Oncology-Baylor Charles A. Sammons Cancer Center

Dallas, Texas, 75246, United States

Location

Texas Oncology - El Paso Cancer Treatment Center Joe Battle

El Paso, Texas, 79938, United States

Location

USOR - Texas Oncology, Fort Worth 12th Ave

Fort Worth, Texas, 76104, United States

Location

Oncology Consultants

Houston, Texas, 77030, United States

Location

Texas Oncology-McAllen South Second Street

McAllen, Texas, 78503, United States

Location

USOR - Texas Oncology, Tyler

Tyler, Texas, 75702, United States

Location

Oncology and Hematology Associates of Southwest Virginia, Inc., DBA Blue Ridge Cancer Care

Roanoke, Virginia, 24014, United States

Location

MeSH Terms

Conditions

Carcinoma, Hepatocellular

Interventions

napabucasin; Sorafenib

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Intervention Hierarchy (Ancestors)

Phenylurea Compounds; Urea; Amides; Organic Chemicals; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Niacinamide; Nicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring

Results Point of Contact

• Title: Matthew Hitron, MD
• Organization: Sumitomo Dainippon Pharma Oncology

mhitron@bostonbiomedical.com

617-674-6800

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 24, 2014
• First Posted: October 31, 2014
• Study Start: December 1, 2014
• Primary Completion: July 1, 2019
• Study Completion: October 1, 2019
• Last Updated: November 15, 2023
• Results First Posted: September 9, 2021

Record last verified: 2023-11

Locations

US (29)