Sirolimus and Bevacizumab in Treating Patients With Liver Cancer That Cannot Be Removed by Surgery

NCT00467194 | Completed Phase 1

• 2 other identifiers: CDR0000540163SINGAPORE-06-17-HEP
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 2

Brief Summary

RATIONALE: Sirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab and sirolimus may also stop the growth of liver cancer by blocking blood flow to the tumor. Giving sirolimus together with bevacizumab may kill more tumor cells. PURPOSE: This phase I trial is studying the side effects and best dose of sirolimus when given together with bevacizumab in treating patients with liver cancer that cannot be removed by surgery.

Conditions

Liver Cancer

Keywords

adult primary hepatocellular carcinoma; localized unresectable adult primary liver cancer; recurrent adult primary liver cancer; advanced adult primary liver cancer

Outcome Measures

Primary Outcomes (2)

• Dose-limiting toxicity

  3 years

• Maximum tolerated dose

  3 years

Secondary Outcomes (9)

• Response rate (complete and partial response and stable disease)

  3 years

• Progression-free survival

  3 years

• Overall survival

  3 years

• Distribution of p70S6K activity in peripheral blood mononuclear cells

  3 years

• Correlation of p70S6K with tumor response

  3 years

Study Arms (1)

Phase I study of rapamycin and bevacizumab

EXPERIMENTAL

Rapamycin (available as 1mg per tablet; Wyeth) will be given orally once in the morning before meal. The starting dose of rapamycin will be 1mg administered once daily. All doses of rapamycin will be preceded by an oral loading dose three times the maintenance dose on day 1. The dose of rapamycin will be increased at each dose level. Bevacizumab (100mg/4ml; Roche) will start concurrently with rapamycin. It will be diluted in a total of 100ml of 0.9% sodium chloride given via intravenous injection. The first dose will be infused over 90 minutes. If the first infusion is tolerated without any adverse infusion-related events (fever and/or chills), the second infusion may be delivered over 60 minutes. If the 60- minute infusion is well tolerated, the subsequent doses may be delivered over 30 minutes.

Drug: Rapamycin; Drug: Bevacizumab

Interventions

Rapamycin DRUG

Phase I study of rapamycin and bevacizumab

Bevacizumab DRUG

Phase I study of rapamycin and bevacizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

DISEASE CHARACTERISTICS: * Meets 1 of the following criteria: * Histologically confirmed unresectable hepatocellular carcinoma, meeting all of the following criteria: * Failed 0-2 lines of chemotherapy * Child-Pugh class A or B for liver cirrhosis * Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm with conventional techniques or ≥ 10 mm with spiral CT scan * No known brain metastases * Bone metastases allowed provided other measurable disease is present * Healthy participant PATIENT CHARACTERISTICS: * ECOG performance status (PS) 0-2 or Karnofsky PS 70-100% * Life expectancy \> 3 months * WBC ≥ 3,000/mm³ * Absolute neutrophil count ≥ 1,500/mm³ * Platelet count ≥ 100,000/mm³ * Bilirubin ≤ 3 times upper limit of normal (ULN) * AST and ALT ≤ 5 times ULN * Creatinine normal * PTT \< 1.5 times ULN * Fasting serum cholesterol ≤ 350 mg/dL * Triglycerides ≤ 300 mg/dL * Proteinuria \< 2+ by urine dipstick OR urine protein ≤ 1 g by 24-hour urine collection * No history of allergic reactions to compounds of similar chemical or biologic composition to sirolimus or bevacizumab * No prior thromboembolic disease that may result in bleeding or clotting problems related to use of bevacizumab including, but not limited to, the following: * Esophageal varices * Bleeding disorders * Deep vein thromboses * No history of hematemesis or hemoptysis * No other uncontrolled illness including, but not limited to, the following: * Ongoing or active infection * Symptomatic congestive heart failure * Unstable angina pectoris * Cardiac arrhythmia * Psychiatric illness or social situations that would preclude study participation * No HIV positivity * Able to take oral medications * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception prior to and during the course of study treatment PRIOR CONCURRENT THERAPY: * See Disease Characteristics * More than 28 days since prior surgery and recovered * No other concurrent investigational agents * No other concurrent anticancer therapy * No concurrent traditional Chinese medicine(s) * No concurrent long term anticoagulation with heparin or warfarin * Concurrent prophylactic low-dose acetylsalicylic acid for patients at risk of an arterial thromboembolic event allowed * Hepatitis B carriers must be on lamivudine during and for 6 months after completion of study treatment

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• National Cancer Centre, Singapore: lead

Study Sites (2)

National Cancer Centre - Singapore

Singapore, 169610, Singapore

Location

Johns Hopkins Singapore International Medical Centre

Singapore, 308433, Singapore

Location

Related Publications (2)

• Treiber G. mTOR inhibitors for hepatocellular cancer: a forward-moving target. Expert Rev Anticancer Ther. 2009 Feb;9(2):247-61. doi: 10.1586/14737140.9.2.247.

  PMID: 19192962 BACKGROUND

• Choo SP, Chowbay B, Ng QS, Thng CH, Lim C, Hartono S, Koh TS, Huynh H, Poon D, Ang MK, Chang S, Toh HC. A Phase 1 dose-finding and pharmacodynamic study of rapamycin in combination with bevacizumab in patients with unresectable hepatocellular carcinoma. Eur J Cancer. 2013 Mar;49(5):999-1008. doi: 10.1016/j.ejca.2012.11.008. Epub 2012 Dec 19.

  PMID: 23265712 DERIVED

MeSH Terms

Conditions

Liver Neoplasms; Carcinoma, Hepatocellular

Interventions

Sirolimus; Bevacizumab

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Choo Su Pin, MD

  National Cancer Centre, Singapore

  PRINCIPAL INVESTIGATOR

• Toh Han Chong, MD, MBBS, MRCP

  National Cancer Centre, Singapore

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Senior Consultant

Study Record Dates

• First Submitted: April 25, 2007
• First Posted: April 27, 2007
• Study Start: December 1, 2006
• Primary Completion: May 1, 2011
• Last Updated: June 17, 2013

Record last verified: 2013-06

Locations

SG (2)