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

Primary Purpose

Liver Cancer

Status

Completed

Phase

Phase 1

Locations

Singapore

Study Type

Interventional

Intervention

Rapamycin

Bevacizumab

About this trial

This is an interventional treatment trial for Liver Cancer focused on measuring adult primary hepatocellular carcinoma, localized unresectable adult primary liver cancer, recurrent adult primary liver cancer, advanced adult primary liver cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

National Cancer Centre - Singapore
Johns Hopkins Singapore International Medical Centre

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Phase I study of rapamycin and bevacizumab

Arm Description

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.

Outcomes

Primary Outcome Measures

Dose-limiting toxicity

Maximum tolerated dose

Secondary Outcome Measures

Response rate (complete and partial response and stable disease)

Progression-free survival

Overall survival

Distribution of p70S6K activity in peripheral blood mononuclear cells

Correlation of p70S6K with tumor response

Expression of tumor tissue biomarkers (PTEN, 4EBP-1, CD31, p70S6K, and vascular endothelial growth factor)

Correlation of tumor biomarkers with response

Best overall response (complete and partial response; stable and progressive disease)

Change in DCE-CT scan assessment of angiogenesis

Full Information

NCT ID

NCT00467194

First Posted

April 25, 2007

Last Updated

June 14, 2013

Sponsor

National Cancer Centre, Singapore

1. Study Identification

Unique Protocol Identification Number

NCT00467194

Brief Title

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

Official Title

A Phase I Study of Rapamycin in Combination With Bevacizumab in Patients With Unresectable Hepatocellular Carcinoma

Study Type

Interventional

2. Study Status

Record Verification Date

June 2013

Overall Recruitment Status

Completed

Study Start Date

December 2006 (undefined)

Primary Completion Date

May 2011 (Actual)

Study Completion Date

undefined (undefined)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

National Cancer Centre, Singapore

4. Oversight

5. Study Description

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.

Detailed Description

OBJECTIVES: Primary Determine the maximum tolerated dose of sirolimus used in combination with bevacizumab in patients with unresectable hepatocellular carcinoma. Determine the toxicity profile of this regimen in these patients. Secondary Determine the clinical activity of this regimen in these patients. Determine the pharmacokinetics of sirolimus in these patients. Determine the biologically active dose range of sirolimus in these patients. Correlate phosphorylated p70S6K activity with clinical response in patients treated with this regimen. Correlate PTEN, 4EBP-1, phosphorylated p70S6K, CD31, and vascular endothelial growth factor expression with clinical response in patients treated with this regimen. Correlate the degree of angiogenesis (as measured by DCE-CT scan) with drug levels and clinical response. OUTLINE: This is a dose-escalation study of sirolimus. Patients receive bevacizumab IV over 30-90 minutes once every 2 weeks and oral sirolimus once daily. Treatment continues for up to 6 months in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of sirolimus until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Six additional patients receive treatment at the MTD. Blood samples are collected from healthy participants to measure p70S6 kinase activity. Patients undergo blood sample collection at baseline and periodically during study for pharmacokinetic and p70S6K activity assessment. Samples are also analyzed by high-performance liquid chromatography and tandem mass spectrophotometry to determine peak drug concentrations. Patients without archived tumor samples undergo tumor tissue biopsy at baseline. Samples are analyzed for PTEN, 4E-BP1, vascular endothelial growth factor, epidermal growth factor, p70S6K, and CD31 by immunohistochemistry. Patients also undergo DCE-CT scan at baseline and on day 29 to assess angiogenesis. After completion of study treatment, patients are followed for 52 weeks. PROJECTED ACCRUAL: A total of 36 patients and 5 healthy participants will be accrued for this study.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Liver Cancer

Keywords

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

27 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Phase I study of rapamycin and bevacizumab

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Rapamycin

Intervention Type

Drug

Intervention Name(s)

Bevacizumab

Primary Outcome Measure Information:

Title

Dose-limiting toxicity

Time Frame

3 years

Title

Maximum tolerated dose

Time Frame

3 years

Secondary Outcome Measure Information:

Title

Response rate (complete and partial response and stable disease)

Time Frame

3 years

Title

Progression-free survival

Time Frame

3 years

Title

Overall survival

Time Frame

3 years

Title

Distribution of p70S6K activity in peripheral blood mononuclear cells

Time Frame

3 years

Title

Correlation of p70S6K with tumor response

Time Frame

3 years

Title

Expression of tumor tissue biomarkers (PTEN, 4EBP-1, CD31, p70S6K, and vascular endothelial growth factor)

Time Frame

3 years

Title

Correlation of tumor biomarkers with response

Time Frame

3 years

Title

Best overall response (complete and partial response; stable and progressive disease)

Time Frame

3 years

Title

Change in DCE-CT scan assessment of angiogenesis

Time Frame

3 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Choo Su Pin, MD

Organizational Affiliation

National Cancer Centre, Singapore

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Toh Han Chong, MD, MBBS, MRCP

Organizational Affiliation

National Cancer Centre, Singapore

Official's Role

Principal Investigator

Facility Information:

Facility Name

National Cancer Centre - Singapore

City

Singapore

ZIP/Postal Code

169610

Country

Singapore

Facility Name

Johns Hopkins Singapore International Medical Centre

City

Singapore

ZIP/Postal Code

308433

Country

Singapore

12. IPD Sharing Statement

Citations:

PubMed Identifier

19192962

Citation

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.

Results Reference

background

PubMed Identifier

23265712

Citation

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.

Results Reference

derived

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

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