A Phase 2 interventional study of Bevacizumab and Temsirolimus in Adult Hepatocellular Carcinoma, Advanced Adult Hepatocellular Carcinoma and Endometrial Serous Adenocarcinoma, sponsored by National Cancer Institute (NCI). Completed at 61 sites in 2 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2019-01-25.
Sponsored by National Cancer Institute (NCI) · Phase 2, Interventional, and Treatment
This phase II trial studies how well temsirolimus and bevacizumab work in treating patients with advanced endometrial, ovarian, liver, carcinoid, or islet cell cancer. Temsirolimus 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 may also stop the growth of cancer by blocking blood flow to the tumor. Giving temsirolimus together with bevacizumab may kill more tumor cells.
PRIMARY OBJECTIVES:
I. To determine the response rate and progression-free survival at 6 months in patients with endometrial, ovarian, hepatocellular carcinoma, carcinoid or islet cell cancer.
II. To determine the toxicity of the combination of temsirolimus and bevacizumab in patients with endometrial, ovarian, hepatocellular carcinoma, carcinoid or islet cell cancer.
SECONDARY OBJECTIVES:
I. To collect blood and tumor specimens from all patients entered on the trial for possible future analysis.
OUTLINE:
Patients receive temsirolimus intravenously (IV) on days 1, 8, 15, and 22, and bevacizumab IV over 30-90 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 3 years.
6,741 studies on the registry are indexed under Carcinoma; 1,163 are open to participants now.
This study's enrollment of 252 is above the median of 45 across 5,174 interventional studies indexed under Carcinoma.
Browse Carcinoma studies →National Cancer Institute (NCI) is the lead sponsor of 3,506 studies on the registry; 334 are open to participants now.
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HCC confirmed by biopsy OR diagnosed by clinical and radiologic criteria; all of the following criteria must be met or a biopsy is required:
Prior regional treatments for liver metastasis are permitted including:
Prior therapies allowed include:
Prior regional treatments for liver metastasis are permitted including:
Exclusion Criteria:
Invasive procedures defined as follows:
Untreated central nervous system (CNS) metastases; exceptions: patients with known CNS metastases can be enrolled if the brain metastases have been adequately treated and there is no evidence of progression or hemorrhage after treatment as ascertained by clinical examination and brain imaging (MRI or CT) =\< 12 weeks prior to registration and no ongoing requirement for steroids
Any of the following, as this regimen may be harmful to a developing fetus or nursing child:
Patients receive temsirolimus IV on days 1, 8, 15, and 22, and bevacizumab IV over 30-90 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Biological: Bevacizumab · Drug: Temsirolimus
Given IV
Also known as: Anti-VEGF, Anti-VEGF Humanized Monoclonal Antibody, Anti-VEGF rhuMAb, Avastin, Bevacizumab Biosimilar BEVZ92, Bevacizumab Biosimilar BI 695502, Bevacizumab Biosimilar CBT 124, Bevacizumab Biosimilar FKB238, Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer, Recombinant Humanized Anti-VEGF Monoclonal Antibody, rhuMab-VEGF
Given IV
Also known as: CCI-779, CCI-779 Rapamycin Analog, Cell Cycle Inhibitor 779, Rapamycin Analog, Rapamycin Analog CCI-779, Torisel
Progression Free Survival Rate
Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. The 6-month progression free survival rate is the proportion of evaluable patients progression-free 6 months from registration. The 6-month progression-free rate is defined as the total number of efficacy evaluable patients on study without documentation of disease progression 6 months from registration divided by the total number of evaluable patients enrolled on study. Kaplan-Meier methodology will be used to estimate the final success proportion (i.e. progression free at 6 months with a 95% confidence interval).
Time frame: 6 months
Tumor Response Rate
Tumor response rate defined as the total number of efficacy-evaluable patients who achieved a complete or partial response according to the RECIST criteria divided by the total number of efficacy evaluable patients enrolled on study. Patients were evaluated using the Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. In brief, a Complete Response (CR) means the complete disappearance of all target lesions and a reduction in each lymph node to \<1 cm. A Partial Response (PR) is defined as a 30% decrease in the sum of the longest diameter of the non-nodal target lesion from baseline. Each requires no new lesions present at evaluation. The proportion of participants with a response is provided here for each cohort. The proportion was calculated as the number of patients that had a best response of CR or PR divided by the number of patients evaluated for a response in each cohort.
Time frame: Up to 3 years
Duration of Response
Duration of response is defined for all evaluable patients who have achieved a response as the date at which the patient's objective status is first noted to be either a CR or PR to the date progression is documented. Objective response was assessed using Response Evaluation Criteria In Solid Tumors (RECIST) as described in Primary Objective 2 in this report. Median duration of response and the confidence interval for the median duration will be computed.
Time frame: Time from date at which the patient's objective status is first noted to be either a complete response (CR) or partial response (PR) to the date progression is documented, assessed up to 3 years
Incidence of Adverse Events
Adverse events are defined as events that are classified as either possibly, probably, or definitely related to study treatment, graded per National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0. The number of patients reporting grade 3 or higher adverse events at least possibly related to treatment are reported here. For a complete list of all reported adverse events, please see the adverse events section of this report.
Time frame: Every cycle of treatment, up to 3 years
Overall Survival
Survival time will be defined as the time from registration to death. Time to event distributions will be estimated using the Kaplan-Meier method.
Time frame: Time from registration to death, assessed up to 3 years
Time to Disease Progression
Time to progression is defined as the time from registration to disease progression. Patients who died without documentation of progression will be considered to have progressed on the date of their death. If a patient starts treatment and fails to return for evaluation, that patient will be censored for progression of disease at day one post-registration.
Time frame: Time from registration to disease progression, assessed up to 3 years
Time to Treatment Failure
Time to treatment failure is defined as the time from study entry to the date patients end treatment.Time to treatment failure will be evaluated using the method of Kaplan-Meier.
Time frame: Time from study entry to the date patients end treatment, assessed up to 3 years
| Milestone | Endometrial Cohort | Ovarian Cohort | Hepatocellular Cohort | Carcinoid Cohort | Islet Cell (Double Agent) Cohort | Islet Cell (Bevacizumab-only) Cohort |
|---|---|---|---|---|---|---|
| Started | 27 | 58 | 28 | 57 | 58 | 24 |
| Completed | 26 | 58 | 27 | 57 | 55 | 24 |
| Not completed | 1 | 0 | 1 | 0 | 3 | 0 |
| Withdrew: Withdrawal by subject | 1 | 0 | 1 | 0 | 3 | 0 |
Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. The 6-month progression free survival rate is the proportion of evaluable patients progression-free 6 months from registration. The 6-month progression-free rate is defined as the total number of efficacy evaluable patients on study without documentation of disease progression 6 months from registration divided by the total number of evaluable patients enrolled on study. Kaplan-Meier methodology will be used to estimate the final success proportion (i.e. progression free at 6 months with a 95% confidence interval).
| proportion of patients | Endometrial Cohort | Ovarian Cohort | Hepatocellular Cohort | Carcinoid Cohort | Islet Cell (Double Agent) Cohort | Islet Cell (Bevacizumab-only) Cohort |
|---|---|---|---|---|---|---|
| Progression Free Survival Rate | 0.52 (0.35 to 0.77) | 0.40 (0.29 to 0.55) | 0.71 (0.54 to 0.94) | 0.84 (0.75 to 0.95) | 0.85 (0.75 to 0.95) | 0.87 (0.74 to 1.00) |
Tumor response rate defined as the total number of efficacy-evaluable patients who achieved a complete or partial response according to the RECIST criteria divided by the total number of efficacy evaluable patients enrolled on study. Patients were evaluated using the Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. In brief, a Complete Response (CR) means the complete disappearance of all target lesions and a reduction in each lymph node to \<1 cm. A Partial Response (PR) is defined as a 30% decrease in the sum of the longest diameter of the non-nodal target lesion from baseline. Each requires no new lesions present at evaluation. The proportion of participants with a response is provided here for each cohort. The proportion was calculated as the number of patients that had a best response of CR or PR divided by the number of patients evaluated for a response in each cohort.
| proportion of participants | Endometrial Cohort | Ovarian Cohort | Hepatocellular Cohort | Carcinoid Cohort | Islet Cell (Double Agent) Cohort | Islet Cell (Bevacizumab-only) Cohort |
|---|---|---|---|---|---|---|
| Tumor Response Rate | 0.31 (0.14 to 0.52) | 0.31 (0.20 to 0.45) | 0.19 (0.06 to 0.38) | 0.12 (0.05 to 0.24) | 0.40 (0.27 to 0.53) | 0.17 (0.05 to 0.37) |
Duration of response is defined for all evaluable patients who have achieved a response as the date at which the patient's objective status is first noted to be either a CR or PR to the date progression is documented. Objective response was assessed using Response Evaluation Criteria In Solid Tumors (RECIST) as described in Primary Objective 2 in this report. Median duration of response and the confidence interval for the median duration will be computed.
| months | Endometrial Cohort | Ovarian Cohort | Hepatocellular Cohort | Carcinoid Cohort | Islet Cell (Double Agent) Cohort | Islet Cell (Bevacizumab-only) Cohort |
|---|---|---|---|---|---|---|
| Duration of Response | 25.1 (0 to 35.5) | 6.4 (3.7 to 10.8) | 6.4 (0 to 11.1) | 15.0 (0 to 18.8) | 11.3 (8.8 to 21.2) | 10.9 (3.7 to 34.1) |
Adverse events are defined as events that are classified as either possibly, probably, or definitely related to study treatment, graded per National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0. The number of patients reporting grade 3 or higher adverse events at least possibly related to treatment are reported here. For a complete list of all reported adverse events, please see the adverse events section of this report.
| Participants | Endometrial Cohort | Ovarian Cohort | Hepatocellular Cohort | Carcinoid Cohort | Islet Cell (Double Agent) Cohort | Islet Cell (Bevacizumab-only) Cohort |
|---|---|---|---|---|---|---|
| Grade 3 Adverse Event | 17 | 32 | 24 | 32 | 36 | 13 |
| Grade 4 Adverse Event | 1 | 6 | 0 | 6 | 8 | 0 |
| Grade 5 Adverse Event | 1 | 0 | 1 | 2 | 0 | 0 |
Survival time will be defined as the time from registration to death. Time to event distributions will be estimated using the Kaplan-Meier method.
| months | Endometrial Cohort | Ovarian Cohort | Hepatocellular Cohort | Carcinoid Cohort | Islet Cell (Double Agent) Cohort | Islet Cell (Bevacizumab-only) Cohort |
|---|---|---|---|---|---|---|
| Overall Survival | 11.5 (6.5 to NA) | 16.3 (11.1 to 21.9) | 14.8 (9.7 to 18.1) | 32.7 (25.2 to 38.3) | 35.0 (14.6 to NA) | NA (30.6 to NA) |
Time to progression is defined as the time from registration to disease progression. Patients who died without documentation of progression will be considered to have progressed on the date of their death. If a patient starts treatment and fails to return for evaluation, that patient will be censored for progression of disease at day one post-registration.
| months | Endometrial Cohort | Ovarian Cohort | Hepatocellular Cohort | Carcinoid Cohort | Islet Cell (Double Agent) Cohort | Islet Cell (Bevacizumab-only) Cohort |
|---|---|---|---|---|---|---|
| Time to Disease Progression | 6.0 (2.5 to 9.8) | 5.6 (4.3 to 6.4) | 8.0 (5.8 to 10.9) | 15.2 (11.4 to 24.2) | 13.1 (11.2 to 16.6) | 18.0 (10.6 to 37.0) |
Time to treatment failure is defined as the time from study entry to the date patients end treatment.Time to treatment failure will be evaluated using the method of Kaplan-Meier.
| months | Endometrial Cohort | Ovarian Cohort | Hepatocellular Cohort | Carcinoid Cohort | Islet Cell (Double Agent) Cohort | Islet Cell (Bevacizumab-only) Cohort |
|---|---|---|---|---|---|---|
| Time to Treatment Failure | 3.8 (2.3 to 6.4) | 4.5 (2.7 to 5.6) | 6.5 (2.3 to 8.0) | 5.5 (4.4 to 8.1) | 11.3 (8.6 to 13.3) | 11.8 (5.8 to 18.0) |
Collected over Adverse events were collected at the end of each 28 day cycle for a maximum of 58 cycles.. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Endometrial Cohort | 2/26 (7.7%) | 16/26 (61.5%) | 26/26 (100%) |
| Ovarian Cohort | 1/58 (1.7%) | 34/58 (58.6%) | 58/58 (100%) |
| Hepatocellular Cohort | 3/27 (11.1%) | 13/27 (48.1%) | 27/27 (100%) |
| Carcinoid Cohort | 3/57 (5.3%) | 36/57 (63.2%) | 56/57 (98.2%) |
| Islet Cell (Double Agent) Cohort | 0/55 (0%) | 27/55 (49.1%) | 55/55 (100%) |
| Islet Cell (Bevacizumab-only) Cohort | 0/24 (0%) | 6/24 (25%) | 24/24 (100%) |
| Event | Endometrial Cohort | Ovarian Cohort | Hepatocellular Cohort | Carcinoid Cohort | Islet Cell (Double Agent) Cohort | Islet Cell (Bevacizumab-only) Cohort |
|---|---|---|---|---|---|---|
| FatigueGeneral disorders | 0/26 | 2/58 | 4/27 | 3/57 | 1/55 | 0/24 |
| Abdominal painGastrointestinal disorders | 2/26 | 5/58 | 3/27 | 8/57 | 6/55 | 0/24 |
| ConfusionPsychiatric disorders | 0/26 | 0/58 | 3/27 | 2/57 | 1/55 | 0/24 |
| DehydrationMetabolism and nutrition disorders | 2/26 | 3/58 | 1/27 | 5/57 | 1/55 | 0/24 |
| Rectal painGastrointestinal disorders | 2/26 | 1/58 | 0/27 | 1/57 | 0/55 | 0/24 |
| VomitingGastrointestinal disorders | 2/26 | 4/58 | 1/27 | 1/57 | 1/55 | 1/24 |
| Urinary tract infectionInfections and infestations | 2/26 | 0/58 | 1/27 | 0/57 | 0/55 | 0/24 |
| Serum cholesterol increasedInvestigations | 2/26 | 0/58 | 0/27 | 0/57 | 0/55 | 0/24 |
| Protein urine positiveRenal and urinary disorders | 2/26 | 2/58 | 0/27 | 0/57 | 2/55 | 1/24 |
| DyspneaRespiratory, thoracic and mediastinal disorders | 2/26 | 1/58 | 1/27 | 1/57 | 1/55 | 0/24 |
| Event | Endometrial Cohort | Ovarian Cohort | Hepatocellular Cohort | Carcinoid Cohort | Islet Cell (Double Agent) Cohort | Islet Cell (Bevacizumab-only) Cohort |
|---|---|---|---|---|---|---|
| Hemoglobin decreasedBlood and lymphatic system disorders | 20/26 | 48/58 | 23/27 | 49/57 | 49/55 | 8/24 |
| Platelet count decreasedInvestigations | 16/26 | 27/58 | 22/27 | 50/57 | 41/55 | 7/24 |
| HypertensionVascular disorders | 16/26 | 34/58 | 10/27 | 39/57 | 35/55 | 21/24 |
| FatigueGeneral disorders | 21/26 | 43/58 | 14/27 | 40/57 | 48/55 | 12/24 |
| Serum cholesterol increasedInvestigations | 22/26 | 38/58 | 12/27 | 38/57 | 46/55 | 7/24 |
| Protein urine positiveRenal and urinary disorders | 14/26 | 30/58 | 17/27 | 35/57 | 37/55 | 12/24 |
| Leukocyte count decreasedInvestigations | 10/26 | 30/58 | 16/27 | 38/57 | 34/55 | 3/24 |
| AnorexiaMetabolism and nutrition disorders | 16/26 | 23/58 | 8/27 | 27/57 | 29/55 | 5/24 |
| Serum triglycerides increasedMetabolism and nutrition disorders | 16/26 | 25/58 | 7/27 | 29/57 | 32/55 | 1/24 |
| Ear, nose and throat examination abnormalGastrointestinal disorders | 12/26 | 18/58 | 4/27 | 28/57 | 33/55 | 3/24 |
| Age, Continuous(years) | Endometrial Cohort | Ovarian Cohort | Hepatocellular Cohort | Carcinoid Cohort | Islet Cell (Double Agent) Cohort | Islet Cell (Bevacizumab-only) Cohort | Total |
|---|---|---|---|---|---|---|---|
| Median | 60 (40 to 80) | 62.5 (35 to 82) | 59 (31 to 74) | 62 (35 to 89) | 58.5 (29 to 81) | 54.5 (40 to 78) | 60 (29 to 89) |
| Sex: Female, Male(Participants) | Endometrial Cohort | Ovarian Cohort | Hepatocellular Cohort | Carcinoid Cohort | Islet Cell (Double Agent) Cohort | Islet Cell (Bevacizumab-only) Cohort | Total |
|---|---|---|---|---|---|---|---|
| Female | 26 | 58 | 5 | 31 | 29 | 10 | 159 |
| Male | 0 | 0 | 22 | 26 | 29 | 14 | 91 |
| Ethnicity (NIH/OMB)(Participants) | Endometrial Cohort | Ovarian Cohort | Hepatocellular Cohort | Carcinoid Cohort | Islet Cell (Double Agent) Cohort | Islet Cell (Bevacizumab-only) Cohort | Total |
|---|---|---|---|---|---|---|---|
| Hispanic or Latino | 4 | 2 | 2 | 0 | 1 | 2 | 11 |
| Not Hispanic or Latino | 19 | 54 | 25 | 54 | 57 | 22 | 231 |
| Unknown or Not Reported | 3 | 2 | 0 | 3 | 0 | 0 | 8 |
| Race (NIH/OMB)(Participants) | Endometrial Cohort | Ovarian Cohort | Hepatocellular Cohort | Carcinoid Cohort | Islet Cell (Double Agent) Cohort | Islet Cell (Bevacizumab-only) Cohort | Total |
|---|---|---|---|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Asian | 0 | 5 | 3 | 0 | 0 | 0 | 8 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 | 1 | 0 | 0 | 1 |
| Black or African American | 3 | 2 | 2 | 6 | 8 | 3 | 24 |
| White | 22 | 49 | 22 | 49 | 50 | 20 | 212 |
| More than one race | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Unknown or Not Reported | 1 | 2 | 0 | 1 | 0 | 1 | 5 |
| Region of Enrollment(participants) | Endometrial Cohort | Ovarian Cohort | Hepatocellular Cohort | Carcinoid Cohort | Islet Cell (Double Agent) Cohort | Islet Cell (Bevacizumab-only) Cohort | Total |
|---|---|---|---|---|---|---|---|
| Canada | 5 | 34 | 8 | 2 | 14 | 0 | 63 |
| United States | 21 | 24 | 19 | 55 | 44 | 24 | 187 |
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