Pilot Study of Liposomal Doxorubicin Combined With Bevacizumab Followed by Bevacizumab Monotherapy in Adults With Advanced Kaposi s Sarcoma
- Registration Number
- NCT00923936
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
Background:
* The drug liposomal doxorubicin is approved by the U.S. Food and Drug Administration (FDA) for the treatment of Kaposi's sarcoma (KS). A second drug, bevacizumab, is a biologic agent (such as antibodies, interleukins, and vaccines) that stops abnormal blood supply to tumors. Bevacizumab is approved by the FDA, in combination with other drugs, for the treatment of breast cancer, colon cancer, and lung cancer.
* Researchers are now studying the combination of liposomal doxorubicin with bevacizumab as a novel approach to the treatment of advanced KS. Researches will be measuring KS tumor responses to this combination to determine whether the drugs might have anti-KS activity.
Objectives:
* To estimate the overall response rate (ORR) of six cycles of liposomal doxorubicin combined with bevacizumab in patients with advanced KS.
* To evaluate the safety of the regimen and to estimate the complete response rate after six cycles, the median number of cycles needed to obtain a partial response, and the 12-month progression-free survival.
Eligibility:
* Patients 18 years or older with relatively severe acquired immune deficiency syndrome (AIDS)-related KS or patients with KS unrelated to AIDS or human immunodeficiency virus (HIV) infection, whose KS that can be evaluated for potential response to therapy and meet a number of other criteria.
* Women who are pregnant or breastfeeding are not eligible.
* Other ineligibility criteria include surgery within 4 weeks, chemotherapy within 3 weeks, heart disease, hemoptysis (coughing up blood), or gastrointestinal bleeding.
Design:
* Researchers will conduct the following tests before the start of the study:
* Physical examination and a detailed medical history.
* A biopsy.
* Blood and urine tests.
* Treatment will include two phases, an induction phase and a maintenance phase:
* Induction phase dose: Intravenous (IV) bevacizumab 15 mg/kg once, followed 7 days later by liposomal doxorubicin mg/m2 and bevacizumab every 3 weeks for six cycles.
Maintenance phase dose: IV bevacizumab every 3 weeks for 11 cycles.
* Monitoring will include a review of side effects, physical exam (including blood pressure), and blood and urine samples; following the induction phase, the patient will receive a multi gated acquisition scan and electrocardiography (EKG) to record electrical activity in the heart.
* Research tests include blood and saliva samples, additional biopsies (optional), and noninvasive imaging.
* Treatment is stopped if any of the following occur: completion of 1 year of therapy, progressive KS, patient preference, or unacceptable toxicity.
* Post-treatment evaluations include clinic visits every 3 months or as needed up to 2 years, and blood and saliva samples (for research).
- Detailed Description
Background:
* Standard treatment for advanced Kaposi's sarcoma (KS) is a liposomal anthracycline, plus antiretroviral therapy (HAART) in patients with human immunodeficiency virus (HIV).
* KS is not curable and relapses are common. Prolonged use of liposomal anthracyclines with cumulative dosing exceeding 550 mg/m(2) is frequently required.
* KS is notable for pathogenic autocrine and paracrine vascular endothelial growth factor (VEGF) signaling. The monoclonal antibody, bevacizumab is a rational agent for the treatment of KS.
* Preliminary results from our phase II study of bevacizumab monotherapy, 03-C0110, suggest that bevacizumab has promising activity in the treatment of KS.
* The combination of anti-angiogenic therapy with cytotoxic chemotherapy has been a successful strategy in KS as well as other solid tumors.
* This pilot study will evaluate the activity and safety of liposomal doxorubicin combined with bevacizumab followed by bevacizumab maintenance in patients with advanced KS. A goal of this combination strategy is to develop a tolerable and highly active regimen that would limit the need for prolonged anthracycline use.
Objectives:
* The primary objective is to estimate the overall response rate (ORR) of six cycles of liposomal doxorubicin combined with bevacizumab in patients with advanced KS.
* Secondary objectives include evaluation of the safety of the regimen, as well as estimation of the complete response rate after 6 cycles, the median number of cycles need to obtain a partial response, and 12-month progression-free survival.
Eligibility:
Inclusion criteria:
* Age greater than or equal to 18
* Biopsy proven KS
* Indication for chemotherapy
* Any HIV status
* Normal multigated acquisition scan (MUGA)
* Able to tolerate aspirin 81 mg
* systolic blood pressure (SBP) \<150, diastolic blood pressure (DBP) \<90
* Urine protein \<1+ or 500mg/24hrs
Exclusion Criteria:
* Surgery within 4 weeks
* Thrombo-embolic disease
* Chemotherapy within 3 weeks
* Hemoptysis or severe gastrointestinal bleeding, unless caused by KS
* Pregnancy or breast feeding
Design:
* This is an open label, single center pilot with 2 cohorts. Cohort 1: HIV negative, HIV infected with stable KS despite 1 year of HAART with HIV viremic control, or HIV infected with progressive KS despite 4 months of HAART with HIV viremic control. Cohort 2: All other patients with advanced AIDS-associated KS.
* Subjects will receive bevacizumab 15 mg/kg and liposomal doxorubicin 20 mg/m(2) every 3 weeks until complete response (CR) or a maximum of 6 cycles. Those with stable disease or better will continue on bevacizumab 15 mg/kg monotherapy every 3 weeks for 11 cycles. HIV infected subjects will receive HAART.
* ORR will be calculated with 80% CI for each cohort separately. If estimates in the two cohorts are similar (p\>0.30 by a Fisher s exact test), they may be combined to form a somewhat more precise estimate of ORR after 6 cycles of treatment.
* A total of 10 evaluable patients will be accrued in each cohort.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 16
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description KS;classic/HIV+not improved on antiviral Liposomal Doxorubicin Kaposi's Sarcoma (KS) in patients who are Human immunodeficiency virus (HIV) Negative, HIV infected with stable disease for one year despite antiretroviral therapy or progressive disease despite 4 months of antiretroviral therapy. All other advanced HIV-asociated KS Liposomal Doxorubicin All other patients with advanced acquired immune deficiency syndrome (AIDS)-associated KS All other advanced HIV-asociated KS Bevacizumab All other patients with advanced acquired immune deficiency syndrome (AIDS)-associated KS KS;classic/HIV+not improved on antiviral Bevacizumab Kaposi's Sarcoma (KS) in patients who are Human immunodeficiency virus (HIV) Negative, HIV infected with stable disease for one year despite antiretroviral therapy or progressive disease despite 4 months of antiretroviral therapy.
- Primary Outcome Measures
Name Time Method Overall Response Rate (ORR) of Six Cycles of Liposomal Doxorubicin Combined With Bevacizumab in Patients With Advanced KS. 6 cycles, an average of 18 weeks Overall response rate is complete response + clinical complete response + partial response. The overall response rate is the fraction of subjects with an overall response after 6 cycles of liposomal doxorubicin in combination with bevacizumab. Response was assessed by a modification of the Acquired Immune Deficiency Syndrome Clinical Trial Group Oncology Committee criteria. Complete response is the absence of any detectable residual disease, including tumor-associated edema, persisting for at least 4 weeks. Clinical complete response is the absence of any detectable residual disease, including tumor associated edema. persisting for at least 4 weeks. Partial response is no progressive disease (increase of 25% or more over baseline in the number of lesions and/or size (sum of the products of the largest perpendicular diameters of the marker lesions) \& noting that single lesions which split up into 2 or more smaller lesions during the course of treatment will still be counted as 1.
- Secondary Outcome Measures
Name Time Method Complete Response Rate After 6 Cycles of Liposomal Doxorubicin Combined With Bevacizumab 6 cycles, an average of 18 weeks Complete response rate is the fraction of subjects with an complete response after 6 cycles of liposomal doxorubicin in combination with bevacizumab. Response was assessed by a modification of the Acquired Immune Deficiency Syndrome Clinical Trial Group Oncology Committee criteria. Complete response is the absence of any detectable residual disease, including tumor-associated edema, persisting for at least 4 weeks. In patients whom pigmented macular skin lesions persist after apparent complete response, biopsy of at least one representative lesion is required to document the absence of malignant cells. In patients known to have had visceral disease, an attempt at restaging with appropriate endoscopic or radiographic procedures should be made. If such procedures are medically contraindicated, the patient may be classified as having a clinical complete response.
Percentage of Participants With 12- Month Progression-free Survival (PFS) 12 months Participants who survived and were progression free for 12 months. Response was assessed by a modification of the Acquired Immune Deficiency Syndrome Clinical Trial Group Oncology Committee criteria. Progressive disease is an increase of 25% or more over baseline in the number of lesions and/or size (sum of the products of the largest perpendicular diameters) of the marker lesions or a change in character from macular to plaque-like or nodular of at least 25% of the lesions or new visceral sites of involvement or progression of visceral disease or the development of new or increasing tumor-associated edema or effusion that lasts at least 1 week and interfered with the patient's normal activities.
Count of Participants With Serious and Non-serious Adverse Events 7 years and 6 months and 21 days Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v3.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
Median Number of Cycles Need to Obtain a Partial Response 6 cycles, an average of 18 weeks Response was assessed by a modification of the Acquired Immune Deficiency Syndrome Clinical Trial Group Oncology Committee criteria. Partial response is no progressive disease (increase of 25% or more over baseline in the number of lesions and/or size (sum of the products of the largest perpendicular diameters of the marker lesions) and noting that single lesions which split up into 2 or more smaller lesions during the course of treatment will still be counted as 1; no new lesions occurring in previously uninvolved areas of the body; no new visceral sites of involvement or the appearance or worsening of tumor-associated edema or effusions and a 50% or greater decrease in the number and/or size of previously existing lesions lasting for at least 4 weeks or complete flattening of at least 50% of all previously raised lesions (i.e., 50% of all previously nodular or plaque-like lesions become macular) lasting for at least 4 weeks.
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center, 9000 Rockville Pike
🇺🇸Bethesda, Maryland, United States