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Sarcoma, Kaposi

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Kaposi Sarcoma

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Doxorubicin

Liposomal doxorubicin

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Enzyme Inhibitors

Doxorubicin hydrochloride (liposomal)

To provide Stealth liposomal doxorubicin hydrochloride ( DOX-SL ) as a therapy for Kaposi's sarcoma patients who have no remaining treatment options other than DOX-SL or patients who have been participating in another DOX-SL protocol and for whom continuation in DOX-SL is medically indicated. Also, to evaluate the safety and efficacy of DOX-SL in patients with Kaposi's sarcoma who have previously received systemic chemotherapy with or without an anthracycline.

Patients receive DOX-SL every 3 weeks for up to 20 cycles.

Use of Stealth Liposomal Doxorubicin HCl ( DOX-SL ) in the Treatment of Moderate to Severe AIDS-Related Kaposi's Sarcoma.

Sequus Pharmaceuticals

Neoplasm Metastasis

Antibodies

Antibodies, Monoclonal

Bevacizumab

Sirolimus

Immunoglobulins

Temsirolimus

MTOR Inhibitors

Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

Growth Inhibitors

Protein Kinase Inhibitors

Immunosuppressive Agents

Immunologic Factors

Clotrimazole

Miconazole

Antifungal Agents

Doxil day 1 of each 21 day cycle, beginning dose level 10 mg/m\^2 by vein over 3 hours.

Bevacizumab day 1 of each 21 day cycle, beginning dose level 5 mg/kg by vein over 90 minutes.

Temsirolimus days 1, 8 \& 15 of 21 Day Cycle, beginning dose level 12.5 mg by vein over 30 to 60 minutes.

Day 1 of each 21 day cycle, beginning dose level 10 mg/m\^2 by vein over 3 hours.

Doxil

Day 1 of each 21 day cycle, beginning dose level 5 mg/kg by vein over 90 minutes.

Days 1, 8 \& 15 of 21 Day Cycle, beginning dose level 12.5 mg by vein over 30 to 60 minutes.

Daniel Karp, MD

The goal of this clinical research study is to learn the highest safe doses of the combination of Doxil (liposomal doxorubicin), Avastin (bevacizumab), and Torisel (Temsirolimus) that can be given to patients with advanced cancer that has spread or is unable to be surgically removed. The safety and effectiveness of this combination of drugs will also be studied.

The Study Drugs:

Liposomal doxorubicin is designed to cause cancer cells to be fragile, which may cause the cancer cells to die.

Bevacizumab is designed to block or slow down the growth of cancer cells by blocking the growth of blood vessels that supply nutrients for tumor growth.

Temsirolimus is designed to block the growth of cancer cells, which may eventually cause the cancer cells to die.

Everolimus is designed to block a protein called mammilian target of rapamycin (mTOR) inside the cancer cells, which is involved in cancer cell growth.

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to a fixed dose level of a combination of liposomal doxorubicin, bevacizumab, and either temsirolimus or everolimus, based on when you joined this study. Up to 9 dose levels of the study drug combination will be tested. Three (3) participants will be enrolled at each dose level. The first group of participants will receive the lowest dose level. Each new group will receive a higher dose than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose of the study drug combination is found.

Study Drug Administration:

Liposomal doxorubicin, bevacizumab, and either temsirolimus or everolimus will be given in "cycles." Cycles will be about 21 days (or longer, depending on any side effects you may experience).

Liposomal doxorubicin is given by vein on Day 1 of each cycle. On Day 1 of Cycle 1, you will receive it over 3 hours. If you tolerate it well in Cycle 1, you will receive it over 60 minutes in Cycle 2. If you tolerate it well in Cycle 2, you will receive it over 60 minutes for all further cycles.

Bevacizumab is given by vein on Day 1 of each cycle. On Day 1 of Cycle 1, you will receive it over 90 minutes. If you tolerate it well in Cycle 1, you will receive it over 60 minutes in Cycle 2. If you tolerate it well in Cycle 2, you will receive it over 30 minutes in Cycle 3. It will continue to be given over 30 minutes in Cycle 4 and further cycles, as long as you still tolerate it well.

Temsirolimus is given by vein on Days 1, 8, and 15 of each cycle. During Day 1 of Cycle 1, you will receive it over 60 minutes. If you tolerate it well on Day 1 of Cycle 1, it will be given over 30 minutes on Days 8 and 15 of Cycle 1 and over 30 minutes in further cycles, as long you still tolerate it well.

Everolimus works the same way and has been shown to be as effective as temsirolimus. Everolimus can also be given by mouth, so it can be substituted for temsirolimus. Everolimus will be taken every day, starting with Day 1 of Cycle 1.

Because of a nationwide shortage of liposomal doxorubicin, you may only receive temsirolimus and bevacizumab until liposomal doxorubicin becomes available.

If you experience certain side effects, your dose level may be lowered. In some cases, your dose may be stopped for 1 week, until the side effect gets better. Your doctor can explain this to you in more detail, if it happens.

Study Visits:

During Cycle 1, you will have a physical exam once and blood will be drawn weekly (about 1 tablespoon) for routine tests.

For Cycle 2 and further cycles, you will have a physical exam and blood drawn (about 1 tablespoon) for routine tests once every 3 weeks.

The status of the disease will be checked by a CT or MRI scan after every 2 cycles, for Cycles 2-6, then every 2-3 cycles.

Additional Procedures for Some Participants:

If you are in the group that receives the highest safe dose of the study drugs, you will have the following additional procedures performed:

* You will have a biopsy performed at the end of Cycle 1. The biopsy will be used for research to see how the study drug combination acts in the body and to learn how it may affect cancer cells.
* You will have a DCE-MRI scan at 24-48 hours after your first study drug infusion (Cycle 1), and at the end of Cycle 1. These DCE-MRI scans will be used for research to see how the study drug combination is affecting blood vessels that supply nutrients and oxygen to tumor cells.

Length of Study Participation:

You may continue to receive additional cycles of the study drugs, unless the cancer goes away completely, gets worse, or if intolerable side effects occur. In that case, you will be taken off study.

Long-Term Follow-Up:

After your last dose of the study drug, you will receive up to 3 phone calls from the study staff. The calls will be 1 month apart, and you will be asked how you are doing.

This is an investigational study. Liposomal doxorubicin, bevacizumab, and temsirolimus are commercially available. Liposomal doxorubicin is FDA approved for the treatment of multiple myeloma, ovarian cancer that has returned, and Kaposi's sarcoma. Bevacizumab is FDA approved for the treatment of colorectal cancer and a type of lung cancer. Temsirolimus is FDA approved for the treatment of kidney cancer that has spread.

The combination of liposomal doxorubicin, bevacizumab, and temsirolimus is not FDA approved. At this time, it is only being used in research.

Up to 206 patients will take part in this study. All will be enrolled at MD Anderson.

Doxil, Bevacizumab and Temsirolimus Trial

A Phase I Trial of Doxil, Bevacizumab and Temsirolimus

MTD defined as dose level below dose at which 2 of 6 patients experience drug-related dose limiting toxicity (DLT) in first cycle. Dose limiting toxicity (DLT) defined as any grade 3 or 4 non-hematologic toxicity defined in the NCI CTC v3.0, even if expected and believed related to the study medications (except nausea and vomiting responsive to appropriate regimens or alopecia), any Grade 4 hematologic toxicity lasting 2 weeks or longer (as defined by NCI-CTCAE), despite supportive care; any Grade 4 nausea or vomiting \> 5 days despite maximum anti-nausea regimens, and any other Grade 3 non-hematologic toxicity including symptoms/signs of vascular leak or cytokine release syndrome; or any severe or life-threatening complication or abnormality not defined in the NCI-CTCAE that is attributable to the therapy.

Anti-tumor efficacy assessed by RECIST criteria.

Anti-tumor efficacy assessed by WHO criteria.

M.D. Anderson Cancer Center

Bleomycin

Vincristine

Tubulin Modulators

Antimitotic Agents

Bleomycin sulfate

Vincristine sulfate

Doxorubicin hydrochloride

To determine the efficacy of Stealth liposomal doxorubicin hydrochloride (DOX-SL) in the treatment of severe AIDS-related Kaposi's sarcoma (KS) by comparison with the established therapy ABV: Adriamycin (doxorubicin)/bleomycin/vincristine. To evaluate the safety and tolerance of DOX-SL compared to ABV in a population of AIDS patients with severe KS.

Patients are randomized to receive either DOX-SL or the ABV combination. Infusions are given on day 1 and every 2 weeks for a total of six cycles. Kaposi's sarcoma lesions are evaluated prior to every cycle, at the end of the last treatment cycle, and 4 weeks following the end of the last treatment. Patients must agree to have one or more representative KS lesions biopsied.

A Comparison of DOX-SL Versus Adriamycin Plus Bleomycin Plus Vincristine in the Treatment of Severe AIDS-Related Kaposi's Sarcoma

Randomized, Comparative Trial of DOX-SL (Stealth Liposomal Doxorubicin Hydrochloride) Versus Adriamycin, Bleomycin, and Vincristine (ABV) in the Treatment of Severe AIDS-Related Kaposi's Sarcoma

Lenograstim

Filgrastim

Mitsuyasu R

Krown S

Von Roenn JH

To evaluate the safety and efficacy of liposomal doxorubicin hydrochloride ( DOX-SL ) alone or in combination with bleomycin and vincristine in the long-term treatment of AIDS-related Kaposi's sarcoma. To determine whether the 3-drug combination enhances progression-free survival and quality of life.

Liposomal formulations of chemotherapeutic agents increase drug accumulation in tumors, which permits disease palliation at relatively low doses and thus decreases some of the dose-limiting toxicity. Multi-agent therapy is considered to be more effective than single-agent therapy; therefore, DOX-SL will be combined with bleomycin and vincristine.

Liposomal formulations of chemotherapeutic agents increase drug accumulation in tumors, which permits disease palliation at relatively low doses and thus decreases some of the dose-limiting toxicity. Multi-agent therapy is considered to be more effective than single-agent therapy; therefore, DOX-SL will be combined with bleomycin and vincristine.

Patients are randomized to receive intravenous DOX-SL alone or in combination with vincristine/bleomycin every 2 weeks. Filgrastim ( granulocyte colony-stimulating factor; G-CSF ) may be given as needed for neutropenia.

AS PER AMENDMENT 11/7/96: Based on interim review data, it is recommended that subjects receiving DOX-SL plus vincristine/bleomycin have vincristine/bleomycin discontinued and receive DOX-SL alone unless, in the opinion of the treating physician, they are benefitting from the DOX-SL plus vincristine/bleomycin regimen.

Comparison of Liposomal Doxorubicin Used Alone or in Combination With Bleomycin Plus Vincristine in the Treatment of Kaposi's Sarcoma in Patients With AIDS

Comparison Study of Liposomal Doxorubicin With or Without Bleomycin and Vincristine for the Treatment of Advanced AIDS-Associated Kaposi's Sarcoma

Amgen

National Institute of Allergy and Infectious Diseases (NIAID)

To determine the efficacy of Stealth liposomal doxorubicin hydrochloride (DOX-SL) in the treatment of moderate to severe AIDS-related Kaposi's sarcoma (KS) by comparison with the established therapy BV (bleomycin/vincristine). To evaluate the safety and tolerance of DOX-SL compared to BV in a population of AIDS patients with moderate to severe KS.

Patients are randomized to receive either DOX-SL or the BV combination. Infusions are given on day 1 and every 3 weeks for a total of six cycles. Kaposi's sarcoma lesions are evaluated prior to every cycle, at the end of the last treatment cycle, and 4 weeks following the end of the last treatment. Patients who respond to therapy will be followed every 2 months for up to 1 year. Patients must agree to have one or more representative KS lesions biopsied.

Randomized, Comparative Trial of DOX-SL (Stealth Liposomal Doxorubicin Hydrochloride) Versus Bleomycin and Vincristine in the Treatment of AIDS-Related Kaposi's Sarcoma

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Use of Stealth Liposomal Doxorubicin HCl ( DOX-SL ) in the Treatment of Moderate to Severe AIDS-Related Kaposi's Sarcoma.	NCT00002147	Sarcoma, Kaposi HIV Infections	Doxorubicin hyd...	18 Years -	NIH AIDS Clinical Trials Information Service
Doxil, Bevacizumab and Temsirolimus Trial	NCT00761644	Advanced Cancer	Doxil Bevacizumab Temsirolimus	12 Years -	M.D. Anderson Cancer Center
Doxil, Bevacizumab and Temsirolimus Trial	NCT00761644	Advanced Cancer	Doxil Bevacizumab Temsirolimus	12 Years -	M.D. Anderson Cancer Center
A Comparison of DOX-SL Versus Adriamycin Plus Bleomycin Plus Vincristine in the Treatment of Severe AIDS-Related Kaposi's Sarcoma	NCT00002318	Sarcoma, Kaposi HIV Infections	Doxorubicin hyd... Bleomycin sulfa... Vincristine sul... Doxorubicin hyd...	18 Years -	NIH AIDS Clinical Trials Information Service
Comparison of Liposomal Doxorubicin Used Alone or in Combination With Bleomycin Plus Vincristine in the Treatment of Kaposi's Sarcoma in Patients With AIDS	NCT00001059	Sarcoma, Kaposi HIV Infections	Doxorubicin hyd... Filgrastim Bleomycin sulfa... Vincristine sul...	18 Years -	National Institute of Allergy and Infectious Diseases (NIAID)
Randomized, Comparative Trial of DOX-SL (Stealth Liposomal Doxorubicin Hydrochloride) Versus Bleomycin and Vincristine in the Treatment of AIDS-Related Kaposi's Sarcoma	NCT00002105	Sarcoma, Kaposi HIV Infections	Doxorubicin hyd... Bleomycin sulfa... Vincristine sul...	18 Years -	NIH AIDS Clinical Trials Information Service

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