Phase I Study of the Combination of Bevacizumab, Everolimus and LBH589 (BEL) for the Treatment of Advanced Solid Tumors
Overview
- Phase
- Phase 1
- Intervention
- Bevacizumab, Everolimus and LBH589
- Conditions
- Advanced Solid Tumors
- Sponsor
- Herbert Hurwitz
- Enrollment
- 14
- Locations
- 1
- Primary Endpoint
- To define the maximal tolerated dose (if any) and the recommended phase II dose for the triplet combination of everolimus plus LBH589 plus bevacizumab in subjects with advanced solid tumors
- Status
- Completed
- Last Updated
- 13 years ago
Overview
Brief Summary
The main purpose of this study is to test the safety of three study drugs, bevacizumab (Avastin™), Everolimus (Afinitor™) and LBH589 (Panobinostat) when they are given together. It is hoped this study drug combination might lead to a greater decrease the in size of the cancer and/or slow down how fast the cancer is growing compared to when these drugs are given alone.
Subjects will be enrolled at Duke University Medical Center (DUMC).
Detailed Description
The main purpose of this study is to test the safety of three study drugs, bevacizumab (Avastin™), Everolimus (Afinitor™) and LBH589 (Panobinostat) when they are given together. It is hoped this study drug combination might lead to a greater decrease the in size of the cancer and/or slow down how fast the cancer is growing compared to when these drugs are given alone. There are two parts of the study. The purpose of part I is to find out the highest and safest levels of these drugs when they are given together. If you are enrolled in part I of the study, you will start all the study drugs at the same time. The amount (dose) of drugs you will get will depend on when you enter the study. The purpose of part II is to see what effects, good and/or bad, the study drugs have when they are given alone and together. In addition, this will also give us a better understanding of how these study drugs work on you and your cancer. If you are enrolled in part II of the study, you will enter one of three study drug arms: Study Drug Arm A: You will receive everolimus alone for two weeks, then add bevacizumab and LBH589 to your study regimen. Study Drug Arm B: You will receive LBH589 alone for two weeks, then add bevacizumab and LBH589 to your study regimen. Study Drug Arm C: You will receive everolimus and LBH589 together for two weeks, then add bevacizumab to your study regimen. ABOUT THE STUDY DRUGS: * Bevacizumab (Avastin™) is an intravenous (I.V., meaning through a vein) medication made from a special type of human and mouse protein called antibodies. Bevacizumab blocks a factor called VEGF (vascular endothelial growth factor) which is important for angiogenesis (the growth of new blood vessels). Blocking this factor is thought to block the growth of tumor-related blood vessels which may stop the growth of cancer. Bevacizumab and other drugs that block VEGF activity are currently being evaluated in clinical research studies in a variety of cancers. * Everolimus (Afintor™) is a pill that works by blocking the activity of a substance in the body known as mTOR (mammalian target of rapamycin). mTOR is important for helping the growth and survival in normal and cancer cells. Blocking mTOR activity has been shown to slow or kill cancer cells in laboratory studies. Everolimus and other drugs that block mTOR activity are currently being evaluated in clinical research studies in a variety of cancers. * LBH589 (Panobinostat) is a new pill that works by blocking a special group of proteins called histone deacetylases (HDACs). HDACs are important for helping the growth and survival in normal and cancer cells and for helping the growth of new tumor-related blood vessels. Blocking HDAC activity has been shown to shown to slow or kill cancer cells in laboratory studies. LBH589 and other drugs that block HDACs activity are currently being evaluated in clinical research studies in a variety of cancers. LBH589 (Panobinostat) is not approved by the U.S. Food and Drug Administration (FDA) for the treatment of cancer is therefore considered an investigational drug.
Investigators
Herbert Hurwitz
Associate Professor of Medicine
Duke University
Eligibility Criteria
Inclusion Criteria
- •Histologically and/or cytologically confirmed malignant solid tumor that is refractory to standard therapies, or for which no standard therapies exist.
- •Patients must have at least one measurable site of disease according to RECIST (see Appendix 1) criteria that has not been previously irradiated. If the patient has had previous radiation to the marker lesion(s), there must be evidence of progression since the radiation
- •Age ≥ 18 years
- •Karnofsky Performance status ≥ 80% (see Appendix 2)
- •Adequate bone marrow function as shown by:
- •ANC ≥ 1.5 x 109/L
- •Platelets ≥ 100 x 109/L
- •Hemoglobin \>9 g/dL; Erythropoietin and transfusion support is permitted provided treatments are not required more than every 8 weeks.
- •Adequate liver function as shown by:
- •serum bilirubin ≤ 1.5 x ULN
Exclusion Criteria
- •Patients currently receiving anticancer therapies or who have received anticancer therapies within 4 weeks from day 1 of study drug (including chemotherapy, radiation therapy, antibody based therapy, etc.)
- •Patients who:
- •have had a major surgery or significant traumatic injury within 4 weeks from day 1 of study drug,
- •have not recovered from the side effects of any major surgery (defined as requiring general anesthesia) or
- •are anticipated to require major surgery during the course of the study.
- •Patients with a known hypersensitivity to experimental drugs (or classes of drugs) or their excipients
- •Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent with the following exceptions:
- •Intermittent steroids ( not to exceed 4 mg every day) may be used on an as-needed basis (e.g. treatment for chemotherapy-related nausea.)
- •Patients on physiologic replacement doses of steroids due to adrenal insufficiency for any reason may remain on these medications.
- •Topical, inhaled or intra-articular corticosteroids
Arms & Interventions
Bevacizumab, Everolimus and LBH589
Dose Escalation Cohort #, Subjects, Bevacizumab, Everolimus, LBH589 1. 3-6, All study drugs administered per dose level 2. 3-6, All study drugs administered per dose level 3. 3-6, All study drugs administered per dose level Expanded Cohorts Cohort #, Subjects, Bevacizumab, Everolimus, LBH589 A, B \& C; 30, Recommended Phase II Dose for all three compounds
Intervention: Bevacizumab, Everolimus and LBH589
Outcomes
Primary Outcomes
To define the maximal tolerated dose (if any) and the recommended phase II dose for the triplet combination of everolimus plus LBH589 plus bevacizumab in subjects with advanced solid tumors
Time Frame: 3 years
Secondary Outcomes
- To describe any dose limiting toxicities of this combination and to describe any non-dose limiting toxicities of this combination.(3 years)
- To describe pharmacokinetic characteristics of everolimus and LBH589 when the two drugs administered in combination.(3 years)
- To describe the effect of this treatment combination on blood based biomarkers for tumor angiogenesis and tumor growth factors.(3 years)
- To describe any signs of clinical activity of this treatment combination, including response rate, time to progression, and duration of response.(3 years)