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Bevacizumab and Temsirolimus Alone or in Combination With Valproic Acid or Cetuximab in Treating Patients With Advanced or Metastatic Malignancy or Other Benign Disease

Primary Purpose

Advanced Malignant Neoplasm, Castleman Disease, Digestive System Carcinoma

Status
Active
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Bevacizumab
Cetuximab
Laboratory Biomarker Analysis
Pharmacological Study
Temsirolimus
Valproic Acid
Sponsored by
M.D. Anderson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Advanced Malignant Neoplasm focused on measuring Temsirolimus, CCI-779, Torisel, Bevacizumab, Avastin, rhuMAb-VEGF, Anti-VEGF Monoclonal Antibody, Advanced Cancers, Advanced Malignancy, Metastatic, cancer, Cetuximab, C225, Erbitux, IMC-C225, Valproic Acid

Eligibility Criteria

undefined - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients with advanced or metastatic cancer that is refractory to standard therapy, relapsed after standard therapy, or have no standard therapy that induces a complete response of at least 10% or improves survival by at least three months; in addition, patients with disease that are "benign" by pathology, but relentlessly progressive, leading to disability, pain, and premature death in the majority of cases (including, but not limited to lymphangioleiomyomatosis [LAM], type 2 neurofibromatosis [NF], Erdheim Chester disease, and Castleman's disease) may also be considered for enrollment
  • Patients should be at least four weeks from the last day of therapeutic radiation or cytotoxic chemotherapy or from antibody therapy, or at least five half-lives from non-cytotoxic targeted or biologic therapy; patients may have received palliative radiation immediately before (or during) treatment provided radiation is not to the only target lesion available
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2
  • Karnofsky >= 60%
  • Lansky performance status of >= 60% for participants 16 years old or younger
  • Absolute neutrophil count >= 1,000/mL
  • Platelets >= 50,000/mL
  • Creatinine =< 3 X upper limit of normal (ULN)
  • Total bilirubin =< 3.0
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 5 X ULN
  • Fasting level of total cholesterol of no more than 350 mg/dL
  • Triglyceride level of no more than 400 mg/dL
  • Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 90 days after the last dose
  • Ability to understand and the willingness to sign a written informed consent document
  • Patients may not be receiving any other investigational agents and/or any other concurrent anticancer agents or therapies

Exclusion Criteria:

  • Patients with clinically significant unexplained bleeding within 28 days prior to entering the study
  • Uncontrolled systemic vascular hypertension (systolic blood pressure > 140 mmHg, diastolic blood pressure > 90 mmHg on medication)
  • Patients with clinically significant cardiovascular disease: History of CVA (cerebrovascular accident) within 6 months, myocardial infarction or unstable angina within 6 months, unstable angina pectoris
  • Pregnant or breast-feeding women
  • History of hypersensitivity to bevacizumab, murine products, or any component of the formulation
  • History of hypersensitivity to temsirolimus or its metabolites (including sirolimus), polysorbate 80, or to any component of the formulation
  • History of hypersensitivity to cetuximab, murine products, or any component of the formulation
  • Patients that are taking cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A4) inducers and/or inhibitors; if a patient has a history of taking CYP3A4 inducers and/or inhibitors prior to enrollment on the protocol, it is strongly recommended that the patient stops the drug and waits at least 5 half-lives of said drug before initiating therapy on protocol
  • Colorectal cancer patients with known v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation (for the arm combining bevacizumab, temsirolimus and cetuximab)
  • Patients who have had major surgery within 6 weeks of enrollment in the study

Sites / Locations

  • M D Anderson Cancer Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Group I (temsirolimus, bevacizumab, cetuximab)

Group II (temsirolimus, bevacizumab, valproic acid)

Group III (temsirolimus, bevacizumab)

Arm Description

Patients receive temsirolimus IV over 30-60 minutes on days 1, 8, 15, and 22; bevacizumab IV over 30-90 minutes on days 1 and 15; and cetuximab IV over 60-120 minutes on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients receive temsirolimus and bevacizumab as in Group I and valproic acid PO on days 1-7 and 15-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients receive temsirolimus and bevacizumab as in Group I. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Outcomes

Primary Outcome Measures

Maximum tolerated dose (MTD) of bevacizumab, defined as the dose level below the dose at which 2 of 6 patients experience drug-related dose limiting toxicity (DLT)
Graded by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.
MTD of temsirolimus, defined as the dose level below the dose at which 2 of 6 patients experience DLT
Graded by the NCI CTCAE version 3.0.

Secondary Outcome Measures

Anti-tumor efficacy of each combination (objective response)
Will be determined by Response Evaluation Criteria In Solid Tumors and World Health Organization criteria
Levels of surrogate anti-angiogenesis markers
Correlated with anti-tumor activity.

Full Information

First Posted
March 7, 2012
Last Updated
September 6, 2023
Sponsor
M.D. Anderson Cancer Center
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT01552434
Brief Title
Bevacizumab and Temsirolimus Alone or in Combination With Valproic Acid or Cetuximab in Treating Patients With Advanced or Metastatic Malignancy or Other Benign Disease
Official Title
A Phase I Trial of Bevacizumab, Temsirolimus Alone and in Combination With Valproic Acid, or Cetuximab in Patients With Advanced Malignancy and Other Indications
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
March 16, 2012 (Actual)
Primary Completion Date
March 31, 2024 (Anticipated)
Study Completion Date
March 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
M.D. Anderson Cancer Center
Collaborators
National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
This phase I trial studies the side effects and best dose of bevacizumab and temsirolimus alone or in combination with valproic acid or cetuximab in treating patients with a malignancy that has spread to other places in the body or other disease that is not cancerous. Immunotherapy with bevacizumab and cetuximab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as valproic acid, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether bevacizumab and temsirolimus work better when given alone or with valproic acid or cetuximab in treating patients with a malignancy or other disease that is not cancerous.
Detailed Description
PRIMARY OBJECTIVES: I. To determine the maximum tolerated doses (MTDs) and dose-limiting toxicities (DLTs) of treatment with bevacizumab and temsirolimus in combination and plus valproic acid or cetuximab. SECONDARY OBJECTIVES: I. Preliminary descriptive assessment of anti-tumor efficacy of each combination. II. Preliminary assessment of the pharmacokinetic, pharmacodynamic markers of target inhibition and correlates of response (optional). OUTLINE: This is a dose-escalation study of bevacizumab and temsirolimus. Patients are assigned to 1 of 3 treatment groups. GROUP I: Patients receive temsirolimus intravenously (IV) over 30-60 minutes on days 1, 8, 15, and 22; bevacizumab IV over 30-90 minutes on days 1 and 15; and cetuximab IV over 1-2 hours on days 1, 8, 15, and 22. GROUP II: Patients receive temsirolimus and bevacizumab as in Group I and valproic acid orally (PO) daily on days 1-7 and 15-21. GROUP III: Patients receive temsirolimus and bevacizumab as in Group I. In all groups, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Advanced Malignant Neoplasm, Castleman Disease, Digestive System Carcinoma, Erdheim-Chester Disease, Lip and Oral Cavity Carcinoma, Lymphangioleiomyomatosis, Malignant Endocrine Neoplasm, Malignant Female Reproductive System Neoplasm, Malignant Male Reproductive System Neoplasm, Malignant Neoplasm, Malignant Respiratory Tract Neoplasm, Malignant Thoracic Neoplasm, Malignant Urinary System Neoplasm, Mesothelial Neoplasm, Metastatic Malignant Neoplasm, Metastatic Urothelial Carcinoma, Neurofibromatosis Type 2, Recurrent Adult Soft Tissue Sarcoma, Recurrent Breast Carcinoma, Recurrent Childhood Soft Tissue Sarcoma, Recurrent Digestive System Carcinoma, Recurrent Female Reproductive System Carcinoma, Recurrent Male Reproductive System Carcinoma, Recurrent Malignant Neoplasm, Recurrent Pharyngeal Carcinoma, Recurrent Thyroid Gland Carcinoma, Refractory Malignant Neoplasm, Soft Tissue Neoplasm, Stage III Breast Cancer AJCC v7, Stage III Pharyngeal Cancer, Stage IIIA Breast Cancer AJCC v7, Stage IIIB Breast Cancer AJCC v7, Stage IIIC Breast Cancer AJCC v7, Stage IV Breast Cancer AJCC v6 and v7, Stage IV Pharyngeal Cancer, Stage IVA Pharyngeal Cancer, Stage IVB Pharyngeal Cancer, Stage IVC Pharyngeal Cancer, Thyroid Gland Neoplasm
Keywords
Temsirolimus, CCI-779, Torisel, Bevacizumab, Avastin, rhuMAb-VEGF, Anti-VEGF Monoclonal Antibody, Advanced Cancers, Advanced Malignancy, Metastatic, cancer, Cetuximab, C225, Erbitux, IMC-C225, Valproic Acid

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
155 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Group I (temsirolimus, bevacizumab, cetuximab)
Arm Type
Experimental
Arm Description
Patients receive temsirolimus IV over 30-60 minutes on days 1, 8, 15, and 22; bevacizumab IV over 30-90 minutes on days 1 and 15; and cetuximab IV over 60-120 minutes on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Arm Title
Group II (temsirolimus, bevacizumab, valproic acid)
Arm Type
Experimental
Arm Description
Patients receive temsirolimus and bevacizumab as in Group I and valproic acid PO on days 1-7 and 15-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Arm Title
Group III (temsirolimus, bevacizumab)
Arm Type
Experimental
Arm Description
Patients receive temsirolimus and bevacizumab as in Group I. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention Type
Biological
Intervention Name(s)
Bevacizumab
Other Intervention Name(s)
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, Bevacizumab Biosimilar MIL60, Bevacizumab Biosimilar QL 1101, BEVACIZUMAB, LICENSE HOLDER UNSPECIFIED, 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
Intervention Description
Given IV
Intervention Type
Biological
Intervention Name(s)
Cetuximab
Other Intervention Name(s)
Cetuximab Biosimilar CMAB009, Chimeric Anti-EGFR Monoclonal Antibody, Chimeric MoAb C225, Chimeric Monoclonal Antibody C225, Erbitux, IMC-C225
Intervention Description
Given IV
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Optional correlative studies
Intervention Type
Other
Intervention Name(s)
Pharmacological Study
Intervention Description
Optional correlative studies
Intervention Type
Drug
Intervention Name(s)
Temsirolimus
Other Intervention Name(s)
CCI-779, CCI-779 Rapamycin Analog, Cell Cycle Inhibitor 779, Rapamycin Analog, Rapamycin Analog CCI-779, Torisel
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Valproic Acid
Other Intervention Name(s)
Depakene, Stavzor, Valproate
Intervention Description
Given PO
Primary Outcome Measure Information:
Title
Maximum tolerated dose (MTD) of bevacizumab, defined as the dose level below the dose at which 2 of 6 patients experience drug-related dose limiting toxicity (DLT)
Description
Graded by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.
Time Frame
4 weeks
Title
MTD of temsirolimus, defined as the dose level below the dose at which 2 of 6 patients experience DLT
Description
Graded by the NCI CTCAE version 3.0.
Time Frame
4 weeks
Secondary Outcome Measure Information:
Title
Anti-tumor efficacy of each combination (objective response)
Description
Will be determined by Response Evaluation Criteria In Solid Tumors and World Health Organization criteria
Time Frame
Up to 6 years
Title
Levels of surrogate anti-angiogenesis markers
Description
Correlated with anti-tumor activity.
Time Frame
Up to week 4 of course 1
Other Pre-specified Outcome Measures:
Title
The properties of the tissue microvasculature.
Description
The properties of the tissue microvasculature measured by Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) include parameters: volume transfer coefficient, (Ktrans), fractional volume (ve), and rate constant (kep).For each of these parameters, an exploratory analysis of change from baseline will be conducted which will include mean, median, standard deviation, and 95% confidence limits.
Time Frame
Up to week 4 of course 1

10. Eligibility

Sex
All
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients with advanced or metastatic cancer that is refractory to standard therapy, relapsed after standard therapy, or have no standard therapy that induces a complete response of at least 10% or improves survival by at least three months; in addition, patients with disease that are "benign" by pathology, but relentlessly progressive, leading to disability, pain, and premature death in the majority of cases (including, but not limited to lymphangioleiomyomatosis [LAM], type 2 neurofibromatosis [NF], Erdheim Chester disease, and Castleman's disease) may also be considered for enrollment Patients should be at least four weeks from the last day of therapeutic radiation or cytotoxic chemotherapy or from antibody therapy, or at least five half-lives from non-cytotoxic targeted or biologic therapy; patients may have received palliative radiation immediately before (or during) treatment provided radiation is not to the only target lesion available Eastern Cooperative Oncology Group (ECOG) performance status =< 2 Karnofsky >= 60% Lansky performance status of >= 60% for participants 16 years old or younger Absolute neutrophil count >= 1,000/mL Platelets >= 50,000/mL Creatinine =< 3 X upper limit of normal (ULN) Total bilirubin =< 3.0 Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 5 X ULN Fasting level of total cholesterol of no more than 350 mg/dL Triglyceride level of no more than 400 mg/dL Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 90 days after the last dose Ability to understand and the willingness to sign a written informed consent document Patients may not be receiving any other investigational agents and/or any other concurrent anticancer agents or therapies Exclusion Criteria: Patients with clinically significant unexplained bleeding within 28 days prior to entering the study Uncontrolled systemic vascular hypertension (systolic blood pressure > 140 mmHg, diastolic blood pressure > 90 mmHg on medication) Patients with clinically significant cardiovascular disease: History of CVA (cerebrovascular accident) within 6 months, myocardial infarction or unstable angina within 6 months, unstable angina pectoris Pregnant or breast-feeding women History of hypersensitivity to bevacizumab, murine products, or any component of the formulation History of hypersensitivity to temsirolimus or its metabolites (including sirolimus), polysorbate 80, or to any component of the formulation History of hypersensitivity to cetuximab, murine products, or any component of the formulation Patients that are taking cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A4) inducers and/or inhibitors; if a patient has a history of taking CYP3A4 inducers and/or inhibitors prior to enrollment on the protocol, it is strongly recommended that the patient stops the drug and waits at least 5 half-lives of said drug before initiating therapy on protocol Colorectal cancer patients with known v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation (for the arm combining bevacizumab, temsirolimus and cetuximab) Patients who have had major surgery within 6 weeks of enrollment in the study
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sarina A Piha-Paul
Organizational Affiliation
M.D. Anderson Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
M D Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States

12. IPD Sharing Statement

Links:
URL
http://www.mdanderson.org
Description
MD Anderson Cancer Center Website

Learn more about this trial

Bevacizumab and Temsirolimus Alone or in Combination With Valproic Acid or Cetuximab in Treating Patients With Advanced or Metastatic Malignancy or Other Benign Disease

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