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Bevacizumab, Temsirolimus, Valproic Acid, Cetuximab

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2014 by M.D. Anderson Cancer Center
Sponsor:
Information provided by (Responsible Party):
M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier:
NCT01552434
First received: March 7, 2012
Last updated: October 17, 2014
Last verified: October 2014
  Purpose

The goal of this clinical research study is to find the highest tolerable dose of Avastin (bevacizumab) and Torisel (temsirolimus) that can be given in combination with either valproic acid or cetuximab to patients with advanced cancer that is refractory. The safety of this drug combination will also be studied.

Bevacizumab is designed to block the growth of blood vessels, which may help to slow or block the growth of cancer.

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

Valproic acid is an anti-seizure drug that may be able to activate tumor-fighting genes, causing cancer cells to die.

Cetuximab is designed to block a certain protein, called EGFR, that is thought to cause cancer cells to grow. This may cause cancer cells to die.


Condition Intervention Phase
Advanced Cancers
Drug: Temsirolimus
Drug: Bevacizumab
Drug: Valproic Acid
Drug: Cetuximab
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Trial of Bevacizumab, Temsirolimus Alone and in Combination With Valproic Acid or Cetuximab in Patients With Advanced Malignancy

Resource links provided by NLM:


Further study details as provided by M.D. Anderson Cancer Center:

Primary Outcome Measures:
  • Maximum Tolerated Dose (MTD) of Bevacizumab and Temsirolimus and/or Cetuximab or Valproic Acid [ Time Frame: 56 days ] [ Designated as safety issue: Yes ]
    MTD defined as dose level below dose at which 2 of 6 patients experience drug-related dose limiting toxicity (DLT) in first cycle. DLT defined as any grade 3 or 4 non-hematologic toxicity as defined in NCI CTC v3.0, any Grade 4 hematologic toxicity lasting 2 weeks or longer, 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 therapy.


Secondary Outcome Measures:
  • Tumor Response [ Time Frame: After two 28 day cycles. ] [ Designated as safety issue: No ]
    Tumor response defined as one or more of the following: (1) stable disease for more than or equal to 4 months, (2) decrease in measurable tumor (sentinel lesions) by more than or equal to 20% by RECIST criteria, (3) decrease in tumor markers by more than or equal to 25% (for example, a >/= 25% decrease in CA125 for patients with ovarian cancer), or (4) a partial response according to Choi criteria, i.e. decrease in size by 10% or more, or a decrease in tumor density, as measured in Hounsfield units (HU), by more than or equal to 15% (28).


Estimated Enrollment: 216
Study Start Date: March 2012
Estimated Primary Completion Date: March 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Temsirolimus + Bevacizumab + Cetuximab

Dose Escalation Group: Starting dose of Temsirolimus 5 mg by vein on Days 1, 8, 15, and 22 of each 28 day cycle. Starting dose of Bevacizumab 2.5 mg/kg by vein on Days 1 and 15 of each 28 day cycle. Starting dose of Cetuximab loading dose 100 mg/m2, and maintenance dose 75 mg/m2 by vein on Days 1, 8, 15, and 22 of each 28 day cycle.

Dose Expansion Group Starting dose: Maximum tolerated dose (MTD) from Dose Escalation Group.

Drug: Temsirolimus

Dose Escalation Group: Starting dose of Temsirolimus 5 mg by vein on Days 1, 8, 15, and 22 of each 28 day cycle.

Dose Expansion Group Starting dose: Maximum tolerated dose (MTD) from Dose Escalation Group.

Other Names:
  • CCI-779
  • Torisel
Drug: Bevacizumab

Starting dose of Bevacizumab 2.5 mg/kg by vein on Days 1 and 15 of each 28 day cycle.

Dose Expansion Group Starting dose: Maximum tolerated dose (MTD) from Dose Escalation Group.

Other Names:
  • Avastin
  • rhuMAb-VEGF
  • Anti-VEGF Monoclonal Antibody
Drug: Cetuximab

Starting dose of Cetuximab loading dose 100 mg/m2, and maintenance dose 75 mg/m2 by vein on Days 1, 8, 15, and 22 of each 28 day cycle.

Dose Expansion Group Starting dose: Maximum tolerated dose (MTD) from Dose Escalation Group.

Other Names:
  • C225
  • Erbitux
  • IMC-C225
Experimental: Temsirolimus + Bevacizumab + Valproic Acid

Dose Escalation Group: Starting dose of Temsirolimus 5 mg by vein on Days 1, 8, 15, and 22 of each 28 day cycle. Starting dose of Bevacizumab 2.5 mg/kg by vein on Days 1 and 15 of each 28 day cycle. Starting dose of Valproic Acid 5 mg/kg rounded to nearest 250 mg by mouth on Days 1 - 7 and 15 - 21 of each 28 day cycle.

Dose Expansion Group Starting dose: Maximum tolerated dose (MTD) from Dose Escalation Group.

Drug: Temsirolimus

Dose Escalation Group: Starting dose of Temsirolimus 5 mg by vein on Days 1, 8, 15, and 22 of each 28 day cycle.

Dose Expansion Group Starting dose: Maximum tolerated dose (MTD) from Dose Escalation Group.

Other Names:
  • CCI-779
  • Torisel
Drug: Bevacizumab

Starting dose of Bevacizumab 2.5 mg/kg by vein on Days 1 and 15 of each 28 day cycle.

Dose Expansion Group Starting dose: Maximum tolerated dose (MTD) from Dose Escalation Group.

Other Names:
  • Avastin
  • rhuMAb-VEGF
  • Anti-VEGF Monoclonal Antibody
Drug: Valproic Acid

Starting dose of Valproic Acid 5 mg/kg rounded to nearest 250 mg by mouth on Days 1 - 7 and 15 - 21 of each 28 day cycle.

Dose Expansion Group Starting dose: Maximum tolerated dose (MTD) from Dose Escalation Group

Other Name: Depakene
Experimental: Temsirolimus + Bevacizumab

Dose Escalation Group: Starting dose of Temsirolimus 5 mg by vein on Days 1, 8, 15, and 22 of each 28 day cycle. Starting dose of Bevacizumab 2.5 mg/kg by vein on Days 1 and 15 of each 28 day cycle.

Dose Expansion Group Starting dose: Maximum tolerated dose (MTD) from Dose Escalation Group.

Drug: Temsirolimus

Dose Escalation Group: Starting dose of Temsirolimus 5 mg by vein on Days 1, 8, 15, and 22 of each 28 day cycle.

Dose Expansion Group Starting dose: Maximum tolerated dose (MTD) from Dose Escalation Group.

Other Names:
  • CCI-779
  • Torisel
Drug: Bevacizumab

Starting dose of Bevacizumab 2.5 mg/kg by vein on Days 1 and 15 of each 28 day cycle.

Dose Expansion Group Starting dose: Maximum tolerated dose (MTD) from Dose Escalation Group.

Other Names:
  • Avastin
  • rhuMAb-VEGF
  • Anti-VEGF Monoclonal Antibody

  Hide Detailed Description

Detailed Description:

Study Groups:

If you are found to be eligible, you will be assigned to a study drug combination that the study doctor thinks is in your best interest:

  • Drug Combination 1: Temsirolimus, bevacizumab, and cetuximab
  • Drug Combination 2: Temsirolimus, bevacizumab, and valproic acid
  • Drug Combination 3: Temsirolimus and bevacizumab

Dose Escalation Group:

You will be assigned to a dose level of your study drug combination based on when you joined this study.

Up to 11 dose levels will be tested for Study Drug Combination 1. Up to 10 dose levels will be tested for Study Drug Combinations 2 and 3. Three (3) participants will be enrolled at each dose level of each combination. 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.

Dose Expansion Group:

After the highest tolerable dose is found, up to an additional 10 participants, called the "dose expansion group," will receive each study drug combination at that dose.

Study Drug Administration:

The study drugs will be given in cycles. Cycles will be about 28 days or longer, depending on any side effects you may have.

You will be given bevacizumab by vein on Days 1 and 15 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 then tolerate it well in Cycle 2, you will receive it over 30 minutes in Cycle 3. As long as you still tolerate it well, you will receive it over 30 minutes in Cycle 4 and further cycles.

You will be given temsirolimus by vein on Days 1, 8, 15, and 22 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 for all future doses, as long you continue to tolerate it well.

If you are taking Drug Combination 1, you will be given cetuximab by vein 1 time every week. The first time you receive cetuximab, it will be given over 2 hours. Every time you receive cetuximab after that, it will be given over 1 hour.

If you are taking Drug Combination 2, you will take valproic acid by mouth 1 time each day in each cycle. The drug can be taken with or without food.

Study Visits:

One (1) time each week during Cycle 1, the following tests and procedures will be performed:

  • You will have a physical exam, including measurement of your weight and vital signs.
  • Blood (about 1 tablespoon) will be collected for routine tests.
  • Urine will be collected for routine tests only during the first week of Cycle 1.

Every 4 weeks during Cycles 2 and beyond:

  • You will have a physical exam, including measurement of your weight and vital signs.
  • Blood (about 1 tablespoon) and urine will be collected for routine tests.

After Cycle 2, you will have a CT or MRI scan after every 2 cycles to check the status of the disease.

Length of Study:

You may continue taking the study drug combination for as long as the doctor thinks it is in your best interest. You will no longer be able to take the study drugs if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

This is an investigational study. Bevacizumab is FDA approved and commercially available for the treatment of colorectal cancer and a type of lung cancer. Temsirolimus is FDA approved and commercially available for the treatment of kidney cancer that has spread. Cetuximab is FDA approved and commercially available for the treatment of colorectal cancer and a type of head and neck cancer. Valproic acid is FDA approved and commercially available to help control seizures.

The combination of bevacizumab and temsirolimus is not FDA approved to treat advanced cancer. The combination of bevacizumab and temsirolimus with cetuximab or valproic acid is not FDA approved to treat advanced cancer. At this time, each study drug combination is being used for research only.

Up to 216 patients will take part in this study. All will be enrolled at MD Anderson.

  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. 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 diseases 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
  2. 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.
  3. ECOG performance status </= 2 (Karnofsky >/= 60%).
  4. Lansky performance status of >/= 60% for participants 16 years old or younger.
  5. Patients must have allowable organ and marrow function defined as: absolute neutrophil count >/= 1,000/mL; platelets >/=50,000/mL; creatinine </= 3 X ULN; total bilirubin </= 3.0; AST(SGOT)/ALT(SGPT) </= 5 X ULN; fasting level of total cholesterol of no more than 350mg/dL; triglyceride level of no more than 400mg/dL.
  6. 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.
  7. Ability to understand and the willingness to sign a written informed consent document.
  8. Patients may not be receiving any other investigational agents and/or any other concurrent anticancer agents or therapies.

Exclusion Criteria:

  1. Patients with clinically significant unexplained bleeding within 28 days prior to entering the study.
  2. Uncontrolled systemic vascular hypertension (Systolic blood pressure > 140 mmHg, diastolic blood pressure > 90 mmHg on medication).
  3. 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
  4. Pregnant or breast-feeding women.
  5. History of hypersensitivity to bevacizumab, murine products, or any component of the formulation.
  6. History of hypersensitivity to Temsirolimus or its metabolites (including sirolimus), polysorbate 80, or to any component of the formulation.
  7. History of hypersensitivity to cetuximab, murine products, or any component of the formulation.
  8. Patients that are taking CYP3A4 inducers and/or inhibitors. Please see section "Drug Information" for details. 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.
  9. Colorectal cancer patients with known KRAS mutation (for the arm combining bevacizumab, temsirolimus and cetuximab)
  10. Patients who have had major surgery within 6 weeks of enrollment in the study.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01552434

Contacts
Contact: Sarina Piha-Paul, MD 713-563-1930

Locations
United States, Texas
University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
Investigators
Principal Investigator: Sarina Piha-Paul, MD M.D. Anderson Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT01552434     History of Changes
Other Study ID Numbers: 2012-0061, NCI-2012-00347
Study First Received: March 7, 2012
Last Updated: October 17, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by M.D. Anderson Cancer Center:
Advanced Cancers
Advanced Malignancy
Metastatic cancer
Temsirolimus
CCI-779
Torisel
Bevacizumab
Avastin
rhuMAb-VEGF
Anti-VEGF Monoclonal Antibody
Cetuximab
C225
Erbitux
IMC-C225
Valproic Acid
Depakene

Additional relevant MeSH terms:
Antibodies, Monoclonal
Bevacizumab
Cetuximab
Everolimus
Sirolimus
Valproic Acid
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Anticonvulsants
Antifungal Agents
Antimanic Agents
Antineoplastic Agents
Central Nervous System Agents
Central Nervous System Depressants
Enzyme Inhibitors
GABA Agents
Growth Inhibitors
Growth Substances
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Pharmacologic Actions
Physiological Effects of Drugs
Psychotropic Drugs
Therapeutic Uses
Tranquilizing Agents

ClinicalTrials.gov processed this record on November 25, 2014