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BRIEF TITLE: Trial of Bevacizumab, Temsirolimus Alone and in Combination With Valproic Acid, or Cetuximab in Patients With Advanced Malignancy and Other Indications

A Phase I Trial of Bevacizumab, Temsirolimus Alone and in Combination With Valproic Acid, or Cetuximab in Patients With Advanced Malignancy and Other Indications

  • Org Study ID: 2012-0061
  • Secondary ID: NCI-2012-00347,2012-0061,P30CA016672
  • NCT ID: NCT01552434
  • NCT Alias:
  • Sponsor: M.D. Anderson Cancer Center - Other
  • Source: M.D. Anderson Cancer Center

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


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


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.

Overal Status Start Date Phase Study Type
Recruiting March 16, 2012 Phase 1 Interventional

Primary Outcomes:

Primary Outcome 1 - Measure: 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)

Primary Outcome 1 - Time Frame: 4 weeks

Primary Outcome 2 - Measure: MTD of temsirolimus, defined as the dose level below the dose at which 2 of 6 patients experience DLT

Primary Outcome 2 - Time Frame: 4 weeks


  • 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


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

- 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

- 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

- 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

- Patients who have had major surgery within 6 weeks of enrollment in the study
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Gender: All

Minimum Age: N/A

Maximum Age: N/A

Healthy Volunteers: No

Official Information

Name: Sarina A Piha-Paul

Role: Principal Investigator

Affiliation: M.D. Anderson Cancer Center

Overall Contact

Name: Sarina Piha-Paul

Phone: 713-563-1930


Link: MD Anderson Cancer Center Website


Facility Status Contact
M D Anderson Cancer Center
Houston, Texas 77030
United States
Recruiting Sarina A. Piha-Paul