Clinical trial NCT01552434: 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
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: 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
Lead sponsor: M.D. Anderson Cancer Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2012-03-13
Enrollment: 155
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
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)
timeFrame: 4 weeks
measure: MTD of temsirolimus, defined as the dose level below the dose at which 2 of 6 patients experience DLT
timeFrame: 4 weeks
Secondary outcomes:
measure: Anti-tumor efficacy of each combination (objective response)
timeFrame: Up to 6 years
measure: Levels of surrogate anti-angiogenesis markers
timeFrame: Up to week 4 of course 1
Other outcomes:
measure: The properties of the tissue microvasculature.
timeFrame: Up to week 4 of course 1
Locations:
city: Houston
country: United States
facility: M D Anderson Cancer Center
state: Texas
Study officials:
affiliation: M.D. Anderson Cancer Center
name: Sarina A Piha-Paul
role: PRINCIPAL_INVESTIGATOR
References: