Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Digestive System Diseases

Breast Neoplasms

Head and Neck Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Antineoplastic Agents

All Drugs and Chemicals

Vasodilator Agents

Fluorouracil

Acetylcholine

Comprised of newly diagnosed cancer patients 21 years or older who have received 5-FU chemotherapy within the past 30 days or are scheduled to receive 5-FU chemotherapy.

Comprised of newly diagnosed cancer patients 21 years or older who have received chemotherapy other than 5-FU within the past 30 days or are scheduled to receive chemotherapy other than 5-FU.

Age, biological sex, and prior health history (excluding cancer diagnosis) matched control for cancer patients

Cancer survivors who have not received cancer therapy during the past year but previously received 5-Fluorouracil chemotherapy.

Measured using an automated non-invasive finger cuff that obtains beat-by-beat blood pressure measurements via finger photoplesmography. Briefly, changes in artery diameter are detected through infrared light in the finger cuff. (Finometer Pro, FMS, The Netherlands).

Arterial blood pressure

Assessed non-invasively in the forearm skin via Laser Doppler flowmetry in response to locally delivered acetylcholine and norepinepherine or phenylepherine via iontophoresis.

Skin microcirculatory blood flow

A GE Ultrasound System will be used to non-invasively assess brachial artery blood flow prior to and following a standard flow mediated dilation protocol.

Brachial artery blood flow

A venous blood sample from the antecubital vein or a vein in the back of the hand will be taken via venipuncure by a nurse or a certified phlebotomist at the beginning of the experimental visit. These blood samples will be analyzed for the presence of reactive oxygen species and inflammatory markers.

Venous blood draw

Carl J Ade, PhD

Steve T Hammond

Carl J Ade, Ph.D.

The primary aim of this study is to investigate potential differences in vascular function between patients receiving 5-Fluorouracil (5-FU) chemotherapy, patients receiving chemotherapies other than 5-FU, cancer survivors who were treated with 5-FU, and an age and sex matched control. 5-FU is the third most commonly administered chemotherapeutic agent and its use is associated with the second most occurrences of cardiotoxicity. Despite the known cardiotoxic effects of 5-FU, it's effects on the human vasculature are not well understood.

To achieve the goals of this project Laser Doppler flowmetry (LDF) will be used to assess blood flow within the skin microcirculation of the forearm in cancer patients who have received 5-Fluoruracil within the past 30 days (Experimental Group), cancer patients receiving radiotherapy and/or chemotherapy other than 5-Fluorouracil, and an age and sex matched control (Control Group). LDF utilizes a small (\~3 cm) non-invasive sensor placed on the skin. The sensor shines light into the skin, and upon contact with red blood cells (RBCs), the light is reflected and scattered. This information is used to evaluate microvascular blood flow and has previously been used in clinical populations.

Although cancer continues to be one of the leading causes of death each year, advancements in cancer treatments and detection have improved patient prognosis across a large number of cancer types. This trend of improved survival rates has made apparent the significant risk of chemotherapy on the cardiovascular system in such a way that cardiotoxicity has become a prime concern in cancer survivors. Indeed, cardiotoxic events have been related to numerous chemotherapy types, including the commonly used 5-Fluorouracil (5-FU). 5-FU is the third most commonly administered form of chemotherapy used in the treatment of solid malignancies. Despite undeniable effectiveness in treating cancer, administration of 5-FU is associated with the second highest incidence of cardiotoxicity out of all chemotherapeutic agents.

Such cardiotoxic manifestations typically appear in the form of chest pain, angina during rest and/or exertion, and acute coronary syndromes, however, other events such as arrythmias, myocarditis, pericarditis, heart failure, or even death have been reported following 5-FU administration. While multiple mechanisms are believed to lead to 5-FU cardiotoxicity, the effects 5-FU has on the vasculature seem to be of particular importance. Initial findings suggest these drugs have a direct toxic effect on the vascular endothelium and smooth muscle, likely through increases in reactive oxygen species (ROS). ROS are known to adversely affect endothelium independent and dependent factors which influence vascular tone. Along with increased ROS, decreases in antioxidant capacity following 5-FU therapy lead to increased vasospasms and altered vasodilator/constrictor responses. Indeed, both coronary artery vasospasms and brachial artery vasoconstriction have been found to occur in some groups directly after injection of 5-FU.

Although the primary signaling pathways for 5-FU induced cardiotoxicity are well documented, many of these studies have been conducted in animal models. Previous work has demonstrated substantial vascular dysfunction in current cancer patients undergoing adjuvant systematic chemotherapy when compared to healthy controls, however, alike investigations specifically focused on vascular dysfunction in patients receiving 5-FU have yet to be conducted. To investigate such mechanisms, microvascular reactivity will be measured with laser Doppler flowmetry combined with iontophoresis of acetylcholine in cancer patients currently undergoing treatment with 5-Fluorouracil, patients receiving chemotherapy treatments other than 5-Fluorouracil, cancer survivors previously treated with 5-Fluorouracil, and age and sex matched controls.

Venous blood samples (5-7 mL) from the antecubital vein or a vein in the back of the hand will be taken via venipuncure by a nurse or a certified phlebotomist at the beginning of the experimental visit. These blood samples will be analyzed for the presence of reactive oxygen species and inflammatory markers.

Microvascular Function in Patients Undergoing 5-Fluorouracil Chemotherapy

Measured once in each group following administration of vasodilatory (Acetylcholine) and vasoconstrictive (Norepinepherine or Phenylephrine) substances.

Systolic, diastolic, and mean arterial pressure will be measured continuously over the course of the visit for each group.

Kansas State University

Assistant Professor

Rare Diseases

Triple Negative Breast Neoplasms

Breast Neoplasms, Male

Breast Diseases

Skin Diseases

Breast Cancer, Male

Anti-Infective Agents

Paclitaxel

Everolimus

Albumin-Bound Paclitaxel

Cisplatin

Complement System Proteins

Tubulin Modulators

Antimitotic Agents

Sirolimus

Temsirolimus

MTOR Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Immunosuppressive Agents

Immunologic Factors

Cisplatin 25 mg/m2 IV weekly + RAD001 5 mg PO daily for 1 week followed by Cisplatin 25 mg/m2 IV + Paclitaxel 80 mg/m2 IV weekly + RAD001 5 mg PO daily for 11 weeks

Cisplatin 25 mg/m2 IV weekly + placebo PO daily for 1 week followed by Cisplatin 25 mg/m2 IV + Paclitaxel 80 mg/m2 IV weekly + placebo PO daily for 11 weeks

cisplatin

everolimus

paclitaxel

placebo

Venous blood (2-3 tablespoons) will be taken for germline DNA analysis to complement the correlative studies in the tumor tissue. Blood can be drawn at any time prior, during, or after completion of study treatment

Ingrid Mayer, M.D.

RATIONALE: Drugs used in chemotherapy, such as cisplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Giving chemotherapy together with everolimus before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. It is not yet known whether cisplatin and paclitaxel are more effective when given together with or without everolimus in treating patients with breast cancer.

PURPOSE: This randomized phase II trial is studying how well cisplatin and paclitaxel work when given together with or without everolimus in treating patients with stage II or stage III breast cancer.

OBJECTIVES:

Primary

* To determine the pathological complete response in patients with triple-negative, stage II or III breast cancer treated with neoadjuvant cisplatin and paclitaxel with or without everolimus.

Secondary

* To determine the safety profile of these treatment regimens.
* To evaluate tumor response to these treatment regimens as measured by ultrasound before definitive surgery.
* To evaluate the rate of breast conservation surgery after treatment with these regimens.
* To determine treatment-mediated changes in cell cycle position, proliferation, and apoptosis as well as status, levels, and phosphorylation state of S6K, p53, p73, and p63 and select p53 family target genes before and after initiation of paclitaxel.
* To isolate RNA and generate microarray data sets from pre- and post-treatment biopsy material to identify a pre-treatment gene signature that will predict response.
* To isolate RNA and generate microarray data sets from pre- and post-treatment biopsy material to identify a change in gene signature after the first treatment that will predict response.
* To isolate RNA and generate microarray data sets from pre- and post-treatment biopsy material to determine if previously established p63 and p73 gene signatures predict response to treatment.
* To isolate RNA and generate microarray data sets from pre- and post-treatment biopsy material to determine if a change will be observed in p63 and p73 gene signatures between pre- and post-treatment biopsies.
* To isolate RNA and generate microarray data sets from pre- and post-treatment biopsy material to determine if triple-negative breast cancers can be clustered into different subtypes on the basis of gene expression, given the size of the microarray data set that will be generated from this clinical trial and previous clinical trials (\> 100 tumors).
* To isolate RNA and generate microarray data sets from pre- and post-treatment biopsy material to determine if p63 and p73 gene signatures can sub-classify triple-negative breast cancers.

OUTLINE: This is a multicenter study. Patients are stratified according to initial lymph node status (positive vs negative involvement) and tumor grade (low or intermediate vs high). Patients are randomized to 1 of 2 treatment arms.

* Arm I: Patients receive cisplatin IV over 1 hour and oral everolimus once weekly in weeks 1-12 and paclitaxel IV over 1 hour once weekly in weeks 4-12 in the absence of disease progression or unacceptable toxicity.
* Arm II: Patients receive cisplatin IV over 1 hour and oral placebo once weekly in weeks 1-12 and paclitaxel IV over 1 hour once weekly in weeks 4-12 in the absence of disease progression or unacceptable toxicity.

Approximately 3-6 weeks after the completion of neoadjuvant therapy, patients undergo partial or total mastectomy with lymph node evaluation. Patients may then receive additional chemotherapy or radiotherapy.

Patients undergo ultrasound-guided core biopsies at baseline and in weeks 1, 4, and 12 for analysis of proliferation, apoptosis, and pathway activity markers via IHC or western blotting and RNA microarrays.

Patients are followed up within 3 weeks after surgery.

Cisplatin and Paclitaxel With or Without Everolimus in Treating Patients With Stage II or Stage III Breast Cancer

A Phase II Neo-Adjuvant Study of Cisplatin, Paclitaxel With or Without RAD001 in Patients With Triple-negative Locally Advanced Breast Cancer.

To determine the relevance of pathway modulation in triple negative breast cancer cell networking

To determine the levels of P63 and p73 in order to correlate these levels with patient response to treatment to help define a biomarker signature associated with p63/p73 dependence in triple negative breast cancers

Pathological complete response is defined as no residual tumor on histopathological analysis of both breast and axillary contents.

Defined as patients that did not undergo complete removal of a cancerous breast (mastectomy).

Per RECIST criteria v. 1.0: measurable lesions: complete response (CR) disappearance of target lesions, partial response (PR) \> 30% decrease in the sum of the longest diameter (LD) of target lesions, progressive disease (PD) \> 20% increase in the sum of the LD of target lesions or appearance of new lesions, stable disease (SD) neither sufficient decrease nor increase of the sum of smallest sum of the LD of target lesions

Tables represent the number of patients with their worst-grade toxicity at each of five grades (grade 1, least severe to grade 5, most severe) following NCI Common Toxicity Criteria. Not all participants necessarily have an adverse event, thus not everyone will be accounted for in worst-grade toxicities. Likewise, one participant can potentially have more than one event in various grades 1-5 which accounts for the difference in number of patients analyzed and total number in the worst-grade toxicity tables.

National Cancer Institute (NCI)

Vanderbilt-Ingram Cancer Center

Assistant Professor of Medicine; Clinical Director, Breast Cancer Program; Medical Oncologist

Cisplatin 25 mg/m2 IV weekly + RAD001 5 mg PO daily for 1 week followed by Cisplatin 25 mg/m2 IV + Paclitaxel 80 mg/m2 IV weekly + RAD001 5 mg PO daily for 11 weeks

cisplatin: Given IV

everolimus: Given orally

paclitaxel: Given IV

Venous blood draw: Venous blood (2-3 tablespoons) will be taken for germline DNA analysis to complement the correlative studies in the tumor tissue. Blood can be drawn at any time prior, during, or after completion of study treatment

Arm I

Cisplatin 25 mg/m2 IV weekly + placebo PO daily for 1 week followed by Cisplatin 25 mg/m2 IV + Paclitaxel 80 mg/m2 IV weekly + placebo PO daily for 11 weeks

cisplatin: Given IV

paclitaxel: Given IV

placebo: Given orally

Venous blood draw: Venous blood (2-3 tablespoons) will be taken for germline DNA analysis to complement the correlative studies in the tumor tissue. Blood can be drawn at any time prior, during, or after completion of study treatment

Arm II

Total

Age, Continuous

Age, Categorical

Sex: Female, Male

United States

Region of Enrollment

The number of participants in each arm will not necessarily coincide with the number of participants affected in the respective arm. Some participants my have more than one event and/or some participants may not have an event at all.

Dr. Ingrid Mayer

Cisplatin and Paclitaxel + RAD001

Cisplatin and Paclitaxel + Placebo

Number of patients that had complete response. Specimens containing only non-invasive disease will be classified as complete pathologic responders

Number of Patients With Pathological Complete Response

participants that had breast conservation surgery

Number of Patients That Underwent Breast Conservation Surgery

Complete Response

Partial Response

Stable Disease

Progressive Disease

Not Evaluable

Patients reported by best overall response data. Patients are excluded if best overall response data is not accessible or not evaluable.

Clinical Tumor Response to Neoadjuvant Therapy as Measured by Ultrasound Immediately Before Surgery

Number of patients with worst-grade toxicity 1

Number of patients with worst-grade toxicity 2

Number of patients with worst-grade toxicity 3

Number of patients with worst-grade toxicity 4

Number of patients with worst-grade toxicity 5

Total number of patients reported with any toxicity related to study treatment.

Number of Patients With Each Worst-grade Toxicity Response

Therapy-mediated Changes in Cell Cycle Position, Proliferation, and Apoptosis as Well as Status, Levels, and Phosphorylation State of p53, p73, and p63 and Select p53 Family Target Genes

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Microvascular Function in Patients Undergoing 5-Fluorouracil Chemotherapy	NCT04042298	Gastrointestina... Head and Neck C... Breast Cancer Chemotherapy Ef... 5-Fluorouracil ...	Arterial blood ... Skin microcircu... Brachial artery... Venous blood dr...	21 Years -	Kansas State University
Microvascular Function in Patients Undergoing 5-Fluorouracil Chemotherapy	NCT04042298	Gastrointestina... Head and Neck C... Breast Cancer Chemotherapy Ef... 5-Fluorouracil ...	Arterial blood ... Skin microcircu... Brachial artery... Venous blood dr...	21 Years -	Kansas State University
Cisplatin and Paclitaxel With or Without Everolimus in Treating Patients With Stage II or Stage III Breast Cancer	NCT00930930	Breast Cancer	cisplatin everolimus paclitaxel placebo Venous blood dr...	18 Years -	Vanderbilt-Ingram Cancer Center

Spots Global Cancer Trial Database for venous blood draw