RAD001 Plus Carboplatin in Breast Cancer Patients

Study Overview
=================
Brief Summary
-----------------
This study investigates the effectiveness of combination of carboplatin and investigational agent RAD001 in triple-negative breast cancer.

Detailed Description
-----------------
The primary objective of this study was to determine clinical benefit rate (CBR) i.e.complete remission (CR) + partial remission (PR) + stable disease (SD) lasting ≥ 6 months, and the toxicity of RAD001 /carboplatin in women with metastatic triple-negative breast cancer. Treatment consisted of intravenous carboplatin at area under the plasma concentration-time curve (AUC) 6, later decreased to AUC 5, and subsequently to AUC 4 every 3 weeks with daily 5mg RAD001.

Official Title
-----------------
Phase II Trial of RAD001 Plus Carboplatin in Patients With Triple-Negative Metastatic Breast Cancer

Conditions
-----------------
Breast Cancer

Intervention / Treatment
-----------------
* Drug: RAD001
* Drug: Carboplatin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Women with metastatic breast cancer (measurable or evaluable including bone metastases only) Histologically confirmed triple negative breast cancer (estrogen receptor (ER)< 10%, progesterone receptor (PR) < 10 %, Her2neu IHC 0 or 1 or FISH negative) Age >= 18 years World Health Organization performance status <= 2 Adequate bone marrow function as shown by: absolute neutrophil count ≥ 1.5 x 10^9/L, Platelets ≥ 100 x 10^9/L, Hb >9 g/dL Adequate liver function as shown by: serum bilirubin ≤ 1.5 x upper limit of normal (ULN) international normalized ratio (INR): Patients not on warfarin INR ≤1.5; Patients on warfarin INR ≤3; Patient on stable dose of low molecular weight heparin for >2 weeks at time of treatment is allowed. alanine aminotransferase and aspartate aminotransferase ≤ 2.5x ULN (≤ 5x ULN in patients with liver metastases) Adequate renal function: serum creatinine ≤ 1.5 x ULN Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides ≤ 2.5 x ULN. NOTE: In case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication. Signed informed consent Patients may have had 0-3 prior regimens for metastatic disease and prior bevacizumab (avastin) is allowed. A baseline lung CT (or PET/CT) O2 sat >= 90% in room air (if <90%, spirometry and diffusion capacity of lung for carbon monoxide (DLCO) above 50% of the normal predicted value of pulmonary function tests) Negative serum pregnancy test within 7 days prior to starting treatment Exclusion Criteria: Patients currently receiving anticancer therapies or who have received anticancer therapies within 2 weeks of the start of study drug (including chemotherapy, radiation therapy, and biologics) Patients, who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia) or patients that may require major surgery during the course of the study Prior treatment with any investigational drug within the preceding 2 weeks Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent, except corticosteroids with a daily dosage equivalent to prednisone ≤ 20 mg. However, patients receiving corticosteroids must have been on a stable dosage regimen for a minimum of 4 weeks prior to the first treatment with RAD001. Topical or inhaled corticosteroids are allowed. Patients should not receive immunization with attenuated live vaccines within one week of study entry or during study period Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases Other malignancies within the past 3 years except for adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin. Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as: Symptomatic congestive heart failure of New York heart Association Class III or IV unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease severely impaired lung function as defined as spirometry and DLCO that is 50% of the normal predicted value and/or 02 saturation that is 88% or less at rest on room air uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN active (acute or chronic) or uncontrolled severe infections liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis. Note: A detailed assessment of Hepatitis B/C medical history and risk factors must be done at screening for all patients. HBV DNA and HCV RNA polymerase chain reaction testing are required at screening for all patients with a positive medical history based on risk factors and/or confirmation of prior HBV/HCV infection. A known history of HIV seropositivity Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of RAD001 (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection) Patients with an active, bleeding diathesis Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods. If barrier contraceptives are being used, these must be continued throughout the trial by both sexes. Hormonal contraceptives are not acceptable as a sole method of contraception. (Women of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to administration of RAD001) Patients who have received prior treatment with an mTOR inhibitor (sirolimus, temsirolimus, everolimus). Patients with a known hypersensitivity to RAD001 (everolimus) or other rapamycins (sirolimus, temsirolimus) or to its excipients History of noncompliance to medical regimens Patients unwilling to or unable to comply with the protocol Ongoing alcohol or drug addiction

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RAD001+carboplatin<br>Carboplatin (starting dose was initially AUC 6, later decreased to AUC 5, then AUC 4) every 3 weeks as IV infusion and RAD001 as 5 mg pill each day until disease progression or unacceptable toxicity. | Drug: RAD001<br> <br> * Other names: Everolimus;Drug: Carboplatin<br> <br> * Other names: Paraplatin;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Benefit Rate (Complete Response, Partial Response, and Stable Disease That Lasts More Than 6 Months) | Clinical benefit rate is defined as the number of patients with complete response (CR), partial response (PR), or stable disease (SD) that lasts at least 6 months. Response was assessed every 2 cycles of treatment (6 weeks) by computed tomography (CT), CT/positron emission tomography (PET), or magnetic resonance imaging (MRI). Overall response evaluation is based on Response Evaluation Criteria In Solid Tumors 1.0 (RECIST 1.0). Per RECIST 1.0 for target lesions: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. | up to 1 year | 
| Toxicity Profile-Hematological | Reported as percentage of patients who experienced grade 3 and higher hematological adverse events (AEs) related to the study drugs. | treatment period (up to 1 year) plus 30 days off treatment | 
| Toxicity Profile-Non Hematological | Reported as percentage of patients who experienced grade 3 and higher non-hematological AEs related to the study drugs. | treatment period (up to 1 year) plus 30 days off treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Progression-free Survival Time | Progression-free survival time is defined as the time from first day of treatment to the first date of disease progression or death as a result of any cause. Progression was assessed every 2 cycles of treatment (6 weeks) by CT, CT/PET, or MRI. Progression is defined using RECIST 1.0, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | up to 1 year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
metastatic, breast, cancer