Clinical trial NCT01031446: Cisplatin, Paclitaxel, and Everolimus in Treating Patients With Metastatic Breast Cancer
Official title: A Phase Ib/II Study of Cisplatin, Paclitaxel, and RAD001 in Patients With Metastatic Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Breast Cancer
Keywords: stage IV breast cancer
Human epidermal growth factor (HER2)-negative breast cancer
triple-negative breast cancer
hormone-resistant breast cancer
Lead sponsor: Vanderbilt-Ingram Cancer Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2009-12-14
Enrollment: 55
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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 cisplatin and paclitaxel together with everolimus may kill more tumor cells.

PURPOSE: This phase I/II trial is studying the side effects of giving cisplatin and paclitaxel together with everolimus and to see how well it works in treating patients with metastatic breast cancer.

Detailed description: OBJECTIVES:

Primary

* Safety profile of cisplatin, paclitaxel, and everolimus (RAD001) in patients with metastatic breast cancer. (Phase I)
* Progression-free survival (Phase II)

Secondary

* Overall response rate
* Time to progression
* Number of patients with worst-grade toxicities Tertiary
* To determine p53, p63, p73, and phosphatase and tensin homolog (PTEN) levels by immunohistochemistry (IHC).
* To screen for exon 9 (E542K and E545K), exon 20 (H1047R), and phosphatidylinositol 3-kinase (PI3K) (p110α) mutations in DNA extracted from paraffin blocks.
* To correlate IHC results with clinical outcome and with the different subtypes of breast cancer determined by molecular classification (basal-type vs luminal A vs luminal B) based on microarrays of RNA extracted from formalin-fixed paraffin-embedded blocks.
* To generate microarrays of RNA extracted from fresh-frozen core biopsies (when available) to identify a pretreatment gene signature that mirrors the established p63 and p73 gene signatures that predict response to treatment.

OUTLINE: This is a multicenter study.

Patients receive oral everolimus once daily on days 1-28 and cisplatin IV over 1 hour and paclitaxel IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Tumor tissue samples are collected at baseline for correlative studies.

After completion of study treatment, patients are followed up at 4 weeks.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Histologically confirmed invasive mammary carcinoma

  * Stage IV disease
  * Basal-like disease (triple-negative, hormone-refractory, HER2-negative)
* No locally recurrent breast cancer
* No symptomatic brain metastases

  * Patients with a history of brain metastases are eligible provided they are clinically stable for \> 3 weeks after completion of radiotherapy and are not taking steroids or therapeutic anticonvulsants that are cytochrome P450 3A4 (CYP3A4) modifiers
  * Patients with asymptomatic brain metastases are eligible provided they are not taking prophylactic anticonvulsants that are CYP3A4 modifiers

PATIENT CHARACTERISTICS:

* Pre- or post-menopausal
* European Cooperative Oncology Group (ECOG) performance status 0-1
* Life expectancy ≥ 6 months
* Absolute neutrophil count (ANC) ≥ 1,000/mm\^3
* Platelet count ≥ 100,000/mm\^3
* Creatinine ≤ 1.5 times upper limit of normal (ULN)
* Total bilirubin ≤ 1.5 times ULN (≤ 3 times ULN in the presence of liver metastasis)

  * Direct bilirubin will be measured in patients with Gilbert syndrome
* serum glutamate oxaloacetate transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) ≤ 1.5 times ULN (≤ 3 times ULN in the presence of liver metastasis)
* Alkaline phosphatase ≤ 3 times ULN (in the presence of liver metastasis)
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective barrier contraception during and for 3 months after completion of study treatment
* Able to swallow and retain oral medication
* No malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel
* No concurrent uncontrolled illness including, but not limited to, any of the following:

  * Ongoing or active infection requiring parenteral antibiotics
  * Impaired lung function (chronic obstructive pulmonary disease or lung conditions requiring oxygen therapy)
  * New York Heart Association class III-IV congestive heart failure
  * Unstable angina pectoris, angioplasty, stenting, or myocardial infarction within the past 6 months
  * Uncontrolled hypertension (systolic BP \> 180 mm Hg or diastolic BP \> 100 mm Hg, found on 2 consecutive measurements separated by a 1-week period and despite adequate medical support)
  * Clinically significant cardiac arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia that is symptomatic or requires treatment \[grade 3 according to NCI Common Toxicity Criteria for Adverse Events v3.0\])
  * Uncontrolled diabetes (hyperosmolar state, ketoacidosis, etc.)
  * Psychiatric illness or social situations that would compromise patient safety or limit compliance with study requirements including maintenance of a compliance/pill diary
* No symptomatic neuropathy ≥ grade 2
* No other invasive cancer within the past 5 years except for completely resected basal cell or squamous cell carcinoma of the skin or successfully treated cervical carcinoma in situ
* No hypersensitivity to paclitaxel or drugs using the vehicle Cremophor, Chinese hamster ovary cell products, or other recombinant human antibodies
* No history of hepatitis B or C

PRIOR CONCURRENT THERAPY:

* See Disease Characteristics
* Recovered from prior therapy
* Prior total cumulative life-time dose of doxorubicin ≤ 360 mg/m\^2 or epirubicin ≤ 640 mg/m\^2
* No more than 4 prior chemotherapy treatments in the metastatic setting (not including endocrine therapy or single-agent biologic therapy)
* At least 2 weeks since prior investigational drugs
* At least 14 days since prior and no concurrent herbal or dietary supplements
* At least 14 days since prior and no concurrent CYP3A4 inducers
* At least 7 days since prior and no concurrent CYP3A4 inhibitors
* Concurrent radiotherapy to painful bone metastases or areas of impending bone fracture allowed provided radiotherapy is initiated before study entry
* No other concurrent anticancer therapy (chemotherapy, radiotherapy, surgery, immunotherapy, hormonal therapy, biologic therapy)

Primary outcomes:
measure: Maximum Feasible Dose in Milligrams Per Meter Squared of Body Surface Area (mg/m2) of Cisplatin and Paclitaxel for Women With Metastatic Breast Cancer
timeFrame: at 8 weeks
measure: Maximum Feasible Dose in mg of RAD001 (Everolimus)for Women With Metastatic Breast Cancer
timeFrame: at 8 weeks
measure: Patients With Progression-free Survival
timeFrame: at 6 months
Secondary outcomes:
measure: Patients With Overall Response
timeFrame: every 12 weeks
measure: Time to Progression
timeFrame: Up to 64 weeks
measure: Time to Progression in Patients With Metastatic Basal-like Breast Cancer.
timeFrame: Up to 64 weeks
Other outcomes:
Locations:
city: Chattanooga
country: United States
facility: Erlanger Cancer Center at Erlanger Hospital - Baroness
state: Tennessee
city: Jackson
country: United States
facility: West Tennessee Cancer Center at Jackson-Madison County General Hospital
state: Tennessee
city: Knoxville
country: United States
facility: Baptist Regional Cancer Center at Baptist Riverside
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Center
state: Tennessee
Study officials:
affiliation: Vanderbilt-Ingram Cancer Center
name: Ingrid Mayer, MD
role: PRINCIPAL_INVESTIGATOR
References: