Cisplatin, Paclitaxel, and Everolimus in Treating Patients With Metastatic Breast Cancer

Vanderbilt University Medical Center

Status and phase

Completed

Phase 2

Phase 1

Conditions

Breast Cancer

Treatments

Drug: paclitaxel

Drug: cisplatin

Drug: everolimus

Other: laboratory biomarker analysis

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT01031446

VU-VICC-BRE-0949

VICC BRE 0949

P30CA068485 (U.S. NIH Grant/Contract)

IRB# 090673

Details and patient eligibility

About

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.

Full 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.

Enrollment

55 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion 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)