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A Phase Ib/II Study of Cisplatin, Paclitaxel, and RAD001 in Patients With Metastatic Breast Cancer

Phase 1/Phase 2
18 Years
Not Enrolling
Breast Cancer

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Trial Information

A Phase Ib/II Study of Cisplatin, Paclitaxel, and RAD001 in Patients With Metastatic Breast Cancer



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

- Progression-free survival (Phase II)


- 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

- 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.

Inclusion Criteria


- 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


- 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

- 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

- 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


- See Disease Characteristics

- Recovered from prior therapy

- Prior total cumulative life-time dose of doxorubicin ≤ 360 mg/m^2 or epirubicin ≤ 640

- 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)

Type of Study:


Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome 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

Outcome Description:

The recommended dose for the Phase II trial will be the most prevalent dose delivered per week in Phase I that allows for safe and feasible administration of the medications.The maximum tolerated dose (MTD) is defined as the dose preceding that at which 2 or more of 3 patients experience dose-limiting toxicity (DLT) during the initial cycle of therapy. DLTs include Common Toxicity Criteria (CTC) Grade 4 neutropenia (absolute neutrophil count [ANC] < 0.5 x 10 9/L for > 5 days), febrile neutropenia (ANC < 1.0 x 10 0/L with fever > 38.5 degrees Centigrade) or documented infection associated with Grade 3-4 neutropenia, CTC Grade 4 thrombocytopenia < 25 x 10 9/L or CTC Grade 3 < 50-25 x 10 9/L thrombocytopenia with bleeding, and Grade 3-4 non-hematologic toxicity despite symptomatic therapy.

Outcome Time Frame:

at 8 weeks

Safety Issue:


Principal Investigator

Ingrid Mayer, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Vanderbilt-Ingram Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

October 2009

Completion Date:

June 2012

Related Keywords:

  • Breast Cancer
  • stage IV breast cancer
  • Human epidermal growth factor (HER2)-negative breast cancer
  • triple-negative breast cancer
  • hormone-resistant breast cancer
  • Breast Neoplasms



Vanderbilt-Ingram Cancer Center Nashville, Tennessee  37232-6838
West Tennessee Cancer Center at Jackson-Madison County General Hospital Jackson, Tennessee  38301
Erlanger Cancer Center at Erlanger Hospital - Baroness Chattanooga, Tennessee  37403
Vanderbilt-Ingram Cancer Center - Cool Springs Nashville, Tennessee  37064
Baptist Regional Cancer Center at Baptist Riverside Knoxville, Tennessee  37901