Clinical trial NCT01617668: A Randomized, Phase 2, Neoadjuvant Study of Weekly Paclitaxel With or Without LCL161 in Patients With Triple Negative Breast Cancer
Official title: A Phase II Multi-center, Open-label, Neoadjuvant, Randomized Study of Weekly Paclitaxel With or Without LCL161 in Patients With Triple Negative Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Breast Cancer
Keywords: Breast cancer,
LCL161,
paclitaxel,
neoadjuvant,
triple negative breast cancer
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2012-06-12
Enrollment: 209
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: To assess whether adding LCL161 to weekly paclitaxel enhances the efficacy of paclitaxel in women with triple negative breast cancer whose tumors are positive for a defined pattern of gene expression

Detailed description: This is a phase 2, randomized, two-arm, open-label, neoadjuvant, multicenter study in newly diagnosed women with triple-negative breast cancer. Eligible patients will be limited to those with clinical stages T2, N0-N2, M0.

For those patients with triple-negative disease identified on diagnostic biopsy, the presence or absence of the gene expression signature will be determined in a molecular pre-screening phase using the diagnostic biopsy material; patients with TNBC that are positive and negative for the gene expression signature will be eligible for enrollment.

Following a Screening/baseline period to determine eligibility, patients will be randomized to either paclitaxel 80 mg/m2 IV given weekly (the control arm) or paclitaxel 80 mg/m2 IV weekly immediately followed by LCL161 1800 mg PO once weekly (the experimental arm). Enrollment on these arms will be balanced within regions of the world and are stratified 1:1 for gene expression signature status. Treatment will be administered each week for 12 weeks (4 cycles). The length of each treatment cycle is 21 days.

A total of 200 patients will be enrolled and treated, 100 patients in each treatment arm of the study; each arm will contain 50 patients with gene expression signature positive disease and 50 patients with gene expression signature negative disease.

An interim analysis is planned for this study when approximately 50 patients with gene expression signature positive disease have been treated and have either completed the study and have undergone surgery, or have permanently discontinued study treatment for any reason.

For all patients, a tumor biopsy will be performed approximately 24 hours after the first or second dose of study treatment (paclitaxel or paclitaxel + LCL161) to compare the extent of apoptosis in tumor treated with control or experimental therapy. Patients will be scheduled for breast-conserving surgery or mastectomy 15 weeks plus a window of not more than 1 week from the date the subject receives her first treatment (no more than 16 weeks after first treatment). All treated patients are planned to undergo surgery. However, to evaluate the presence of persistent disease those patients with apparent substantial residual or progressive disease or who do not undergo surgery for any reason must have a core needle biopsy of the primary tumor after completing study treatment. At the completion of study treatment, patients are expected to continue post-operative treatment with a standard anthracycline-based chemotherapy regimen such as FAC (5-FU/doxorubicin/cyclophosphamide), FEC (5-FU/epirubicin/cyclophosphamide) or AC (doxorubicin/cyclophosphamide). The specific regimen will be chosen by the treating physician.

Eligibility criteria: Inclusion Criteria:

* Histologically confirmed diagnosis of invasive triple negative breast cancer
* Known status for the LCL161 predictive gene expression signature as determined during molecular pre-screening
* Candidates for mastectomy or breast-conserving surgery
* Primary tumor of greater than 20 mm and less than or equal to 50 mm diameter measured by imaging (previous Amendment #3 was tumor size greater than 10 mm)
* Regional nodes N0-N2
* Absence of distant metastatic disease
* ECOG performance status 0-1
* Adequate bone marrow function
* Adequate liver function and serum transaminases
* Adequate renal function

Exclusion Criteria:

* Bilateral or inflammatory breast cancer (bilateral mammography is required during Screening/baseline); locally recurrent breast cancer
* Patients currently receiving systemic therapy for any other malignancy, or having received systemic therapy for a malignancy in the preceding 3 months
* Uncontrolled cardiac disease
* Patients who are currently receiving chronic treatment (\>3 months) with corticosteroids at a dose ≥ 10 mg of prednisone (or its glucocorticoid equivalent) per day (inhaled and topical steroids are allowed), or any other chronic immunosuppressive treatment that cannot be discontinued prior to starting study drug
* Impaired GI function that may affect the absorption of LCL161
* Pregnant or breast feeding (lactating) women
* Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 180 days after study treatment
* Other protocol-defined inclusion/exclusion criteria may apply

Primary outcomes:
measure: Pathological Complete Response (pCR) Rate in Breast After 12 Weeks of Therapy
timeFrame: 12 weeks
measure: Number of Participants With Pathological Complete Response (pCR) in Breast After 12 Weeks of Therapy
timeFrame: 12 weeks
measure: Difference in pCR Rates Between Treatment Arms
timeFrame: 12 weeks
Secondary outcomes:
measure: Posterior Distribution of Difference of pCR Rates After Treatment With LCL161 + Paclitaxel Between Patients With Gene Expression Positive and Negative Tumors
timeFrame: 12 weeks
measure: Posterior Distribution of Difference in pCR Rates After Treatment With Paclitaxel Only Between Gene Expression Positive and Negative Tumors
timeFrame: 12 weeks
measure: pCR Rate in Breast After 12 Weeks of Therapy With Single Agent LCL161 and LCL161 + Paclitaxel, Regardless of Gene Signature Status
timeFrame: 12 weeks
measure: pCR Rate in Breast, Regional Nodes and Axilla
timeFrame: 12 weeks
measure: Rates of Breast Conserving Surgery and Mastectomy - Assessed by Percentage of Patients Who Underwent Breast Conserving Surgery, Masectomy and no Surgery
timeFrame: 16 weeks
measure: Caspase 3 Activation in Tumor by Immunohistochemistry (IHC) - EAS1
timeFrame: Baseline, Post-baeline at Cycle 1, Day 2 (C1D2) or Cycle 1, Day 9 (C1D9)
measure: Caspase 3 Activation in Tumor by Immunohistochemistry (IHC) - EAS2
timeFrame: Baseline, Post-baeline at Cycle 1, Day 2 or Cycle 1, Day 9
measure: Pharmacokinetics (PK) Parameters of LCL161 Only for Cmax
timeFrame: cycle 1 day 1, cycle 4 day 15
measure: Pharmacokinetics (PK) Parameters of LCL161 Only for Tmax
timeFrame: cycle 1 day 1, cycle 4 day 15
measure: Pharmacokinetics (PK) Parameters of LCL161 Only for AUClast
timeFrame: cycle 1 day 1, cycle 4 day 15
Other outcomes:
Locations:
city: Fayetteville
country: United States
facility: Highlands Oncology Group Dept of Highlands Oncology Grp
state: Arkansas
city: Los Angeles
country: United States
facility: Cedars Sinai Medical Center SC
state: California
city: Los Angeles
country: United States
facility: University of California at Los Angeles UCLA SC
state: California
city: Stanford
country: United States
facility: Stanford University Medical Center Stanford
state: California
city: New Haven
country: United States
facility: Yale University School of Medicine Yale Univ
state: Connecticut
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center & Research Institute H. Lee Moffitt SC
state: Florida
city: Boston
country: United States
facility: Massachusetts General Hospital Mass General 2
state: Massachusetts
city: NY
country: United States
facility: Memorial Sloan Kettering Cancer Center Dept Onc
state: New York
city: Columbus
country: United States
facility: Ohio State Comprehensive Cancer Center/James Cancer Hospital Ohio State
state: Ohio
city: Nashville
country: United States
facility: Vanderbilt University Medical Center Vanderbilt - Thompson Ln
state: Tennessee
city: Houston
country: United States
facility: Baylor College of Medicine Dept of Oncology
state: Texas
city: San Antonio
country: United States
facility: Cancer Therapy & Research Center / UT Health Science Center InstituteForDrugDevelopment(5)
state: Texas
city: Madison
country: United States
facility: University of Wisconsin / Paul P. Carbone Comp Cancer Center Univ Wisc 2
state: Wisconsin
city: Nedlands
country: Australia
facility: Novartis Investigative Site
state: Western Australia
city: Itajai
country: Brazil
facility: Novartis Investigative Site
state: SC
city: São Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: São Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Brno
country: Czech Republic
facility: Novartis Investigative Site
city: Olomouc
country: Czech Republic
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Düsseldorf
country: Germany
facility: Novartis Investigative Site
city: Erlangen
country: Germany
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Frankfurt
country: Germany
facility: Novartis Investigative Site
city: Freiburg
country: Germany
facility: Novartis Investigative Site
city: Heidelberg
country: Germany
facility: Novartis Investigative Site
city: Kiel
country: Germany
facility: Novartis Investigative Site
city: Lubeck
country: Germany
facility: Novartis Investigative Site
city: München
country: Germany
facility: Novartis Investigative Site
city: Dublin 4
country: Ireland
facility: Novartis Investigative Site
city: Dublin
country: Ireland
facility: Novartis Investigative Site
city: Padova
country: Italy
facility: Novartis Investigative Site
state: PD
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Korea
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Korea
city: Saint Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: St. Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Sevilla
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Valencia
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: Valencia
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: Santiago de Compostela
country: Spain
facility: Novartis Investigative Site
state: Galicia
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
state: Taiwan, ROC
city: Kuei-Shan Chiang
country: Taiwan
facility: Novartis Investigative Site
state: Taoyuan/ Taiwan ROC
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Brighton
country: United Kingdom
facility: Novartis Investigative Site
state: East Sussex
city: Kingston Upon Thames
country: United Kingdom
facility: Novartis Investigative Site
state: Surrey
city: Sutton
country: United Kingdom
facility: Novartis Investigative Site
state: Surrey
city: London
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: