A Randomized, Phase 2, Neoadjuvant Study of Weekly Paclitaxel With LCL161 in Patients With Triple Negative Breast Cancer

Breast Cancer Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01617668
• Other study ID #: CLCL161A2201
• Secondary ID: 2012-000677-23
• Status: Completed
• Phase: Phase 2
• First received: May 30, 2012
• Last updated: December 1, 2014
• Start date: August 2012
• Est. completion date: September 2014

Study information

• Verified date: December 2014
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationSpain: Agencia Española de Medicamentos y Productos SanitariosAustralia: Department of Health and Ageing Therapeutic Goods AdministrationTaiwan: Department of HealthUnited Kingdom: Medicines and Healthcare Products Regulatory AgencyTurkey: Ministry of HealthIreland: Irish Medicines BoardBelgium: Federal Agency for Medicinal Products and Health ProductsItaly: Ministry of HealthCzech Republic: State Institute for Drug ControlSouth Korea: Korea Food and Drug Administration (KFDA)Brazil:: ANVISA - Agência Nacional de Vigilância SanitáriaGermany: Federal Institute for Drugs and Medical DevicesRussia: Ministry of Health of the Russian Federation
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 210
• Est. completion date: September 2014
• Est. primary completion date: September 2014
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms
• Triple Negative Breast Neoplasms

Intervention

Drug:
• Paclitaxel + LCL161

• paclitaxel
iv 80mg/m2

Locations

Country	Name	City	State
Australia	Novartis Investigative Site	Perth	Western Australia
Brazil	Novartis Investigative Site	Itajai	SC
Brazil	Novartis Investigative Site	São Paulo	SP
Czech Republic	Novartis Investigative Site	Brno
Czech Republic	Novartis Investigative Site	Olomouc
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Düsseldorf
Germany	Novartis Investigative Site	Erlangen
Germany	Novartis Investigative Site	Essen
Germany	Novartis Investigative Site	Frankfurt
Germany	Novartis Investigative Site	Freiburg
Germany	Novartis Investigative Site	Heidelberg
Germany	Novartis Investigative Site	Kiel
Germany	Novartis Investigative Site	Lübeck
Germany	Novartis Investigative Site	München
Ireland	Novartis Investigative Site	Dublin
Ireland	Novartis Investigative Site	Dublin 4
Italy	Novartis Investigative Site	Padova	PD
Korea, Republic of	Novartis Investigative Site	Seoul	Korea
Korea, Republic of	Novartis Investigative Site	Seoul
Russian Federation	Novartis Investigative Site	Saint Petersburg
Russian Federation	Novartis Investigative Site	St. Petersburg
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Santiago de Compostela	Galicia
Spain	Novartis Investigative Site	Sevilla	Andalucia
Spain	Novartis Investigative Site	Valencia	Comunidad Valenciana
Spain	Novartis Investigative Site	Valencia	Comunidad Valenciana
Taiwan	Novartis Investigative Site	Kuei-Shan Chiang	Taoyuan/ Taiwan ROC
Taiwan	Novartis Investigative Site	Taipei
Taiwan	Novartis Investigative Site	Taipei	Taiwan, ROC
United Kingdom	Novartis Investigative Site	Brighton	East Sussex
United Kingdom	Novartis Investigative Site	Kingston Upon Thames	Surrey
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	Sutton	Surrey
United States	Massachusetts General Hospital Mass General 2	Boston	Massachusetts
United States	Ohio State Comprehensive Cancer Center/James Cancer Hospital Ohio State	Columbus	Ohio
United States	Highlands Oncology Group Dept of Highlands Oncology Grp	Fayetteville	Arkansas
United States	Baylor College of Medicine Dept of Oncology	Houston	Texas
United States	Cedars Sinai Medical Center SC	Los Angeles	California
United States	University of California at Los Angeles UCLA SC	Los Angeles	California
United States	University of Wisconsin / Paul P. Carbone Comp Cancer Center Univ Wisc 2	Madison	Wisconsin
United States	Vanderbilt University Medical Center Vanderbilt - Thompson Ln	Nashville	Tennessee
United States	Yale University School of Medicine Yale Univ	New Haven	Connecticut
United States	Memorial Sloan Kettering Cancer Center Dept Onc	New York	New York
United States	Cancer Therapy & Research Center / UT Health Science Center InstituteForDrugDevelopment(5)	San Antonio	Texas
United States	Stanford University Medical Center Stanford	Stanford	California
United States	H. Lee Moffitt Cancer Center & Research Institute H. Lee Moffitt SC	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Australia,  Brazil,  Czech Republic,  Germany,  Ireland,  Italy,  Korea, Republic of,  Russian Federation,  Spain,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Pathological complete response (pCR) rate in breast after 12 weeks of therapy	To assess whether adding LCL161 to weekly paclitaxel enhances the efficacy of paclitaxel in women with triple negative breast cancer, analyzed separately in the gene expression signature negative and positive groups	12 weeks	No
Secondary	Frequency of adverse events	To characterize the safety and tolerability of the LCL161/paclitaxel combination compared to weekly paclitaxel alone	18 weeks	Yes
Secondary	Caspase 3 activation in tumor by IHC	To evaluate whether combination treatment with LCL161 and paclitaxel is associated with increased apoptosis compared to weekly paclitaxel alone	12 weeks	No
Secondary	PK parameters including Area Under Curve (AUC)	To evaluate the PK of LCL161 when given in combination with paclitaxel	pre-dose, 0.5, 1, 2, 4 hours post-dose	No
Secondary	Rates of breast conserving surgery and mastectomy	To assess other indicators of disease response for the LCL161 + paclitaxel combination compared to paclitaxel alone	16 weeks	No
Secondary	Clinical response	To assess other indicators of disease response for the LCL161 + paclitaxel combination compared to paclitaxel alone	12 weeks	No
Secondary	Disease response using RECIST 1.1 criteria	To assess other indicators of disease response for the LCL161 + paclitaxel combination compared to paclitaxel alone	12 weeks	No
Secondary	pCR rate in breast, regional nodes and axilla	To assess other indicators of disease response for the LCL161 + paclitaxel combination compared to paclitaxel alone	12 weeks	No
Secondary	Frequency of serious adverse events	To characterize the safety and tolerability of the LCL161/paclitaxel combination compared to weekly paclitaxel alone	18 weeks	Yes
Secondary	Frequency of clinical laboratory abnormalities	To characterize the safety and tolerability of the LCL161/paclitaxel combination compared to weekly paclitaxel alone	18 weeks	Yes
Secondary	pCR rate after treatment with LCL161 + paclitaxel	To assess whether use of the gene expression signature identifies tumors more likely to respond to treatment with LCL161 and paclitaxel	12 weeks	No
Secondary	PCRrate in breast after 12 weeks of therapy- Full study population	To assess whether adding LCL161 to weekly paclitaxel enhances the efficacy of paclitaxel in women with triple negative breast cancer regardless of tumor gene expression signature status	12 weeks	No
Secondary	PCR rate in breast after 12 weeks of therapy with gene signature + or - treated with paclitaxel alone	To assess whether the gene expression signature is correlated with response to single agent paclitaxel	12 weeks	No
Secondary	Gene expression profiling (whole genome microarray profiling) and pCR rate in breast	Evaluate whether specific patterns of gene expression correlate with response to LCL161 + paclitaxel and mechanisms of resistance	12 weeks	No
Secondary	Sequencing of tumor DNA for genetic alterations in cancer relevant genes	Evaluate whether tumor genotype influences response to treatment with LCL161	12 weeks	No