A Randomized, Phase 2, Neoadjuvant Study of Weekly Paclitaxel With or Without LCL161 in Patients With Triple Negative Breast Cancer

A Phase II Multi-center, Open-label, Neoadjuvant, Randomized Study of Weekly Paclitaxel With or Without LCL161 in Patients With Triple Negative Breast Cancer

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

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: LCL161; Drug: paclitaxel

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.

• Study Type: Interventional
• Enrollment (Actual): 209
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Novartis Investigative Site
• Brazil
  • SC
    • Itajai, SC, Brazil, 88301-229
      • Novartis Investigative Site
  • SP
    • São Paulo, SP, Brazil, 01317-002
      • Novartis Investigative Site
    • São Paulo, SP, Brazil, 01323-900
      • Novartis Investigative Site
• Czech Republic
  • Brno, Czech Republic, 65653
    • Novartis Investigative Site
  • Olomouc, Czech Republic, 775 20
    • Novartis Investigative Site
• Germany
  • Berlin, Germany, 13125
    • Novartis Investigative Site
  • Düsseldorf, Germany, 40235
    • Novartis Investigative Site
  • Erlangen, Germany, 91054
    • Novartis Investigative Site
  • Essen, Germany, 45136
    • Novartis Investigative Site
  • Frankfurt, Germany, 60389
    • Novartis Investigative Site
  • Freiburg, Germany, D 79106
    • Novartis Investigative Site
  • Heidelberg, Germany, 69120
    • Novartis Investigative Site
  • Kiel, Germany, 24105
    • Novartis Investigative Site
  • Lubeck, Germany, 23538
    • Novartis Investigative Site
  • München, Germany, 81675
    • Novartis Investigative Site
• Ireland
  • Dublin, Ireland, 9
    • Novartis Investigative Site
  • Dublin 4, Ireland
    • Novartis Investigative Site
• Italy
  • PD
    • Padova, PD, Italy, 35100
      • Novartis Investigative Site
• Korea, Republic of
  • Korea
    • Seoul, Korea, Korea, Republic of, 05505
      • Novartis Investigative Site
    • Seoul, Korea, Korea, Republic of, 03080
      • Novartis Investigative Site
• Russian Federation
  • Saint Petersburg, Russian Federation, 191104
    • Novartis Investigative Site
  • St. Petersburg, Russian Federation, 197758
    • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28041
    • Novartis Investigative Site
  • Madrid, Spain, 28050
    • Novartis Investigative Site
  • Andalucia
    • Sevilla, Andalucia, Spain, 41013
      • Novartis Investigative Site
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
  • Comunidad Valenciana
    • Valencia, Comunidad Valenciana, Spain, 46010
      • Novartis Investigative Site
    • Valencia, Comunidad Valenciana, Spain, 46009
      • Novartis Investigative Site
  • Galicia
    • Santiago de Compostela, Galicia, Spain, 15706
      • Novartis Investigative Site
• Taiwan
  • Taipei, Taiwan, 10002
    • Novartis Investigative Site
  • Taiwan, ROC
    • Taipei, Taiwan, ROC, Taiwan, 112
      • Novartis Investigative Site
  • Taoyuan/ Taiwan ROC
    • Kuei-Shan Chiang, Taoyuan/ Taiwan ROC, Taiwan, 33305
      • Novartis Investigative Site
• United Kingdom
  • London, United Kingdom, SW3 6JJ
    • Novartis Investigative Site
  • East Sussex
    • Brighton, East Sussex, United Kingdom, BN2 5BE
      • Novartis Investigative Site
  • Surrey
    • Kingston Upon Thames, Surrey, United Kingdom, KT2 7QB
      • Novartis Investigative Site
    • Sutton, Surrey, United Kingdom, SM2 5PT
      • Novartis Investigative Site
• United States
  • Arkansas
    • Fayetteville, Arkansas, United States, 72703
      • Highlands Oncology Group Dept of Highlands Oncology Grp
  • California
    • Los Angeles, California, United States, 90095
      • University of California at Los Angeles UCLA SC
    • Los Angeles, California, United States, 90048
      • Cedars Sinai Medical Center SC
    • Stanford, California, United States, 94304
      • Stanford University Medical Center Stanford
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale University School of Medicine Yale Univ
  • Florida
    • Tampa, Florida, United States, 33612
      • H. Lee Moffitt Cancer Center & Research Institute H. Lee Moffitt SC
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital Mass General 2
  • New York
    • NY, New York, United States, 90033
      • Memorial Sloan Kettering Cancer Center Dept Onc
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State Comprehensive Cancer Center/James Cancer Hospital Ohio State
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center Vanderbilt - Thompson Ln
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine Dept of Oncology
    • San Antonio, Texas, United States, 78229
      • Cancer Therapy & Research Center / UT Health Science Center InstituteForDrugDevelopment(5)
  • Wisconsin
    • Madison, Wisconsin, United States, 53792-6164
      • University of Wisconsin / Paul P. Carbone Comp Cancer Center Univ Wisc 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Paclitaxel with LCL161; Patients randomized to the experimental arm received paclitaxel 80 mg/m2 weekly + LECL161 1800 mg once weekly for 12 weeks. Equal numbers of patients with gene expression signature positive and negative disease were included in each treatment arm.	Drug: LCL161; LCL161 was available as 300 mg, tablets, which was supplied in child-resistant bottles.; Drug: paclitaxel; Commercially available paclitaxel was sourced locally by each study site. Generic paclitaxel could be used for study treatment. iv 80mg/m2
ACTIVE_COMPARATOR: Paclitaxel without LCL161; Patients randomized to the control arm received paclitaxel 80 mg/m2 weekly for 12 weeks. Equal numbers of patients with gene expression signature positive and negative disease were included in each treatment arm.	Drug: paclitaxel; Commercially available paclitaxel was sourced locally by each study site. Generic paclitaxel could be used for study treatment. iv 80mg/m2

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathological Complete Response (pCR) Rate in Breast After 12 Weeks of Therapy	pCR rate was defined as histopathologically confirmed absence of invasive disease in the breast. To assess whether adding LCL161 to weekly paclitaxel enhances the efficacy of paclitaxel in women with triple negative breast cancer. Analyses were performed separately in the gene expression signature negative and positive groups. This analysis was based on Bayesian design using a binomial distribution for the data with a beta prior. The measurement type used for this analysis is posterior median and the method of dispersion is Credible Interval (Crl) and not Confidence Interval (CI). Median values are posterior medians of pCR rate for each group.	12 weeks
Number of Participants With Pathological Complete Response (pCR) in Breast After 12 Weeks of Therapy	To assess the number of patients who experienced a pathological response in breast.	12 weeks
Difference in pCR Rates Between Treatment Arms	pCR rate was defined as histopathologically confirmed absence of invasive disease in the breast. To assess whether adding LCL161 to weekly paclitaxel enhances the efficacy of paclitaxel in women with triple negative breast cancer. Analyses were performed separately in the gene expression signature negative and positive groups. This analysis was based on the posterior distribution of the difference in pCR rates between the experimental and control arms of the study, within each gene expression signature group.The measurement type used for this analysis is posterior median and the method of dispersion is Credible Interval (Crl) and not Confidence Interval (CI). 95% Confidence interval is actually 95% credible interval.	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Posterior Distribution of Difference of pCR Rates After Treatment With LCL161 + Paclitaxel Between Patients With Gene Expression Positive and Negative Tumors	To assess whether use of the gene expression signature identifies tumors more likely to respond to treatment with LCL161 and paclitaxel. The measurement type used for this analysis is posterior median and the method of dispersion is Credible Interval (Crl) and not Confidence Interval (CI). 95% Confidence interval is actually 95% credible interval.	12 weeks
Posterior Distribution of Difference in pCR Rates After Treatment With Paclitaxel Only Between Gene Expression Positive and Negative Tumors	To assess whether use of the gene expression signature identifies tumors more likely to respond to treatment with paclitaxel only. The measurement type used for this analysis is posterior median and the method of dispersion is Credible Interval (Crl) and not Confidence Interval (CI). 95% Confidence interval is actually 95% credible interval.	12 weeks
pCR Rate in Breast After 12 Weeks of Therapy With Single Agent LCL161 and LCL161 + Paclitaxel, Regardless of Gene Signature Status	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. This comparison is between the 2 study treatments, regardless of gene signature status. The measurement type used for this analysis is posterior median and the method of dispersion is Credible Interval (Crl) and not Confidence Interval (CI). 95% Confidence interval is actually 95% credible interval.	12 weeks
pCR Rate in Breast, Regional Nodes and Axilla	To assess other indicators of disease response for the LCL161 + paclitaxel combination compared to paclitaxel alone. The pCR in breast, regional nodes, and axilla were determined based on the America Joint Committee on Cancer Staging [AJCC] stages T1c, T2, N0-N2, M0) were (AJCC) pathologic staging recorded on the eCRF: a patient was considered to be a responder in breast, regional nodes, and axilla if the pathological complete response was reported for breast and if the regional lymph nodes staging was pN0 (including i-, mol-, mol+).The measurement type used for this analysis is posterior median and the method of dispersion is Credible Interval (Crl) and not Confidence Interval (CI). 95% Confidence interval is actually 95% credible interval.	12 weeks
Rates of Breast Conserving Surgery and Mastectomy - Assessed by Percentage of Patients Who Underwent Breast Conserving Surgery, Masectomy and no Surgery	To assess other indicators of disease response for the LCL161 + paclitaxel combination compared to paclitaxel alone. Rates of breast conserving surgery and mastectomy also contributed to the overall assessment of disease response and were summarized by treatment arm within each gene expression signature status. For this analysis, patients with multicentric breast cancer were excluded, as all patients in this group were expected to be treated with mastectomy.	16 weeks
Caspase 3 Activation in Tumor by Immunohistochemistry (IHC) - EAS1	To evaluate whether combination treatment with LCL161 and paclitaxel is associated with increased apoptosis compared to weekly paclitaxel alone. To evaluate whether combination treatment with LCL161 and paclitaxel was associated with increased apoptosis compared to weekly paclitaxel alone, cleaved caspase 3 activation in tumor by IHC was examined. Gene expression signature status is derived based on continuous gene expression signature score using cut-off 0.6661 (positive: score ≥ 0.6661; negative: score <0.6661); cycle = 28 days; each patient had either C1D2 or C1D9	Baseline, Post-baeline at Cycle 1, Day 2 (C1D2) or Cycle 1, Day 9 (C1D9)
Caspase 3 Activation in Tumor by Immunohistochemistry (IHC) - EAS2	To evaluate whether combination treatment with LCL161 and paclitaxel is associated with increased apoptosis compared to weekly paclitaxel alone. To evaluate whether combination treatment with LCL161 and paclitaxel was associated with increased apoptosis compared to weekly paclitaxel alone, cleaved caspase 3 activation in tumor by IHC was examined. Cycle = 28 days; each patient had either C1D2 or C1D9	Baseline, Post-baeline at Cycle 1, Day 2 or Cycle 1, Day 9
Pharmacokinetics (PK) Parameters of LCL161 Only for Cmax	To evaluate the PK of LCL161 when given in combination with paclitaxel.	cycle 1 day 1, cycle 4 day 15
Pharmacokinetics (PK) Parameters of LCL161 Only for Tmax	To evaluate the PK of LCL161 when given in combination with paclitaxel. The pharmacokinetic analysis set (PAS) consisted of all patients who had at least one blood sample providing evaluable PK data for LCL161.	cycle 1 day 1, cycle 4 day 15
Pharmacokinetics (PK) Parameters of LCL161 Only for AUClast	To evaluate the PK of LCL161 when given in combination with paclitaxel	cycle 1 day 1, cycle 4 day 15

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start: August 1, 2012
• Primary Completion (ACTUAL): September 1, 2014
• Study Completion (ACTUAL): September 1, 2014

Study Registration Dates

• First Submitted: May 30, 2012
• First Submitted That Met QC Criteria: June 8, 2012
• First Posted (ESTIMATE): June 12, 2012

Study Record Updates

• Last Update Posted (ESTIMATE): October 17, 2016
• Last Update Submitted That Met QC Criteria: August 30, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Keywords: Breast cancer,; triple negative breast cancer; paclitaxel,; LCL161,; neoadjuvant,
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Triple Negative Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Paclitaxel
• Other Study ID Numbers: CLCL161A2201; 2012-000677-23 (EUDRACT_NUMBER)