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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: LCL161
* Drug: paclitaxel


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Paclitaxel with LCL161<br>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<br>* LCL161 was available as 300 mg, tablets, which was supplied in child-resistant bottles.<br>Drug: paclitaxel<br>* Commercially available paclitaxel was sourced locally by each study site. Generic paclitaxel could be used for study treatment. iv 80mg/m2<br>|
| Active Comparator: Paclitaxel without LCL161<br>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<br>* Commercially available paclitaxel was sourced locally by each study site. Generic paclitaxel could be used for study treatment. iv 80mg/m2<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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paclitaxel,, Breast cancer,, LCL161,, neoadjuvant,, triple negative breast cancer