Trial Outcomes & Findings for A Randomized, Phase 2, Neoadjuvant Study of Weekly Paclitaxel With or Without LCL161 in Patients With Triple Negative Breast Cancer (NCT NCT01617668)

NCT ID: NCT01617668

Last Updated: 2016-10-17

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

209 participants

Primary outcome timeframe

12 weeks

Results posted on

2016-10-17

Participant Flow

215 patients were randomized to receive the study treatment. 105 gene expression signature positive patients were randomized to LCL161+paclitaxel (N=51) or paclitaxel only (N=54). 110 gene expression signature negative patients were randomized to LCL161+paclitaxel (N=55) or paclitaxel only (N=55).

Only 50 of 54 pts in the Paclitaxel without LCL161 (Positive group) received study drug; Only 53 of 55 pts in the Paclitaxel without LCL161 (Negative group) received study drug.

Participant milestones

Participant milestones
Measure
Paclitaxel With LCL161 (Positive Group)
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.
Paclitaxel Without LCL161 (Positive Group)
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.
Paclitaxel With LCL161 (Negative Group)
Patients randomized to the experimental arm received paclitaxel 80 mg/m2 weekly + LCL161 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.
Paclitaxel Without LCL161 (Negative Group)
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.
Overall Study
STARTED
51
50
55
53
Overall Study
Randomized Patients
51
54
55
55
Overall Study
COMPLETED
38
41
32
38
Overall Study
NOT COMPLETED
13
9
23
15

Reasons for withdrawal

Reasons for withdrawal
Measure
Paclitaxel With LCL161 (Positive Group)
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.
Paclitaxel Without LCL161 (Positive Group)
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.
Paclitaxel With LCL161 (Negative Group)
Patients randomized to the experimental arm received paclitaxel 80 mg/m2 weekly + LCL161 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.
Paclitaxel Without LCL161 (Negative Group)
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.
Overall Study
Adverse Event
7
0
12
5
Overall Study
Physician Decision
1
2
3
0
Overall Study
Progressive Disease
4
4
6
9
Overall Study
Subject/guardian decision
1
3
2
1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure
Paclitaxel With LCL161
n=106 Participants
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.
Paclitaxel Without LCL161
n=103 Participants
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.
Total
n=209 Participants
Total of all reporting groups
Age, Continuous
48.6 Years
STANDARD_DEVIATION 10.14 • n=5 Participants
48.7 Years
STANDARD_DEVIATION 9.98 • n=7 Participants
48.7 Years
STANDARD_DEVIATION 10.04 • n=5 Participants
Age, Customized
< 65 years
98 Participants
n=5 Participants
96 Participants
n=7 Participants
194 Participants
n=5 Participants
Age, Customized
>= 65 years
8 Participants
n=5 Participants
7 Participants
n=7 Participants
15 Participants
n=5 Participants
Sex: Female, Male
Female
106 Participants
n=5 Participants
103 Participants
n=7 Participants
209 Participants
n=5 Participants
Sex: Female, Male
Male
0 Participants
n=5 Participants
0 Participants
n=7 Participants
0 Participants
n=5 Participants

PRIMARY outcome

Timeframe: 12 weeks

Population: The Full Analysis Set (FAS) was composed of all patients who received at least one full or partial dose of LCL161 + paclitaxel or one full or partial dose of paclitaxel alone.

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.

Outcome measures

Outcome measures
Measure
LCL161 + Paclitaxel (Gene Expression Signature Positive)
n=51 Participants
Patients randomized to the experimental arm for gene expression signature positive received LCL161 1800 mg once weekly + 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.
Paclitaxel Only (Gene Expression Signature Positive)
n=50 Participants
Patients randomized to the control arm for gene expression signature positive 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.
LCL161 + Paclitaxel (Gene Expression Signature Negative)
n=55 Participants
Patients randomized to the experimental arm for gene expression signature negative received paclitaxel 80 mg/m2 weekly + LCL161 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.
Paclitaxel Only (Gene Expression Signature Negative)
n=53 Participants
Patients randomized to the control arm for gene expression signature negative 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.
Pathological Complete Response (pCR) Rate in Breast After 12 Weeks of Therapy
24.9 Percentage of Participants
Interval 14.5 to 37.8
23.4 Percentage of Participants
Interval 13.3 to 36.2
6.9 Percentage of Participants
Interval 2.2 to 15.5
9.1 Percentage of Participants
Interval 3.3 to 18.6

PRIMARY outcome

Timeframe: 12 weeks

Population: The Full Analysis Set (FAS) was composed of all patients who received at least one full or partial dose of LCL161 + paclitaxel or one full or partial dose of paclitaxel alone.

To assess the number of patients who experienced a pathological response in breast.

Outcome measures

Outcome measures
Measure
LCL161 + Paclitaxel (Gene Expression Signature Positive)
n=51 Participants
Patients randomized to the experimental arm for gene expression signature positive received LCL161 1800 mg once weekly + 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.
Paclitaxel Only (Gene Expression Signature Positive)
n=50 Participants
Patients randomized to the control arm for gene expression signature positive 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.
LCL161 + Paclitaxel (Gene Expression Signature Negative)
n=55 Participants
Patients randomized to the experimental arm for gene expression signature negative received paclitaxel 80 mg/m2 weekly + LCL161 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.
Paclitaxel Only (Gene Expression Signature Negative)
n=53 Participants
Patients randomized to the control arm for gene expression signature negative 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.
Number of Participants With Pathological Complete Response (pCR) in Breast After 12 Weeks of Therapy
13 Participants
Interval 14.5 to 37.8
12 Participants
Interval 13.3 to 36.2
4 Participants
Interval 2.2 to 15.5
5 Participants
Interval 3.3 to 18.6

PRIMARY outcome

Timeframe: 12 weeks

Population: FAS are patients who received at least 1 full or partial dose of LCL161 + paclitaxel or 1 full or partial dose of paclitaxel alone. These values are medians of posterior distribution of difference of pCR rate between treatment arms based on a Bayesian model. 95% Confidence interval is actually 95% credible interval.

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.

Outcome measures

Outcome measures
Measure
LCL161 + Paclitaxel (Gene Expression Signature Positive)
n=51 Participants
Patients randomized to the experimental arm for gene expression signature positive received LCL161 1800 mg once weekly + 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.
Paclitaxel Only (Gene Expression Signature Positive)
n=50 Participants
Patients randomized to the control arm for gene expression signature positive 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.
LCL161 + Paclitaxel (Gene Expression Signature Negative)
n=55 Participants
Patients randomized to the experimental arm for gene expression signature negative received paclitaxel 80 mg/m2 weekly + LCL161 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.
Paclitaxel Only (Gene Expression Signature Negative)
n=53 Participants
Patients randomized to the control arm for gene expression signature negative 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.
Difference in pCR Rates Between Treatment Arms
1.5 Difference in percentage of participants
Interval -15.0 to 18.0
NA Difference in percentage of participants
NA = Difference in pCR rate between treatments is presented under LCL161 + paclitaxel column (gene expression signature positive)
-2.0 Difference in percentage of participants
Interval -12.7 to 8.3
NA Difference in percentage of participants
NA = Difference in pCR rate between treatments is presented under LCL161 + paclitaxel column (gene expression signature negative)

SECONDARY outcome

Timeframe: 12 weeks

Population: Efficacy Analysis Set 1 (EAS1) are patients who received at least 1 full or partial dose of LCL161 + paclitaxel or of paclitaxel alone with a valid gene expression signature score. 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)

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.

Outcome measures

Outcome measures
Measure
LCL161 + Paclitaxel (Gene Expression Signature Positive)
n=105 Participants
Patients randomized to the experimental arm for gene expression signature positive received LCL161 1800 mg once weekly + 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.
Paclitaxel Only (Gene Expression Signature Positive)
Patients randomized to the control arm for gene expression signature positive 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.
LCL161 + Paclitaxel (Gene Expression Signature Negative)
Patients randomized to the experimental arm for gene expression signature negative received paclitaxel 80 mg/m2 weekly + LCL161 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.
Paclitaxel Only (Gene Expression Signature Negative)
Patients randomized to the control arm for gene expression signature negative 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.
Posterior Distribution of Difference of pCR Rates After Treatment With LCL161 + Paclitaxel Between Patients With Gene Expression Positive and Negative Tumors
18.2 Difference in percentage of participants
Interval 5.0 to 32.4

SECONDARY outcome

Timeframe: 12 weeks

Population: Efficacy Analysis Set 1 (EAS1) are patients who received at least 1 full or partial dose of LCL161 + paclitaxel or of paclitaxel alone with a valid gene expression signature score. 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)

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.

Outcome measures

Outcome measures
Measure
LCL161 + Paclitaxel (Gene Expression Signature Positive)
n=102 Participants
Patients randomized to the experimental arm for gene expression signature positive received LCL161 1800 mg once weekly + 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.
Paclitaxel Only (Gene Expression Signature Positive)
Patients randomized to the control arm for gene expression signature positive 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.
LCL161 + Paclitaxel (Gene Expression Signature Negative)
Patients randomized to the experimental arm for gene expression signature negative received paclitaxel 80 mg/m2 weekly + LCL161 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.
Paclitaxel Only (Gene Expression Signature Negative)
Patients randomized to the control arm for gene expression signature negative 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.
Posterior Distribution of Difference in pCR Rates After Treatment With Paclitaxel Only Between Gene Expression Positive and Negative Tumors
13.3 Difference in percentage of participants
Interval -0.4 to 27.5

SECONDARY outcome

Timeframe: 12 weeks

Population: Efficacy Analysis Set 1 (EAS1) are patients who received at least 1 full or partial dose of LCL161 + paclitaxel or of paclitaxel alone with a valid gene expression signature score. 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)

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.

Outcome measures

Outcome measures
Measure
LCL161 + Paclitaxel (Gene Expression Signature Positive)
n=105 Participants
Patients randomized to the experimental arm for gene expression signature positive received LCL161 1800 mg once weekly + 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.
Paclitaxel Only (Gene Expression Signature Positive)
n=102 Participants
Patients randomized to the control arm for gene expression signature positive 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.
LCL161 + Paclitaxel (Gene Expression Signature Negative)
Patients randomized to the experimental arm for gene expression signature negative received paclitaxel 80 mg/m2 weekly + LCL161 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.
Paclitaxel Only (Gene Expression Signature Negative)
Patients randomized to the control arm for gene expression signature negative 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.
pCR Rate in Breast After 12 Weeks of Therapy With Single Agent LCL161 and LCL161 + Paclitaxel, Regardless of Gene Signature Status
15.5 Percentage of participants
Interval 9.6 to 22.8
15.7 Percentage of participants
Interval 9.8 to 23.3

SECONDARY outcome

Timeframe: 12 weeks

Population: Efficacy Analysis Set 1 (EAS1) are patients who received at least 1 full or partial dose of LCL161 + paclitaxel or of paclitaxel alone with a valid gene expression signature score. 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)

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.

Outcome measures

Outcome measures
Measure
LCL161 + Paclitaxel (Gene Expression Signature Positive)
n=50 Participants
Patients randomized to the experimental arm for gene expression signature positive received LCL161 1800 mg once weekly + 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.
Paclitaxel Only (Gene Expression Signature Positive)
n=51 Participants
Patients randomized to the control arm for gene expression signature positive 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.
LCL161 + Paclitaxel (Gene Expression Signature Negative)
n=55 Participants
Patients randomized to the experimental arm for gene expression signature negative received paclitaxel 80 mg/m2 weekly + LCL161 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.
Paclitaxel Only (Gene Expression Signature Negative)
n=51 Participants
Patients randomized to the control arm for gene expression signature negative 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.
pCR Rate in Breast, Regional Nodes and Axilla
21.5 Percentage of participants
Interval 11.8 to 34.0
19.1 Percentage of participants
Interval 10.0 to 31.2
6.9 Percentage of participants
Interval 2.2 to 15.5
5.5 Percentage of participants
Interval 1.4 to 13.9

SECONDARY outcome

Timeframe: 16 weeks

Population: EAS1 - patients receiving at least 1 full or partial dose of LCL161 + paclitaxel or of paclitaxel alone with a valid gene expression signature (GES) score. GES status is derived based on continuous GES score using cut-off 0.6661(pos: score ≥ 0.6661; neg: score \<0.6661). Patients with multicentric breast cancer were excluded.

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.

Outcome measures

Outcome measures
Measure
LCL161 + Paclitaxel (Gene Expression Signature Positive)
n=48 Participants
Patients randomized to the experimental arm for gene expression signature positive received LCL161 1800 mg once weekly + 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.
Paclitaxel Only (Gene Expression Signature Positive)
n=45 Participants
Patients randomized to the control arm for gene expression signature positive 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.
LCL161 + Paclitaxel (Gene Expression Signature Negative)
n=51 Participants
Patients randomized to the experimental arm for gene expression signature negative received paclitaxel 80 mg/m2 weekly + LCL161 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.
Paclitaxel Only (Gene Expression Signature Negative)
n=47 Participants
Patients randomized to the control arm for gene expression signature negative 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.
Rates of Breast Conserving Surgery and Mastectomy - Assessed by Percentage of Patients Who Underwent Breast Conserving Surgery, Masectomy and no Surgery
Breast Conserving Surgery
60.4 Percentage of participants
60.0 Percentage of participants
49.0 Percentage of participants
44.7 Percentage of participants
Rates of Breast Conserving Surgery and Mastectomy - Assessed by Percentage of Patients Who Underwent Breast Conserving Surgery, Masectomy and no Surgery
Mastectomy
25.0 Percentage of participants
26.7 Percentage of participants
23.5 Percentage of participants
29.8 Percentage of participants
Rates of Breast Conserving Surgery and Mastectomy - Assessed by Percentage of Patients Who Underwent Breast Conserving Surgery, Masectomy and no Surgery
No Surgery
14.6 Percentage of participants
13.3 Percentage of participants
27.5 Percentage of participants
25.5 Percentage of participants

SECONDARY outcome

Timeframe: Baseline, Post-baeline at Cycle 1, Day 2 (C1D2) or Cycle 1, Day 9 (C1D9)

Population: Efficacy Analysis Set 1 (EAS1) is patients (pts) who received at least 1 full or partial dose of LCL161 + paclitaxel or of paclitaxel alone with valid gene expression signature score. All pts were considered for analysis (N). Only pts (n) with baseline \& post baseline values for the given time point were analyzed for that time point.

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

Outcome measures

Outcome measures
Measure
LCL161 + Paclitaxel (Gene Expression Signature Positive)
n=50 Participants
Patients randomized to the experimental arm for gene expression signature positive received LCL161 1800 mg once weekly + 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.
Paclitaxel Only (Gene Expression Signature Positive)
n=51 Participants
Patients randomized to the control arm for gene expression signature positive 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.
LCL161 + Paclitaxel (Gene Expression Signature Negative)
n=55 Participants
Patients randomized to the experimental arm for gene expression signature negative received paclitaxel 80 mg/m2 weekly + LCL161 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.
Paclitaxel Only (Gene Expression Signature Negative)
n=51 Participants
Patients randomized to the control arm for gene expression signature negative 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.
Caspase 3 Activation in Tumor by Immunohistochemistry (IHC) - EAS1
EAS1-Baseline (n: 20, 16, 21, 22)
1.5 % of positive tumor cells
Standard Deviation 1.6
1.4 % of positive tumor cells
Standard Deviation 1.3
1.4 % of positive tumor cells
Standard Deviation 3.3
2.1 % of positive tumor cells
Standard Deviation 2.8
Caspase 3 Activation in Tumor by Immunohistochemistry (IHC) - EAS1
EAS1 Post-Baseline (n: 20, 16, 21, 22)
2.6 % of positive tumor cells
Standard Deviation 1.4
2.4 % of positive tumor cells
Standard Deviation 1.7
3.1 % of positive tumor cells
Standard Deviation 3.1
3.1 % of positive tumor cells
Standard Deviation 6.1

SECONDARY outcome

Timeframe: Baseline, Post-baeline at Cycle 1, Day 2 or Cycle 1, Day 9

Population: The Efficacy Analysis Set 2 (EAS2) was the same as EAS1 except that the threshold for classifying a patient into the positive gene group was 0.7716. All the EAS2 set participants were considered for the analysis (N). Only participants (n) who had baseline and post baseline values for the given time point were analyzed for that time point.

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

Outcome measures

Outcome measures
Measure
LCL161 + Paclitaxel (Gene Expression Signature Positive)
n=34 Participants
Patients randomized to the experimental arm for gene expression signature positive received LCL161 1800 mg once weekly + 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.
Paclitaxel Only (Gene Expression Signature Positive)
n=29 Participants
Patients randomized to the control arm for gene expression signature positive 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.
LCL161 + Paclitaxel (Gene Expression Signature Negative)
n=71 Participants
Patients randomized to the experimental arm for gene expression signature negative received paclitaxel 80 mg/m2 weekly + LCL161 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.
Paclitaxel Only (Gene Expression Signature Negative)
n=73 Participants
Patients randomized to the control arm for gene expression signature negative 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.
Caspase 3 Activation in Tumor by Immunohistochemistry (IHC) - EAS2
EAS2-Baseline (n: 13, 11, 28, 27)
1.3 % of positive tumor cells
Standard Deviation 1.8
1.6 % of positive tumor cells
Standard Deviation 1.4
1.5 % of positive tumor cells
Standard Deviation 2.9
1.9 % of positive tumor cells
Standard Deviation 2.6
Caspase 3 Activation in Tumor by Immunohistochemistry (IHC) - EAS2
EAS2 Post-Baseline (n:13, 11, 28, 27)
2.3 % of positive tumor cells
Standard Deviation 1.4
2.7 % of positive tumor cells
Standard Deviation 1.9
3.2 % of positive tumor cells
Standard Deviation 2.7
2.9 % of positive tumor cells
Standard Deviation 5.6

SECONDARY outcome

Timeframe: cycle 1 day 1, cycle 4 day 15

Population: The pharmacokinetic analysis set (PAS) consisted of all patients who had at least one blood sample providing evaluable PK data for LCL161. Only sparse/limited PK samples were collected and analyzed.

To evaluate the PK of LCL161 when given in combination with paclitaxel.

Outcome measures

Outcome measures
Measure
LCL161 + Paclitaxel (Gene Expression Signature Positive)
n=97 Participants
Patients randomized to the experimental arm for gene expression signature positive received LCL161 1800 mg once weekly + 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.
Paclitaxel Only (Gene Expression Signature Positive)
Patients randomized to the control arm for gene expression signature positive 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.
LCL161 + Paclitaxel (Gene Expression Signature Negative)
Patients randomized to the experimental arm for gene expression signature negative received paclitaxel 80 mg/m2 weekly + LCL161 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.
Paclitaxel Only (Gene Expression Signature Negative)
Patients randomized to the control arm for gene expression signature negative 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.
Pharmacokinetics (PK) Parameters of LCL161 Only for Cmax
Cycle 1 Day 1 (n:97)
2230.00 ng/mL
Full Range 1113.41 • Interval 186.0 to 4740.0
Pharmacokinetics (PK) Parameters of LCL161 Only for Cmax
Cycle 4 Day 15 (n:47)
2310.00 ng/mL
Full Range 1161.75 • Interval 491.0 to 5250.0

SECONDARY outcome

Timeframe: cycle 1 day 1, cycle 4 day 15

Population: The pharmacokinetic analysis set (PAS) consisted of all patients who had at least one blood sample providing evaluable PK data for LCL161. Only sparse/limited PK samples were collected and analyzed.

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.

Outcome measures

Outcome measures
Measure
LCL161 + Paclitaxel (Gene Expression Signature Positive)
n=97 Participants
Patients randomized to the experimental arm for gene expression signature positive received LCL161 1800 mg once weekly + 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.
Paclitaxel Only (Gene Expression Signature Positive)
Patients randomized to the control arm for gene expression signature positive 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.
LCL161 + Paclitaxel (Gene Expression Signature Negative)
Patients randomized to the experimental arm for gene expression signature negative received paclitaxel 80 mg/m2 weekly + LCL161 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.
Paclitaxel Only (Gene Expression Signature Negative)
Patients randomized to the control arm for gene expression signature negative 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.
Pharmacokinetics (PK) Parameters of LCL161 Only for Tmax
Cycle 1 Day 1 (n:97)
3.72 h
Full Range 1113.41 • Interval 0.5 to 5.8
Pharmacokinetics (PK) Parameters of LCL161 Only for Tmax
Cycle 4 Day 15 (n:47)
3.50 h
Full Range 1161.75 • Interval 1.0 to 4.2

SECONDARY outcome

Timeframe: cycle 1 day 1, cycle 4 day 15

Population: The pharmacokinetic analysis set (PAS) consisted of all patients who had at least one blood sample providing evaluable PK data for LCL161. Only sparse/limited PK samples were collected and analyzed.

To evaluate the PK of LCL161 when given in combination with paclitaxel

Outcome measures

Outcome measures
Measure
LCL161 + Paclitaxel (Gene Expression Signature Positive)
n=97 Participants
Patients randomized to the experimental arm for gene expression signature positive received LCL161 1800 mg once weekly + 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.
Paclitaxel Only (Gene Expression Signature Positive)
Patients randomized to the control arm for gene expression signature positive 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.
LCL161 + Paclitaxel (Gene Expression Signature Negative)
Patients randomized to the experimental arm for gene expression signature negative received paclitaxel 80 mg/m2 weekly + LCL161 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.
Paclitaxel Only (Gene Expression Signature Negative)
Patients randomized to the control arm for gene expression signature negative 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.
Pharmacokinetics (PK) Parameters of LCL161 Only for AUClast
Cycle 1 Day 1 (n:97)
5250.70 ng*hr/mL
Full Range 1113.41 • Interval 465.8 to 13379.0
Pharmacokinetics (PK) Parameters of LCL161 Only for AUClast
Cycle 4 Day 15 (n:47)
5522.58 ng*hr/mL
Full Range 1161.75 • Interval 1070.8 to 13745.5

Adverse Events

LCL161+PACLITAXEL

Serious events: 45 serious events
Other events: 106 other events
Deaths: 0 deaths

PACLITAXEL

Serious events: 7 serious events
Other events: 101 other events
Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure
LCL161+PACLITAXEL
n=106 participants at risk
Patients randomized to the experimental arm for gene expression signature positive/negative received LCL161 1800 mg once weekly + 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.
PACLITAXEL
n=103 participants at risk
Patients randomized to the control arm for gene expression signature positive/negative 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.
Blood and lymphatic system disorders
Anaemia
0.94%
1/106
0.97%
1/103
Blood and lymphatic system disorders
Disseminated intravascular coagulation
0.94%
1/106
0.00%
0/103
Blood and lymphatic system disorders
Febrile neutropenia
0.94%
1/106
0.97%
1/103
Blood and lymphatic system disorders
Lymph node pain
0.94%
1/106
0.00%
0/103
Blood and lymphatic system disorders
Neutropenia
1.9%
2/106
0.00%
0/103
Cardiac disorders
Sinus tachycardia
0.94%
1/106
0.00%
0/103
Gastrointestinal disorders
Abdominal pain upper
0.00%
0/106
0.97%
1/103
Gastrointestinal disorders
Diarrhoea
1.9%
2/106
0.00%
0/103
Gastrointestinal disorders
Nausea
0.94%
1/106
0.00%
0/103
General disorders
Chills
1.9%
2/106
0.00%
0/103
General disorders
Feeling cold
0.94%
1/106
0.00%
0/103
General disorders
Influenza like illness
0.94%
1/106
0.00%
0/103
General disorders
Pyrexia
17.9%
19/106
0.97%
1/103
Immune system disorders
Anaphylactic reaction
0.94%
1/106
0.97%
1/103
Immune system disorders
Anaphylactic shock
0.94%
1/106
0.00%
0/103
Immune system disorders
Cytokine release syndrome
0.94%
1/106
0.00%
0/103
Immune system disorders
Drug hypersensitivity
1.9%
2/106
0.00%
0/103
Immune system disorders
Hypersensitivity
2.8%
3/106
0.97%
1/103
Infections and infestations
Atypical pneumonia
2.8%
3/106
0.97%
1/103
Infections and infestations
Febrile infection
0.94%
1/106
0.00%
0/103
Infections and infestations
Herpes zoster
0.94%
1/106
0.00%
0/103
Infections and infestations
Infection
0.94%
1/106
0.00%
0/103
Infections and infestations
Lower respiratory tract infection
0.94%
1/106
0.00%
0/103
Infections and infestations
Pneumocystis jirovecii pneumonia
3.8%
4/106
0.00%
0/103
Infections and infestations
Pneumonia
3.8%
4/106
0.97%
1/103
Infections and infestations
Upper respiratory tract infection
0.00%
0/106
0.97%
1/103
Infections and infestations
Urinary tract infection
0.94%
1/106
0.00%
0/103
Injury, poisoning and procedural complications
Post procedural haemorrhage
0.00%
0/106
0.97%
1/103
Investigations
Alanine aminotransferase increased
0.94%
1/106
0.00%
0/103
Investigations
Blood creatinine increased
0.94%
1/106
0.00%
0/103
Investigations
White blood cell count decreased
0.94%
1/106
0.00%
0/103
Metabolism and nutrition disorders
Decreased appetite
0.94%
1/106
0.00%
0/103
Metabolism and nutrition disorders
Hyperkalaemia
0.94%
1/106
0.00%
0/103
Metabolism and nutrition disorders
Hyponatraemia
1.9%
2/106
0.00%
0/103
Musculoskeletal and connective tissue disorders
Polyarthritis
0.94%
1/106
0.00%
0/103
Psychiatric disorders
Depression
0.94%
1/106
0.00%
0/103
Renal and urinary disorders
Acute kidney injury
0.94%
1/106
0.00%
0/103
Respiratory, thoracic and mediastinal disorders
Cough
0.94%
1/106
0.97%
1/103
Respiratory, thoracic and mediastinal disorders
Dyspnoea
0.94%
1/106
0.00%
0/103
Respiratory, thoracic and mediastinal disorders
Hypoxia
0.94%
1/106
0.00%
0/103
Respiratory, thoracic and mediastinal disorders
Interstitial lung disease
0.94%
1/106
0.00%
0/103
Respiratory, thoracic and mediastinal disorders
Pleural effusion
0.94%
1/106
0.00%
0/103
Respiratory, thoracic and mediastinal disorders
Pneumonitis
9.4%
10/106
0.00%
0/103
Respiratory, thoracic and mediastinal disorders
Pneumothorax
0.94%
1/106
0.00%
0/103
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism
1.9%
2/106
0.00%
0/103
Respiratory, thoracic and mediastinal disorders
Respiratory failure
0.94%
1/106
0.00%
0/103
Skin and subcutaneous tissue disorders
Dermatitis
0.94%
1/106
0.00%
0/103
Skin and subcutaneous tissue disorders
Rash
1.9%
2/106
0.00%
0/103
Social circumstances
Immobile
0.94%
1/106
0.00%
0/103
Vascular disorders
Hypotension
1.9%
2/106
0.00%
0/103

Other adverse events

Other adverse events
Measure
LCL161+PACLITAXEL
n=106 participants at risk
Patients randomized to the experimental arm for gene expression signature positive/negative received LCL161 1800 mg once weekly + 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.
PACLITAXEL
n=103 participants at risk
Patients randomized to the control arm for gene expression signature positive/negative 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.
Blood and lymphatic system disorders
Anaemia
25.5%
27/106
12.6%
13/103
Blood and lymphatic system disorders
Neutropenia
31.1%
33/106
8.7%
9/103
Eye disorders
Vision blurred
6.6%
7/106
0.97%
1/103
Gastrointestinal disorders
Abdominal pain
10.4%
11/106
7.8%
8/103
Gastrointestinal disorders
Abdominal pain upper
6.6%
7/106
3.9%
4/103
Gastrointestinal disorders
Constipation
22.6%
24/106
23.3%
24/103
Gastrointestinal disorders
Diarrhoea
71.7%
76/106
22.3%
23/103
Gastrointestinal disorders
Dry mouth
9.4%
10/106
2.9%
3/103
Gastrointestinal disorders
Dyspepsia
11.3%
12/106
9.7%
10/103
Gastrointestinal disorders
Nausea
42.5%
45/106
31.1%
32/103
Gastrointestinal disorders
Stomatitis
24.5%
26/106
17.5%
18/103
Gastrointestinal disorders
Vomiting
19.8%
21/106
15.5%
16/103
General disorders
Asthenia
15.1%
16/106
10.7%
11/103
General disorders
Chills
11.3%
12/106
3.9%
4/103
General disorders
Fatigue
45.3%
48/106
36.9%
38/103
General disorders
Influenza like illness
5.7%
6/106
0.00%
0/103
General disorders
Oedema peripheral
11.3%
12/106
2.9%
3/103
General disorders
Pyrexia
41.5%
44/106
8.7%
9/103
Immune system disorders
Drug hypersensitivity
7.5%
8/106
0.97%
1/103
Immune system disorders
Hypersensitivity
6.6%
7/106
5.8%
6/103
Infections and infestations
Urinary tract infection
9.4%
10/106
2.9%
3/103
Injury, poisoning and procedural complications
Procedural pain
6.6%
7/106
8.7%
9/103
Investigations
Alanine aminotransferase increased
14.2%
15/106
10.7%
11/103
Investigations
Aspartate aminotransferase increased
12.3%
13/106
7.8%
8/103
Investigations
Haemoglobin decreased
7.5%
8/106
2.9%
3/103
Investigations
Neutrophil count decreased
9.4%
10/106
1.9%
2/103
Investigations
White blood cell count decreased
7.5%
8/106
2.9%
3/103
Metabolism and nutrition disorders
Decreased appetite
11.3%
12/106
4.9%
5/103
Metabolism and nutrition disorders
Hyperglycaemia
5.7%
6/106
7.8%
8/103
Musculoskeletal and connective tissue disorders
Arthralgia
19.8%
21/106
14.6%
15/103
Musculoskeletal and connective tissue disorders
Back pain
9.4%
10/106
7.8%
8/103
Musculoskeletal and connective tissue disorders
Musculoskeletal pain
10.4%
11/106
5.8%
6/103
Musculoskeletal and connective tissue disorders
Myalgia
21.7%
23/106
17.5%
18/103
Musculoskeletal and connective tissue disorders
Pain in extremity
10.4%
11/106
5.8%
6/103
Nervous system disorders
Dizziness
11.3%
12/106
6.8%
7/103
Nervous system disorders
Dysgeusia
22.6%
24/106
8.7%
9/103
Nervous system disorders
Headache
33.0%
35/106
17.5%
18/103
Nervous system disorders
Hypoaesthesia
1.9%
2/106
5.8%
6/103
Nervous system disorders
Neuropathy peripheral
12.3%
13/106
27.2%
28/103
Nervous system disorders
Neurotoxicity
10.4%
11/106
9.7%
10/103
Nervous system disorders
Paraesthesia
8.5%
9/106
3.9%
4/103
Nervous system disorders
Peripheral sensory neuropathy
23.6%
25/106
16.5%
17/103
Psychiatric disorders
Anxiety
7.5%
8/106
7.8%
8/103
Psychiatric disorders
Insomnia
20.8%
22/106
16.5%
17/103
Reproductive system and breast disorders
Breast pain
8.5%
9/106
9.7%
10/103
Respiratory, thoracic and mediastinal disorders
Cough
28.3%
30/106
9.7%
10/103
Respiratory, thoracic and mediastinal disorders
Dyspnoea
22.6%
24/106
6.8%
7/103
Respiratory, thoracic and mediastinal disorders
Epistaxis
14.2%
15/106
8.7%
9/103
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain
15.1%
16/106
3.9%
4/103
Respiratory, thoracic and mediastinal disorders
Pneumonitis
5.7%
6/106
0.00%
0/103
Skin and subcutaneous tissue disorders
Alopecia
67.9%
72/106
67.0%
69/103
Skin and subcutaneous tissue disorders
Erythema
9.4%
10/106
7.8%
8/103
Skin and subcutaneous tissue disorders
Nail disorder
4.7%
5/106
5.8%
6/103
Skin and subcutaneous tissue disorders
Palmar-Plantar erythrodysaesthesia syndrome
7.5%
8/106
2.9%
3/103
Skin and subcutaneous tissue disorders
Pruritus
26.4%
28/106
8.7%
9/103
Skin and subcutaneous tissue disorders
Rash
41.5%
44/106
26.2%
27/103
Vascular disorders
Flushing
5.7%
6/106
6.8%
7/103
Vascular disorders
Hot flush
16.0%
17/106
14.6%
15/103
Vascular disorders
Hypertension
2.8%
3/106
5.8%
6/103

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Results disclosure agreements

  • Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of pooled data (i.e.,data from all sites) in clinical trial or disclosure of trial results in their entirety.
  • Publication restrictions are in place

Restriction type: OTHER