GBG90

GBG Forschungs GmbH

Martin Behaim Str. 12, Neu-Isenburg, Germany, 63263

Medicine and Research, GBG Forschungs GmbH, +49 610274800, publications@gbg.de

Medicine and Research, GBG Forschungs GmbH, +49 610274800, publications@gbg.de

No

No

No

Final

06 Feb 2020

Yes

23 Jan 2019

Yes

27 Feb 2019

No

To assess the pathological complete response rate (pCR=ypT0/is ypN0) of neoadjuvant paclitaxel plus olaparib followed by epirubicin and cyclophosphamide in patients with early breast cancer and HRD tumors defined as either tumor (t) or known germline (g) BRCA1/2 mutation or HRD score high.

The trial protocol including amendments, the patient information and the informed consent were reviewed and approved from a properly constituted IRB/IEC for each site prior to the study start. The trial was in compliance with the International Conference on Harmonization (ICH) - Harmonized Tripartite Guideline for Good Clinical Practice (GCP) (E6), and the Commission Directives in the European Community as well as with the applicable German national laws and regulations, and with Declaration of Helsinki and its revisions in all aspects of preparation, monitoring, reporting, auditing, and archiving. IDMC was to ensure the ethical conduct of the trial and to protect patients' safety interests in this study.

21 Sep 2016

Yes

Yes

Germany: 106

106

106

0

0

0

0

0

0

100

6

0

overall trial (overall period)

Randomised - controlled

Yes

Lynparza® (Olaparib)

EU/1/14/959/001

Tablet

Oral use

Olaparib 4 x 25mg tablets twice daily for 12 weeks

Carboplatinum

39079.00.00

Infusion

Intravenous use

Carboplatin: i.v. infusion over 15 – 60 minutes; AUC 2 given on day 1, 8, 15, q d 22 for 4 cycles. It was administered according to recommendations of the manufacturers.

olaparib plus paclitaxel

carboplatinum plus paclitaxel

olaparib plus paclitaxel

carboplatinum plus paclitaxel

The primary endpoint was summarized as pCR (ypT0/is ypN0) rate for the olaparib group. One group chi-square test was performed to exclude a pCR rate of 55% or lower in the olaparib arm. Two-sided 90% CIs were calculated according to Pearson and Clopper (Pearson and Clopper 1934). The significance level was set to two-sided α=0.1. The analysis was performed in the modified intention-to-treat (mITT) set that icluded all patients who were randomized and started therapy. Note, the primary endpoint was to assess pCR=ypT0/is ypN0 rate only in olabarib plus paclitaxel arm but the pCR rate in carboplatinum plus paclitaxel arm is also shown as required by the system

Primary

from start of treatment to surgery, 12 weeks

This is a non-comparative phase II study design investigating an addition of olaparib to paclitaxel as part of neoadjuvant chemotherapy in early HER2-negative BC patients with HRD. One group chi-square test was performed to exclude a pCR rate of 55% or lower in the olaparib plus paclitaxel arm. Note, for the primary endpoint there was not a comparison group.

olaparib plus paclitaxel v carboplatinum plus paclitaxel

106

Pre-specified

55.1

2-sided

pCR rate (ypT0/is ypN0) in carboplatinum plus paclitaxel arm and the absolute difference of pCR rates (ypT0/is ypN0) between the two treatment arms. The analysis was performed in the modified intention-to-treat (mITT) set that icluded all patients who were randomized and started therapy.

Secondary

from start of treatment to surgery, 12 weeks

The difference in the pCR (ypT0/is ypN0) rates between the treatment arms was evaluated as odds ratio (OR) and the significance was tested with a two-sided continuity corrected chi-square test.

olaparib plus paclitaxel v carboplatinum plus paclitaxel

106

Pre-specified

6.4

2-sided

pCR (ypT0/is ypN0) comparison between treatment arms; pCR rates between treatment arms were assessed by two-sided continuity corrected chi-square tests with 90% confidence intervals, and the difference in the pCR rates between the two treatment arms was evaluated as odds ratio and its 95% CI. The analysis was performed in the modified intention-to-treat (mITT) set that icluded all patients who were randomized and started therapy.

Secondary

12 weeks

Comparison of pCR (ypT0/is ypN0) rates between olaparib plus paclitaxel and carbiplatinum plus paclitaxel arms based on the mITT set was evaluated as odds ratio with 95% CI.

olaparib plus paclitaxel v carboplatinum plus paclitaxel

106

Pre-specified

1.29

2-sided

pCR of breast and lymph nodes defined as ypT0 ypN0 between treatment arms. The analysis was performed in the modified intention-to-treat (mITT) set that icluded all patients who were randomized and started therapy.

Secondary

12 weeks

Two-sided continuity corrected chi-square tests were used to compare pCR=ypT0 ypN0 rates between treatment arms

olaparib plus paclitaxel v carboplatinum plus paclitaxel

106

Pre-specified

3.3

2-sided

To assess breast conservation rate defined as tumorectomy, segmentectomy or quadrantectomy as most radical surgery after each treatment. The analysis was performed in the modified intention-to-treat (mITT) set that icluded all patients who were randomized and started therapy.

Secondary

12 weeks

Breast conservation rates were analyzed in the mITT set.

olaparib plus paclitaxel v carboplatinum plus paclitaxel

106

Pre-specified

To determine the clinical/imaging response rates after taxane treatment based on physical examination and imaging tests (sonography, mammography, or MRI) in both treatment arms. Clinical /imaging response of the breast was defined as: -Complete response (CR): complete disappearance of all tumor signs in the breast as assessed by all imaging tests -Partial response (PR): reduction in the product of the two largest perpendicular diameters of the primary tumor size by 50% or more assessed by imaging test or palpation -Stable disease (SD): no significant change in tumor size during treatment. This category includes no change, an estimated reduction of the tumor area by less than 50%, or an estimated increase in the size of the tumor area lesion of less than 25% measured by imaging test or palpation -Progressive disease (PD): development of new, previously undetected lesions, or an estimated increase in the size of pre-existing lesions by 25% or more after at least 6 weeks therapy.

Secondary

12 weeks

ORR (overall response rate) after taxane treatment was defined as complete or partial response of the breast and analyzed in the mITT set, and the two-sided 90% CI was calculated according to Pearson and Clopper (Pearson & Clopper, 1934).

olaparib plus paclitaxel v carboplatinum plus paclitaxel

106

Pre-specified

-6.4

2-sided

To determine the clinical/imaging response rates before surgery based on physical examination and imaging tests (sonography, mammography, or MRI) in both treatment arms. Clinical /imaging response of the breast was defined as: -Complete response (CR): complete disappearance of all tumor signs in the breast as assessed by all imaging tests -Partial response (PR): reduction in the product of the two largest perpendicular diameters of the primary tumor size by 50% or more assessed by imaging test or palpation -Stable disease (SD): no significant change in tumor size during treatment. This category includes no change, an estimated reduction of the tumor area by less than 50%, or an estimated increase in the size of the tumor area lesion of less than 25% measured by imaging test or palpation -Progressive disease (PD): development of new, previously undetected lesions, or an estimated increase in the size of pre-existing lesions by 25% or more after at least 6 weeks therapy.

Secondary

before surgery (end of treatment)

ORR (overall response rate) before surgery was defined as complete or partial response of the breast and analyzed in the mITT set, and the two-sided 90% CI was calculated according to Pearson and Clopper (Pearson & Clopper, 1934).

olaparib plus paclitaxel v carboplatinum plus paclitaxel

106

Pre-specified

6.1

2-sided

pCR=ypT0 ypN(any) rates were defined based on the TNM classification and analyzed between treatment arms in the modified intention-to-treat (mITT) set that icluded all patients who were randomized and started therapy.

Secondary

12 weeks

Two-sided continuity corrected chi-square tests were used to compare pCR (ypT0 ypNany) rates between treatment arms.

olaparib plus paclitaxel v carboplatinum plus paclitaxel

106

Pre-specified

3.7

2-sided

pCR defined as ypT0/is ypN(any) based on the TNM classification was evaluated between treatment arms in the modified intention-to-treat (mITT) set that icluded all patients who were randomized and started therapy.

Secondary

12 weeks

Two-sided continuity corrected chi-square test was used to compare pCR (ypT0/is ypNany) rates between treatment arms.

olaparib plus paclitaxel v carboplatinum plus paclitaxel

106

Pre-specified

6.8

2-sided

pCR defined as ypT(any) ypN0 based on the TNM classification was analyzed between treatment arms in the modified intention-to-treat (mITT) set that icluded all patients who were randomized and started therapy.

Secondary

12 weeks

Two-sided continuity corrected chi-square test was used to compare pCR=ypT(any) ypN0 rates between treatment arms.

olaparib plus paclitaxel v carboplatinum plus paclitaxel

106

Pre-specified

3.8

2-sided

The pCR rates (ypT0/is ypN0) were analyzed in subgroups defined by: a) Stratification factors • hormone-receptor status (HR-positive vs HR-negative) • age (< 40 years vs ≥ 40 years) b) Other baseline factors • tumor (t) BRCA1/2 status (mutated tBRCA1/2 vs non-mutated tBRCA1/2) • clinical nodal status (cN-negative [cN0] vs cN-positive [cN+]) assessed by sonography or if missing by palpation. This subgroup was not specified in the study protocol and was added post-hoc. The analysis was performed in the modified intention-to-treat (mITT) set that icluded all patients who were randomized and started therapy.

Secondary

12 weeks

In subgroup analyses according to the stratification parameters, all patients were included as stratified. Patients with missing values defining the subgroup were excluded from the corresponding analyses. There was no adjustment for multiple comparisons in the subgroup analyses. The subgroup analysis was to be considered explorative. pCR was analyzed separately for the subgroups according to HR status, age, tBRCA1/2 status and clinical nodal status (cN).

olaparib plus paclitaxel v carboplatinum plus paclitaxel

106

Pre-specified

32.6

2-sided

In subgroup analyses according to the stratification parameters, all patients were included as stratified. Patients with missing values defining the subgroup were excluded from the corresponding analyses. There was no adjustment for multiple comparisons in the analyses in subgroups which are to be considered explorative.

olaparib plus paclitaxel v carboplatinum plus paclitaxel

106

Pre-specified

-3.3

2-sided

In subgroup analyses according to the stratification parameters, all patients were included as stratified. Patients with missing values defining the subgroup were excluded from the corresponding analyses. There was no adjustment for multiple comparisons in the subgroup analyses. The subgroup analysis was to be considered explorative. pCR was analyzed separately for the subgroups according to HR status, age, tBRCA1/2 status and clinical nodal status (cN)

olaparib plus paclitaxel v carboplatinum plus paclitaxel

106

Pre-specified

30.7

2-sided

In subgroup analyses according to the stratification parameters, all patients were included as stratified. Patients with missing values defining the subgroup were excluded from the corresponding analyses. There was no adjustment for multiple comparisons in the subgroup analyses. The subgroup analysis was to be considered explorative. pCR was analyzed separately for the subgroups according to HR status, age, tBRCA1/2 status and clinical nodal status (cN).

olaparib plus paclitaxel v carboplatinum plus paclitaxel

106

Pre-specified

-4.2

2-sided

In subgroup analyses according to the stratification parameters, all patients were included as stratified. Patients with missing values defining the subgroup were excluded from the corresponding analyses. There was no adjustment for multiple comparisons in the subgroup analyses. The subgroup analysis was to be considered explorative. pCR was analyzed separately for the subgroups according to HR status, age, tumor BRCA1/2 status and clinical nodal status (cN).

olaparib plus paclitaxel v carboplatinum plus paclitaxel

106

Pre-specified

0

2-sided

In subgroup analyses according to the stratification parameters, all patients were included as stratified. Patients with missing values defining the subgroup were excluded from the corresponding analyses. There was no adjustment for multiple comparisons in the subgroup analyses. The subgroup analysis was to be considered explorative. pCR was analyzed separately for the subgroups according to HR status, age, tumor BRCA1/2 status and clinical nodal status (cN).

olaparib plus paclitaxel v carboplatinum plus paclitaxel

106

Pre-specified

12.5

2-sided

In subgroup analyses according to the stratification parameters, all patients were included as stratified. Patients with missing values defining the subgroup were excluded from the corresponding analyses. There was no adjustment for multiple comparisons in the subgroup analyses. The subgroup analysis was to be considered explorative. pCR was analyzed separately for the subgroups according to HR status, age, tumor BRCA1/2 status and clinical nodal status (cN).

olaparib plus paclitaxel v carboplatinum plus paclitaxel

106

Post-hoc

13.5

2-sided

In subgroup analyses according to the stratification parameters, all patients were included as stratified. Patients with missing values defining the subgroup were excluded from the corresponding analyses. There was no adjustment for multiple comparisons in the subgroup analyses. The subgroup analysis was to be considered explorative. pCR was analyzed separately for the subgroups according to HR status, age, tumor BRCA1/2 status and clinical nodal status (cN).

olaparib plus paclitaxel v carboplatinum plus paclitaxel

106

Post-hoc

-20.6

2-sided

The pCR rates (ypT0 ypN0) were analyzed in subgroups defined by: a) Stratification factors • hormone-receptor status (HR-positive vs HR-negative) • age (< 40 years vs ≥ 40 years) b) Other baseline factors • tumor (t) BRCA1/2 status (mutated tBRCA1/2 vs non-mutated tBRCA1/2) • clinical nodal status (cN-negative [cN0] vs cN-positive [cN+]) assessed by sonography or if missing by palpation. This subgroup was not specified in the study protocol and was added post-hoc. The analysis was performed in the modified intention-to-treat (mITT) set that icluded all patients who were randomized and started therapy.

Secondary

12 weeks

The compliance endpoints referred to dose reductions, treatment delays, treatment interruptions (including skipped intake of medication (infusions or tablets)) and premature treatment discontinuations. Frequencies of patients, whose treatment had to be reduced, delayed or prematurely discontinued, were given for both treatment arms. The reasons for discontinuation included aspects of efficacy (e.g. termination due to tumor progression), safety (e.g. termination due to adverse events) and compliance (e.g. termination due to patient's withdrawal of consent). Compliance analysis was performed in the mITT set. The incidence and reasons of permanent discontinuation were reported per patient, for each treatment arm and overall.

Secondary

12 weeks

The compliance endpoints referred to dose reductions, treatment delays, treatment interruptions (including skipped intake of medication (infusions or tablets)) and premature treatment discontinuations. Frequencies of patients, whose treatment had to be reduced, delayed or prematurely discontinued, were given for both treatment arms. Compliance analysis was performed in the mITT set. The incidence and reasons of dose reductions and interruptions were reported per patient, for each treatment arm and overall; the premature discontinuation of a single drug was counted as an interruption. For dose reductions of olaparib, it was reported whether the reduction has been prescribed or not.

Secondary

12 weeks

The compliance endpoints referred to dose reductions, treatment delays, treatment interruptions (including skipped intake of medication (infusions or tablets)) and premature treatment discontinuations. Frequencies of patients, whose treatment had to be reduced, delayed or prematurely discontinued, were given for both treatment arms. Compliance analysis was performed in the mITT set. The incidence and reasons of delays in paclitaxel, carboplatin and EC treatment was reported per patient for each treatment arm and overall. There were no delays of olaparib since patients had to take olaparib twice daily and were not to take an extra dose to make up for a missing one.

Secondary

12 weeks

All adverse events occurring during the study treatment period were reported.

Non-serious AEs are reported per patient; any grade (1-4) during the complete treatment duration for the overall safety population. AEs per patient occurring more frequently (> 20%) in both arms are shown. Note, overall number of single AE occurrences per term was not assessed, only per patient.

19.1

olaparib plus paclitaxel

carboplatinum plus paclitaxel