A Study of Neoadjuvant Letrozole + Taselisib Versus Letrozole + Placebo in Post-Menopausal Women With Breast Cancer (LORELEI)

Study Overview
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Brief Summary
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This is a two-arm, randomized, double-blind, multicenter, pre-operative study to evaluate the effect of combining letrozole and GDC-0032 (also known as taselisib) versus letrozole and placebo in postmenopausal women with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2 (HER2) untreated, Stage I-III operable breast cancer. Participants will be randomized into one of the two treatment arms with a 1:1 randomization ratio. Letrozole at 2.5 milligrams (mg) will be dosed once daily plus either Taselisib at 4 mg (two 2-mg tablets) or placebo on a 5 days-on/ 2 days-off schedule for a total of 16 weeks.

Official Title
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A Phase II Randomized, Double-Blind Study of Neoadjuvant Letrozole Plus GDC-0032 Versus Letrozole Plus Placebo in Postmenopausal Women With ER-positive/HER2-negative, Early Stage Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Letrozole
* Other: Placebo
* Drug: Taselisib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female participants Postmenopausal status Histologically confirmed invasive breast carcinoma, with all of the following characteristics: (i) Primary tumor greater than or equal to (>/=) 2 centimeters (cm) in largest diameter (cT1-3) by MRI; (ii) Stage I to operable Stage III breast cancer; (iii) Documented absence of distant metastases (M0) Estrogen receptor-positive (ER+) and human epidermal growth factor receptor 2-negative (HER2-) breast cancer Breast cancer eligible for primary surgery Tumor tissue from formalin-fixed paraffin-embedded cores (FFPE) core biopsy of breast primary tumor that is confirmed as evaluable for phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutation status by central histopathology laboratory Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Fasting glucose less than or equal to (</=) 125 milligrams per deciliter (mg/dL) Adequate hematological, renal, and hepatic function Absence of any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule Ability and willingness to comply with study visits, treatment, testing, and to comply with the protocol, in the investigator's judgment Exclusion Criteria: Any prior treatment for primary invasive breast cancer Participants with cT4 or cN3 stage breast tumors Bilateral invasive, multicentric, or metastatic breast cancer Participants who have undergone excisional biopsy of primary tumor and/or axillary lymph nodes or sentinel lymph node biopsy Type 1 or 2 diabetes requiring antihyperglycemic medication Inability or unwillingness to swallow pills Malabsorption syndrome or other condition that would interfere with enteric absorption History of prior or currently active small or large intestine inflammation (such as Crohn's disease or ulcerative colitis). Any predisposition for gastrointestinal (GI) toxicity requires prior approval from the Medical Monitor. Congenital long QT syndrome or QT interval corrected using Fridericia's formula (QTcF) >470 milliseconds (msec) Diffusing capacity of the lungs for carbon monoxide (DLCO) <60% of the predicted values Clinically significant (i.e., active) cardiovascular disease, uncontrolled hypertension, unstable angina, history of myocardial infarction, cardiac failure class II-IV Any contraindication to MRI examination Active infection requiring intravenous antibiotics Participants requiring any daily supplemental oxygen Clinically significant history of liver disease, including viral or other known hepatitis, current alcohol abuse, or cirrhosis Any other diseases, active or uncontrolled pulmonary dysfunction, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, that may affect the interpretation of the results, or renders the participants at high risk from treatment complications Significant traumatic injury within 3 weeks prior to initiation of study treatment Major surgical procedure within 4 weeks prior to initiation of study treatment Inability to comply with study and follow-up procedures History of other malignancy within 5 years prior to screening, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or Stage I uterine cancer

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Letrozole + Placebo<br>Participants will receive 2.5 mg letrozole tablets orally QD along with placebo on a 5-days-on/2-days-off schedule for a total of 16 weeks. | Drug: Letrozole<br>* Letrozole tablets will be administered orally at 2.5 mg QD for 16 weeks.<br>Other: Placebo<br>* Placebo tablets matched to taselisib formulation will be administered orally daily on 5 days-on/2 days-off schedule for up to 16 weeks.<br>|
| Experimental: Letrozole + Taselisib<br>Participants will receive 2.5 milligrams (mg) letrozole tablets orally once daily (QD) along with taselisib tablets at 4 mg (two 2 mg tablets) orally on a 5 days-on/2 days-off schedule for a total of 16 weeks. | Drug: Letrozole<br>* Letrozole tablets will be administered orally at 2.5 mg QD for 16 weeks.<br>Drug: Taselisib<br>* Taselisib will be administered orally at 4 mg (two 2 mg tablets) daily.<br>* Other names: GDC-0032;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Objective Response (OR) by Centrally Assessed Breast Magnetic Resonance Imaging (MRI) Via Modified Response Evaluation Criteria in Solid Tumors (mRECIST) Version 1.1 | Objective response rate (ORR) was defined as proportion of participants achieving complete response (CR) or partial response (PR). As per modified RECIST v1.1, CR: disappearance of all target lesions, PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. | From Baseline to 16 weeks | 
| Percentage of Participants With Total Pathologic Complete Response (Total pCR), Defined as Having pCR in Both Breast and Axilla, Using American Joint Committee on Cancer (AJCC) Staging System | Total pCR was assessed by local pathology review on samples taken at surgery following completion of neoadjuvant therapy. tpCR was defined as the absence of any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes ( i.e., ypT0/Tis, ypN0 in the AJCC staging system, 7th edition). | From Baseline to 16 weeks | 
| Percentage of Participants With OR by Centrally Assessed Breast MRI Via mRECIST Version 1.1 in Phosphatidylinositol-4,5-Bisphosphate 3-Kinase, Catalytic Subunit Alpha (PIK3CA) Mutant (MT) Participants | ORR was defined as proportion of participants achieving CR or PR. As per modified RECIST v1.1, CR: disappearance of all target lesions, PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. | From Baseline to 16 weeks | 
| Percentage of Participants With Total pCR , Defined as Having pCR in Both Breast and Axilla, Using AJCC Staging System in PIK3CA MT Participants | Total pCR was assessed by local pathology review on samples taken at surgery following completion of neoadjuvant therapy. tpCR was defined as the absence of any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes (i.e., ypT0/Tis, ypN0 in the AJCC staging system, 7th edition). | From Baseline to 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With OR by Centrally Assessed Breast MRI Via mRECIST Version 1.1 in PIK3CA Wildtype (WT) Participants | ORR was defined as proportion of participants achieving CR or PR. As per modified RECIST v1.1, CR: disappearance of all target lesions, PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. | From Baseline to 16 weeks | 
| Percentage of Participants With Total pCR Defined as Having pCR in Both Breast and Axilla, Using AJCC Staging System in PIK3CA WT Participants | Total pCR was assessed by local pathology review on samples taken at surgery following completion of neoadjuvant therapy. tpCR was defined as the absence of any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes (i.e., ypT0/Tis, ypN0 in the AJCC staging system, 7th edition). | From Baseline to 16 weeks | 
| Percentage of Participants With OR by Breast Ultrasound Via mRECIST Version 1.1 in PIK3CA MT Participants | ORR was defined as proportion of participants achieving CR or PR. As per modified RECIST v1.1, CR: disappearance of all target lesions, PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. | From Baseline to 16 weeks | 
| Percentage of Participants With OR by Breast Ultrasound Via mRECIST Version 1.1 in PIK3CA WT Participants | ORR was defined as proportion of participants achieving CR or PR. As per modified RECIST v1.1, CR: disappearance of all target lesions, PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. | From Baseline to 16 weeks | 
| Percentage of Participants With OR by Mammography Via mRECIST Version 1.1 in PIK3CA MT Participants | ORR was defined as proportion of participants achieving CR or PR. As per modified RECIST v1.1, CR: disappearance of all target lesions, PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. | From Baseline to 16 weeks | 
| Percentage of Participants With OR by Mammography Via mRECIST Version 1.1 in PIK3CA WT Participants | ORR was defined as proportion of participants achieving CR or PR. As per modified RECIST v1.1, CR: disappearance of all target lesions, PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. | From Baseline to 16 weeks | 
| Percentage of Participants With OR by Clinical Breast Exam (Palpation) Via mRECIST Version 1.1 in PIK3CA MT Participants | ORR was defined as proportion of participants achieving CR or PR. As per modified RECIST v1.1, CR: disappearance of all target lesions, PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. | From Baseline to 16 weeks | 
| Percentage of Participants With OR by Clinical Breast Exam (Palpation) Via mRECIST Version 1.1 in PIK3CA WT Participants | ORR was defined as proportion of participants achieving CR or PR. As per modified RECIST v1.1, CR: disappearance of all target lesions, PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. | From Baseline to 16 weeks | 
| Central Assessments of Changes in Ki67 Levels | Ki67 is a prognostic marker and is used to evaluate the proliferative activity of breast cancer. | From Baseline to Week 3 and Surgery (Weeks 17-18); and Week 3 to Surgery (Weeks 17-18) | 
| Preoperative Endocrine Prognostic Index (PEPI ) Score | To obtain the PEPI score, risk points for relapse-free survival (RFS) and breast cancer-specific survival (BCSS) are assigned depending on the hazard ratio (HR) from the multivariable analysis. The total PEPI score assigned to each participant is the sum of the risk points derived from the primary tumor (pT) stage, regional lymph nodes (pN) stage, Ki67 level, and estrogen receptor status of the surgical specimen. A HR in the range of 1 to 2 receives one risk point; a HR in the 2 to 2.5 range, two risk points; a HR greater than 2.5, three risk points. The total risk point score for each participant is the sum of all the risk points accumulated from the four factors in the model, ranges from 0 (best possible outcome) to 12 (worst possible outcome). | Week 16 | 
| Percent Change From Baseline to Surgery in Enhancing Tumor Volume as Measured by Breast MRI |  | From Baseline to Surgery (Weeks 17-18) | 
| Mean Score for Health-Related Quality of Life Measured by the European Organization for Research C30 (EORTC QLQ-C30) | EORTC QLQ-C30 is a cancer-specific instrument with 30 questions used to assess the overall quality of life (QOL) in cancer participants. The first 28 questions used a 4-point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much) for evaluating 5 functional scales (physical, role, social, cognitive, emotional), 8 symptom scales/items (diarrhea, fatigue, dyspnea, appetite loss, insomnia, nausea and vomiting [N/V], constipation, and pain) and a single item (financial difficulties). The last 2 questions represented the participant's assessment of overall health and quality of life, used 7-point scale (1=very poor to 7=excellent). EORTC QLQ-C30 global scores were linearly transformed on a scale of 0 to 100, with a high score indicating better QOL. Negative change from Baseline values indicated deterioration in QOL or functioning and positive values indicated improvement. Here, Post surgery= PS. | Weeks 1, 5, 9, 13, 16, 4-week Post-Surgery | 
| Mean Score for Treatment of Cancer Quality of Life Questionnaire BR23 (QLQ-BR23) | EORTC-QLQ-BR23 is a 23-item breast cancer-specific companion module to the EORTC-QLQ-C30 and consists of four functional scales (body image, sexual enjoyment, sexual functioning, future perspective [FP]) and four symptom scales (systemic side effects [SE], upset by hair loss, arm symptoms, breast symptoms). Questions used 4-point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Scores were averaged and transformed to 0-100 scale. High score for functional scale indicated high/better level of functioning/healthy functioning. Negative change from Baseline indicated deterioration in QOL and positive change from Baseline indicated an improvement in QOL. Here, Post surgery= PS. | Weeks 1, 5, 9, 13, 16, 4-week Post-Surgery | 
| Percentage of Participants With Adverse Events | An adverse event (AE) is any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. | Baseline up to 22 weeks |