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

• ClinicalTrials.gov Identifier: NCT02273973
• Recruitment Status: Completed
• First Posted: October 24, 2014
• Results First Posted: May 21, 2018
• Last Update Posted: May 21, 2018
• Sponsor: Genentech, Inc.
• Collaborators: SOLTI Breast Cancer Research Group; Breast International Group; Austrian Breast and Colorectal Cancer Group
• Information provided by (Responsible Party): Genentech, Inc.

Tracking Information

• First Submitted Date: October 22, 2014
• First Posted Date: October 24, 2014
• Results First Submitted Date: March 6, 2018
• Results First Posted Date: May 21, 2018
• Last Update Posted Date: May 21, 2018
• Actual Study Start Date: November 12, 2014
• Actual Primary Completion Date: March 13, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 20, 2018)

• 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 [ Time Frame: From Baseline to 16 weeks ]
  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.
• 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 [ Time Frame: From Baseline to 16 weeks ]
  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).
• 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 [ Time Frame: From Baseline to 16 weeks ]
  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.
• Percentage of Participants With Total pCR , Defined as Having pCR in Both Breast and Axilla, Using AJCC Staging System in PIK3CA MT Participants [ Time Frame: From Baseline to 16 weeks ]
  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).

Original Primary Outcome Measures (submitted: October 23, 2014)

• Objective Reponse Rate (ORR) [ Time Frame: Up to 16 weeks ]
• Pathologic complete response (pCR) rate in breast and axilla (total pCR) [ Time Frame: Up to 16 weeks ]

Current Secondary Outcome Measures (submitted: April 20, 2018)

• Percentage of Participants With OR by Centrally Assessed Breast MRI Via mRECIST Version 1.1 in PIK3CA Wildtype (WT) Participants [ Time Frame: From Baseline to 16 weeks ]
  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.
• Percentage of Participants With Total pCR Defined as Having pCR in Both Breast and Axilla, Using AJCC Staging System in PIK3CA WT Participants [ Time Frame: From Baseline to 16 weeks ]
  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).
• Percentage of Participants With OR by Breast Ultrasound Via mRECIST Version 1.1 in PIK3CA MT Participants [ Time Frame: From Baseline to 16 weeks ]
  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.
• Percentage of Participants With OR by Breast Ultrasound Via mRECIST Version 1.1 in PIK3CA WT Participants [ Time Frame: From Baseline to 16 weeks ]
  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.
• Percentage of Participants With OR by Mammography Via mRECIST Version 1.1 in PIK3CA MT Participants [ Time Frame: From Baseline to 16 weeks ]
  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.
• Percentage of Participants With OR by Mammography Via mRECIST Version 1.1 in PIK3CA WT Participants [ Time Frame: From Baseline to 16 weeks ]
  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.
• Percentage of Participants With OR by Clinical Breast Exam (Palpation) Via mRECIST Version 1.1 in PIK3CA MT Participants [ Time Frame: From Baseline to 16 weeks ]
  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.
• Percentage of Participants With OR by Clinical Breast Exam (Palpation) Via mRECIST Version 1.1 in PIK3CA WT Participants [ Time Frame: From Baseline to 16 weeks ]
  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.
• Central Assessments of Changes in Ki67 Levels [ Time Frame: From Baseline to Week 3 and Surgery (Weeks 17-18); and Week 3 to Surgery (Weeks 17-18) ]
  Ki67 is a prognostic marker and is used to evaluate the proliferative activity of breast cancer.
• Preoperative Endocrine Prognostic Index (PEPI ) Score [ Time Frame: Week 16 ]
  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).
• Percent Change From Baseline to Surgery in Enhancing Tumor Volume as Measured by Breast MRI [ Time Frame: 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) [ Time Frame: Weeks 1, 5, 9, 13, 16, 4-week Post-Surgery ]
  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.
• Mean Score for Treatment of Cancer Quality of Life Questionnaire BR23 (QLQ-BR23) [ Time Frame: Weeks 1, 5, 9, 13, 16, 4-week Post-Surgery ]
  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.
• Percentage of Participants With Adverse Events [ Time Frame: Baseline up to 22 weeks ]
  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.

Original Secondary Outcome Measures (submitted: October 23, 2014)

• Change in Ki67 levels [ Time Frame: Up to Week 17 or 18 ]
• Preoperative endocrine prognostic index (PEPI) scroe [ Time Frame: 16 weeks ]
• Change in tumor volume [ Time Frame: 16 weeks ]
• Incidence of adverse events [ Time Frame: 21-22 weeks ]
• Health-related quality of life measured by using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30/BR23 [ Time Frame: 16 weeks ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Neoadjuvant Letrozole + Taselisib Versus Letrozole + Placebo in Post-Menopausal Women With Breast Cancer (LORELEI)
• Official Title: 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
• Brief Summary: 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Breast Cancer

Intervention

• Drug: Letrozole
  Letrozole tablets will be administered orally at 2.5 mg QD for 16 weeks.
• Other: Placebo
  Placebo tablets matched to taselisib formulation will be administered orally daily on 5 days-on/2 days-off schedule for up to 16 weeks.
• Drug: Taselisib
  Taselisib will be administered orally at 4 mg (two 2 mg tablets) daily.
  Other Name: GDC-0032

Study Arms

• Placebo Comparator: Letrozole + Placebo
  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.
  Interventions:

  • Drug: Letrozole
  • Other: Placebo
• Experimental: Letrozole + Taselisib
  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.
  Interventions:

  • Drug: Letrozole
  • Drug: Taselisib

Publications *

• Eiger D, Brandao M, de Azambuja E. Lessons learned at SABCS 2019 and to-dos from immunotherapy in breast cancer. ESMO Open. 2020 Mar;5(2):e000688. doi: 10.1136/esmoopen-2020-000688. No abstract available.
• Eiger D, Franzoi MA, Ponde N, Brandao M, de Angelis C, Schmitt Nogueira M, de Hemptinne Q, de Azambuja E. Cardiotoxicity of trastuzumab given for 12 months compared to shorter treatment periods: a systematic review and meta-analysis of six clinical trials. ESMO Open. 2020 Feb;5(1):e000659. doi: 10.1136/esmoopen-2019-000659.
• Saura C, Hlauschek D, Oliveira M, Zardavas D, Jallitsch-Halper A, de la Pena L, Nuciforo P, Ballestrero A, Dubsky P, Lombard JM, Vuylsteke P, Castaneda CA, Colleoni M, Santos Borges G, Ciruelos E, Fornier M, Boer K, Bardia A, Wilson TR, Stout TJ, Hsu JY, Shi Y, Piccart M, Gnant M, Baselga J, de Azambuja E. Neoadjuvant letrozole plus taselisib versus letrozole plus placebo in postmenopausal women with oestrogen receptor-positive, HER2-negative, early-stage breast cancer (LORELEI): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2019 Sep;20(9):1226-1238. doi: 10.1016/S1470-2045(19)30334-1. Epub 2019 Aug 8.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 22, 2017): 334
• Original Estimated Enrollment (submitted: October 23, 2014): 330
• Actual Study Completion Date: March 13, 2017
• Actual Primary Completion Date: March 13, 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Austria, Belgium, Brazil, Chile, Czechia, El Salvador, France, Germany, Guatemala, Hungary, Italy, Korea, Republic of, Mexico, Panama, Peru, Poland, Portugal, Spain, Switzerland, United Kingdom, United States
• Removed Location Countries: Czech Republic

Administrative Information

• NCT Number: NCT02273973
• Other Study ID Numbers: GO28888; 2013-000568-28 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Genentech, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Genentech, Inc.
• Original Study Sponsor: Same as current

Collaborators

• SOLTI Breast Cancer Research Group
• Breast International Group
• Austrian Breast and Colorectal Cancer Group

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

• PRS Account: Genentech, Inc.
• Verification Date: April 2018