NCT02273973

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

Completed Phase 2 Results posted Last updated 21 May 2018

What this trial tests

Phase 2 trial testing Letrozole in Breast Cancer in 334 participants. Completed in 13 March 2017.

Timeline

12 November 2014

Primary endpoint
13 March 2017

13 March 2017

Quick facts

Lead sponsor	Genentech, Inc.
Phase	Phase 2
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	double
Primary purpose	treatment
Enrollment	334
Start date	12 November 2014
Primary completion	13 March 2017
Estimated completion	13 March 2017
Sites	117 locations across Italy, Panama, Poland, South Korea, Guatemala, Belgium, Mexico, El Salvador

Drugs / interventions tested

• Letrozole — full drug profile →
• Placebo
• Taselisib — full drug profile →

Conditions studied

• Breast Cancer — all drugs for Breast Cancer →

Sponsor

Genentech, Inc. — full company profile →

Who can join

18 and older, female only, with Breast Cancer. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

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 Primary · 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.

Group	Value	95% CI
Experimental: Taselisib + Letrozole	50.0
Placebo Comparator: Placebo + Letrozole	39.3

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 Primary · 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).

Group	Value	95% CI
Experimental: Taselisib + Letrozole	1.8
Placebo Comparator: Placebo + Letrozole	0.6

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 Primary · 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.

Group	Value	95% CI
Experimental: Taselisib + Letrozole	56.2
Placebo Comparator: Placebo + Letrozole	38.0

Percentage of Participants With Total pCR , Defined as Having pCR in Both Breast and Axilla, Using AJCC Staging System in PIK3CA MT Participants Primary · 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).

Group	Value	95% CI
Experimental: Taselisib + Letrozole	1.4
Placebo Comparator: Placebo + Letrozole	0

Percentage of Participants With OR by Centrally Assessed Breast MRI Via mRECIST Version 1.1 in PIK3CA Wildtype (WT) Participants Secondary · 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.

Group	Value	95% CI
Experimental: Taselisib + Letrozole	45.7
Placebo Comparator: Placebo + Letrozole	40.4

Percentage of Participants With Total pCR Defined as Having pCR in Both Breast and Axilla, Using AJCC Staging System in PIK3CA WT Participants Secondary · 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).

Group	Value	95% CI
Experimental: Taselisib + Letrozole	2.2
Placebo Comparator: Placebo + Letrozole	1.1

Percentage of Participants With OR by Breast Ultrasound Via mRECIST Version 1.1 in PIK3CA MT Participants Secondary · 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.

Group	Value	95% CI
Experimental: Taselisib + Letrozole	61.6
Placebo Comparator: Placebo + Letrozole	40.5

Percentage of Participants With OR by Breast Ultrasound Via mRECIST Version 1.1 in PIK3CA WT Participants Secondary · 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.

Group	Value	95% CI
Experimental: Taselisib + Letrozole	54.3
Placebo Comparator: Placebo + Letrozole	51.7

Percentage of Participants With OR by Mammography Via mRECIST Version 1.1 in PIK3CA MT Participants Secondary · 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.

Group	Value	95% CI
Experimental: Taselisib + Letrozole	41.1
Placebo Comparator: Placebo + Letrozole	31.6

Percentage of Participants With OR by Mammography Via mRECIST Version 1.1 in PIK3CA WT Participants Secondary · 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.

Group	Value	95% CI
Experimental: Taselisib + Letrozole	40.2
Placebo Comparator: Placebo + Letrozole	32.6

Percentage of Participants With OR by Clinical Breast Exam (Palpation) Via mRECIST Version 1.1 in PIK3CA MT Participants Secondary · 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.

Group	Value	95% CI
Experimental: Taselisib + Letrozole	74.0
Placebo Comparator: Placebo + Letrozole	63.3

Percentage of Participants With OR by Clinical Breast Exam (Palpation) Via mRECIST Version 1.1 in PIK3CA WT Participants Secondary · 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.

Group	Value	95% CI
Experimental: Taselisib + Letrozole	62.0
Placebo Comparator: Placebo + Letrozole	59.6

Adverse events — posted to ClinicalTrials.gov

Time frame: Baseline up to 22 weeks. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Experimental: Taselisib + Letrozole

Serious: 20/167 (12%)

Deaths: 1/167

Placebo Comparator: Placebo + Letrozole

Serious: 4/167 (2%)

Deaths: 0/167

Serious adverse events (24 terms)

Reaction	System	Experimental: Taselisib + …	Placebo Comparator: Placeb…
Diarrhoea	Gastrointestinal disorders	—	—
Postoperative wound infection	Infections and infestations	—	—
Erysipelas	Infections and infestations	—	—
Colitis	Gastrointestinal disorders	—	—
Bacterial diarrhoea	Infections and infestations	—	—
Cytomegalovirus infection	Infections and infestations	—	—
Diarrhoea infectious	Infections and infestations	—	—
Gastroenteritis	Infections and infestations	—	—
Haematoma infection	Infections and infestations	—	—
Pneumonia	Infections and infestations	—	—
Urinary tract infection	Infections and infestations	—	—
Enterocolitis	Gastrointestinal disorders	—	—
Enterocolitis haemorrhagic	Gastrointestinal disorders	—	—
Stomatitis	Gastrointestinal disorders	—	—
Impaired healing	General disorders	—	—
Sudden death	General disorders	—	—
Hypertensive encephalopathy	Nervous system disorders	—	—
Memory impairment	Nervous system disorders	—	—
Erythema multiforme	Skin and subcutaneous tissue disorders	—	—
Rash	Skin and subcutaneous tissue disorders	—	—
Cardiac failure acute	Cardiac disorders	—	—
Dehydration	Metabolism and nutrition disorders	—	—
Breast pain	Reproductive system and breast disorders	—	—
Pneumonitis	Respiratory, thoracic and mediastinal disorders	—	—

Other adverse events (26 terms — click to expand)

Reaction	System	Experimental: Taselisib + …	Placebo Comparator: Placeb…
Diarrhoea	Gastrointestinal disorders	—	—
Fatigue	General disorders	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—
Nausea	Gastrointestinal disorders	—	—
Hot flush	Vascular disorders	—	—
Hyperglycaemia	Metabolism and nutrition disorders	—	—
Stomatitis	Gastrointestinal disorders	—	—
Headache	Nervous system disorders	—	—
Asthenia	General disorders	—	—
Rash	Skin and subcutaneous tissue disorders	—	—
Dry mouth	Gastrointestinal disorders	—	—
Alopecia	Skin and subcutaneous tissue disorders	—	—
Viral upper respiratory tract infection	Infections and infestations	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—
Insomnia	Psychiatric disorders	—	—
Hypertension	Vascular disorders	—	—
Constipation	Gastrointestinal disorders	—	—
Vomiting	Gastrointestinal disorders	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—
Dry skin	Skin and subcutaneous tissue disorders	—	—
Dyspepsia	Gastrointestinal disorders	—	—
Urinary tract infection	Infections and infestations	—	—
Alanine aminotransferase increased	Investigations	—	—
Dizziness	Nervous system disorders	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—
Pruritus	Skin and subcutaneous tissue disorders	—	—

Most-reported serious reactions: Diarrhoea, Postoperative wound infection, Erysipelas, Colitis, Bacterial diarrhoea, Cytomegalovirus infection, Diarrhoea infectious, Gastroenteritis.

Data from ClinicalTrials.gov NCT02273973 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Breast Cancer Treatments: Updates and New Challenges.
   Burguin A, Diorio C, Durocher F. · · 2021 · cited 297× · PMID 34442452 · DOI 10.3390/jpm11080808
2. Activation of PI3K/AKT/mTOR Pathway Causes Drug Resistance in Breast Cancer.
   Dong C, Wu J, Chen Y, Nie J, et al · · 2021 · cited 260× · PMID 33790792 · DOI 10.3389/fphar.2021.628690
3. PI3K Inhibitors in Cancer: Clinical Implications and Adverse Effects.
   Mishra R, Patel H, Alanazi S, Kilroy MK, et al · · 2021 · cited 207× · PMID 33801659 · DOI 10.3390/ijms22073464
4. Targeting PI3K/AKT/mTOR Signaling Pathway in Breast Cancer.
   Li H, Prever L, Hirsch E, Gulluni F. · · 2021 · cited 132× · PMID 34298731 · DOI 10.3390/cancers13143517
5. PI3K/AKT/mTOR-Targeted Therapy for Breast Cancer.
   Zhu K, Wu Y, He P, Fan Y, et al · · 2022 · cited 117× · PMID 36010585 · DOI 10.3390/cells11162508
6. Efficacy of PI3K inhibitors in advanced breast cancer.
   Verret B, Cortes J, Bachelot T, Andre F, et al · · 2019 · cited 92× · PMID 31859349 · DOI 10.1093/annonc/mdz381
7. Inhibition of autophagy by chloroquine prevents resistance to PI3K/AKT inhibitors and potentiates their antitumor effect in combination with paclitaxel in triple negative breast cancer models.
   Cocco S, Leone A, Roca MS, Lombardi R, et al · · 2022 · cited 85× · PMID 35761360 · DOI 10.1186/s12967-022-03462-z
8. Receptor tyrosine kinases and downstream pathways as druggable targets for cancer treatment: the current arsenal of inhibitors.
   Montor WR, Salas AROSE, Melo FHM. · · 2018 · cited 80× · PMID 29455659 · DOI 10.1186/s12943-018-0792-2