Study of Letrozole With or Without BYL719 or Buparlisib, for the Neoadjuvant Treatment of Postmenopausal Women

Breast Cancer Clinical Trial

Official title:

A Phase II Randomized, Double-blind Placebo Controlled, Study of Letrozole With or Without BYL719 or Buparlisib, for the Neoadjuvant Treatment of Postmenopausal Women With Hormone Receptor-positive HER2-negative Breast Cancer

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01923168
• Other study ID #: CBYL719A2201
• Secondary ID: 2013-001862-41
• Status: Completed
• Phase: Phase 2
• Start date: March 11, 2014
• Est. completion date: July 8, 2017

Study information

• Verified date: August 2018
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of the study was to determine whether treatment with a PI3K inhibitor plus letrozole led to an increase in pathologic clinical response and Objective Response Rate compared to treatment with placebo plus letrozole in patients with Breast cancer.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 340
• Est. completion date: July 8, 2017
• Est. primary completion date: July 7, 2017
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Patient is an adult, female = 18 years old at the time of informed consent

2. Patient has a histologically and/or cytologically confirmed diagnosis of breast cancer

3. Patient is postmenopausal.

4. Patient has T1c-T3, any N, M0, operable breast cancer

5. Patients must have measurable disease

6. Patient has diagnostic biopsy available for the analysis of PIK3CA mutation and Ki67 level.

7. Patient has estrogen-receptor and/or progesterone positive breast cancer as per local laboratory testing

8. Patient has HER2 negative breast cancer defined as a negative in situ hybridization test or an IHC status of 0 or 1+ as per local laboratory testing

Exclusion Criteria:

1. Patient has locally recurrent or metastatic disease

2. Patient has received any systemic therapy (e.g. chemotherapy, targeted therapy, immunotherapy) or radiotherapy for current breast cancer disease before randomization.

3. Patient with type 1 diabetes mellitus or not adequately controlled type 2 diabetes mellitus

4. History of acute pancreatitis within 1 year of study entry

5. Uncontrolled hypertension

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

Drug:
• alpelisib
BYL719 + Letrozole
• buparlisib
BKM120 + Letrozole
• Placebo
Placebo (of BYL719 or BKM120) + Letrozole

Locations

Country	Name	City	State
Australia	Novartis Investigative Site	Kingswood	New South Wales
Austria	Novartis Investigative Site	Dornbirn	Vorarlberg
Austria	Novartis Investigative Site	Innsbruck	Tyrol
Austria	Novartis Investigative Site	Leoben
Austria	Novartis Investigative Site	Rankweil
Austria	Novartis Investigative Site	Salzburg
Austria	Novartis Investigative Site	Vienna
Austria	Novartis Investigative Site	Villach
Austria	Novartis Investigative Site	Wien
Belgium	Novartis Investigative Site	Edegem	Antwerpen
Belgium	Novartis Investigative Site	Leuven
Belgium	Novartis Investigative Site	Sint Niklaas
Brazil	Novartis Investigative Site	Goiania	GO
Brazil	Novartis Investigative Site	Porto Alegre	Rio Grande Do Sul
Brazil	Novartis Investigative Site	Ribeirao Preto	SP
Brazil	Novartis Investigative Site	Sao Paulo	SP
Brazil	Novartis Investigative Site	Sao Paulo	SP
Bulgaria	Novartis Investigative Site	Shumen
Bulgaria	Novartis Investigative Site	Sofia
Bulgaria	Novartis Investigative Site	Varna
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	Quebec
Canada	Novartis Investigative Site	Vancouver	British Columbia
Colombia	Novartis Investigative Site	Bogota
Colombia	Novartis Investigative Site	Medellin	Antioquia
Czechia	Novartis Investigative Site	Olomouc	CZE
Czechia	Novartis Investigative Site	Praha
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Erlangen
Germany	Novartis Investigative Site	Essen
Germany	Novartis Investigative Site	Kiel
Germany	Novartis Investigative Site	Koeln
Hong Kong	Novartis Investigative Site	Hong Kong SAR
Israel	Novartis Investigative Site	Haifa
Israel	Novartis Investigative Site	Ramat Gan
Israel	Novartis Investigative Site	Tel Aviv
Italy	Novartis Investigative Site	Brescia	BS
Italy	Novartis Investigative Site	Cremona	CR
Italy	Novartis Investigative Site	Macerata	MC
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Napoli
Japan	Novartis Investigative Site	Bunkyo-ku	Tokyo
Japan	Novartis Investigative Site	Hiroshima-city	Hiroshima
Japan	Novartis Investigative Site	Koto-ku	Tokyo
Japan	Novartis Investigative Site	Nagoya-city	Aichi
Japan	Novartis Investigative Site	Niigata
Japan	Novartis Investigative Site	Osaka-city	Osaka
Lebanon	Novartis Investigative Site	Ashrafieh
Lebanon	Novartis Investigative Site	Beirut
Lebanon	Novartis Investigative Site	Saida
Netherlands	Novartis Investigative Site	Delft
Netherlands	Novartis Investigative Site	Den Haag
Netherlands	Novartis Investigative Site	Leiden
Netherlands	Novartis Investigative Site	Tilburg
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Hospitalet de LLobregat	Catalunya
Spain	Novartis Investigative Site	La Coruna	Galicia
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	San Sebastián	Pais Vasco
Spain	Novartis Investigative Site	Sevilla	Andalucia
Spain	Novartis Investigative Site	Valencia	Comunidad Valenciana
United States	Emory University School of Medicine/Winship Cancer Institute SC	Atlanta	Georgia
United States	Mercy Medical Center Medical Oncology & Hematology	Baltimore	Maryland
United States	Sidney Kimmel Comprehensive Cancer Center/Johns Hopkins Med. Johns Hopkins Med. BYL719A2201	Baltimore	Maryland
United States	Texas Oncology, P.A.	Bedford	Texas
United States	University of Alabama at Birmingham/ Kirklin Clinic Univ AL - PI	Birmingham	Alabama
United States	Dana Farber Cancer Institute BYL719A2201	Boston	Massachusetts
United States	Presbyterian Hospital of Dallas TexasOncology@PresbyterianHosp	Dallas	Texas
United States	Texas Oncology Texas Oncology - Sammons	Dallas	Texas
United States	Duke University Medical Center Duke University Medical Center	Durham	North Carolina
United States	Highlands Oncology Group	Fayetteville	Arkansas
United States	Texas Oncology Houston Memorial City SC	Houston	Texas
United States	Los Angeles Hematology/Oncology Medical Group Onc Dept.	Los Angeles	California
United States	University of California at Los Angeles UCLA SC	Los Angeles	California
United States	Vanderbilt Ingram Cancer Center Vanderbilt Health 100 Oaks	Nashville	Tennessee
United States	Cancer Institute of New Jersey	New Brunswick	New Jersey
United States	Virginia Oncology Associates SC	Norfolk	Virginia
United States	Northwest Cancer Specialists Vancouver Loc	Portland	Oregon
United States	Mayo Clinic - Rochester BYL719A2201 - SC	Rochester	Minnesota
United States	Cancer Care Centers of South Texas HOAST CCC of So. TX- San Antonio(2)	San Antonio	Texas
United States	Cancer Therapy & Research Center UT Health Science Center InstituteForDrugDevelopment(5)	San Antonio	Texas
United States	University of California San Francisco BYL719A2201 - SC	San Francisco	California
United States	Seattle Cancer Care Alliance SC-3	Seattle	Washington
United States	Northwest Medical Specialties Dept.ofNW Med. Specialties	Tacoma	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Brazil,  Bulgaria,  Canada,  Colombia,  Czechia,  Germany,  Hong Kong,  Israel,  Italy,  Japan,  Lebanon,  Netherlands,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Pathological Complete Response (pCR) Per Investigator Assessment for Alpelisib vs. Placebo for PIK3CA Mutant Cohort	Pathologic complete response (pCR) defined as absence of any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes following completion of 24 weeks of treatment by local assessment (ypT0/Tis ypN0). Patients who experienced progression of disease while undergoing neoadjuvant therapy, or who did not receive surgery for any reason, or received antineoplastic treatment other than study drug(s) before surgery were considered as non-responders for the calculation of pCR rate.	After 24 weeks of treatment
Primary	Pathological Complete Response (pCR) Per Investigator Assessment for Alpelisib vs. Placebo for PIK3CA Wild-type Cohort	Pathologic complete response (pCR) defined as absence of any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes following completion of 24 weeks of treatment by local assessment (ypT0/Tis ypN0). Patients who experienced progression of disease while undergoing neoadjuvant therapy, or who did not receive surgery for any reason, or received antineoplastic treatment other than study drug(s) before surgery were considered as non-responders for the calculation of pCR rate.	After 24 weeks of treatment
Primary	Objective Response Rate Per Investigator Assessment According to RECIST 1.1 for Alpelisib vs. Placebo - PIK3CA Mutant Cohort	Objective Response Rate (ORR) defined as the proportion of patients with a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) based on local investigator's assessment according to Response Evaluation Criteria In Solid Tumors Criteria (RECIST) 1.1.; BOR was assessed per MRI or Ultrasound and defined as per RECIST 1.1 as CR for a disappearance of all non-nodal target lesions (TL)/non-target lesions (NTL) and a reduction in short axis to < 10 mm of any pathological lymph nodes assigned as TL/NTL and no new lesion; as PR if not qualifying for CR but with a decrease from baseline = 30% in the sum of diameter of all TL, no progression of NTL and no new lesion.	After 24 weeks of treatment
Primary	Objective Response Rate According to RECIST 1.1 Per Investigator Assessment for Alpelisib vs. Placebo - PIK3CA Wild-type Cohort	Objective Response Rate (ORR) defined as the proportion of patients with a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) based on local investigator's assessment according to Response Evaluation Criteria In Solid Tumors Criteria (RECIST) 1.1.; BOR was assessed per MRI or Ultrasound and defined as per RECIST 1.1 as CR for a disappearance of all non-nodal target lesions (TL)/non-target lesions (NTL) and a reduction in short axis to < 10 mm of any pathological lymph nodes assigned as TL/NTL and no new lesion; as PR if not qualifying for CR but with a decrease from baseline = 30% in the sum of diameter of all TL, no progression of NTL and no new lesion.	After 24 weeks of treatment
Secondary	pCR and Objective Response Rate According to RECIST 1.1 Criteria Per Investigator Assessment for Alpelisib vs. Placebo in PIK3CA Mutant Cohort Based on ctDNA	pCR and Objective response rate according to RECIST 1.1 per investigator assessment after 24 weeks of treatment	After 24 weeks of treatment
Secondary	pCR and Objective Response Rate According to RECIST 1.1 Criteria Per Investigator Assessment for Alpelisib vs. Placebo in PIK3CA Wild-type Cohort Based on ctDNA	pCR and Objective response rate according to RECIST 1.1 per investigator assessment after 24 weeks of treatment	After 24 weeks of treatment
Secondary	Rate of Breast Conserving Surgery for Alpelisib vs. Placebo - PIK3CA Mutant Cohort	Breast conserving surgery is defined for participants who underwent surgery and did not have a mastectomy. The row "no surgery" provides the number of patients who did not undergo surgery at all for various reasons.	After 24 weeks of treatment
Secondary	Rate of Breast Conserving Surgery for Alpelisib vs. Placebo - PIK3CA Wild-type Cohort	Breast conserving surgery is defined as the percentage of participants with no mastectomy following completion of 24 weeks of treatment. Breast conserving surgery is defined for participants who underwent surgery and did not have a mastectomy. The row "no surgery" provides the number of patients who did not undergo surgery at all for various reasons.	After 24 weeks of treatment
Secondary	Association Between pCR and Changes in Ki67 From Baseline for Alpelisib vs. Placebo - PIK3CA Mutant Cohort: Responders as Per pCR	Association Between pCR and Changes in Ki67 From Baseline for Alpelisib vs. Placebo - PIK3CA Mutant Cohort: Responders as Per pCR	Baseline, Cycle 1 Day 15 (each cycle is 28 days) and surgery (End of Treatment (EOT) expected after 24 weeks of treatment)
Secondary	Association Between pCR and Changes in Ki67 From Baseline for Alpelisib vs. Placebo - PIK3CA Mutant Cohort: Non-responders as Per pCR	Association Between pCR and Changes in Ki67 From Baseline for Alpelisib vs. Placebo - PIK3CA Mutant Cohort: Non-responders as Per pCR.	Baseline, Cycle 1 Day 15 (each cycle is 28 days ) and surgery (End of Treatment (EOT) expected after 24 weeks of treatment)
Secondary	Association Between pCR and Changes in Ki67 From Baseline for Alpelisib vs. Placebo - PIK3CA Wild-type Cohort: Responders as Per pCR	Association between pCR and changes in Ki67 from baseline for alpelisib vs. placebo - PIK3CA wild-type cohort: responders as per pCR	Baseline, Cycle 1 Day 15 (each cycle is 28 days) and surgery (End of Treatment (EOT) expected after 24 weeks of treatment)
Secondary	Association Between pCR and Changes in Ki67 From Baseline for Alpelisib vs. Placebo - PIK3CA Wild-type Cohort: Non-responders as Per pCR	Association between pCR and changes in Ki67 from baseline for alpelisib vs. placebo - PIK3CA wild-type cohort: non-responders as per pCR	Baseline, Cycle 1 Day 15 (each cycle is 28 days) and surgery (End of Treatment (EOT) expected after 24 weeks of treatment)
Secondary	Preoperative Endocrine Prognostic Index (PEPI) Response as Per Central Assessment for Alpelisib vs. Placebo - PIK3CA Mutant Cohort	Preoperative endocrine prognostic index (PEPI) response as per central assessment for alpelisib vs. placebo - PIK3CA mutant cohort. The total PEPI score assigned to each patient is the sum of the risk points derived from the pT stage, pN stage, Ki67 level, and ER status of the surgical specimen (Ellis et al, Contemp Clin Trials 2008). The PEPI score ranges from 0 to to 12, and a higher score means a worse outcome. PEPI response is defined as a PEPI score of 0.	At the time of surgery (expected after 24 weeks of treatment)
Secondary	Preoperative Endocrine Prognostic Index (PEPI) Response as Per Central Assessment for Alpelisib vs. Placebo - PIK3CA Wild-type Cohort	Preoperative endocrine prognostic index (PEPI) response as per central assessment for alpelisib vs. placebo - PIK3CA wild-type cohort. The total PEPI score assigned to each patient is the sum of the risk points derived from the pT stage, pN stage, Ki67 level, and ER status of the surgical specimen (Ellis et al, Contemp Clin Trials 2008). The PEPI score ranges from 0 to to 12, and a higher score means a worse outcome. PEPI response is defined as a PEPI score of 0.	At the time of surgery (expected after 24 weeks of treatment)
Secondary	Alpelisib PK Parameters: AUC0-24, AUClast at Cycle 1 Day 1	Summary of primary PK parameters for alpelisib plasma concentration	0, 0.5, 1, 3, 6, 9 and 24 hours post-dose at Cycle 1 Day 1 (each cycle is 28 days)
Secondary	Alpelisib PK Parameter: Cmax at Cycle 1 Day 1	Summary of primary PK parameters for alpelisib plasma concentration	Cycle 1 Day 1 (each cycle is 28 days)
Secondary	Alpelisib and PK Parameter: Tmax at Cycle 1 Day 1	Summary of primary PK parameters for alpelisib plasma concentration	Cycle 1 Day 1 (each cycle is 28 days)
Secondary	Alpelisib PK Parameters: AUC0-24, AUClast at Cycle 4 Day 1	Summary of primary PK parameters for alpelisib plasma concentration	0, 0.5, 1, 3, 6, 9 and 24 hours post-dose at Cycle 4 Day 1 (each cycle is 28 days)
Secondary	Alpelisib PK Parameter: Cmax at Cycle 4 Day 1	Summary of primary PK parameters for alpelisib plasma concentration	Cycle 4 Day 1 (each cycle is 28 days)
Secondary	Alpelisib PK Parameter: Tmax at Cycle 4 Day 1	Summary of primary PK parameters for alpelisib plasma concentration	Cycle 4 Day 1 (each cycle is 28 days)
Secondary	Letrozole and PK Parameters: AUC0-24, AUClast at Cycle 1 Day 1	Summary of primary PK parameters for Letrozole plasma concentration	0, 0.5, 1, 3, 6, 9 and 24 hours post-dose at Cycle 1 Day 1 (each cycle is 28 days)
Secondary	Letrozole PK Parameter: Cmax at Cycle 1 Day 1	Summary of primary PK parameters for letrozole plasma concentration	Cycle 1 Day 1 (each cycle is 28 days)
Secondary	Letrozole PK Parameter: Tmax at Cycle 1 Day 1	Summary of primary PK parameters for letrozole plasma concentration	Cycle 1 Day 1 (each cycle is 28 days)
Secondary	Letrozole PK Parameters: AUC0-24, AUClast at Cycle 4 Day 1	Summary of primary PK parameters for Letrozole plasma concentration	0, 0.5, 1, 3, 6, 9 and 24 hours post-dose at Cycle 4 Day 1 (each cycle is 28 days)
Secondary	Letrozole PK Parameter: Cmax at Cycle 4 Day 1	Summary of primary PK parameters for letrozole plasma concentration	Cycle 4 Day 1 (each cycle is 28 days)
Secondary	Letrozole PK Parameter: Tmax at Cycle 4 Day 1	Summary of primary PK parameters for letrozole plasma concentration	Cycle 4 Day 1 (each cycle is 28 days)
Secondary	Buparlisib PK Parameters: AUC0-24, AUClast at Cycle 1 Day 1	Summary of primary PK parameters for Buparlisib plasma concentration	0, 0.5, 1, 3, 6, 9 and 24 hours post-dose at Cycle 1 Day 1 (each cycle is 28 days)
Secondary	Buparlisib PK Parameter: Cmax at Cycle 1 Day 1	Summary of primary PK parameters for buparlisib plasma concentration	Cycle 1 Day 1 (each cycle is 28 days)
Secondary	Buparlisib PK Parameter: Tmax at Cycle 1 Day 1	Summary of primary PK parameters for buparlisib plasma concentration	Cycle 1 Day 1 (each cycle is 28 days)
Secondary	Buparlisib PK Parameter: AUClast at Cycle 4 Day 1	Summary of primary PK parameters for Buparlisib plasma concentration	0, 0.5, 1, 3, 6, 9 and 24 hours post-dose at Cycle 4 Day 1 (each cycle is 28 days)
Secondary	Buparlisb PK Parameter: Cmax at Cycle 4 Day 1	Summary of primary PK parameters for buparlisib plasma concentration	Cycle 4 Day 1 (each cycle is 28 days)
Secondary	Buparlisib PK Parameter: Tmax at Cycle 4 Day 1	Summary of primary PK parameters for buparlisib plasma concentration	Cycle 4 Day 1 (each cycle is 28 days)