A Phase Ib Dose De-escalation Study With BYL719 in Premenopausal Patients With Locally Advanced or Metastatic Breast Cancer

NCT02058381 | Completed Phase 1 DMC

• 1 other identifier: CBYL719XIC01
• Study Type: interventional
• Target: 40
• Locations: 4 countries
• Sites: 15

Brief Summary

Based on the evidence acquired in the post-menopausal setting with everolimus and on pre-clinical evidences supporting the investigation of PI3K inhibitors, such as alpelisib and buparlisib, in combination with endocrine therapy in hormone receptor-positive MBC, the purpose of this phase Ib trial is to assess the maximum tolerated dose (MTD) and/or the RP2D(s), to characterize the safety and tolerability, to determine the single and multiple dose PK profile and assess the preliminary anti-tumor activity of alpelisib and buparlisib in combination with tamoxifen plus goserelin acetate in premenopausal hormone receptor-positive advanced breast cancer patientsgroup.

Conditions

Pre-menopausal Breast Cancer; PI3K Pathway Inhibition

Outcome Measures

Primary Outcomes (1)

• Maximum Tolerated Dose (MTD) and/or Recommended Phase II Dose (RP2D)

  To estimate the MTD(s) and/or the RP2D(s) of a) alpelisib in combination with tamoxifen plus goserelin acetate (Group 1) and b) buparlisib in combination with Tamoxifen plus goserelin acetate (Group 2) in premenopausal hormone receptor-positive locally advanced or MBC patients.

  12 months

Secondary Outcomes (4)

• Incidence, type, intensity, severity and seriousness of Adverse Events (AEs) during the first 2 cycles dose interruptions, reductions and dose intensity during the study

  12 months

• Alpelisib/buparlisib: plasma concentrations and PK parameters, including but not limited to AUC0-t, AUC0-inf, AUC0-24, Cmax, tmax, CL/F, half-life t1/2 and other PK parameters if deemed appropriate. Tamoxifen: trough plasma concentrations

  12 months

• Preliminary anti-tumor activity acccording to RECIST 1.1 : It will include overall response rate, clinical benefit, progression free survival and proportion of patients who are alive without progression at 9 months from the date of treatment start

  12 months

• Index score from the EQ-5D-5L; and WPAI-GH scores for work time missed, impairment while working, overall work impairment, and activity impairment

  12 months

Study Arms (2)

Group 1 (alpelisib)

EXPERIMENTAL

Alpelisib plus Tamoxifen and Goserelin (Group 1)

Drug: alpelisib (BYL719)

Group 2 (buparlisib)

EXPERIMENTAL

Buparlisib plus Tamoxifen and Goserelin (Group 2)

Drug: buparlisib (BKM120)

Interventions

alpelisib (BYL719) DRUG

BYL 719 350 mg will be administered orally once daily on a continuous dosing schedule starting on day 1 (Group 1 only).

Group 1 (alpelisib)

buparlisib (BKM120) DRUG

BKM120 100 mg will be administered orally once daily on a continuous dosing schedule starting on day 1 (Group 2 only)

Group 2 (buparlisib)

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patient has histologically and/or cytologically confirmed diagnosis of breast cancer
• Patient has radiological or objective evidence of inoperable locally advanced or metastatic breast cancer
• Patient has HER2-negative breast cancer (based on most recently analyzed tumor sample)
• Patient has ER positive and/or PgR positive breast cancer by local laboratory testing
• Patient is premenopausal. Premenopausal status is defined as either:
• patient had last menstrual period within the last 12 months, OR
• if on tamoxifen within the past 3 months, with a plasma estradiol ≥10 pg/mL and FSH ≤40 IU/l or in the premenopausal range, according to local laboratory definition , OR
• in case of chemotherapy induced amenorrhea, with a plasma estradiol ≥10 pg/mL) and/or FSH ≤40 IU/l or in the premenopausal range according to local laboratory definition.
• Patient has no previous history of endocrine therapy in the metastatic setting.
• Note:
• Patients who received oral endocrine therapy with duration less than 3 weeks or ≤1 injection of LHRH agonist and discontinued for a reason other than suspicious or evidence of disease progression are eligible
• Adjuvant treatment with tamoxifen monotherapy and LHRH analogue monotherapy is allowed. Patients who received tamoxifen plus LH-RH agonist/antagonist in the adjuvant setting are eligible provided they start investigational treatment at least 12 months after the last dose of tamoxifen or LH-RH agonist/antagonist, whichever came later.
• Patients who were already established on bisphosphonate therapy may continue on bisphosphonates.
• Patient has received ≤1 prior chemotherapy line for MBC
• For patient who received prior systemic therapy, radiological or objective evidence of recurrence or progression on or after the last systemic therapy is needed

You may not qualify if:

• Patient is post-menopausal.
• Patient has received previous endocrine treatments in the metastatic setting.
• Patient has received previous treatment with PI3K inhibitors, AKT inhibitors, mTOR inhibitors
• Patient has received more than one chemotherapy line for metastatic disease
• Patient has symptomatic CNS metastases
• Patient who has received wide field radiotherapy ≦ 4 weeks or limited field radiation for palliation ≦ 2 weeks prior to starting study drug or who have not recovered to grade 1 or better from related side effects of such therapy (with exception of alopecia alopecia)
• Patient has not recovered to grade 1 or better (except alopecia) from related side effects of any prior antineoplastic therapy
• Patient is currently receiving increasing or chronic treatment (\> 5 days) with corticosteroids or another immunosuppressive agent, as chronic administration of corticosteroids (\> 5 days) can induce CYP3A4
• Patient is currently receiving warfarin or other coumarin derived anti-coagulant, for treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin (LMWH), or fondaparinux is allowed
• Patient is currently receiving treatment with drugs known to be moderate or strong inhibitors or inducers of isoenzyme CYP3A. The patient must have discontinued strong inducers for at least one week and must have discontinued strong inhibitors before the treatment phase is initiated.
• Patient has a score ≧ 12 on the PHQ-9 questionnaire
• Patient selects a response of "1, 2 or 3" to question number 9 on the PHQ-9 questionnaire regarding potential for suicidal thoughts or ideation (independent of the total score of the PHQ-9)
• Patient has a GAD-7 mood scale score ≧ 15
• Patient has a medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (e.g. risk of doing harm to self or others) or patients with active severe personality disorders (defined according to DSM- IV) are not eligible.
• Patient has ≧ Common Terminology Criteria for Adverse Events (CTCAE) grade 3 anxiety

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (15)

Novartis Investigative Site

Hong Kong, Hong Kong

Location

Novartis Investigative Site

Seongnam-si, Gyeonggi-do, 13620, South Korea

Location

Novartis Investigative Site

Gyeonggi-do, Korea, 10408, South Korea

Location

Novartis Investigative Site

Seoul, Korea, 05505, South Korea

Location

Novartis Investigative Site

Seoul, Korea, 06351, South Korea

Location

Novartis Investigative Site

Seoul, 03722, South Korea

Location

Novartis Investigative Site

Kuei-Shan Chiang, Taoyuan/ Taiwan ROC, 33305, Taiwan

Location

Novartis Investigative Site

New Taipei City, TWN, 23561, Taiwan

Location

Novartis Investigative Site

Kaohsiung City, 83301, Taiwan

Location

Novartis Investigative Site

Taichung, 407, Taiwan

Location

Novartis Investigative Site

Taipei, 10002, Taiwan

Location

Novartis Investigative Site

Taipei, 10449, Taiwan

Location

Novartis Investigative Site

Taipei, 112, Taiwan

Location

Novartis Investigative Site

Bangkok, 10330, Thailand

Location

Novartis Investigative Site

Chiang Mai, 50200, Thailand

Location

Related Publications (1)

• Lu YS, Lee KS, Chao TY, Tseng LM, Chitapanarux I, Chen SC, Liu CT, Sohn J, Kim JH, Chang YC, Yang Y, Shotelersuk K, Jung KH, Valenti R, Slader C, Gao M, Park YH. A Phase Ib Study of Alpelisib or Buparlisib Combined with Tamoxifen Plus Goserelin in Premenopausal Women with HR-Positive HER2-Negative Advanced Breast Cancer. Clin Cancer Res. 2021 Jan 15;27(2):408-417. doi: 10.1158/1078-0432.CCR-20-1008. Epub 2020 Jul 27.

  PMID: 32718997 DERIVED

MeSH Terms

Interventions

Alpelisib; NVP-BKM120

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 16, 2014
• First Posted: February 10, 2014
• Study Start: May 6, 2014
• Primary Completion: June 19, 2018
• Study Completion: June 19, 2018
• Last Updated: March 9, 2020

Record last verified: 2018-12

Locations

HK (1); TH (2); KR (5); TW (7)