BYL719 Plus Letrozole or Exemestane for Patients With Hormone-Receptor Positive Locally-Advanced Unresectable or Metastatic Breast Cancer

NCT01870505 | Completed Phase 1 Results

• 1 other identifier: 13-027
• Study Type: interventional
• Target: 52
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to test the safety of a drug called BYL719 at different dose levels. The investigators want to find out what effects, good and/or bad, BYL719 has on the patient and breast cancer. BYL719 will be given with either letrozole or exemestane to patients with HR+ locally-advanced or metastatic breast cancer. When the recommended phase II dose of BYL719 in combination with letrozole or exemestane has been determined in the dose-finding phase, an additional 10 patients will be enrolled onto each arm in an expansion phase of the study. The purpose of the expansion phase is to further define the safety and feasibility of BYL719 in combination with letrozole or exemestane at the recommended phase II dose, and to estimate efficacy.

Conditions

Metastatic or Locally-advanced Unresectable Breast Cancer

Keywords

BYL719; Letrozole; Exemestane; 13-027

Outcome Measures

Primary Outcomes (2)

• Phase II Dose of BYL719/Alpelisib (Arm A and Arm B)

  Participants started BYL719 dose of 300mg daily for cohort 0. Consecutive cohorts were administered increasing or decreasing dose levels of BYL719. All participants within a cohort will be observed for toxicity for one cycle (28 days) prior to entering additional patients.

  28 days (1 Cycle)

• Phase II Dose of BYL719 (Arm C and Arm D)

  Participants started BYL719 dose of 250 daily for cohort 0. Consecutive cohorts were administered increasing or decreasing dose levels of BYL719.

  28 days (1 cycle)

Secondary Outcomes (3)

• Number of Participants Evaluated for Safety and Tolerability of BYL719 (Arm A, B, C and D)

  28 days (1 cycle)

• Efficacy of BYL719 (Arm A, Arm B, Arm C and Arm D)

  2 years

• Median Time to Treatment Failure/TTF

  through study completion, an average of 3.5 years

Study Arms (4)

Arm A: BYL719 plus Letrozole

EXPERIMENTAL

For both the dose-finding phase and the expansion phase, patients may have stable or progressive disease on letrozole, and BYL719 will be added. A treatment cycle will consist of 28 days. Treatment doses for each AI will be fixed at the established dose. Patients will continue on treatment until progression of disease or unacceptable toxicity. The initial scan interval to assess disease status will be every two cycles (8 weeks) for the first four cycles (16 weeks), and then every 3rd cycle (12 weeks) thereafter.

Drug: BYL719; Drug: Letrozole

Arm B: BYL719 plus Exemestane

EXPERIMENTAL

For both the dose-finding phase and the expansion phase, patients may have stable or progressive disease on Exemestane, and BYL719 will be added. A treatment cycle will consist of 28 days. Treatment doses for each AI will be fixed at the established dose. Patients will continue on treatment until progression of disease or unacceptable toxicity. The initial scan interval to assess disease status will be every two cycles (8 weeks) for the first four cycles (16 weeks), and then every 3rd cycle (12 weeks) thereafter.

Drug: BYL719; Drug: Exemestane

Arm C: BYL719 plus Letrozole

EXPERIMENTAL

For both the dose-finding and expansion phases of Arms C and D, patients may have stable or progressive disease on letrozole or exemestane, and BYL719 will be added.Letrozole 2.5mg orally once daily with BYL719 given on days 1-7 and 15-21 of a 28 day cycle. The starting dose of BYL719 in Arms C will be 250mg daily. Patients who are on study under Amendment 13, the scan interval will become every 4th cycle (16 weeks ±4 weeks) from their last scan.

Drug: BYL719; Drug: Letrozole

Arm D: BYL719 plus Exemestane

EXPERIMENTAL

For both the dose-finding and expansion phases of Arms C and D, patients may have stable or progressive disease on letrozole or exemestane, and BYL719 will be added. Exemestane 25mg orally once daily BYL719 Days 1-5, 8-12, 15-19, 22-26 of 28 day cycle. For Arm D, the established dose is 350mg for BYL719, 10 patients will be assigned to the corresponding arm in the expansion phase of the study. Patients who are on study under Amendment 13, the scan interval will become every 4th cycle (16 weeks ±4 weeks) from their last scan.

Drug: BYL719; Drug: Exemestane

Interventions

BYL719 DRUG

Arm A: BYL719 plus Letrozole; Arm B: BYL719 plus Exemestane; Arm C: BYL719 plus Letrozole; Arm D: BYL719 plus Exemestane

Letrozole DRUG

Arm A: BYL719 plus Letrozole; Arm C: BYL719 plus Letrozole

Exemestane DRUG

Arm B: BYL719 plus Exemestane; Arm D: BYL719 plus Exemestane

Eligibility Criteria

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

You may qualify if:

• Women age ≥ 18 years
• Willing and able to comply with scheduled visits, treatment plan and laboratory tests
• Willing and able to consent for biopsy of locally-advanced or metastatic breast cancer prior to treatment
• Metastatic or locally-advanced unresectable breast cancer (includes metastatic or locally-advanced unresectable breast cancer which is diagnosed while on adjuvant letrozole or exemestane)
• Histologically documented HR+ breast cancer in either the primary or metastatic setting, as defined by ER or PR ≥ 1%; results from the local lab are acceptable. Eligibility will not be affected by HER2 status.
• The most recent treatment prior to enrollment must be one of the following (duration of treatment ≥2 weeks), and must have been adequately tolerated according the treating physician's judgment:
• Letrozole
• Exemestane
• Exemestane + everolimus (everolimus must be discontinued for ≥ 3 weeks prior to starting study treatment)
• Letrozole or exemestane in combination with an experimental agent(s) on a clinical trial, provided that the experimental agent(s) is not a PI3K inhibitor or AKT inhibitor (experimental agent(s) must be discontinued for ≥ 3 weeks prior to starting study treatment)
• Any number of prior endocrine therapies (including tamoxifen, fulvestrant and/or aromatase inhibitors in either the adjuvant or metastatic setting) and any number of prior chemotherapy regimens. Anti-cancer systemic therapy, such as chemotherapy or biologics or endocrine therapy, other than the AI, must be discontinued for ≥ 3 weeks prior to starting study treatment.
• For the dose-finding phase, patients must also have stable disease OR progression of disease on the most recent treatment. For the expansion phase, patients must have progression of disease on the most recent treatment. Progression of disease is defined as new or worsening disease on objective imaging. Progression of disease includes recurrence diagnosed while on adjuvant letrozole or exemestane.
• Postmenopausal women, as defined by one of the following (estradiol assay cutoff takes into account that the patient is on aromatase inhibitor therapy):
• Age ≥ 55 years and one year or more of amenorrhea
• Age \< 55 years and one year or more of amenorrhea, with an estradiol assay within the post-menopausal range

You may not qualify if:

• Pregnant patients or women who are breast-feeding (patients must be postmenopausal, see Section 6.1.9)
• Patients with central nervous system (CNS) involvement may participate if:
• Clinically stable with respect to the CNS tumor at the time of screening and \>4 weeks from prior therapy completion (including radiation and/or surgery) to the start of study treatment
• Not receiving steroid therapy
• Not receiving enzyme inducing anti-epileptic medications that were started for brain metastases (these include carbamazepine, phenytoin, phenobarbital, primidone, oxcarbazepine, topiramate, and vigabatrin) Prior PI3K inhibitor or AKT inhibitor (patients previously treated with everolimus are eligible, see rationale in Section 3.6)
• History of toxicity to the most recent AI (letrozole or exemestane) that warrants cessation of the AI
• Patients who have received radiotherapy ≤ 2 weeks prior to starting study treatment
• Patients who have undergone major surgery ≤ 4 weeks prior to starting study treatment, who have not recovered from side effects of such procedure
• Uncontrolled diabetes (as defined by fasting glucose ≥ 140mg/dL) and/or insulin-dependent diabetes. Fasting glucose measurement must be obtained at least 8 hours after the most recent caloric intake. Patients currently requiring the use of antiglycemic agents (other than insulin) may be enrolled if fasting glucose \<140mg/dL.
• Current need for chronic corticosteroid therapy (≥10mg of prednisone daily or an equivalent dose of other corticosteroid), or patients who have received systemic corticosteroids ≤ 2 weeks prior to starting study drug
• Current therapeutic anticoagulation with warfarin (or coumarin derivatives) Active infection or serious underlying medical condition that would impair the patient's ability to receive protocol treatment
• Clinically significant cardiac disease or impaired cardiac function, such as:
• Congestive heart failure requiring treatment (e.g., New York Heart Association Class II, III or IV) Acute coronary syndromes \< 3 months prior to screening (including myocardial infarction, unstable angina, coronary artery bypass graft, coronary angioplasty, or stenting)
• Uncontrolled arterial hypertension defined by blood pressure \> 140/100 mm Hg at rest (average of 3 consecutive readings)
• History or current evidence of unstable, clinically significant cardiac arrhythmias or patients that require medications with a narrow therapeutic window, atrial fibrillation and/or conduction abnormality, e.g. congenital long QT syndrome, high-Grade/complete AV-blockage

Sponsors & Collaborators

• Memorial Sloan Kettering Cancer Center: lead
• Novartis Pharmaceuticals: collaborator

Study Sites (1)

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Related Publications (1)

• Razavi P, Dickler MN, Shah PD, Toy W, Brown DN, Won HH, Li BT, Shen R, Vasan N, Modi S, Jhaveri K, Caravella BA, Patil S, Selenica P, Zamora S, Cowan AM, Comen E, Singh A, Covey A, Berger MF, Hudis CA, Norton L, Nagy RJ, Odegaard JI, Lanman RB, Solit DB, Robson ME, Lacouture ME, Brogi E, Reis-Filho JS, Moynahan ME, Scaltriti M, Chandarlapaty S. Alterations in PTEN and ESR1 promote clinical resistance to alpelisib plus aromatase inhibitors. Nat Cancer. 2020 Apr;1(4):382-393. doi: 10.1038/s43018-020-0047-1. Epub 2020 Mar 23.

  PMID: 32864625 DERIVED

Related Links

• Memorial Sloan Kettering Cancer Center

MeSH Terms

Conditions

Neoplasm Metastasis

Interventions

Alpelisib; Letrozole; exemestane

Condition Hierarchy (Ancestors)

Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Dr. Sarat Chandarlapaty, MD, PhD
• Organization: Memorial Sloan Kettering Cancer Center

ChandarS@MSKCC.ORG

646-888-4311

Study Officials

• Sarat Chandarlapaty, MD, PhD

  Memorial Sloan Kettering Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

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

Study Record Dates

• First Submitted: June 3, 2013
• First Posted: June 6, 2013
• Study Start: May 1, 2013
• Primary Completion: February 28, 2022
• Study Completion: February 28, 2022
• Last Updated: December 9, 2024
• Results First Posted: December 9, 2024

Record last verified: 2022-03

Locations

US (1)