Metastatic or Locally-advanced Unresectable Breast Cancer
Conditions
Keywords
BYL719, Letrozole, Exemestane, 13-027
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.
Interventions
DRUGBYL719
DRUGLetrozole
DRUGExemestane
Sponsors
Novartis Pharmaceuticals
Memorial Sloan Kettering Cancer Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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 * Age \< 55 years with prior hysterectomy but intact ovaries, with an estradiol assay within the post-menopausal range * Surgical menopause with bilateral oophorectomy * Ovarian suppression with a LH-RH agonist, with an estradiol assay within the post-menopausal range at baseline and periodically on-study Measurable or non-measurable disease per RECIST criteria v1.1 * ECOG performance status 0-1 * Adequate organ function, as defined by all of the following: Hematologic parameters: * Absolute neutrophil count (ANC) ≥ 1500/μl (without growth factor support) * Platelets ≥ 100,000/μl (no transfusion allowed within 2 weeks) * Hemoglobin ≥ 9.0 g/dl (may be reached by transfusion) * Liver function: * Serum bilirubin ≤ 1.5 x upper limit of normal (ULN) unless attributable to Gilbert's syndrome * AST ≤ 2.5 x ULN, or ≤ 5 x ULN if liver metastases are present * ALT ≤ 2.5 x ULN, or ≤ 5 x ULN if liver metastases are present Kidney function: * Creatinine ≤ 1.5 ULN * Endocrine function: * Fasting plasma glucose \<140 mg/dl (may be on antiglycemic agents other than insulin). Fasting glucose measurement must be obtained at least 8 hours after the most recent caloric intake. * Ability to swallow oral medication * Willing to discontinue all herbal preparations / medications at least 7 days prior to the first dose of study drug and throughout the study. These include, but not limited to,St. John's wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng.
Exclusion criteria
* 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 * Corrected QT interval (QTc) \> 480 msec on screening ECG Patients who are currently receiving medication with a known risk of prolonging the QT interval or inducing Torsades de Pointes (TdP) and the treatment cannot either be discontinued or switched to a different medication prior to starting study drug treatment (see Section 9.6.3 and Appendix F) * Impaired gastrointestinal function or poorly controlled gastrointestinal disease that may significantly alter the absorption of oral BYL719 (e.g. Crohn's disease, ulcerative colitis, malabsorption syndrome, small bowel resection, uncontrolled nausea or vomiting, or grade ≥ 3 diarrhea of any etiology) based on treating physician assessment * Patients may not have a currently active second malignancy other than non-melanoma skin cancers. Patients are not considered to have a currently active malignancy if they have completed therapy and are considered by their physician to be at less than 30% risk of relapse.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase II Dose of BYL719/Alpelisib (Arm A and Arm B) | 28 days (1 Cycle) | 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. |
| Phase II Dose of BYL719 (Arm C and Arm D) | 28 days (1 cycle) | Participants started BYL719 dose of 250 daily for cohort 0. Consecutive cohorts were administered increasing or decreasing dose levels of BYL719. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Evaluated for Safety and Tolerability of BYL719 (Arm A, B, C and D) | 28 days (1 cycle) | Toxicity will be tabulated using the NCI Common Toxicity Criteria (CTCAE), version 4.0. A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value assessed as at least possibly related to the study medication, meeting any of the criteria listed in the table below, and occurring during Cycle 1 (≤ 28 days following the first dose of BYL719, including those in which the event started in Cycle 1 and the confirmation of the DLT occurs in a subsequent cycle). |
| Efficacy of BYL719 (Arm A, Arm B, Arm C and Arm D) | 2 years | Overall response rate |
| Median Time to Treatment Failure/TTF | through study completion, an average of 3.5 years | Time to Treatment Failure/TTF defined as the time from on-study date to off-study date for any reason |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| DOSE FINDING PHASE, Arm A, Cohort 0 Period 1: DOSE FINDING PHASE, Arm A, Cohort 0: BYL719 300mg PO, Letrozole 2.5mg PO | 4 |
| DOSE FINDING PHASE, Arm A, Cohort -1 Period 2: DOSE FINDING PHASE, Arm A, Cohort -1: BYL719 250 mg PO, Letrozole 2.5mg PO | 3 |
| DOSE FINDING PHASE, Arm B, Cohort 0 Period 1: DOSE FINDING PHASE, Arm B, Cohort 0: BYL719 300mg PO, Exemestane 25mg PO | 7 |
| Arm D Arm D : Exemestane 25 mg PO + BYL719 MTD: 350mg PO | 10 |
| Dose Finding Phase, Arm C, Cohort 0 Period 1: Dose Finding Phase, Arm C, Cohort 0: Letrozole 2.5mg PO daily & BYL719 250 mg 7days on and 7days off. | 6 |
| Dose Finding Phase, Arm C, Cohort 1 Period 2: Dose Finding Phase, Arm C, Cohort 1: Letrozole 2.5mg PO daily & BYL719 300 mg 7days on and 7days off. | 6 |
| Dose Finding Phase, Arm D, Cohort 0 Period 1: Dose Finding Phase, Arm D, Cohort 0: Exemestane 25mg PO daily & BYL719 250 mg 5days on and 2days off. | 3 |
| Dose Finding Phase, Arm D, Cohort 1 Period 2: Dose Finding Phase, Arm D, Cohort 1: Exemestane 25mg PO daily & BYL719 300 mg 5days on and 2days off. | 6 |
| Dose Finding Phase, Arm D, Cohort 2 Period 3: Dose Finding Phase, Arm D, Cohort 2: Exemestane 25mg PO daily & BYL719 350 mg 5days on and 2days off. | 7 |
| Total | 52 |
Baseline characteristics
| Characteristic | DOSE FINDING PHASE, Arm A, Cohort 0 | Total | Dose Finding Phase, Arm D, Cohort 2 | Dose Finding Phase, Arm D, Cohort 1 | Dose Finding Phase, Arm D, Cohort 0 | Dose Finding Phase, Arm C, Cohort 1 | Dose Finding Phase, Arm C, Cohort 0 | Arm D | DOSE FINDING PHASE, Arm B, Cohort 0 | DOSE FINDING PHASE, Arm A, Cohort -1 |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 61 years | 55 years | 58 years | 57 years | 52 years | 62 years | 55 years | 52 years | 50 years | 48 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 49 Participants | 7 Participants | 6 Participants | 3 Participants | 6 Participants | 5 Participants | 9 Participants | 6 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 7 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 40 Participants | 5 Participants | 6 Participants | 2 Participants | 6 Participants | 5 Participants | 5 Participants | 4 Participants | 3 Participants |
| Region of Enrollment United States | 4 Participants | 52 Participants | 7 Participants | 6 Participants | 3 Participants | 6 Participants | 6 Participants | 10 Participants | 7 Participants | 3 Participants |
| Sex: Female, Male Female | 4 Participants | 52 Participants | 7 Participants | 6 Participants | 3 Participants | 6 Participants | 6 Participants | 10 Participants | 7 Participants | 3 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 3 | 2 / 7 | 0 / 10 | 1 / 6 | 0 / 6 | 0 / 3 | 0 / 6 | 1 / 7 |
| other Total, other adverse events | 4 / 4 | 1 / 3 | 7 / 7 | 10 / 10 | 6 / 6 | 6 / 6 | 0 / 3 | 6 / 6 | 7 / 7 |
| serious Total, serious adverse events | 1 / 4 | 0 / 3 | 4 / 7 | 2 / 10 | 3 / 6 | 2 / 6 | 0 / 3 | 1 / 6 | 2 / 7 |
Outcome results
Primary
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.
Time frame: 28 days (1 Cycle)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: BYL719 Plus Letrozole | Phase II Dose of BYL719/Alpelisib (Arm A and Arm B) | 250 mg |
| Arm B: BYL719 Plus Exemestane | Phase II Dose of BYL719/Alpelisib (Arm A and Arm B) | 250 mg |
Primary
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.
Time frame: 28 days (1 cycle)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: BYL719 Plus Letrozole | Phase II Dose of BYL719 (Arm C and Arm D) | 250 mg |
| Arm B: BYL719 Plus Exemestane | Phase II Dose of BYL719 (Arm C and Arm D) | 350 mg |
Secondary
Efficacy of BYL719 (Arm A, Arm B, Arm C and Arm D)
Overall response rate
Time frame: 2 years
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A: BYL719 Plus Letrozole | Efficacy of BYL719 (Arm A, Arm B, Arm C and Arm D) | Stable Disease (SD) | 4 Participants |
| Arm A: BYL719 Plus Letrozole | Efficacy of BYL719 (Arm A, Arm B, Arm C and Arm D) | Partial Response (PR) | 1 Participants |
| Arm A: BYL719 Plus Letrozole | Efficacy of BYL719 (Arm A, Arm B, Arm C and Arm D) | Unevaluable | 2 Participants |
| Arm A: BYL719 Plus Letrozole | Efficacy of BYL719 (Arm A, Arm B, Arm C and Arm D) | Progression of Disease (POD) | 0 Participants |
| Arm A: BYL719 Plus Letrozole | Efficacy of BYL719 (Arm A, Arm B, Arm C and Arm D) | Complete Response (CR) | 0 Participants |
| Arm B: BYL719 Plus Exemestane | Efficacy of BYL719 (Arm A, Arm B, Arm C and Arm D) | Progression of Disease (POD) | 3 Participants |
| Arm B: BYL719 Plus Exemestane | Efficacy of BYL719 (Arm A, Arm B, Arm C and Arm D) | Complete Response (CR) | 0 Participants |
| Arm B: BYL719 Plus Exemestane | Efficacy of BYL719 (Arm A, Arm B, Arm C and Arm D) | Unevaluable | 1 Participants |
| Arm B: BYL719 Plus Exemestane | Efficacy of BYL719 (Arm A, Arm B, Arm C and Arm D) | Partial Response (PR) | 0 Participants |
| Arm B: BYL719 Plus Exemestane | Efficacy of BYL719 (Arm A, Arm B, Arm C and Arm D) | Stable Disease (SD) | 3 Participants |
| Arm C: BYL719 Plus Letrozole | Efficacy of BYL719 (Arm A, Arm B, Arm C and Arm D) | Progression of Disease (POD) | 1 Participants |
| Arm C: BYL719 Plus Letrozole | Efficacy of BYL719 (Arm A, Arm B, Arm C and Arm D) | Partial Response (PR) | 0 Participants |
| Arm C: BYL719 Plus Letrozole | Efficacy of BYL719 (Arm A, Arm B, Arm C and Arm D) | Stable Disease (SD) | 6 Participants |
| Arm C: BYL719 Plus Letrozole | Efficacy of BYL719 (Arm A, Arm B, Arm C and Arm D) | Complete Response (CR) | 0 Participants |
| Arm C: BYL719 Plus Letrozole | Efficacy of BYL719 (Arm A, Arm B, Arm C and Arm D) | Unevaluable | 5 Participants |
| Arm D | Efficacy of BYL719 (Arm A, Arm B, Arm C and Arm D) | Complete Response (CR) | 1 Participants |
| Arm D | Efficacy of BYL719 (Arm A, Arm B, Arm C and Arm D) | Stable Disease (SD) | 13 Participants |
| Arm D | Efficacy of BYL719 (Arm A, Arm B, Arm C and Arm D) | Partial Response (PR) | 4 Participants |
| Arm D | Efficacy of BYL719 (Arm A, Arm B, Arm C and Arm D) | Progression of Disease (POD) | 5 Participants |
| Arm D | Efficacy of BYL719 (Arm A, Arm B, Arm C and Arm D) | Unevaluable | 3 Participants |
Secondary
Median Time to Treatment Failure/TTF
Time to Treatment Failure/TTF defined as the time from on-study date to off-study date for any reason
Time frame: through study completion, an average of 3.5 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: BYL719 Plus Letrozole | Median Time to Treatment Failure/TTF | 21 weeks |
| Arm B: BYL719 Plus Exemestane | Median Time to Treatment Failure/TTF | 8 weeks |
| Arm C: BYL719 Plus Letrozole | Median Time to Treatment Failure/TTF | 12 weeks |
| Arm D | Median Time to Treatment Failure/TTF | 17 weeks |
Secondary
Number of Participants Evaluated for Safety and Tolerability of BYL719 (Arm A, B, C and D)
Toxicity will be tabulated using the NCI Common Toxicity Criteria (CTCAE), version 4.0. A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value assessed as at least possibly related to the study medication, meeting any of the criteria listed in the table below, and occurring during Cycle 1 (≤ 28 days following the first dose of BYL719, including those in which the event started in Cycle 1 and the confirmation of the DLT occurs in a subsequent cycle).
Time frame: 28 days (1 cycle)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A: BYL719 Plus Letrozole | Number of Participants Evaluated for Safety and Tolerability of BYL719 (Arm A, B, C and D) | 4 Participants |
| Arm B: BYL719 Plus Exemestane | Number of Participants Evaluated for Safety and Tolerability of BYL719 (Arm A, B, C and D) | 3 Participants |
| Arm C: BYL719 Plus Letrozole | Number of Participants Evaluated for Safety and Tolerability of BYL719 (Arm A, B, C and D) | 7 Participants |
| Arm D | Number of Participants Evaluated for Safety and Tolerability of BYL719 (Arm A, B, C and D) | 10 Participants |
| Dose Finding Phase, Arm C, Cohort 0 | Number of Participants Evaluated for Safety and Tolerability of BYL719 (Arm A, B, C and D) | 6 Participants |
| Dose Finding Phase, Arm C, Cohort 1 | Number of Participants Evaluated for Safety and Tolerability of BYL719 (Arm A, B, C and D) | 6 Participants |
| Dose Finding Phase, Arm D, Cohort 0 | Number of Participants Evaluated for Safety and Tolerability of BYL719 (Arm A, B, C and D) | 3 Participants |
| Dose Finding Phase, Arm D, Cohort 1 | Number of Participants Evaluated for Safety and Tolerability of BYL719 (Arm A, B, C and D) | 6 Participants |
| Dose Finding Phase, Arm D, Cohort 2 | Number of Participants Evaluated for Safety and Tolerability of BYL719 (Arm A, B, C and D) | 7 Participants |