BYL719 and Nab-Paclitaxel in Locally Recurrent or Metastatic HER-2 Negative Breast Cancer

Study Overview
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Brief Summary
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Investigate the use of BYL719 (alpelisib) as combination therapy with Nab-Paclitaxel in locally recurrent or metastatic HER-2 negative breast cancer.

Detailed Description
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Breast cancer is the most common cancer and the second leading cause of cancer related death in American women. Despite recent improvement in the treatment of breast cancer, 40,000 women still die each year in the US as a result of breast cancer. Chemotherapy (usually consisting of sequential single agent) remains the backbone of treatment for patients with HER-2 negative metastatic breast cancer. A majority of patients show an initial response to treatment, but all eventually show disease progression. The purpose of this study is to determine the highest dose of BYL719 (alpelisib) combined with Nab-Paclitaxel that results in no serious side effects. The safety and effectiveness of BYL719 combined with Nab-Paclitaxel to treat patients with HER-2 negative metastatic breast cancer will be assessed, along with the determination of how long this drug combination will keep the disease from getting worse. The study will be done in two parts: Part 1 will determine the highest dose of BYL719 that is safe and tolerable to take in combination with Nab-Paclitaxel. Part 1 will be completed before Part 2 begins. Part 2 will investigate whether taking BYL719 (at the dose determined in Part 1) + Nab-Paclitaxel is safe and effective for patients with HER-2 negative metastatic breast cancer.

Official Title
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Phase I/II Study of BYL719 and Nab-Paclitaxel in Subjects With Locally Recurrent or Metastatic HER-2 Negative Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: BYL-719 (alpelisib)
* Drug: Nab-paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to understand and the willingness to sign a written Informed Consent Form. Age ≥ 18 years Histologically proven HER-2 negative breast cancer (HER-2 negative defined as HER IHC 0 or 1+ and/or HER-2 FISH negative); HER-2 negative breast cancer includes hormone positive (ER and/or PR positive) breast cancer and TNBC HER-2 negative breast cancer that at the time of study entry is either stage III (locally advanced) disease not amenable to curative therapy or stage IV disease. Histological confirmation of recurrent/metastatic disease is encouraged but not required if clinical evidence of stage IV disease is available Have measurable (defined as at least one lesion that can be accurately measured in at least one dimension [longest diameter to be recorded] with minimum lesion size of ≥ 2 cm on conventional measurement techniques or ≥ 1 cm on spiral computed tomography (CT) scan No limitations to number of prior chemotherapies for metastatic disease. Treatment with prior taxanes (except Nab-Paclitaxel) is allowed as long as it has been 6 months or more since exposure to prior taxane. NOTE: For subjects who are, or who have previously received endocrine therapy for breast cancer, the treating investigator will decide how many days should pass between the last dose of endocrine therapy and the first dose of study treatment. All patients should have received at least one line of chemotherapy in either the advanced or adjuvant setting and hormonal therapy (where appropriate) Performance status of 2 or better as per ECOG criteria (See Appendix A for details) Subject is able to swallow and retain oral medicines Adequate marrow and organ function as defined below (labs must be performed within 14 days of subject registration) Absolute neutrophil count ≥ 1500/uL Platelets 100,000/uL (no transfusion allowed within 2 weeks) Hemoglobin > 9 g/dL (which may be reached by transfusion) Total bilirubin within normal range or ≤ 1.5X IULN if liver metastases are present or total bilirubin ≤ 3.0X IULN with direct bilirubin within normal range in subjects with well-documented Gilbert's Syndrome, which is defined as presence of unconjugated hyperbilirubinemia with normal results from CBC (including normal reticulocyte count and blood smear), normal liver function test results and absence of other contributing disease processes at the time of diagnosis AST(SGOT)/ALT(SPGT) ≤ 2.5X IULN or ≤ 5X IULN if liver metastases are present Serum creatinine ≤ 1.5X IULN INR ≤ 1.5 Fasting plasma glucose ≤ 140 mg/dL or 7.8 mmol/L (NOTE: Fasting whole blood glucose testing is acceptable if fasting plasma glucose is not feasible.) HBA1c ≤ 8% Potassium, calcium (corrected for serum albumin) and magnesium within IULN Serum Amylase < 2 x ULN and serum lipase within normal limits IV bisphosphate and denosumab for bony metastatic disease will be allowed Prior palliative radiation therapy to bony metastases is allowed. There should be a minimum of 14 days between the end of radiation treatment and start of study treatment Subjects with previously treated brain metastases who are free of CNS symptoms and are > 3 months from treatment of brain metastases are eligible Subjects should be > 2 weeks from prior systemic chemotherapy for breast cancer AND should have recovered to Grade 1 or better (except alopecia) from related side effects of any prior antineoplastic therapy prior to study entry NOTE: For subjects who are, or who have previously received endocrine therapy for breast cancer, the treating investigator will decide how many days should pass between the last dose of endocrine therapy and the first dose of study treatment. Women of child bearing potential (WOCBP) and their partners must agree to use adequate contraception (barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 90 days following completion of therapy. After confirmation of negative pregnancy test at screening, should a WOCBP become pregnant or suspect that she is pregnant while participating in this study, she should inform her treating physician and the investigator immediately. WOCBP are defined as any females (regardless of sexual orientation, having undergone tubal ligation, or remaining celibate by choice) who meet the following criteria: Have not undergone a hysterectomy or bilateral oophorectomy OR Have not been naturally postmenopausal for at least 12 consecutive months (i.e. has had menses at any time in the preceding 12 consecutive months) Exclusion criteria: Subject has any other medical or psychiatric disorder that, in the opinion of the treating physician, would contraindicate the use of drugs in this protocol or place the subject at undue risk for treatment complications Subject is pregnant or lactating Subject has previously been treated with Nab-Paclitaxel NOTE: Subjects who have had previous treatment with Nab-Paclitaxel will NOT be excluded if given in the adjuvant or neoadjuvant setting Only in the metastatic setting, will subjects previously treated with Nab-Paclitaxel be excluded from this trial. Exceptions may be made for subjects who discontinued treatment with a previous Nab-Paclitaxel inhibitor for reasons other than progression and as long as it has been > 12 months since discontinuation of the previous Nab-Paclitaxel. This exception will require prior approval from the study PI at KUMC. Subject has inflammatory breast cancer Subject has a known hypersensitivity to any of the excipients of Nab-Paclitaxel or BYL719/alpelisib Subject has a concurrent malignancy or malignancy within 3 years of study enrollment (with the exception of adequately treated, basal or squamous cell carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer) Subject has clinically manifest diabetes mellitus or documented steroid-induced diabetes mellitus Subject has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection) Subject is classified into Child-Pugh class C Subject has a known history of HIV infection (testing not mandatory) Subject has active, uncontrolled infection Subject has symptomatic/untreated CNS disease Subject has ≥ Grade 2 peripheral neuropathy Subject has active cardiac disease or a history of cardiac dysfunction including any of the following: Unstable angina pectoris within 6 months prior to study entry Symptomatic peritonitis Documented myocardial infarction within 6 months prior to study entry History of documented congestive heart failure (New York Heart Association functional classification III-IV) Documented cardiomyopathy Subject has a Left Ventricular Ejection Fraction (LVEF) < 50% as determined by Multiple Gated Acquisition (MUGA) scan or echocardiogram (ECHO) Subject has any of the following cardiac conduction abnormalities Ventricular arrhythmias except for benign premature ventricular contractions Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medicine Conduction abnormality requiring a pacemaker Other cardiac arrhythmia not controlled with medication Subject has a QTcF > 480 msec on the screening ECG (using the QTcF formula) Subject is currently receiving treatment with a medication that has a known risk to prolong the QT interval or induce Torsades de Pointes and the treatment cannot be discontinued or switched to a different medication prior to randomization Subject has had major surgery within 14 days prior to starting study drug or has not recovered from major side effects Subject is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to starting study drug or who have not fully recovered from side effects of such treatment Subject is currently receiving treatment with drugs known to be moderate or strong inhibitors or inducers of isoenzyme CYP3A. The subject must have discontinued strong inducers for at least one week and must have discontinued strong inhibitors before the start of treatment Subject 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 Subject has received previous treatment with a PI3K inhibitor. Exceptions may be made for subjects who discontinued treatment with a previous PI3K inhibitor for reasons other than toxicity or progression and as long as it has been > 12 months since discontinuation of the previous PI3K inhibitor. This exception will require prior approval from the study PI at KUMC. Subjects who have received an investigational agent within 30 days OR within 5 half-lives of the investigational agent (whichever is shorter) prior to the possible enrollment date on this study. Subject with history of acute within one year of study entry or past medical history of chronic pancreatitis.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose level 1 BYL-719/alpelisib (250mg)+Nab-paclitaxel<br>BYL-719 (alpelisib): 250mg daily on day 1-28 Nab-paclitaxel: 100mg/m2 IV days 1, 8, 15 of each 28 day cycle (Window for Nab-paclitaxel is +/- 1 day) | Drug: BYL-719 (alpelisib)<br>* Oral PI3K inhibitor<br>* Other names: Piqray;Drug: Nab-paclitaxel<br>* IV taxane<br>* Other names: Abraxane;|
| Experimental: Dose level 2 BYL-719 (alpelisib) (300mg)+Nab-paclitaxel<br>BYL-719 (alpelisib): 300mg by mouth daily on day 1-28 of each 28 day cycle Nab-paclitaxel: 100mg/m2 given IV on days 1, 8, 15 of each 28 day cycle (Window for Nab-paclitaxel is +/- 1 day) | Drug: BYL-719 (alpelisib)<br>* Oral PI3K inhibitor<br>* Other names: Piqray;Drug: Nab-paclitaxel<br>* IV taxane<br>* Other names: Abraxane;|
| Experimental: Dose level 3 BYL-719 (alpelisib) (350mg)+Nab-paclitaxel<br>BYL-719 (alpelisib): 350mg by mouth daily on day 1-28 of each 28 day cycle Nab-paclitaxel: 100mg/m2 given IV on days 1, 8, 15 of each 28 day cycle (Window for Nab-paclitaxel is +/- 1 day) | Drug: BYL-719 (alpelisib)<br>* Oral PI3K inhibitor<br>* Other names: Piqray;Drug: Nab-paclitaxel<br>* IV taxane<br>* Other names: Abraxane;|
| Experimental: BYL-719 (alpelisib) Dose Expansion<br>BYL-719 (alpelisib): RP2D from Phase I by mouth daily on day 1-28 of each 28 day cycle Nab-paclitaxel: 100mg/m2 given IV on days 1, 8, 15 of each 28 day cycle (Window for Nab-paclitaxel is +/- 1 day) | Drug: BYL-719 (alpelisib)<br>* Oral PI3K inhibitor<br>* Other names: Piqray;Drug: Nab-paclitaxel<br>* IV taxane<br>* Other names: Abraxane;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I: Recommended Phase II Dose (RP2D) of BYL-719 (Alpelisib) + Nab-paclitaxel to be Used in Combination to Treat Advanced HER2-negative Breast Cancer | Phase I was a 3+3 dose escalation design (three dose levels of alpelisib: 250mg, 300mg, and 350mg orally once daily, continuous dosing) with dose-limiting toxicities (DLT) assessed during the first treatment cycle. If two or more of the six patients experienced a dose-limiting toxicity, dosing escalation would cease and maximum tolerated dose (MTD) would be reached. RP2D was the next lower dose at which <1/6 subjects experienced a DLT. | 12 months | 
| Phase II: Overall Response Rate (ORR) of Subjects Treated at the Recommended Phase II Dose (RP2D) | ORR includes complete response (CR) plus partial response (PR). As evaluated per RECIST version 1.1. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Benefit Rate (CBR) at 16 Weeks of Study Treatment | CBR includes complete response (CR), partial response (PR), plus stable disease (SD) ≥16 weeks. As evaluated per RECIST version 1.1. | 16 weeks | 
| Pharmacokinetics of BYL-719 (Alpelisib) When Administered With Nab-paclitaxel | Area under the curve (AUC): sampling pre-dose and 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-alpelisib dose | In cycle 1 day 1, from prior to alpelisib dosing through 8 hours after alpelisib dosing | 
| Pharmacokinetics of (Total) Nab-paclitaxel When Administered With BYL-719 (Alpelisib) | Area under the curve (AUC): sampling pre-dose and 1.5, 2, 2.5, 3, 3.5, 4, and 6 hours post-alpelisib dose | In cycle 1 day 1, from prior to alpelisib dosing through 8 hours after alpelisib dosing | 
| Progression-free Survival (PFS) and Overall Survival (OS) | PFS was defined as the time in months from the date of enrollment to the date of progression or death, whichever was earlier. OS was defined as the time in months from the date of enrollment to death as a result of any cause. Survival curves were assessed by the Kaplan-Meier method. | 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HER-2 Negative, Metastatic Breast Cancer