Breast Cancer
Conditions
Keywords
HER-2 Negative, Metastatic Breast Cancer
Brief summary
Investigate the use of BYL719 (alpelisib) as combination therapy with Nab-Paclitaxel in locally recurrent or metastatic HER-2 negative breast cancer.
Detailed description
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.
Interventions
DRUGBYL-719 (alpelisib)
Oral PI3K inhibitor
DRUGNab-paclitaxel
IV taxane
Sponsors
Novartis Pharmaceuticals
Priyanka Sharma
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Ability to understand and the willingness to sign a written Informed Consent Form. 2. Age ≥ 18 years 3. 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 4. 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 5. 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 6. 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. 7. All patients should have received at least one line of chemotherapy in either the advanced or adjuvant setting and hormonal therapy (where appropriate) 8. Performance status of 2 or better as per ECOG criteria (See Appendix A for details) 9. Subject is able to swallow and retain oral medicines 10. 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 11. IV bisphosphate and denosumab for bony metastatic disease will be allowed 12. 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 13. 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. 14. 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
1. 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 2. Subject is pregnant or lactating 3. 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. 4. Subject has inflammatory breast cancer 5. Subject has a known hypersensitivity to any of the excipients of Nab-Paclitaxel or BYL719/alpelisib 6. 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) 7. Subject has clinically manifest diabetes mellitus or documented steroid-induced diabetes mellitus 8. 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) 9. Subject is classified into Child-Pugh class C 10. Subject has a known history of HIV infection (testing not mandatory) 11. Subject has active, uncontrolled infection 12. Subject has symptomatic/untreated CNS disease 13. Subject has ≥ Grade 2 peripheral neuropathy 14. 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 15. Subject has a QTcF \> 480 msec on the screening ECG (using the QTcF formula) 16. 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 17. Subject has had major surgery within 14 days prior to starting study drug or has not recovered from major side effects 18. 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 19. 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 20. 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 21. 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. 22. 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. 23. Subject with history of acute within one year of study entry or past medical history of chronic pancreatitis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase II: Overall Response Rate (ORR) of Subjects Treated at the Recommended Phase II Dose (RP2D) | 24 months | ORR includes complete response (CR) plus partial response (PR). As evaluated per RECIST version 1.1. |
| 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 | 12 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics of BYL-719 (Alpelisib) When Administered With Nab-paclitaxel | In cycle 1 day 1, from prior to alpelisib dosing through 8 hours after alpelisib dosing | 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 |
| Progression-free Survival (PFS) and Overall Survival (OS) | 36 months | 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. |
| Pharmacokinetics of (Total) Nab-paclitaxel When Administered With BYL-719 (Alpelisib) | In cycle 1 day 1, from prior to alpelisib dosing through 8 hours after alpelisib dosing | Area under the curve (AUC): sampling pre-dose and 1.5, 2, 2.5, 3, 3.5, 4, and 6 hours post-alpelisib dose |
| Clinical Benefit Rate (CBR) at 16 Weeks of Study Treatment | 16 weeks | CBR includes complete response (CR), partial response (PR), plus stable disease (SD) ≥16 weeks. As evaluated per RECIST version 1.1. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Correlation of PIK3CA Mutation With Clinical Benefit Rate | 24 months | Comparison of clinical benefit rate between participants with and without PIK3CA mutation in tumor tissue and/or circulating tumor DNA. Clinical benefit rate includes complete response (CR), partial response (PR), plus stable disease (SD) ≥16 weeks, as evaluated per RECIST version 1.1. Tumor DNA was isolated from archived formalin-fixed, paraffin-embedded tumor tissue (primary or metastatic site) and subjected to next-generation sequencing for assessment of PIK3CA mutation using ONCOReveal Multi-Cancer Panel (Pillar Biosciences). Circulating tumor DNA was isolated from pre-treatment plasma samples and subjected to next-generation sequencing for assessment of PIK3CA mutation using FoundationOne CDx testing or ONCOReveal Multi-Cancer Panel. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dose Level 1 BYL-719/Alpelisib (250mg)+Nab-paclitaxel 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) BYL-719 (alpelisib): Oral PI3K inhibitor Nab-paclitaxel: IV taxane | 3 |
| Dose Level 2 BYL-719/Alpelisib (300mg)+Nab-paclitaxel BYL-719 (alpelisib): 300mg 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) BYL-719 (alpelisib): Oral PI3K inhibitor Nab-paclitaxel: IV taxane | 3 |
| Dose Level 3 BYL-719/Alpelisib (350mg)+Nab-paclitaxel BYL-719 (alpelisib): 350mg 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) BYL-719 (alpelisib): Oral PI3K inhibitor Nab-paclitaxel: IV taxane | 7 |
| BYL-719/Alpelisib Dose Expansion BYL-719 (alpelisib): RP2D from Phase I by mouth daily on day 1-28 of each 28 day cycle Nab-paclitaxel: 100mg/m2 IV days 1, 8, 15 of each 28 day cycle (Window for Nab-paclitaxel is +/- 1 day) BYL-719 (alpelisib): Oral PI3K inhibitor Nab-paclitaxel: IV taxane | 30 |
| Total | 43 |
Baseline characteristics
| Characteristic | Dose Level 1 BYL-719/Alpelisib (250mg)+Nab-paclitaxel | Dose Level 2 BYL-719/Alpelisib (300mg)+Nab-paclitaxel | Dose Level 3 BYL-719/Alpelisib (350mg)+Nab-paclitaxel | BYL-719/Alpelisib Dose Expansion | Total |
|---|---|---|---|---|---|
| Age, Continuous | 61 years | 61 years | 59 years | 54 years | 55 years |
| Measurable disease | 3 Participants | 3 Participants | 7 Participants | 30 Participants | 43 Participants |
| Metastatic disease subtype Estrogen receptor and/or progesterone receptor positive | 1 Participants | 2 Participants | 4 Participants | 23 Participants | 30 Participants |
| Metastatic disease subtype Triple-negative | 2 Participants | 1 Participants | 3 Participants | 7 Participants | 13 Participants |
| Prior CDK4/6 inhibitor No | 2 Participants | 3 Participants | 7 Participants | 19 Participants | 31 Participants |
| Prior CDK4/6 inhibitor Yes | 1 Participants | 0 Participants | 0 Participants | 11 Participants | 12 Participants |
| Prior lines of chemotherapy for metastatic disease 0 | 0 Participants | 1 Participants | 2 Participants | 7 Participants | 10 Participants |
| Prior lines of chemotherapy for metastatic disease 1 | 3 Participants | 2 Participants | 3 Participants | 12 Participants | 20 Participants |
| Prior lines of chemotherapy for metastatic disease ≥2 | 0 Participants | 0 Participants | 2 Participants | 11 Participants | 13 Participants |
| Prior taxane Metastatic only | 1 Participants | 0 Participants | 0 Participants | 6 Participants | 7 Participants |
| Prior taxane Neoadjuvant or adjuvant | 2 Participants | 2 Participants | 5 Participants | 17 Participants | 26 Participants |
| Prior taxane Neoadjuvant or adjuvant AND metastatic | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 3 Participants |
| Prior taxane None | 0 Participants | 1 Participants | 2 Participants | 4 Participants | 7 Participants |
| Race and Ethnicity Not Collected | — | — | — | — | 0 Participants |
| Region of Enrollment United States | 3 Participants | 3 Participants | 7 Participants | 30 Participants | 43 Participants |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 7 Participants | 30 Participants | 43 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Visceral disease Absent | 0 Participants | 0 Participants | 1 Participants | 6 Participants | 7 Participants |
| Visceral disease Present | 3 Participants | 3 Participants | 6 Participants | 24 Participants | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 3 | 3 / 3 | 5 / 7 | 19 / 30 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 7 / 7 | 28 / 30 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 | 0 / 7 | 0 / 30 |
Outcome results
Primary
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.
Time frame: 24 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I | Phase II: Overall Response Rate (ORR) of Subjects Treated at the Recommended Phase II Dose (RP2D) | 17 Participants |
Primary
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.
Time frame: 12 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I | 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 | 350 mg |
Secondary
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.
Time frame: 16 weeks
Population: Per protocol the endpoint of CBR at 16 weeks is to be reported for all participants in phase I and phase II who were evaluable for response, thus participants from all assigned dose levels are combined for this analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I | Clinical Benefit Rate (CBR) at 16 Weeks of Study Treatment | 35 Participants |
Secondary
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
Time frame: In cycle 1 day 1, from prior to alpelisib dosing through 8 hours after alpelisib dosing
Population: Pharmacokinetic measures were assessed only among participants in phase I.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase I | Pharmacokinetics of BYL-719 (Alpelisib) When Administered With Nab-paclitaxel | 6846 h*ng/mL | Standard Deviation 3410 |
| Dose Level 2 | Pharmacokinetics of BYL-719 (Alpelisib) When Administered With Nab-paclitaxel | 12436 h*ng/mL | Standard Deviation 6174 |
| Dose Level 3 | Pharmacokinetics of BYL-719 (Alpelisib) When Administered With Nab-paclitaxel | 13359 h*ng/mL | Standard Deviation 5798 |
Secondary
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
Time frame: In cycle 1 day 1, from prior to alpelisib dosing through 8 hours after alpelisib dosing
Population: Pharmacokinetic measures were assessed only among participants in phase I. One phase I participant assigned to the 350 mg BYL-719 (alpelisib) dose level did not have an end-of-infusion sample for paclitaxel measurement. Data are based on 12 participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase I | Pharmacokinetics of (Total) Nab-paclitaxel When Administered With BYL-719 (Alpelisib) | 8488 h*ng/mL | Standard Deviation 1537 |
| Dose Level 2 | Pharmacokinetics of (Total) Nab-paclitaxel When Administered With BYL-719 (Alpelisib) | 9938 h*ng/mL | Standard Deviation 1735 |
| Dose Level 3 | Pharmacokinetics of (Total) Nab-paclitaxel When Administered With BYL-719 (Alpelisib) | 6979 h*ng/mL | Standard Deviation 2492 |
Secondary
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.
Time frame: 36 months
Population: Per protocol the endpoints of PFS and OS are to be reported for all participants in phase I and phase II who were evaluable for response, thus participants from all assigned dose levels are combined for this analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase I | Progression-free Survival (PFS) and Overall Survival (OS) | Progression-free survival | 8.7 months |
| Phase I | Progression-free Survival (PFS) and Overall Survival (OS) | Overall survival | 18.5 months |
Other Pre-specified
Correlation of PIK3CA Mutation With Clinical Benefit Rate
Comparison of clinical benefit rate between participants with and without PIK3CA mutation in tumor tissue and/or circulating tumor DNA. Clinical benefit rate includes complete response (CR), partial response (PR), plus stable disease (SD) ≥16 weeks, as evaluated per RECIST version 1.1. Tumor DNA was isolated from archived formalin-fixed, paraffin-embedded tumor tissue (primary or metastatic site) and subjected to next-generation sequencing for assessment of PIK3CA mutation using ONCOReveal Multi-Cancer Panel (Pillar Biosciences). Circulating tumor DNA was isolated from pre-treatment plasma samples and subjected to next-generation sequencing for assessment of PIK3CA mutation using FoundationOne CDx testing or ONCOReveal Multi-Cancer Panel.
Time frame: 24 months
Population: Among 42 participants evaluable for response, 17 had PIK3CA mutation in tumor tissue and/or circulating tumor DNA, while 25 did not. Clinical benefit rate was assessed among participants with PIK3CA mutation separately from participants without PIK3CA mutation for the purpose of correlating clinical benefit rate with PIK3CA mutation status. Per protocol the analysis is reported for all participants evaluable for response, thus participants from all dose levels are combined for this analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I | Correlation of PIK3CA Mutation With Clinical Benefit Rate | PIK3CA mutation present | 17 participants |
| Phase I | Correlation of PIK3CA Mutation With Clinical Benefit Rate | PIK3CA mutation absent | 17 participants |