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Trial registered on ANZCTR


Registration number
ACTRN12615000850572
Ethics application status
Approved
Date submitted
14/07/2015
Date registered
14/08/2015
Date last updated
22/06/2021
Date data sharing statement initially provided
22/06/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase II exploratory, open-label, single arm study of BYL719 monotherapy, a selective PI3K alpha inhibitor, in adult patients with advanced breast cancer progressing after first line therapy
Scientific title
A Phase II exploratory, open-label, single arm study of the efficacy of BYL719 monotherapy in adult patients with advanced breast cancer progressing after first line therapy.
Secondary ID [1] 287079 0
NCT02506556
Universal Trial Number (UTN)
Trial acronym
PIKNIC study: PI3K alpha iNhibition In advanced breast Cancer
Linked study record

Health condition
Health condition(s) or problem(s) studied:
breast cancer 295658 0
Condition category
Condition code
Cancer 295858 295858 0 0
Breast

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
BYL719 is administered at one tablet at 350mg orally daily. Each cycle is 4 weeks though the drug is administered continuously.
Patients will return drug bottles to monitor compliance.
Drug will be continued until disease progression, unacceptable toxicity or requirement for new anti-cancer therapy. The latter decision will be made by the consultant oncologist. Dose reductions may be considered if significant toxicity is experienced, as assessed by the consultant oncologist
Intervention code [1] 292316 0
Treatment: Drugs
Comparator / control treatment
no control arm
Control group
Uncontrolled

Outcomes
Primary outcome [1] 295539 0
The primary endpoint in this trial is objective response rate (ORR). This is defined as the percentage of patients who have achieved a complete and partial response by RECIST v 1.1 per ER+/HER2- and TNBC cohorts separately.
Timepoint [1] 295539 0
Response is assessed every 2 cycles for the first 24 weeks and every 12 weeks after that or as clinically indicated.
Secondary outcome [1] 315801 0
Clinical Benefit Rate (CBR)- defined as Complete or partial responses according to RECIST 1.1 criteria or stable disease for 6 months or greater
Timepoint [1] 315801 0
Response is assessed every 2 cycles for the first 24 weeks and every 12 weeks after that or as clinically indicated.
Secondary outcome [2] 315802 0
Progression free survival- defined as the time from study entry until documented disease progression
Timepoint [2] 315802 0
Defined as the time from study entry until documented disease progression. Patients will be followed up for a maximum of 2 years.
Secondary outcome [3] 315803 0
Safety and tolerability of single agent BYL719
Timepoint [3] 315803 0
Safety and tolerability is assessed by incident of adverse events according to NCI CTCAE version 4 thoughout the study whilst on study medication. Visits to the oncologist are at the start of each cycle which is 4 weekly.

Eligibility
Key inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:

Males and females of any menopausal status

Patient has signed the Informed Consent Form (ICF) prior to any screening procedures being performed and is able to comply with protocol requirements

Age > or = 18 years old

Eastern Cooperative Oncology Group (ECOG) 0-2 that the investigator believes is stable at the time of screening

Patient has locally recurrent (incurable) or metastatic disease

Patient is able to swallow and retain oral medication

Known HER2 status (local lab) that is negative on IHC (IHC=0) and/or non-amplified.

Known estrogen receptor (ER) and progesterone receptor (PR) status (local lab)

Recent tumor tissue must be available from a metastatic or recurrent lesion for next generation sequencing targeted gene panel

Patients with TNBC disease (ER<1%, HER2-negative) should have documented progression on at least one line of prior systemic therapy in the metastatic setting or within 12 months of adjuvant therapy completion. There is no limit on previous therapies. There will be no molecular selection of these patients.

Patients with ER-positive (ER=1%, HER2-negative) disease should have documented progression on at least one line of prior systemic endocrine therapy in the metastatic setting. There is no limit on previous therapies. Prior everolimus is allowed.

*Patients are defined as “PI3K abnormal” if they have documented gene mutation in AKT1,2,3,ALK, EGFR, ERBB2,3,4, HRAS, INPP4B, KRAS, NRAS, PTEN, PIK3CA, PIK3R1, PIK3R3, PTEN or gene amplification in EGFR, PIK3CA, PIK3R1 or loss in PTEN and INPP4B as per a next generation targeted gene sequencing panel

Measurable disease by RECIST v 1.1 criteria or non- measurable disease that is clinically evaluable (bone only disease allowed if evaluable)

Patient has adequate bone marrow and organ function assessed within 72 hours prior to first dose:
*Absolute neutrophil count (ANC) > or = 1.5 x 109/L
*Platelets > or = 100 x 109/L
*Hemoglobin (Hgb) > or = 9.0 g/dL
*Serum creatinine > or = 1.5 x ULN
*Total serum bilirubin > or = 1.5 x ULN (in patients with known Gilbert's syndrome, a total bilirubin < or = 3.0 x ULN with direct bilirubin < = 1.5 x ULN)
*AST and ALT < or = 2.5 x ULN (alternatively < 5 x ULN if evidence of liver metastases)
*Fasting blood glucose < = 140mg/dL or <= 7.8 mmol/L
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients eligible for this study must not meet any of the following criteria:

Patient has a primary CNS tumor or CNS tumor involvement.
*However patients with metastatic CNS tumors may participate in this study if the patient is:
*Four weeks from prior therapy completion (including radiation and surgery) to starting study treatment
*Clinically stable with respect to the CNS tumor at the time of screening
*Not receiving steroid therapy

Patient with diabetes mellitus (fasting glucose >120mg/dl or 6.7 mmol/L), or documented steroid-induced diabetes mellitus

Patient has a history of another malignancy within 2 years prior to starting study treatment, except for cured basal cell carcinoma of the skin or excised carcinoma in situ of the cervix.

Patient who has not recovered to grade 1 or better (except alopecia) from related side effects of any prior antineoplastic therapy

Patient who has had systemic chemotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to study entry.

Patient who has received radiotherapy < or = 4 weeks prior to starting study drugs, with exception of palliative radiotherapy (= 2 weeks prior to starting study drugs), who has not recovered from side effects of such therapy to baseline or Grade < or = 1 and/or from whom > or = 30% of the bone marrow was irradiated. Target lesions should not have had previous irradiation unless have progressed post treatment.

Patient who has undergone major surgery < or = 4 weeks prior to starting study treatment or who has not recovered from side effects of such procedure.

Patient has a clinically significant cardiac disease or impaired cardiac function, such as:
*Congestive heart failure (CHF) requiring treatment (New York Heart Association (NYHA) Grade > or = 2), left ventricular ejection fraction (LVEF) < 50% as determined by multi-gated acquisition (MUGA) scan or echocardiogram (ECHO)
*History or current evidence of clinically significant cardiac arrhythmias, atrial fibrillation and/or conduction abnormality, e.g. congenital long QT syndrome, high-grade/complete AV-blockage
*Acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass graft (CABG), coronary angioplasty, or stenting), < 3 months prior to screening
*QT interval adjusted according to Fredericia (QTcF) > 480 msec on screening ECG.

Patient who has any severe and/or uncontrolled medical conditions such as:
*Active or uncontrolled severe infection,
*Liver disease such as cirrhosis, decompensated liver disease, and chronic hepatitis (i.e. quantifiable HBV-DNA and/or positive HbsAg, quantifiable HCV-RNA)
*Known severely impaired lung function (spirometry and DLCO 50% or less of normal and O2 saturation 88% or less at rest on room air)
*Active, bleeding diathesis;
*Uncontrolled arterial hypertension defined by blood pressure > 140/100 mm Hg at rest (average of 3 consecutive readings 5 min apart)
*Chronic treatment with corticosteroids or other immunosuppressive agent
*Patient who is 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.

Patient who has participated in a prior investigational study within 30 days prior to enrollment.

Patient who is currently receiving treatment with drugs known to be moderate or strong inhibitors or inducers of isoenzymes CYP34A or CYP2C8. The patient must have discontinued moderate and strong inducers of both enzymes for at least one week and must have discontinued strong and moderate inhibitors before the start of treatment. Switching to a different medication prior to start of treatment is allowed;
Patient with impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral BYL719 (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).

Patient with known positive serology for human immunodeficiency virus (HIV).

Patients who have received live attenuated vaccines within 1 week of start of study drug and during the study. Patient should also avoid close contact with others who have received live attenuated vaccines. Examples of live attenuated vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella and TY21a typhoid vaccines.

Pregnant or nursing (lactating) woman, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mIU/mL).

Patient who does not apply highly effective contraception during the study and through the duration as defined below after the final dose of study treatment

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis
This study is an investigator initiated, phase II, open label single arm study that will investigate the efficacy of BYL719 in the setting of potential Pi3K pathway dependency. It will generate hypotheses about the efficacy of BYL719 in advanced breast cancer characterized by PI3K-related genomic alterations.
The study will have two cohorts.
In the first cohort, patients with unselected metastatic TNBC will be recruited, with a two-stage Optimum design. The null hypothesis is that the ORR will be 5% or less. The alternative hypothesis is that the ORR will be at least 25%. Further study of BYL719 will be warranted if there is sufficient evidence to reject the null hypothesis. As TNBC has been shown to have a very high frequency of PI3K pathway genetic abnormalities, we will enroll all eligible TNBC patients.
Therefore, for the unselected TNBC with a Simon’s two-stage design with a significance level of 5% and a power of 80%, the first stage will accrue 9 patients. If no responses are seen, the TNBC cohort will stop further accrual. If at least one response is seen, the study will proceed to the second stage for a total of 17 accrued. If greater than 2 responses are seen, then the null hypothesis will be rejected.
Therefore a minimum of 9 TNBC will be recruited.
For the second cohort, patients with metastatic/advanced ER+/HER2- breast cancer will be recruited.
Again with a P0=5% and a P1=25%, 80% power, a maximum of 17 patients will be recruited. We will not have two stages here, given the potential for mutational heterogeneity in ER+/HER2- patients. If greater than 2 responses are seen, then the null hypothesis will be rejected.
Therefore, there will be a minimum of 26 patients and a maximum of 34 patients in this study.
With the exception of the primary endpoint, which is the basis of the study sample size, this study’s other objectives will be hypothesis generating. All genetic aberrations will be grouped together for the primary endpoint.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
19/08/2015
Actual
26/08/2015
Date of last participant enrolment
Anticipated
31/12/2017
Actual
21/10/2019
Date of last data collection
Anticipated
Actual
23/11/2020
Sample size
Target
34
Accrual to date
Final
45
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 4047 0
Peter MacCallum Cancer Institute - East Melbourne
Recruitment postcode(s) [1] 34434 0
3000 - Melbourne

Funding & Sponsors
Funding source category [1] 291640 0
Commercial sector/Industry
Name [1] 291640 0
Novartis Pharma Australia
Country [1] 291640 0
Australia
Funding source category [2] 291679 0
Other
Name [2] 291679 0
Loi Lab funds (philantropy)
Country [2] 291679 0
Australia
Primary sponsor type
Hospital
Name
Peter MacCallum Cancer Centre
Address
St Andrew's Place, East Melbourne 3002, Victoria, Australia
Country
Australia
Secondary sponsor category [1] 290310 0
None
Name [1] 290310 0
Address [1] 290310 0
Country [1] 290310 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293169 0
Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
Ethics committee address [1] 293169 0
305 Grattan Street, Melbourne, Vic 3002
Ethics committee country [1] 293169 0
Australia
Date submitted for ethics approval [1] 293169 0
Approval date [1] 293169 0
25/06/2015
Ethics approval number [1] 293169 0
14/176

Summary
Brief summary
The primary purpose of this study is to determine whether BYL719, an oral selective PI3K alpha specific inhibitor, is a safe and effective drug treatment for adult patients with advanced breast cancer who have progressed after first line anti-cancer therapy. Patients who enrol in this study are required to have their breast cancer genetically characterised so we can understand the mutational profiles of their tumor.

Who is it for?
You may be eligible to join this study if you are over 18 years old, male or female, with advanced metastatic or locally recurring breast cancer which has progressed after first line therapy. It is a requirement of the study that some of your tumor tissue will evaluated in the laboratory for genetic alterations in their DNA. Regular blood tests will also be required to try to understand if we can detect the breast cancer's abnormal DNA in the blood.

Study details
All participants enrolled in this study will take the study drug, BYL719, which is an oral selective PI3K alpha specific inhibitor. Dose will commence at 350mg orally daily. This will involve taking tablets daily. Even though the study medication is taken daily, cycles are considered every 4 weeks. Visits to the Oncologist will be required every 4 weeks. Study medication will be continued until disease progression, unacceptable toxicity or requirement for new anti-cancer therapy.

Participants will attend regular follow-up visits for up to 2 years in order to evaluate objective response rate, clinical benefit rate, progression free survival, safety and tolerability of treatment. Regular CT and/ or bone scans as well as blood tests will be performed.

There will be two cohorts of participants involved in this study – those with advanced/ metastatic TNBC and those with advanced/metastatic ER+/HER2- breast cancers with a genetic mutation in the PI3K pathway. We plan to evaluate the efficacy and safety of BYL719 in these patients and associations with genetic features in order to try to identify biomarkers that can indicate those breast cancers more likely to respond to the study medication.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 58754 0
Prof Sherene Loi
Address 58754 0
Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, 3000
Country 58754 0
Australia
Phone 58754 0
+61 3 8559 5000
Fax 58754 0
Email 58754 0
[email protected]
Contact person for public queries
Name 58755 0
Felicity Sutton
Address 58755 0
Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, 3000
Country 58755 0
Australia
Phone 58755 0
+61 3 96561111 (ask for clinical trials unit)
Fax 58755 0
Email 58755 0
[email protected]
Contact person for scientific queries
Name 58756 0
Sherene Loi
Address 58756 0
Peter MacCallum Cancer Centre,
St Andrew's Place
East Melbourne 3002
Victoria
Country 58756 0
Australia
Phone 58756 0
+61 3 8559 5000
Fax 58756 0
+61 3 8559 5039
Email 58756 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseAlpelisib Monotherapy for PI3K-Altered, Pretreated Advanced Breast Cancer: A Phase II Study.2022https://dx.doi.org/10.1158/2159-8290.CD-21-1696
N.B. These documents automatically identified may not have been verified by the study sponsor.