A Study of BYL719 in Adult Patients With Advanced Solid Malignancies, Whose Tumors Have an Alteration of the PIK3CA Gene

Study Overview
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Brief Summary
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This is a first-in-man trial, in which BYL719 will be administered to adult patients with advanced solid tumors, whose tumors have an alteration of the PIK3CA gene and whose disease has progressed despite standard therapy or for whom no standard therapy exists. A combination of BYL719 with fulvestrant will also be investigated in post-menopausal patients with locally advanced or metastatic breast cancer whose tumors have an alteration of the PIK3CA gene. The single agent MTD dose expansion cohort and the fulvestrant combination MTD dose expansion cohort will also include ER+/HER2- breast cancer patients whose tumors have the wild type PIK3CA gene

Official Title
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A Phase IA, Multicenter, Open-label Dose Escalation Study of Oral BYL719, in Adult Patients With Advanced Solid Malignancies, Whose Tumors Have an Alteration of the PIK3CA Gene

Conditions
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Advanced Solid Tumors With an Alteration of the PIK3CA Gene, Estrogen Receptor Positive Breast Cancer

Intervention / Treatment
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* Drug: BYL719
* Drug: Fulvestrant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with histologically-confirmed, advanced unresectable solid tumors who have progressed within three months before screening/baseline visit Only patients who have confirmed PIK3CA status (wild type, mutation or amplification) will be allowed for screening (patients participating in the combination arm must be eligible for treatment with fulvestrant) Availability of a representative formalin fixed paraffin embedded tumor tissue sample At least one measurable or non-measurable lesion Age ≥ 18 years World Health Organization (WHO) Performance Status ≤ 2 Good organ (hepatic, kidney, BM) function at screening/baseline visit Exclusion Criteria: Brain metastasis unless treated and free of signs/symptoms attributable to brain metastasis in the absence of corticosteroid therapy (anti-epileptic therapy is allowed). Prior treatment with PI3K, AKT or mTOR inhibitor and failure to benefit Patient with peripheral neuropathy NCI-CTC Grade ≥ 3 Patient with diarrhea NCI-CTC Grade ≥ 2 Patient with acute or chronic pancreatitis Impaired cardiac function or clinically significant cardiac disease incl. unstable angina pectoris ≤ 3 months prior to starting study drug and Acute Myocardial Infarction (AMI) ≤ 3 months prior to starting study drug. Patients with clinically manifest diabetes mellitus, history of gestational diabetes mellitus or documented steroid-induced diabetes mellitus Women who are pregnant or breast feeding or adults of reproductive potential not employing an effective method of birth control Other protocol-defined inclusion/exclusion criteria may apply

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: BYL719<br>In adult patients with advanced solid malignancies whose tumors have an alteration (mutation or amplification) of the PIK3CA gene, and in patients whose tumors are have wild-type PIK3CA gene | Drug: BYL719<br>* BYL719 is an oral α-specific phosphatidylinositol-3-kinase (PI3K) inhibitor.<br>|
| Experimental: BYL719 + fulvestrant<br>In post-menopausal patients with estrogen receptor positive locally advanced or metastatic breast cancer whose tumors have an alteration of the PIK3CA gene, and in patients whose tumors are have wild-type PIK3CA gene | Drug: Fulvestrant<br>* In adult patients with advanced solid malignancies whose tumors have an alteration (mutation or amplification) of the PIK3CA gene. Fulvestrant is an estrogen receptor antagonist, administered by monthly intramuscular injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence rate of dose limiting toxicities (DLT). | MTD (or RP2D) of oral BYL719 as single agent and in combination with fulvestrant. | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall safety and tolerability of BYL719 as single agent and in combination with fulvestrant | Safety and tolerability: type, intensity, severity and seriousness of adverse events (AE) according to NCI CTCAE v. 4.0. | 10 years | 
| PK parameters of BYL719 as single agent and in combination with fulvestrant - AUC-tlast and AUC0-inf. | PK parameters AUC-tlast and AUC0-inf | 5 years | 
| PK parameters of BYL719 as single agent and in combination with fulvestrant - Cmax. | PK parameter Cmax | 5 years | 
| Pharmacokinetics of BYL719 as single agent and in combination with fulvestrant - Tmax. | PK parameter Tmax | 5 years | 
| Pharmacokinetics of BYL719 as single agent and in combination with fulvestrant - CL/F. | PK parameter CL/F | 5 years | 
| Pharmaconkinetics of BYL719 as single agent and in combination with fulvestrant - Vz/F. | PK parameter Vz/F | 5 years | 
| Pharmacokinetics of BYL719 as single agent and in combination with fulvestrant - Terminal half-life (t1/2) | PK parameter t1/2 | 5 years | 
| Preliminary efficacy of BYL719 as single agent and in combination with fulvestrant by measuring ORR. | Objective tumor response rate (ORR), defined as the sum of complete response and partial response as best reported response by RECIST 1.0 criteria (Novartis v2.0 guideline) | 5 years | 
| Progression-free survival at maximum tolerated dose | PFS at MTD | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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wild type, advanced solid tumors, mutation, amplification, PIK3CA gene, dose-escalation, estrogen receptor positive breast cancer