Clinical trial NCT01219699: A Study of BYL719 in Adult Patients With Advanced Solid Malignancies, Whose Tumors Have an Alteration of the PIK3CA Gene
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Advanced Solid Tumors With an Alteration of the PIK3CA Gene
Estrogen Receptor Positive Breast Cancer
Keywords: advanced solid tumors
mutation
amplification
wild type
PIK3CA gene
dose-escalation
estrogen receptor positive breast cancer
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2010-10-13
Enrollment: 221
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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


Eligibility criteria: 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

Primary outcomes:
measure: Incidence rate of dose limiting toxicities (DLT).
timeFrame: 5 years
Secondary outcomes:
measure: Overall safety and tolerability of BYL719 as single agent and in combination with fulvestrant
timeFrame: 10 years
measure: PK parameters of BYL719 as single agent and in combination with fulvestrant - AUC-tlast and AUC0-inf.
timeFrame: 5 years
measure: PK parameters of BYL719 as single agent and in combination with fulvestrant - Cmax.
timeFrame: 5 years
measure: Pharmacokinetics of BYL719 as single agent and in combination with fulvestrant - Tmax.
timeFrame: 5 years
measure: Pharmacokinetics of BYL719 as single agent and in combination with fulvestrant - CL/F.
timeFrame: 5 years
measure: Pharmaconkinetics of BYL719 as single agent and in combination with fulvestrant - Vz/F.
timeFrame: 5 years
measure: Pharmacokinetics of BYL719 as single agent and in combination with fulvestrant - Terminal half-life (t1/2)
timeFrame: 5 years
measure: Preliminary efficacy of BYL719 as single agent and in combination with fulvestrant by measuring ORR.
timeFrame: 5 years
measure: Progression-free survival at maximum tolerated dose
timeFrame: 5 years
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: UCSF Medical Center
state: California
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Nashville
country: United States
facility: Sarah Cannon Research Institute Dept.ofSarahCannonCancerCtr(4)
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt Univeristy SC
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center/University of Texas MD Anderson
state: Texas
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Wuerzburg
country: Germany
facility: Novartis Investigative Site
city: Amsterdam
country: Netherlands
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Hospitalet de LLobregat
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Oxford
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Juric D, Janku F, Rodon J, Burris HA, Mayer IA, Schuler M, Seggewiss-Bernhardt R, Gil-Martin M, Middleton MR, Baselga J, Bootle D, Demanse D, Blumenstein L, Schumacher K, Huang A, Quadt C, Rugo HS. Alpelisib Plus Fulvestrant in PIK3CA-Altered and PIK3CA-Wild-Type Estrogen Receptor-Positive Advanced Breast Cancer: A Phase 1b Clinical Trial. JAMA Oncol. 2019 Feb 1;5(2):e184475. doi: 10.1001/jamaoncol.2018.4475. Epub 2019 Feb 14.
citation: Juric D, Rodon J, Tabernero J, Janku F, Burris HA, Schellens JHM, Middleton MR, Berlin J, Schuler M, Gil-Martin M, Rugo HS, Seggewiss-Bernhardt R, Huang A, Bootle D, Demanse D, Blumenstein L, Coughlin C, Quadt C, Baselga J. Phosphatidylinositol 3-Kinase alpha-Selective Inhibition With Alpelisib (BYL719) in PIK3CA-Altered Solid Tumors: Results From the First-in-Human Study. J Clin Oncol. 2018 May 1;36(13):1291-1299. doi: 10.1200/JCO.2017.72.7107. Epub 2018 Feb 5.
citation: Vora SR, Juric D, Kim N, Mino-Kenudson M, Huynh T, Costa C, Lockerman EL, Pollack SF, Liu M, Li X, Lehar J, Wiesmann M, Wartmann M, Chen Y, Cao ZA, Pinzon-Ortiz M, Kim S, Schlegel R, Huang A, Engelman JA. CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors. Cancer Cell. 2014 Jul 14;26(1):136-49. doi: 10.1016/j.ccr.2014.05.020. Epub 2014 Jul 4.