A phase IA, multicenter, open-label dose escalation study of oral BYL719, in adult patients with advanced solid malignancies, whose tumors have a alteration of the PIK3CA gene.
- Conditions
- Tumors with a genetic abnormality in PIK3CA10027655
- Registration Number
- NL-OMON37998
- Lead Sponsor
- ovartis
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- Not specified
- Target Recruitment
- 10
* Patients with solid tumors who have progressed on the last line of therapy within three months before screening/baseline, or not been able to tolerate standard therapy or for whom no standard anticancer therapy exists.
* Patients participating in the combination arm of BYL719 and fulvestrant must be eligible for treatment with fulvestrant with ER+ locally advanced or metastatic breast cancer whose tumors have an alteration of the PIK3CA gene and have had disease progression during or following anti-estrogen therapy
* Archival tissue and locally documented PIK3CA alteration
* At least one measurable or non-measurable lesion (RECIST 1.0 criteria)
* WHO Performance Status * 2
* Laboratory:
-Serum total Bilirubin * 1.5 x ULN and AST/SGOT and ALT/SGPT * 2.5 x ULN or * 5 x ULN if liver metastases are present
- Serum creatinine * 1.5 x ULN or 24-hour clearance * 50 ml/min
- Platelets * 100 x 109/L, Hemoglobin * 9 g/dL<= 5.58 mmol/L
- Absolute Neutrophil Count * 1.5 x 109/L
- Calcium, potassium and magnesium within normal limits
- Fasting glucose < 140 mg/dL / 7.8 mmol/L
* Brain metastasis unless treated and free of signs/symptoms in the absence of corticosteroid therapy (anti-epileptic therapy is allowed).
* Enrolment of patients who had prior treatment with PI3K, AKT or mTOR inhibitor requires approval by the Novartis.
* Peripheral neuropathy NCI-CTC Grade * 3.
* Diarrhea NCI-CTC Grade * 2.
* Acute or chronic pancreatitis
* Any of the following concurrent severe and/or uncontrolled medical conditions:
- Impaired cardiac function or clinically significant cardiac disease, including any of the following: Clinical significant heart disease (NYH grade * 2), LVEF < 45% as determined by MUGA scan or echocardiogram, or uncontrolled hypertension.
- ST depression or elevation of * 1.5 mm in 2 or more leads
- QTcF > 480 msec on screening ECG
- Congenital long QT syndrome
- History or presence of clinically significant ventricular arrhythmias or atrial fibrillation
- Clinically significant resting bradycardia (< 50 beats / min)
- Complete left bundle branch block (LBBB)
- Right bundle branch block (RBBB) + left anterior hemiblock (LAHB -bifascicular block)
- Unstable angina pectoris * 3 months prior to starting study drug
- Acute Myocardial Infarction (AMI) * 3 months prior to starting studydrug
* Clinically manifest diabetes mellitus (fasting glucose * 7.8 mmol/L)
* Other concurrent severe and/or uncontrolled concomitant medical condition
* Medication that has the potential to prolong the QT interval or inducing Torsades de Pointes
* Therapeutic doses of any coumarin-derivative anticoagulants.
* Impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral BYL719
* Hematopoietic colony-stimulating growth factors * 2 weeks prior to start of study.
* Systemic corticosteroids * 2 weeks prior to starting study drug
* Chemotherapy, targeted therapy, endocrine therapy or immunotherapy * 4 weeks (6 weeks for nitrosourea and mitomycin-C) prior to starting study drug
* Radiotherapy * 4 weeks prior to starting studydrug.
* Major surgery within the last 2 weeks prior to starting study drug.
* Hepatic impairment of Child-Pugh status of B or C for those patients participating in the combination arm
* Bleeding disorders interfering with I.M. administration for those patients participating
in the combination arm
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>Incidence rate of dose limiting toxicities (DLT) (in the first cycle (of 28<br /><br>days) of each investigated dose level).</p><br>
- Secondary Outcome Measures
Name Time Method <p>1. Safety and tolerability: type, intensity, severity and seriousness of<br /><br>adverse events (AE) according to NCI CTCAE v. 4.0.<br /><br>2. Levels of pS6 in skin and tumor tissue and pAkt in tumor tissue.<br /><br>3. Pharmacokinetics: BYL719 plasma concentration<br /><br>4. Objective tumor response rate<br /><br>5. Progression Free Survival (only at MTD / RP2D)</p><br>