Alpelisib and Paclitaxel in PIK3CA-altered Gastric Cancer

  • End date
    Dec 1, 2024
  • participants needed
  • sponsor
    Seoul National University Bundang Hospital
Updated on 1 September 2021
measurable disease
human chorionic gonadotropin
neutrophil count
cancer chemotherapy
metastatic gastric cancer
adjuvant chemotherapy


Alpelisib (BYL719) is a PIK3CA-specific inhibitor, which was developed by Novartis (Basel, Switzerland). Our group conducted pre-clinical study of alpelisib in eight gastric cancer cell lines: four PIK3CA wild-type (SNU638, SNU668, SNU1, and SNU16) and four PIK3CA mutant (SNU719, AGS, SNU601, and MKN). As a result, alpelisib preferentially inhibited the growth of gastric cancer cells with PIK3CA mutations. In addition, alpelisib inhibited cell growth via G1 arrest and subsequently induces apoptosis in GC cells, and this effect is more remarkable in cells harboring PIK3CA mutations. Moreover, alpelisib in combination with paclitaxel showed synergistic cytotoxic effects and significantly increased apoptosis compared with alpelisib or paclitaxel monotherapy in GC cells.

The purpose of the study is to define the maximal tolerated dose (MTD) and recommended phase II dose (RP2D) of paclitaxel and alpelisib combination therapy in patients with advanced tumors and to evaluate the efficacy of paclitaxel and AZD8186 combination therapy as a second-line therapy in patients with advanced gastric cancer with PTEN aberrations. This study is divided into Phase IB and Phase II.

Condition Gastric Cancer, Gastric Carcinoma, Stomach Discomfort, Stomach Cancer, Solid Neoplasm, Solid Tumour, Gastropathy, gastric cancers, Solid Tumor, Solid Tumors
Treatment Paclitaxel, Alpelisib
Clinical Study IdentifierNCT04526470
SponsorSeoul National University Bundang Hospital
Last Modified on1 September 2021


Yes No Not Sure

Inclusion Criteria

Subject has signed the Informed Consent Form (ICF) prior to any screening procedures being performed
Age 20 years old of male and female
At each phase of the trial, subjects who meet the following requirements in each phase will be enrolled
Phase IB: Subjects with a histologically-confirmed, advanced/recurrent solid tumor who have progressed on standard therapy or whose disease does not have established standard therapy
Phase II: Subjects with histologically confirmed locally advanced or metastatic gastric cancer that have progressed after treatment with first-line fluoropyrimidine-based chemotherapy (Tissue samples of gastric cancer must contain PIK3CA gene alterations (e.g. single nucleotide variants, small indels, amplifications, structural variations, etc.) identified by central or local next generation sequencing (NGS). If the subject received adjuvant chemotherapy after curative gastric resection and lymph node dissection, the adjuvant chemotherapy is considered to be the first-line palliative chemotherapy if the disease recurred during adjuvant chemotherapy or within 6 months after the completion of adjuvant chemotherapy
Phase IB: Patient has evaluable disease as per RECIST 1.1. (Measurable lesions are not mandatory for study inclusion.) Phase II: Patient has at least one measurable lesion as per RECIST 1.1
ECOG performance status 0-1
Patient has adequate bone marrow and organ function as defined by the following laboratory values
Absolute neutrophil count (ANC) 1.5 x 109/L
Hemoglobin 9.0 g/dL
Platelet 100 x 109/L
Serum creatinine ULN (upper limit of normal) or serum creatinine clearance 50 mL/min (by Cockcroft-Gault formula, or 24h urine collection)
Total bilirubin: 1.5 ULN Subjects with a bile duct obstruction will be eligible if they meet the criteria after appropriate bile drainage; Patients with Gilbert syndrome should also be included after confirming that the total bilirubin level is 1.5 x ULN in a follow-up screening test
Phase Ib: Alanine aminotransferase (AST) and aspartate aminotransferase (ALT) 3 x ULN (regardless of liver metastases)
Phase II: AST and ALT 3 x ULN if liver metastases are absent, or AST and ALT 5 x ULN if liver metastases are present
The subject is able to swallow and retain oral medication
Serum -HCG test negative within 14 days before the first administration of the study treatment (women of childbearing potential only)
Requirement for contraception must be observed by the subject

Exclusion Criteria

Patient has received previous treatment with a PI3K or AKT inhibitor. (Note: prior mTOR inhibitor treatment is allowed.)
Patient has a known or suspicious hypersensitivity to paclitaxel or other products containing Cremophor
Any cytotoxic chemotherapy from a previous treatment regimen within 14 days. If the subject received an investigational drug from another clinical trial, the subject can be enrolled after 2 weeks of last administration and more than 5 x half-life of the investigational drug. If monoclonal antibody therapy was given, the subject can be enrolled after four weeks after the last does
Active central nervous system (CNS) lesions (i.e., those with radiologically unstable or symptomatic brain lesions). For those who receive radiation or surgical treatment, the subject can be enrolled if the subject is maintained without steroid therapy and the evidence of CNS disease progression for more than 4 weeks. However, patients with leptomeningeal metastases are excluded
Patient has not recovered to grade 1 (except alopecia) from related adverse effects of any prior antineoplastic therapy
Radiotherapy with a wide field (more than 30% of the bone marrow) of radiation within 4 weeks or radiotherapy with a limited field of radiation for palliation within 2 weeks of the first dose of study treatment
Patient who has undergone major surgery 4 weeks prior to starting study treatment or who has not recovered from adverse effects of such procedure
Patient has a clinically significant cardiac disease or impaired cardiac function, such as
Acute coronary syndrome within the 6 months prior to the initiation of study drug (including myocardial infarction or unstable angina, Coronary Artery Bypass Graft surgery, percutaneous coronary intervention and stenting)
Heart failure grade 2 by New York Heart Association (NYHA) functional classification or that requires treatment
Ejection fraction (EF) <50% on multi-gated acquisition (MUGA) scan or echocardiography examination. MUGA scan or echocardiography is not required as a screening test if there is no current suspicious symptom and past history of heart failure
Persistent uncontrolled hypertension as defined by: systolic >180 mmHg or diastolic >100 mmHg despite medical treatment
Current or past history of clinically significant cardiac arrhythmia, atrial fibrillation, and/or conduction abnormality including complete AV block, long QT syndrome, congenital long QT syndrome, or QTcF >470 msec at screening (if the average QTcF value > 470 msec by measuring 3 times consecutively in total)
Any risk factors that prolong QTc or increase the probability of arrhythmia, including medication (e.g. heart failure, hypokalemia, congenital long QT syndrome, history of Torsades de Pointes)
If the subject was diagnosed with diabetes (irrespective of treatment or symptom) or if the subject has Korean Diabetes Prediction Score (Appendix A) more than 7 plus impaired glucose tolerance (with blood glucose of 140-199 mg/dL after 2-hour oral glucose tolerance test (75g)), previous history of gestational diabetes, or steroid-induced diabetes
Patients with impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral BYL719 (e.g. untreated peptic ulcer disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or wide small bowel resection)
Patient has a known positive serology for human immunodeficiency virus (HIV), active Hepatitis B, and/or active Hepatitis C infection. Hepatitis B carriers may be enrolled if prophylactic use of an antiviral agent with minimal interaction with CYP3A4 is administered to inhibit HBV activation (e.g., entecavir, adefovir)
Concomitant medication of strong or moderate inducers or inhibitors of CYP3A4 (Table
before the first dose of study treatment (In this case, if the drug is stopped for 1 week or more (according to Table 11) and changed to another drug that does not affect CYP3A4, then the subject can be enrolled.)
History of other primary cancer. Exceptions are as follows
Adequately treated non-melanoma skin cancer (basal cell or squamous cell carcinoma), curatively treated in situ cancer of the cervix or stage I bladder cancer, completely resected thyroid cancer without distant metastasis in which all treatment has been completed (Appropriate wound healing is required prior to clinical trial enrollment)
Other curatively treated solid tumors except for gastric cancer with no evidence of disease recurrence at least 24 months before participating in this trial
History of allogeneic bone marrow transplantation or organ transplantation
As judged by the Investigator, all other symptoms and associated disease for which the investigator determined that participation in this study is contraindicated (e.g. Infection/inflammation; severe liver dysfunction; bilateral diffuse interstitial lung disease; uncontrolled renal disease; unstable heart and lung disease; hemorrhagic disease; intestinal obstruction; unable to swallow oral pills; social and psychological problems, etc.)
Medical, psychiatric, cognitive, or other conditions that may interfere with the ability of the subject to understand the subject information, provide the informed consent, follow the protocol process, or complete the clinical trial
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