PI3K Inhibitor BYL719 in Combination With the HSP90 Inhibitor AUY922 in Patients With Advanced or Metastatic Gastric Cancer

A Phase IB, Multicenter, Open-label Dose Escalation Study of the PI3K Inhibitor BYL719 in Combination With the HSP90 Inhibitor AUY922 in Patients With Advanced or Metastatic Gastric Cancer Carrying a Molecular Alteration of PIK3CA or an Amplification of HER2

The study is intended to investigate the safety of BYL719 and AUY922 in patients with advanced gastric cancer, and to determine the MTD and/or RDE of both drugs in combination. In addition, the preliminary efficacy of BYL719 in combination with AUY922, and the pharmacokinetics of both drugs will be assessed. Patients will be eligible for this study, if their tumors carry either a molecular alteration of PIK3CA, or an amplification of HER2.

The study includes a dose escalation part followed by a safety expansion phase.

Inclusion Criteria:

• Patients with advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction;

• Patients must not have a complete gastrectomy;

• gastric tumors carrying PIK3CA mutation or amplification, or HER2-overexpression, or both;

• at least one but no more than three previous lines of treatment for advanced or metastatic disease;

• Patients with PIK3CA mutated or amplified tumors must have failed at least one line but no more than three lines of standard chemotherapy and/or targeted agents;Patients with HER2 amplified tumor must have failed at least one line, but no more than three lines, with or without anti-HER2 therapy. All HER2 positive patients are expected to have received trastuzumab unless contraindications were present or trastuzumab was unavailable;

• Performance Status (PS) ≤ 1 ;

• Adequate bone marrow, liver and other organ functions and laboratory parameters;

• Recovery from all AEs of previous anti-cancer therapies, including surgery and radiotherapy, to baseline or to CTCAE Grade ≤ 1, except for alopecia;Negative serum pregnancy (β hCG) test within 72 hrs before starting study treatment in all pre-menopausal women and women < 12 months after the onset of menopause.

  * Exclusion Criteria:

• Progressive disease during or after prior combination treatment with PI3K-inhibitors and HSP90- inhibitors;

• history of prior significant toxicity from another PI3K- or HSP90- inhibitor requiring discontinuation of treatment;

• primary CNS tumor or uncontrolled CNS metastasest;

• Patients who are currently receiving medication with a known risk of prolonging the QT interval or inducing Torsades de Pointes and the treatment cannot either be discontinued or switched to a different medication prior to starting study drug treatment;

• Patients with diabetes mellitus requiring insulin treatment and/or with clinical signs or with fasting glucose ≥ 140 mg/dL / 7.8 mmol/L, history of clinically significant gestational diabetes mellitus or documented steroid-induced diabetes mellitus;Patients with diarrhea CTCAE Grade ≥ 2 ;

• Patients with acute or chronic pancreatitis; History or current evidence of central serous retinopathy (CSR), retinal vein occlusion (RVO) or ophthalmopathy as assessed by ophthalmologic examination at baseline that would be considered a risk factor for CSR/RVO;

• Impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral BYL719;

• Patients receiving chronic slow-release formulation of Proton Pump Inhibitors (PPI), H2-antagonists or other gastric pH elevating agents;

• Treatment with therapeutic doses of coumarin-based anticoagulants (e.g., warfarin sodium, Coumadin®). Low doses of courmarin-based anticoagulants;

• Patients receiving chronic or high dose corticosteroids therapy; other protocol-defined inclusion/exclusion criteria may apply.