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

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2014 by Novartis
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01613950
First received: May 31, 2012
Last updated: February 24, 2014
Last verified: February 2014
  Purpose

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.


Condition Intervention Phase
Stomach Neoplasms; Esophageal Neoplasms; Metastatic Gastric Cancer; Mutated PI3KCA Protein; Overexpressed HER2 Protein;
Drug: AUY922
Drug: BYL719
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Incidence rate of Dose Limiting Toxicities. [ Time Frame: cycle 1 ] [ Designated as safety issue: Yes ]
    To determine the maximum tolerated dose (MTD) and/or Recommended dose for expansion (RDE) and schedule of BYL719 and AUY922 when used as a combination in patients with advanced or metastatic gastric cancer carrying a molecular alteration of PIK3CA and/or an amplification of HER2. 1 cycle = 28days


Secondary Outcome Measures:
  • Frequency of adverse events (AEs) [ Time Frame: duration of the study, an expected average of 24 months ] [ Designated as safety issue: Yes ]
    To characterize the safety and tolerability of BYL719 and AUY922 in combination.

  • Best Overall Response (BOR) as per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 [ Time Frame: every 6 weeks ] [ Designated as safety issue: No ]
    To assess the preliminary anti-tumor activity of BYL719/AUY922 combination from Treatment start to disease progression

  • Plasma concentration versus time profiles of BYL719 as single agent an in combination with AUY922. [ Time Frame: 2 months ] [ Designated as safety issue: No ]
    To determine the single dose PK of BYL719 single dose, and multiple doses PK of BYL719.

  • Overall response rate (ORR) as per RECIST version 1.1 [ Time Frame: an expected average of 12 months ] [ Designated as safety issue: No ]
    To assess the preliminary anti-tumor activity of BYL719/AUY922 combination.

  • Progression free survival (PFS) as per RECIST version 1.1 [ Time Frame: every 6 weeks ] [ Designated as safety issue: No ]
    To assess the preliminary anti-tumor activity of BYL719/AUY922 combination.

  • Overall survival (OS) [ Time Frame: approximately 1 year ] [ Designated as safety issue: No ]
    To assess the preliminary anti-tumor activity of BYL719/AUY922 combination.

  • Overall survival rate at 6 months (OS6) [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    To assess the preliminary anti-tumor activity of BYL719/AUY922 combination.

  • Frequency and severity of serious adverse events (SAEs) [ Time Frame: duration of the study, an expected average of 24 months ] [ Designated as safety issue: Yes ]
    To characterize the safety and tolerability of BYL719 and AUY922 in combination.

  • Plasma concentration versus time profile of AUY922 as single agent and in combination with BYL719 [ Time Frame: 2 months ] [ Designated as safety issue: No ]
    To determine the single dose and multiple dose pharmacokinetics of AUY922

  • Plasma concentration versus time profile of the AUY922 metabolite BJP762 [ Time Frame: 2 months ] [ Designated as safety issue: No ]
    To determine pharmacokinetics of BJP762 after single dose and multiple dose of AUY922

  • Severity of adverse events (AEs) [ Time Frame: duration of the study, an expected average of 24 months ] [ Designated as safety issue: Yes ]
    To characterize the safety and tolerability of BYL719 and AUY922 in combination.


Estimated Enrollment: 41
Study Start Date: December 2012
Estimated Study Completion Date: May 2014
Estimated Primary Completion Date: March 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: BYL719 + AUY922
Dose finding study to estimate the maximum tolerated dose(s) (MTD) and/or recommended dose(s) for safety expansion (RDE) followed by an expansion phase to further assess the safety and preliminary activity of the combination. BYL719 tablets will be administered orally on a daily schedule (q.d.). a b.i.d. regimen may be explored. AUY922 will be administered by IV infusion once per week.
Drug: AUY922
AUY922 is a non-geldanamycin inhibitor of the heat shock protein 90 (HSP90).
Drug: BYL719
BYL719 is an oral α-specific phosphatidylinositol-3-kinase (PI3K) inhibitor.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01613950

Contacts
Contact: Novartis Pharmaceuticals 1-888-669-6682
Contact: Novartis Pharmaceuticals

Locations
United States, California
University of California at Los Angeles SC-5 Not yet recruiting
Los Angeles, California, United States, 90095
Contact: Vanity Campbell    +1 310-582-4069    vancampbell@mednet.ucla.edu   
Principal Investigator: Joel Randolph Hecht         
United States, Massachusetts
Massachusetts General Hospital Mass General 2 Not yet recruiting
Boston, Massachusetts, United States, 02114
Contact: Karen Sommer    617-724-0865    cquadrino@partners.org   
Principal Investigator: Jose Baselga         
United States, Texas
MD Anderson Cancer Center/University of Texas Gastrointestinal Med. Oncology Recruiting
Houston, Texas, United States, 77030-4009
Contact: Gail Bland    713-745-3917    gbland@mdanderson.org   
Principal Investigator: Jaffer A. Ajani         
Germany
Novartis Investigative Site Recruiting
Würzburg, Germany, 97080
Korea, Republic of
Novartis Investigative Site Not yet recruiting
Seoul, Korea, Korea, Republic of, 110 744
Novartis Investigative Site Not yet recruiting
Seoul, Korea, Republic of, 738-736
Switzerland
Novartis Investigative Site Recruiting
Bellinzona, Switzerland, 6500
Taiwan
Novartis Investigative Site Recruiting
Taipei, Taiwan, 10048
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

No publications provided

Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT01613950     History of Changes
Other Study ID Numbers: CBYL719X2103, 2011-005978-40
Study First Received: May 31, 2012
Last Updated: February 24, 2014
Health Authority: United States: Food and Drug Administration
Canada: Health Canada
Germany: Federal Institute for Drugs and Medical Devices (BfArM)
Netherlands: Medicines Evaluation Board (MEB)
Singapore: Health Sciences Authority
South Korea: Korea Food and Drug Administration (KFDA)
Switzerland: Swissmedic
Taiwan: Department of Health

Keywords provided by Novartis:
gastric cancer; advanced gastric or metastatic gastric cancer; PI3K; PIK3CA mutation; Her2 amplification; HSP90 inhibitor; PI3K inhibitor; PIK3CA amplification

Additional relevant MeSH terms:
Stomach Neoplasms
Neoplasms
Esophageal Neoplasms
Neoplasms, Second Primary
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Head and Neck Neoplasms
Digestive System Diseases
Esophageal Diseases
Gastrointestinal Diseases
Stomach Diseases

ClinicalTrials.gov processed this record on August 27, 2014