advanced solid neoplasm and HER2+ malignant breast neoplasm advanced solid tumors HER2+ Breast Cancer
Conditions
Interventions
BEZ235, oral formulation: Special Drug delivery System(SDS) capsules or sachets
BEZ235 SDS capsules or sachets in combination with trastuzumab.
MTD not yet reached for both formulations
BEZ235 SDS c
Sponsors
Novartis
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: 1. [Combination Dose Escalation arm] (amendment 4): Female patients with histologically confirmed, metastatic HER2+ Breast Cancer, after failure of trastuzumab treatment. Eligible patients will have to have tumors carrying molecular alterations of PIK3CA and/or PTEN. Failure of trastuzumab treatment is defined as disease progression during trastuzumab maintenance treatment given as part of an adjuvant treatment regimen or as part of a treatment regimen for metastatic disease. The following rules should be used for the assessment of the HER2 expression status: * IHC +++: IHC results, if obtained with standard IHC methods, is acceptable * IHC++ or IHC+: Confirmation by FISH is needed. Tumors tested by FISH must be positive by the specific FISH assay for the amplification of HER2.;[Single agent safety expansion arm] Patients with histologically-confirmed, advanced unresectable solid tumors including CS patients who have progressed on (or not been able to tolerate) standard therapy within three months before screening visit or for whom no standard anticancer therapy exists. Patients will be prescreened for molecular alterations affecting PIK3CA and/or PTEN. Patients with NSCLC will be pre-screened for EGFR mutation. 2. [Safety expansion arm] All patients must have at least one measurable as defined by RECIST criteria for solid tumors. Prostate cancer and ovarian cancer patients may be enrolled on the basis of elevated PSA and CA-125 levels, respectively, in the absence of any measurable lesion. Patients with Cowden Syndrome with a genetically confirmed and documented mutation of the susceptibility gene 10q22-23. 3. Patients who fulfill the following criteria will be eligible for PET assessments: * Indications: tumor types known to have a high FDG uptake, such as breast, lung, GIST, melanoma, colorectal, lymphoma * At least one lesion must be measurable ( >2cm) * To be eligible for follow-up scans, patients should have uptake of the tracer in at least one lesion where the tumor-muscle ratio is >2. * Able to lie still and flat on the PET table. 4. Availability of a representative tumor tissue specimen. Archival tumor tissue is allowed. 5. Age * 18 6. World Health Organization (WHO) Performance Status of * 2 7. Life expectancy of * 12 weeks 8. Patients must have the following laboratory values: * Absolute Neutrophil Count (ANC) * 1.5 x 109/L * Hemoglobin (Hgb) * 9 g/dl * Platelets (plt) * 100 x 109/L * Potassium, total calcium and magnesium within normal limits or correctable * Phosphorus * the lower limit of normal or correctable * AST/SGOT and ALT/SGPT * 2.5 x Upper Limit of Normal (ULN) or * 5.0 x ULN if liver metastases are present * Serum bilirubin * 1.5 x ULN * Serum creatinine * 1.5 x ULN or 24-hour clearance * 50 mL/min * Serum amylase * ULN * Serum lipase * ULN * PT/INR and PTT * ULN * Negative serum pregnancy test within 48 hours before starting study treatment
Exclusion criteria
Exclusion criteria: 1. Patients who have signs/symptoms attributable to brain metastases and have not been assessed with radiologic imaging to rule out the presence of brain metastases 2. Fulminant disease 3. Prior treatment with a PI3K inhibitor 4. Lytic bone metastasis if the sole lesion of the patient is a bone metastasis 5. Acute or chronic liver disease or renal disease 6. Acute or chronic pancreatitis 7. Patients with any peripheral neuropathy * CTCAE grade 2 8. Diarrhea * CTCAE grade 2 9. Any of the following concurrent severe and/or uncontrolled medical conditions: * Impaired cardiac function or clinically significant cardiac diseases, including any of the following: 1. LVEF 460 msec on screening ECG 8. Right bundle branch block + left anterior hemiblock (bifascicular block) 9. Unstable angina pectoris * 3 months prior to starting the study drug 10. Acute myocardial infarction * 3 months prior to starting the study drug 11. Other clinically significant heart disease such as congestive heart failure requiring treatment or uncontrolled hypertension * Patients with diabetes mellitus requiring insulin treatment, history of gestational diabetes mellitus * Patients with known coagulopathies * Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g. active or uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with the protocol 10. Patients with a history of photosensitivity reactions to other drugs 11. Any of the following ophthalmological findings: * Progressive eye disease that could lead to severe loss of visual acuity or visual field loss during the study period * Inability to perform the ophthalmic procedures required in this protocol 12. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of BEZ235 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection). 13. Patients who have been treated with any hematopoietic colony-stimulating growth factors (e.g., G-CSF, GM-CSF) * 2 weeks prior to starting study drug. Erythropoietin or darbepoetin therapy, if initiated before enrollment, may be continued 14. Patients who are currently receiving treatment with medication that has the potential to prolong the QT interval or inducing Torsades de Pointes 15. Patients who are currently receiving treatment with therapeutic doses of warfarin sodium (Coumadin®) 16. Patients who have received chemotherapy, immunotherapy (except for trastuzumab) or investigational drugs * 4 weeks prior to starting study drug or who have not recovered from side effects of such therapy 17. Patients who have received any continuous-dosing * 5 half lives prior to starting study drug or who have not recovered from side effects of such therapy 18. Patients who have received corticosteroids * 2 weeks prior to starting study drug or who have not recovered from the side effects of such treatment 19. Patient
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary endpoint - dose escalation part: * Incidence rate of DLT at each dose level and formulation Primary endpoint - dose expansion part: * Safety: Type, frequency and severity of adverse drug reactions | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary endpoints: * Safety: Type, frequency and severity of adverse drug reactions * Preliminary efficacy * PK and PD Evaluation criteria: * Safety: CTCAE Version 3.0 unless otherwise specified * Efficacy: RECIST criteria * PK: Cmax, Tmax, AUC0-last and AUC0-inf * PD: PET response, blood, tumor at baseline and post-therapy | — |
Countries
Netherlands
Outcome results
None listed