Subjects with Metastatic Breast Cancer who have Progressed on a Previous Trastuzumab-Based Regimen MedDRA version: 12.1 Level: LLT Classification code 10027475 Term: Metastatic breast cancer
Conditions
Interventions
Product Name: XL147
Product Code: XL147
Pharmaceutical Form: Tablet
Current Sponsor code: XL147
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
Trade Name: He
Sponsors
Exelixis INC.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. The subject has pathologically and radiologically confirmed metastatic HER2 positive breast cancer (Stage IV disease). The following restrictions to prior anti-cancer therapy apply: a. Subjects must have received and progressed on at least one prior trastuzumab-containing regimen for metastatic disease, or have received trastuzumab as adjuvant treatment and progressed within 1 year of their last dose of trastuzumab. b. Subjects must have received at least one prior taxane-containing regimen as adjuvant treatment or for metastatic disease (Arm 2). c. Subjects must have received no more than five prior cytotoxic chemotherapeutic regimens for MBC (Phase 2). Note: consecutive re-treatment with the same regimen does count as one regimen. NOTE: Drugs used to control bone pain and/or osteoporosis (eg, bisphosphonates) are allowed if started at least 2 months prior to screening activities or may be initiated during the course of the study with the agreement of the sponsor. 2. The subject has at least one lesion that is not within a previously radiated field and measurable on computerized tomography (CT) or magnetic resonance imaging scan (MRI) per RECIST Version 1.1. NOTE: Bone lesions are not considered measurable by definition. Primary breast lesions are not considered measurable if assessed only by physical examination. 3. The subjects enrolled in Phase 2 of both treatment arms must be willing to undergo a biopsy of the primary tumor or a tumor metastasis at baseline, if tumor tissue is amenable to biopsy. Fresh tissue from this biopsy must be in the possession of the participating site/institution, and designated for shipment to the sponsor or a laboratory designated by the sponsor. 4. The subject’s primary tumor and/or metastatic lesion must overexpress HER2. Acceptable methods of measurement of HER2 overexpression/amplification include immunohistochemical (IHC) based assessments and fluorescence in situ hybridization (FISH). Tumors tested by IHC must be 3+ positive. Tumors tested by FISH must have a ratio of HER2:CEP17 > 2.0. 5. The subject is = 18 years old. 6. For subjects enrolled in Phase 2 of both treatment arms: at least fifteen (15) 4-10 micron tissue sections (= 15 unstained slides [20 preferable], without cover slips) from archival or fresh tissue, or a tissue block of the subject’s tumor should be identified, in the possession of the participating site/institution, and designated for shipment to the sponsor or a laboratory designated by the sponsor. • If, after the enrollment of the first 10 subjects in each arm, the incidence of molecular alterations directly affecting the PI3K pathway in these 10 subjects in each arm is not between 40 and 60%, subject pre-selection may be implemented and subsequent enrollment may be gated by alteration status to ensure that the frequency of PI3K pathway alterations falls within the range of 40-60% for the study population in each arm. 7. The subject has an Eastern Cooperative Oncology Group (ECOG) performance status of = 2. 8. The subject has organ and marrow function as follows: a. Absolute neutrophil count (ANC) = 1500/mm3. b. Platelets = 100,000/mm3. c. Hemoglobin = 9 g/dL. d. Bilirubin = 1.5 × the upper limit of normal (ULN). e. Serum creatinine = 1.5 × the ULN or calculated creatinine clearance = 60 mL/min. f. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) = 2.5 × the ULN if no liver involvement, or = 5 × the ULN with liver involvement. 9. The subject is capable o
Exclusion criteria
Exclusion criteria: 1. The subject has previously been treated with a selective inhibitor of PI3K and / or AKT. 2. The following restrictions on prior therapy apply: a. Small molecule targeted (non-cytotoxic) inhibitors (including investigational kinase inhibitors) within 2 weeks or 5 half-lives of the compound or active metabolites, whichever is longer, before the first dose of study treatment. b.Radiation therapy within 2 weeks before the first dose of study treatment. c. Hormonal therapy within 2 weeks before the first dose of study treatment. d.Cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) within 3 weeks, or nitrosoureas or mitomycin C within 6 weeks before the first dose of study treatment. e. Biologic therapy (including antibodies {other than trastuzumab}, immune modulators, cytokines) within 4 weeks before the first dose of study treatment. Note: There is no washout period required for trastuzumab. f. Any other type of investigational agent within 4 weeks g. Major surgery, or not recovered from major surgery, within 4 weeks before the first dose of study treatment. 3. The subject has not recovered from toxicity due to prior therapy to Grade = 1 or to pre-therapy baseline. Grade 2 alopecia related to prior therapies will not affect the eligibility of the subject in Arm 1 and Arm 2. Grade 2 peripheral neuropathy will not affect the eligibility in Arm 1 but is an exclusion criterion for Arm 2. 4. The subject has untreated, symptomatic, or progressive brain metastases. Subjects must have no radiographic or other signs of progression in the brain for =1 month after completion of local therapy. Any corticosteroid use for brain metastases must have been discontinued without the subsequent appearance of symptoms for =4 weeks prior to first study treatment. 5. The subject has prothrombin time/International Normalized Ratio (PT/INR) or partial thromboplastin time (PTT) test results at screening that are = 1.3 x the laboratory ULN. 6. The subject has a diagnosis of uncontrolled diabetes mellitus (glycosylated hemoglobin A1C = 8%) or has a fasting plasma glucose > 160 mg/dL 7. The subject has uncontrolled significant intercurrent illness including, but not limited to, ongoing or active infection requiring systemic treatment, or stroke within 3 months of screening. 8. The subject has uncontrolled hypertension (persistent values of = 150 mm Hg systolic or 100 mm Hg diastolic despite anti hypertensive therapy); or significant cardiovascular disease, eg, = New York Heart Association (NYHA) Class III congestive heart failure (CHF); or uncontrolled clinically significant atrial or ventricular cardiac arrhythmias; or any of the following in the past 6 months: a. myocardial infarction b. evidence of transmural infarction on ECG c. unstable angina d. coronary angioplasty 9. The subject has left ventricular ejection fraction (LVEF) = 50% of the expected LVEF as documented by multiple-gated acquisition (MUGA) or echocardiogram (ECHO) performed within 28 days prior to the first dose of study drug. 10. The subject has a baseline corrected QT interval = 460 ms. 11. The subject is currently receiving anticoagulation with therapeutic doses of warfarin (low-dose warfarin = 1mg/day is permitted). 12. The subject is taking oral corticosteroids (equivalent to prednisone > 7.5 mg daily) chronically. 13. The subject is pregnant or breastfeeding. 14. The subject is known to be positive for the human immunodeficiency virus (HIV) (a test for HIV at scre
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objectives are: • To evaluate the safety and tolerability of XL147 in combination with trastuzumab and in combination with trastuzumab and paclitaxel. • To determine the maximum tolerated dose (MTD) of XL147 when administered in combination with trastuzumab and in combination with trastuzumab and paclitaxel (Phase 1). • To estimate the efficacy endpoint of objective tumor response rate (ORR) in the study population and in subpopulations based on the presence or absence of tumor PI3K pathway alterations (ie, molecular alterations that directly affect the PI3K pathway: PIK3CA mutation/amplification and/or PTEN deficiency) (Phase 2).;Secondary Objective: The secondary objectives are: • To estimate duration of response (DOR) and progression-free survival (PFS), including landmarks such as PFS at 6 months (Phase 2). • To assess the pharmacokinetics (PK) and pharmacodynamics of XL147 and trastuzumab when given in combination, and of XL147, trastuzumab, and paclitaxel when given in combination.;Primary end point(s): • To evaluate the safety and tolerability of XL147 in combination with trastuzumab and in combination with trastuzumab and paclitaxel. • To determine the MTD of XL147 when administered in combination with trastuzumab and in combination with trastuzumab and paclitaxel (Phase 1). • To estimate the efficacy endpoint of objective tumor response rate (ORR) in the study population and in subpopulations based on the presence or absence of tumor PI3K pathway alterations (ie, molecular alterations that directly affect the PI3K pathway: PIK3CA mutation/ amplification and/or PTEN deficiency) (Phase 2). | — |
Countries
France
Outcome results
None listed