HER2 positive, triple negative breast cancer (TNBC) and hormone-receptor (ER/PR)-positive breast cancer. MedDRA version: 16.1 Level: PT Classification code 10065430 Term: HER-2 positive breast cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 16.1 Level: PT Classification code 10054057 Term: Progesterone receptor assay positive System Organ Class: 10022891 - Investigations MedDRA version: 16.1 Level: LLT Classification co
Conditions
Sponsors
Synta Pharmaceuticals Corp.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1.Female = 18 years of age; 2. Pathologically confirmed diagnosis of invasive breast cancer, classified as HER2-positive, hormone-receptor positive, or TNBC; Inflammatory breast (IBC) is permitted based on the following criteria: clinically evaluable skin disease (erythema, edema, peau d' orange, or ulcerations), with underlying mass detected by PET; and/or the presence of measurable disease detected by CT/MRI - NOTE: If the disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by cytology or histology. 3. Stage IIIB, IIIC or IV disease (AJCC Cancer Staging Manual, 7th edition, 2010) NOTE: Lesions should not be amenable to surgery or radiation therapy of curative intent. 4. Prior therapy: Cohort A: Patients with HER2-positive disease must have relapsed following prior trastuzumab or other approved anti-HER2 agent in the adjuvant setting. At least 6 months must have elapsed since the discontinuation of prior adjuvant therapy. Cohort D: Patients with ER- and/or PR-positive disease must have relapsed following at least 1 prior endocrine therapy, in either the adjuvant or metastatic setting. 5. Documented HER2 and hormonal receptor status according to local laboratory analysis. 6. ECOG Performance Status =1. 7. A biopsy is to be taken at study entry for all patients with an accessible tumor. Patients with inaccessible tumor may substitute with available archived tumor tissue block with sufficient tumor tissue for biomarker testing; alternatively, unstained slides with sufficient tumor tissue may be substituted. 8. Clinically or radiologically measurable disease - Metastatic disease: - Measurable disease per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1, with the exception of patients with IBC for whom disease visible on PET is acceptable. - Measurable disease may be in the field of prior irradiation; however, at least 4 weeks must have elapsed between the completion of radiation therapy and the baseline scan documenting disease status. - Bone disease is considered radiologically measurable only if there is at least a 50% lytic component. NOTE: Bone disease consisting of blastic lesion only is not measurable. - Locally advanced breast cancer - Clinically measurable tumor disease per RECIST 1.1, as detected by physical examination, ultrasound, mammogram, and/or MRI NOTE: Patients with a non-palpable primary tumor with histologically confirmed lymph node involvement detected by palpation or ultrasonography are eligible. 9. Adequate hematologic function defined as: Absolute neutrophil count (ANC) =1.5 x 109/L; Hemoglobin =9 g/dL; Platelets =100 x 109/L. 10. Adequate hepatic function defined as: Albumin =3 g/dL; Serum total bilirubin =1.5 x upper limit of normal (ULN); Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =1.5 x ULN without liver metastases; =5 x ULN if documented liver metastases. 11. Adequate renal function defined as: Serum creatinine =2.5 mg/dL x ULN or calculated creatinine clearance (CrCl) per Cockcroft-Gault formula =50 mL/min (see Appendix 2). 12. Negative serum pregnancy test at study entry for patients of childbearing potential. Patients of childbearing potential must agree to use two adequate contraception methods (eg, hormonal or barrier method of birth control; abstinence) for the duration of study treatment and for 30 days after the last dose of study drug. 13. Ability to understand, and willingness to sign, a written informed consent docume
Exclusion criteria
Exclusion criteria: 1. Prior chemotherapy in the 1st-line setting for MBC NOTE: Prior therapy of IBC patients in the 1st-line setting is permitted given the rarity of the disease. 2. De novo diagnosed patients with HER2+ or ER/PR+ disease. 3. Presence of active or symptomatic or stable untreated CNS metastases - NOTE: Patients with asymptomatic or stable CNS metastases are eligible; 4. Active malignancies other than MBC within the last 5 years except cancers adequately treated with surgery and/or adjuvant therapy. 5. Bone as the only site of metastatic disease from breast cancer; 6. Prophylactic use of supportive therapy for skeletal related events in patients without bone disease - NOTE: Supportive therapy for skeletal-related events (eg, bisphosphonate, pamidronate, or denosumab) is allowed; however, treatment must be initiated prior to, or within 7 days after, the first dose of ganetespib; 7. Prior radiotherapy to the only area of measurable disease, unless there is documented disease progression, defined as an increase of at least 1 cm in the longest diameter compared to nadir scan - NOTE: Patients must have completed treatment and recovered from all acute treatment-related toxicities prior to administration of the first dose of study drug. 8. Pregnancy or lactation. 9. Known serious cardiac illness or medical conditions including but not confined to: i. Clinically unstable cardiac disease, including unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, active myocardial ischemia, or indwelling temporary pacemaker; ii. Ventricular tachycardia or a supraventricular tachycardia that requires treatment with a Class Ia antiarrhythmic drug (eg, quinidine, procainamide, disopyramide) or Class III antirrhythmic drug (eg, sotalol, amiodarone, dofetilide). Use of other antirrhythmic drugs is permitted; iii. Use of medications that have been linked to QT interval prolongation and the occurrence of torsades de pointes (see Appendix 4 for the list of such medications); iv. Second- or third-degree atrioventricular (AV) block unless treated with a permanent pacemaker; v. Complete left bundle branch block (LBBB); vi. History of long QT Syndrome or a family member with this condition; viii. QTc >470 ms (average of triplicate ECG recordings); a consistent method of QTc calculation must be used for each patient's QTc measurements. QTcF (Fridericia's formula) is preferred. viii. Serum potassium, magnesium, or calcium levels outside the laboratory's reference range. 10. Weight loss =10% within the 4 weeks prior to administration of first dose of ganetespib. 11. Unresolved Grade 3 and 4 toxicities from prior cancer therapy. 12. Uncontrolled intercurrent illness including, but not limited to, human immunodeficiency virus (HIV) positive patients receiving combination antiretroviral therapy, severe or systemic infection, or psychiatric illness/social situations that would limit compliance with study requirements; 13. Other severe acute or chronic medical condition or abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, or that in the judgment of the investigator would make the patient inappropriate for entry into the study. 14. History of severe (Grade 3 or 4) allergic or hypersensitivity reactions to excipients (eg, Polyethylene glycol [PEG] 300 and Polysorbate 80). 15. History of intolerance or hypersensitivity ot paclitaxel o
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Determine the objective response rate of ganetespib monotherapy in patients with these subtypes of breast cancer: HER2+, TNBC, and hormone-receptor (ER/PR)-positive disease.;Secondary Objective: Evaluate the change in F-18 fluorodeoxyglucose (FDG) tumor uptake as a predictor of clinical response following one cycle of treatment with ganetespib monotherapy; Evaluate the clinical benefit rate (CBR), duration of response (DOR), and PFS with ganetespib monotherapy; Determine the qualitative and quantitative toxicities associated with ganetespib monotherapy; Evaluate the relationship of clinical outcome with relevant biomarkers and, genetic changes, and proteome and transcriptome profiles present in tumor tissues and serum and plasma samples for both ganetespib monotherapy and ganetespib in combination with paclitaxel; Evaluate the ORR, CBR, DOR, and PFS with ganetespib and weekly paclitaxel in patients whose disease progresses on ganetespib monotherapy; Determine the qualitative and quantitative toxicities associated with ganetespib and weekly paclitaxel;Primary end point(s): The primary endpoint of the study is objective response rate (ORR), defined as the proportion of evaluable patients in each disease cohort achieving a complete or partial response according to the modified RECIST 1.1 regardless of confirmation (e.g., a single timepoint response will be included in the ORR analysis) within the treatment phase. Up to 33 evaluable patients per cohort will be enrolled. An evaluable patient is defined as having received at least one dose of ganetespib and a subsequent followup scan. Clinical activity analyses will be conducted in both the intent-to-treat (ITT) and per-protocol (PP) populations. In general, continuous variables will be summarized by descriptive statistics (number of observations, mean, standard deviation, median, minimum and maximum); categorical variables will be presented with the number of observations and percentage (non-missing) | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Evaluate the change in F-18 fluorodeoxyglucose (FDG) tumor uptake as a predictor of clinical response following one cycle of treatment with ganetespib monotherapy. Evaluate the clinical benefit rate (CBR), duration of response (DOR), and PFS with ganetespib monotherapy. Determine the qualitative and quantitative toxicities associated with ganetespib monotherapy. Evaluate the relationship of clinical outcome with relevant biomarkers & genetic changes and proteome and transcriptome profiles present in tumor tissues & serum and plasma samples for both ganetespib monotherapy and ganetespib in combination with paclitaxel. Evaluate the ORR, CBR, DOR, and PFS with ganetespib and weekly paclitaxel in patients whose disease progresses on ganetespib monotherapy. Determine the qualitative and quantitative toxicities associated with ganetespib and weekly paclitaxel.;Timepoint(s) of evaluation of this end point: At weeks 3, 6, 12 treatment phase or beyond. | — |
Countries
Argentina, Belgium, Brazil, Peru, Spain, United Kingdom, United States
Contacts
Public ContactMedical Monitor
Synta Pharmaceuticals Corp.
Outcome results
None listed