ABCSG 38/Lorelei Details

A phase II, randomized, double-blind study of neoadjuvant letrozole + GDC-0032 vs. letrozole + placebo in postmenopausal women with ER+/ HER2- negative primary breast cancer

Start:
09/2014
Randomizing:
open

Contact ABCSG-Trial office

E-mail: info@abcsg.at
Phone: +43 1 408 92 30
Fax: +43 1 409 09 90

Design

ABCSG-38
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Objectives:

Efficacy objectives:

  • The primary objective of this study is to evaluate the efficacy of letrozole plus GDC-0032 versus letrozole plus placebo in women with ER+/HER2- early stage breast cancer, as measured by the following co-primary endpoints:
  • Tumor overall objective response rate (ORR) by centrally assessed breast magnetic resonance imaging (MRI) via modified Response Evaluation Criteria in Solid Tumors (RECIST) in all enrolled patients and PIK3CA MT patients
  • pCR rate in breast and axilla (ypT0/Tis ypN0) by local evaluation in all enrolled patients and PIK3CA MT patients

The secondary efficacy objectives of this study are the following:

  • Tumor ORR, assessed by centrally assessed breast MRI via modified Response Evaluation Criteria in Solid Tumors (RECIST) in PIK3CA WT patients
  • pCR rate in breast and axilla (total pCR ypT0/Tis ypN0) by local evaluation in PIK3CA WT patients

The following secondary objectives will be performed in all enrolled patients and separated by PIK3CA mutation status:

  • Compare letrozole plus GDC-0032 with letrozole plus placebo in terms of locally assessed ORR as measured by modified RECIST criteria (Appendix 3) using the following methods:
  • Breast ultrasound
  • Clinical breast exam (i.e., palpation)
  • Mammography
  • Central assessment of changes in Ki67 levels upon treatment with letrozole plus GDC-0032 versus letrozole plus placebo from baseline to Week 3; baseline to surgery; and Week 3 to surgery
  • Compare the centrally derived, preoperative endocrine prognostic index (PEPI) score upon treatment with letrozole plus GDC-0032 versus letrozole plus placebo.
  • Evaluate the changes in enhancing tumor volume from baseline to surgery as measured by breast MRI via central assessment
  • Evaluate different definitions of pCR including the following: a) ypT0, ypN0, and b) ypT0/is, ypNX (breast pCR)

The safety objective for this study is as follows:

  • Evaluate the safety of letrozole plus GDC-0032 versus letrozole plus placebo

The patient-reported outcome (PRO) objectives for this study are as follows:

  • Evaluate and compare PROs of treatment-related symptoms, patient functioning, and health-related quality of life (HRQoL) between treatment arms as measured by the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and the modified Breast Cancer Module (QLQ-BR23)

The exploratory objectives for this study are as follows:

  • To evaluate changes in tumor cellular composition as assessed by diffusion-weighted MRI
  • To assess whether biomarkers from tumor tissue or blood, including but not limited to somatic cancer associated mutations, PTEN expression, pro-survival pathways (such as PI3K/AKT, MAPK etc.), apoptotic markers, hormone receptor expression levels, and levels of RNA and DNA expression are predictive of response
  • To determine whether inhibition of PI3K with GDC-0032 results in changes in downstream markers in tumor tissue and to examine the relationship to anti-tumor activity
  • To assess concordance and percentage of PIK3CA mutation status from baseline biopsy and surgical specimen
  • To assess emergence of resistance alleles from tumor tissue or blood
  • To assess concordance of the different imaging modalities (MRI [volume, enhancement, diffusion metrics], ultrasound, mammography) in measuring tumor response
  • To assess the pharmacokinetics and possible drug interaction between letrozole and GDC-0032 upon concomitant administration
  • To assess the correlation of GDC-0032 drug levels and GDC-0032 related response (efficacy or adverse events [e.g., colitis, rash])
  • To assess the influence of pharmacogenetic polymorphisms on GDC-0032 and/or letrozole on pharmacokinetics and response (either efficacy and/or adverse events)
  • Compare the rates of breast-conserving surgery (BCS) and conversion to BCS in letrozole plus GDC-0032 versus letrozole plus placebo.

Patients for this study include postmenopausal patients with ER+/HER2- untreated, Stage I-III operable breast cancer. The size of the primary tumor should be ≥ 2 cm by MRI.

Inclusion criteria:

Patients must meet the following criteria for study entry:

  1. Signed Informed Consent Form (ICF) prior to any study-specific procedure
  2. Female patients
  3. Postmenopausal status and age ≥ 18 years. Postmenopausal status is defined as follows:
    • Age ≥ 60 years or
    • Age < 60 years and 12 months of amenorrhea plus follicle stimulating hormone (FSH) and plasma estradiol levels within postmenopausal range by local laboratory assessment or
    • Prior bilateral oophorectomy ( ≥ 28 days prior to Day 1 of treatment)
  4. Histologically confirmed invasive breast carcinoma, with all of the following characteristics:
    • Primary tumor ≥ 2 cm in largest diameter (cT1-3) by MRI. In the case of a multifocal tumor (defined as the presence of two or more foci of cancer within the same breast quadrant), the largest lesion must be ≥ 2 cm and designated as the “target” lesion for all subsequent tumor evaluations.
    • Stage I to operable Stage III breast cancer
    • Documentation confirming the absence of distant metastasis (M0) as determined by institutional practice (in patients where there may be a reasonable suspicion of advanced disease e.g., large tumors, clinically positive axillary lymph nodes, signs and symptoms)
  5. ER-positive and HER2-negative breast cancer, as per local laboratory or regional definition
  6. Breast cancer eligible for primary surgery
  7. Tumor tissue from FFPE core biopsy of breast primary tumor that is confirmed as evaluable for PIK3CA mutation status by central histopathology laboratory
  8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  9. Fasting glucose ≤125 mg/dL
  10. Adequate hematological, renal, and hepatic function, as follows:
    • Absolute neutrophil count ≥ 1500/μL
    • Platelets count ≥100,000/μL
    • Hemoglobin ≥ 9 g/dL
    • Serum bilirubin ≤ 1.5 × the upper limit of normal (ULN)
    • Patients with known Gilbert’s disease who have serum bilirubin ≤ 3 × ULN may be enrolled
  11. Aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase ≤ 1.5 × ULN
  12. Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL/min on the basis of´the Cockcroft−Gault glomerular filtration rate estimation:
    • (140 − age) × (weight in kg) × (0.85)
    • 72 × (serum creatinine in mg/dL)
  13. International normalized ratio (INR) < 1.5 × upper limit of normal (ULN) and activated partial thromboplastin time (aPTT) < 1.5 ×ULN

    For patients requiring anticoagulation therapy with warfarin, a stable INR between 2−3 is required. If anticoagulation is required for a prosthetic heart valve, then INR should be between 2.5−3.5

  14. Absence of any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
  15. Ability and willingness to comply with study visits, treatment, testing, and to comply with the protocol, in the investigator’s judgment

Exclusion criteria:

Patients who meet any of the following criteria will be excluded from study entry:

  1. Any prior treatment for primary invasive breast cancer
  2. Patients with cT4 or cN3 stage breast tumors
  3. Metastatic (Stage IV) breast cancer
  4. Bilateral invasive breast cancer
  5. Multicentric breast cancer (the presence of more than one tumor in different quadrants of the breast)
  6. Patients who have undergone excisional biopsy of primary tumor and/or axillary lymph nodes
  7. Patients who have undergone sentinel lymph node biopsy prior to study treatment
  8. Patients for whom upfront chemotherapy is clinically judged appropriate as optimal neoadjuvant treatment
  9. Patients for whom immediate surgery is indicated
  10. Type 1 or 2 diabetes requiring antihyperglycemic medication
  11. Inability or unwillingness to swallow pills
  12. Malabsorption syndrome or other condition that would interfere with enteric absorption
  13. History of prior or currently active small or large intestine inflammation (such as Crohn’s disease or ulcerative colitis). Any patient with a baseline medical condition involving the gastrointestinal (GI) tract or who may have a predisposition for GI toxicity requires prior approval from the Medical Monitor.
  14. Congenital long QT syndrome or QT interval corrected using Fridericia’s formula (QTcF) > 470 msec
  15. DLCO < 60% of the predicted values
  16. Clinically significant (i.e., active) cardiovascular disease, uncontrolled hypertension, unstable angina, history of myocardial infarction, cardiac failure class II-IV (New York Heart Association), or any other that in the judgment of the investigator could jeopardize patient safety or study outcomes
  17. Any contraindication to MRI examination, including the following:
    • Neurostimulators
    • Pacemakers
    • Implanted metallic material or devices (metal implants or large tattoos in the field of view)
    • Severe claustrophobia
    • Physical characteristics (weight and/or size) that exceed the capabilities of the MRI scanner
    • Known allergy or hypersensitivity reactions to gadolinium, versetamide, or any of the inert ingredients in gadolinium-based contrast agents
    • Severe renal insufficiency, e.g., estimated glomerular filtration rate < 30 mL/min
  18. Active infection requiring intravenous (IV) antibiotics
  19. Patients requiring any daily supplemental oxygen
  20. Clinically significant history of liver disease, including viral or other known hepatitis, current alcohol abuse, or cirrhosis
  21. Known human immunodeficiency virus (HIV) infection
  22. Any other diseases, active or uncontrolled pulmonary dysfunction, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, that may affect the interpretation of the results, or renders the patients at high risk from treatment complications
  23. Significant traumatic injury within 3 weeks prior to initiation of study treatment
  24. Major surgical procedure within 4 weeks prior to initiation of study treatment
  25. Inability to comply with study and follow-up procedures
  26. History of other malignancy within 5 years prior to screening, except for appropriately treated carcinomain situ of the cervix, non-melanoma skin carcinoma,or Stage I uterine cancer