Phase II Study of Herzuma® Plus Gedatolisib in Patients With HER-2 Positive Metastatic Breast Cancer

Inclusion Criteria:

• Breast tumor with suspected PI3K-pathway dependence (either by mutation or by knownbiologic rationale. PI3K dependence includes the presence of a PIK3CA-mutant hotspotmutation, PIK3CA copy number gain, mTOR hotspot mutation, or PTEN loss in the archivalor fresh tumor tissue specimen identified in K-MASTER panel. All genetic findings mustbe reviewed by the study PI, prior to study entry.).
• Patient is an adult, female ≥ 19 years old at the time of informed consent.
• Patient has histologically and/or cytologically confirmed diagnosis of HER2-positivebreast cancer. HER2-positive breast cancer as defined by an immunohistochemistry (IHC)score of 3+ or gene amplified by in situ hybridization (ISH) as defined by a ratio of ≥ 2.0 for the number of HER2 gene copies to the number of chromosome 17copies.Metastatic or unresectable disease documented on diagnostic imaging studies.
• Metastatic or unresectable disease documented on diagnostic imaging studies.
• Prior 2 or more HER-2 directed therapy including trastuzumab for metastatic disease ismandatory.
• Patient must have at least one measurable lesion according to Response valuationCriteria in Solid Tumors version 1.1 (RECIST v.1.1).
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1.
• Adequate bone marrow and organ function including: WBC ≥ 3500/mL; Platelets ≥ 100,000/uL; Hemoglobin >9.0 g/dL; Total bilirubin ≤ 1.5x ULN; AST and ALT < 2.5 x ULN;Alkaline phosphatase <2.5x ULN; Creatinine ≤ 1.5x ULN or CCr >60 ml/min for patientswith abnormal serum Cr level function.
• Adequate glucose control, as defined by HbA1c < 7% and fasting blood glucose ≤ 126mg/dL (7.0 mmoL/L).
• Adequate glucose control, as defined by HbA1c < 7% and fasting blood glucose ≤ 126mg/dL (7.0 mmoL/L).
• Life expectancy higher than 3 months
• Patient has an adequate left ventricular ejection function of at least 50 % atbaseline, as measured by echocardiography.
• Written informed consent

Exclusion Criteria:

• Patient is pregnant or lactating, where pregnancy is defined as the state of a femaleafter conception and until the termination of gestation, confirmed by a positive humanchorionic gonadotropin (hCG) laboratory test.
• Patient has received previous treatment with a mechanistic target of rapamycin (mTOR)inhibitor or phosphoinositide 3-kinase (PI3K) inhibitor.
• Patient has symptomatic and unstable CNS metastases, except for treated brainmetastases. Treated brain metastases are defined as having no evidence of progressionor hemorrhage after treatment and no ongoing requirement for dexamethasone, asascertained by clinical examination and brain imaging (MRI or CT) during the screeningperiod. Anticonvulsants (stable dose) are allowed.
• Active and clinically significant bacterial, fungal or viral infection includinghepatitis B (HBV), hepatitis C (HCV), known human immunodeficiency virus syndrome (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness. Baseline viralassessment is not required in patients with no known infection.
• Current use or anticipated need for food or medications that are known moderate orgreater CYP3A4 inhibitors, including their administration within 7-days prior to thefirst gedatolisib dose and while receiving investigational product (ie, strong CYP3A4inhibitors: grapefruit juice or grapefruit/grapefruit related citrus fruits [e.g.,Seville oranges, pomelos], ketoconazole, miconazole, itraconazole, voriconazole,posaconazole, clarithromycin, telithromycin, indinavir, saquinavir, ritonavir,nelfinavir, amprenavir, fosamprenavir nefazodone, lopinavir, troleandomycin,mibefradil, conivaptan; moderate CYP3A4 inhibitors: erythromycin, verapamil,atazanavir, delavirdine, fluconazole, darunavir, diltiazem, aprepitant, imatinib,tofisopam, ciprofloxacin, and cimetidine).
• Concurrent use or anticipated need for medications that are mainly metabolized byUGT1A9 including their administration within 7-days prior to the first dose ofinvestigational product (e.g., propofol, propranolol, dapagliflozin, darexaban,mycophenolic acid, and tapentadol).
• Acetaminophen use within 24 hours before or after the first dose of gedatolisib.
• Current use or anticipated need for food or medications that are metabolized byCYP2D6, and of narrow therapeutic index including their administration within 10-daysprior to the first gedatolisib dose and while receiving investigational product.
• Concurrent use of herbal preparations.
• Major surgery within 4 weeks of first dose of investigational product or not fullyrecovered from any side effects of previous procedures.
• Any other malignancy within 3 years prior to first dose of investigational productexcept for adequately treated basal cell or squamous cell skin cancer, or carcinoma insitu of the cervix.
• QTc interval >480 msec (based on the mean value of the triplicate ECGs), family orpersonal history of long or short QT syndrome, Brugada syndrome or known history ofQTc prolongation or Torsade de Pointes.
• Any of the following within 6 months of first dose of investigational productmyocardial infarction, severe/unstable angina, ongoing cardiac dysrhythmias of NCICTCAE v. 5.0 Grade ≤2, atrial fibrillation of any grade, coronary/peripheral arterybypass graft, symptomatic congestive heart failure, cerebrovascular accident includingtransient ischemic attack, or symptomatic pulmonary embolism.
• History of interstitial pneumonitis.
• Other severe acute or chronic medical or psychiatric condition, including recent (within the past year) or active suicidal ideation or behavior, or laboratoryabnormality that may increase the risk associated with study participation orinvestigational product administration or may interfere with the interpretation ofstudy results and, in the judgment of the investigator, would make the patientinappropriate for entry into this study.