Buparlisib or Alpelisib and Olaparib in Treating Patients with Recurrent Triple Negative Breast Cancer or High Grade Serous Ovarian Cancer

Inclusion Criteria

• Participants must have histologically or cytologically confirmed diagnosis of either: * Ovarian, fallopian tube, or primary peritoneal cancer of high grade serous histology which has recurred despite standard therapy or * Triple-negative breast cancer which has recurred despite standard therapy
• High grade serous ovarian cancer patients with either platinum refractory, platinum-resistant disease or platinum-sensitive disease are eligible; platinum refractory is defined as either relapse less than 2 months after the last platinum based therapy or relapse during platinum therapy; platinum-resistance is defined as relapse within 2 to 6 months after last dose of platinum-based chemotherapy; platinum sensitivity is defined as a relapse greater than 6 months after last dose of platinum-based chemotherapy; participants with platinum-sensitive disease must have progressed after receiving 2 prior platinum-based chemotherapy regimens
• Participants must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria or evaluable cancer via cancer antigen (CA)125 Gynecologic Cancer Intergroup (GCIG) criteria
• Triple negative breast cancer patients: participants may have either measurable disease via RECIST 1.1 criteria or evaluable disease
• If an ovarian cancer patient has a different histology than HGSC, but has a known germline BRCA1 or BRCA2 mutation and meets all other criteria listed, that patient is eligible
• Prior therapy: * Patients with recurrent, metastatic triple negative breast cancer must have had at least 1 chemotherapy regimen for metastatic breast cancer or have developed metastatic breast cancer within 1 year of completion of adjuvant chemotherapy * Prior therapy for high grade serous platinum-sensitive ovarian cancer patients must have included 2 prior platinum-based chemotherapy regimens * Participants must be at least 4 weeks since prior radiation therapy, 3 weeks since prior chemotherapy, and 6 weeks if the last regimen included carmustine (BCNU) or mitomycin C * No small-molecular kinase inhibitors or any other type of investigational agent within 4 weeks before the first dose of study treatment or 5 half-lives of the compound or active metabolite, whichever is shorter * For any hormonal therapy, participants must have stopped them at least 1 week prior to initiating therapy * Amount of prior radiotherapy: participants may not have had > 25% of their bone marrow radiated
• Estimated life expectancy of greater than 4 months
• Eastern Cooperative Oncology Group (ECOG) performance status =< 1
• Absolute neutrophil count (ANC) >= 1,500/mcL
• White blood cells (WBC) > 3000/mcL
• No features suggestive of myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) on peripheral blood smear or bone marrow biopsy
• Platelets >= 100,000/mcL
• Hemoglobin >= 9.0 g/dL
• Total bilirubin =< upper limit of normal (ULN) (except for patients with Gilbert’s syndrome who may only be included if the total bilirubin is =< 3.0 x institutional ULN or direct bilirubin =< 1.5 x ULN)
• In absence of liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN; if the patient has liver metastases, ALT and AST =< 5.0 x institutional ULN
• Total calcium (corrected for serum albumin) within institutional normal limits, or =< grade 1 according to National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 if judged clinically not significant by the investigator (bisphosphonate use for malignant hypercalcemia control is not allowed)
• Serum creatinine =< ULN or calculated creatinine clearance >= 35 mL/min using Cockcroft-Gault formula
• International normalized ratio (INR) =< 1.5
• Fasting serum amylase =< 2 x institutional ULN
• Fasting serum lipase =< institutional ULN
• Magnesium >= within institutional normal limits, or =< grade 1 according to NCI-CTCAE version 4.03 if judged clinically not significant by the investigator
• Potassium within normal limits for the institution, or corrected with supplements
• Fasting plasma glucose (FPG) =< 140 mg/dL (7.7 mmol/L) and glycosylated hemoglobin (HbA1c) =< 6.4% (both criteria have to be met) * For patients with FPG >= 100 mg/dL and/or HbA1c >= 5.7% (i.e. threshold for pre-diabetes) at screening, recommend lifestyle changes according to American Diabetes Association (ADA) guidelines, i.e. dietary advice (e.g. small frequent meals, low carbohydrate content, high fiber, balancing carbohydrate intake over the course of the day, three small meals and 2 small snacks rather than one large meal) and exercise; a consultation with a diabetologist is highly recommended
• Patients with treated limited stage basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the breast or cervix are eligible; patients with stage IA endometrial cancer are eligible if the following conditions are met: without vascular or lymphatic invasion AND no serous, clear cell or grade 3 histology; patients with early stage I or II cancers treated with curative intent who have no evidence of recurrent cancer 3 years following diagnosis and judged by the investigator to be at low risk or recurrence are eligible
• Patient is able to tolerate oral medications and does not have gastrointestinal illnesses that would preclude absorption of either olaparib or BKM120 or BYL719
• Willingness and ability to swallow study drugs
• No evidence of a bowel obstruction, abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months of study entry
• No current dependency on intravenous (IV) hydration or total parental nutrition (TPN)
• No line limit on prior therapies as long as the patient meets all other eligibility criteria; patients who have received prior PARP inhibitors and/or PI3kinase inhibitors are allowed to participate on the dose escalation portion; prior PARP inhibitors and/or PI3Kinase inhibitors excludes patients from the dose expansion cohort, but TNBC patients with BRCA mutations can go on if they had previously received a PARP inhibitor
• Evidence of non-child-bearing status for women of childbearing potential; negative urine or serum pregnancy test within 28 days of study treatment, confirmed prior to treatment on day 1
• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
• Ability to understand and the willingness to sign a written informed consent document
• Patients with stable and controlled brain metastases for at least 3 months who also do not require steroids

Exclusion Criteria

• TNBC participants with BRCA mutation, unless they've had prior PARP inhibitor
• Participants who are receiving any other study or off protocol anti-cancer agents
• History of grade 3 or 4 toxicities with previous PI3kinase inhibitor or PARP inhibitor exposure with the exception of hematologic toxicities
• No current or active dermatologic diagnoses that would preclude interpretation of skin toxicities of BKM120 and BYL719
• Patients receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4)
• Patient has a history of cardiac dysfunction or disease including any of the following: * Myocardial infarction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of left ventricular ejection fraction (LVEF) function * History of documented congestive heart failure (New York Heart Association functional classification III-IV) or documented cardiomyopathy * Corrected QT (QTc) interval > 470 msec on screening electrocardiogram (EKG) (using the QTc-Fridericia [QTcF] formula) * Angina pectoris that requires the use of anti-anginal medication * Ventricular arrhythmias except for benign premature ventricular contractions * Left ventricular ejection fraction (LVEF) < 50% as determined by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO) * Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medications * Conduction abnormality requiring a pacemaker * Valvular disease with documented compromise in cardiac function * Known history of QT/QTc prolongation or torsades de pointes (TdP); patients who are currently receiving treatment with medication with a known risk to prolong the QT interval or inducing torsades de pointes and the treatment cannot either be discontinued or switched to a different medication prior to starting study drugs * Symptomatic pericarditis * ST depression or elevation of >= 1.5 mm in 2 or more leads
• Persistent toxicities (>= CTCAE grade 2) caused by previous cancer therapy
• Major surgery within 14 days of starting study treatment and patients must have recovered from any effects of any major surgery
• Evidence of coagulopathy or bleeding diathesis; therapeutic anticoagulation for prior thromboembolic events is permitted; patients who are currently taking therapeutic doses of warfarin sodium or any other Coumadin-derivative anticoagulant are ineligible
• For participants on the BKM120 cohort only: * Any patient with a history of major depressive episode, bipolar disorder, obsessive/compulsive disorder, schizophrenia, a history of suicide attempt or ideation, or homicide/homicidal ideation as judged by the investigator and/or based on recent psychiatric assessment will not qualify for study participation * >= CTCAE grade 3 anxiety at the time of study entry regardless of whether the anxiety is being treated with medications * Patients with the following mood disorders as judged by the investigator or a psychiatrist, or as a result of patient’s mood assessment questionnaire: ** Medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (immediate risk of doing harm to others) ** >= CTCAE grade 3 anxiety ** Meets the cut-off score of >= 10 in the Patient Health Questionnaire (PHQ)-9 or a cut-off of >= 15 in the Generalized Anxiety Disorder (GAD)-7 mood scale, respectively, or selects a positive response of “1, 2, or 3” to question number 9 regarding potential for suicidal thoughts in the PHQ-9 (independent of the total score of the PHQ-9)
• Uncontrolled intercurrent illness including, but not limited to ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements
• Patients with acute or chronic liver, renal, lung disease or pancreatitis
• Grade 2 or higher proteinuria and hematuria
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of BKM120, BYL719, and/or olaparib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection); patients with unresolved diarrhea will be excluded
• Women who are pregnant or breast feeding or adults of reproductive potential not employing an effective method of birth control; breastfeeding should be discontinued if the mother is treated with BKM120 and olaparib or BYL719 and olaparib; double barrier contraceptives must be used through the trial by both sexes; oral, implantable, or injectable contraceptives may be affected by cytochrome P450 interactions, and are therefore not considered effective for this study; women of child-bearing potential, defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months (i.e., who has had menses any time in the preceding 12 consecutive months), must have a negative serum pregnancy test =< 72 hours prior to initiating treatment * Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum follicle-stimulating hormone (FSH) levels > 40 mIU/mL (for United States [US] only: and estradiol < 20 pg/mL) or have had surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks ago; in the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential * Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, must use highly effective contraception during treatment for 5 T1/2 (8 days) after stopping treatment and for additional 12 weeks (3 months in total after study drug discontinuation); the highly effective contraception is defined as either: ** True abstinence: when this is in line with the preferred and usual lifestyle of the subject; periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception ** Sterilization: have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago; in case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment ** Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate); for female subjects on the study, the vasectomized male partner should be the sole partner for that patient ** Use of a combination of any two of the following: *** Placement of an intrauterine device (IUD) or intrauterine system (IUS) *** Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository * Oral contraception, injected or implanted hormonal methods are not allowed * Fertile males, defined as all males physiologically capable of conceiving offspring must use condom during treatment, for 5 T1/2 (8 days) after stopping treatment and for additional 12 weeks (3 months in total after study drug discontinuation) and should not father a child in this period
• Known human immunodeficiency virus (HIV)-positive individuals on combination antiretroviral therapy are ineligible
• Patients receiving chronic treatment with steroids or another immunosuppressive agent * Note: topical applications (e.g. rash), inhaled sprays (e.g. obstructive airways diseases), eye drops or local injections (e.g. intra-articular) are allowed; patients with previously treated brain metastases, who are on stable low dose corticosteroids treatment (e.g. dexamethasone 2 mg/day, prednisolone 10 mg/day) for at least 14 days before start of study treatment are eligible
• Patients who have taken herbal medications and certain fruits within 7 days prior to starting study drug; herbal medications include, but are not limited to St. John's wort, kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng; fruits include the cytochrome P450, family 3, subfamily A (CYP3A) inhibitors Seville oranges, grapefruit, pummelos, or exotic citrus fruits