Testing the Addition of Copanlisib to Eribulin in Metastatic Triple Negative Breast Cancer

Inclusion Criteria:

• Male or female patients must have metastatic or unresectable carcinoma of the breastthat is estrogen receptor (ER) negative (less than 10%), progesterone receptor (PR)negative (less than 10%), and HER2 negative/unamplified

• Patients must have had prior treatment with an anthracycline and taxane in theneoadjuvant, adjuvant, or metastatic setting, unless contraindicated or deemed to besuboptimal therapy per the treating physician

• Patients must have progressed on at least one and not more than five priorchemotherapy regimens, including in the neoadjuvant, adjuvant, and metastaticsettings. Prior chemotherapy in the neoadjuvant and/or adjuvant setting counts asone prior line. Prior endocrine therapy, anti-HER2 directed therapies, PARPinhibitors, immunotherapy alone, or other targeted therapy will not count as a priortherapy line, as long as the patient meets the eligibility criteria prior toenrollment. Immunotherapy combined with chemotherapy will be considered one line

• All patients must agree to provide archival tumor material (most recent archivaltumor tissue immediately prior to enrollment is strongly preferred) for research andmust agree to undergo research tumor biopsy before treatment if presence of easilyaccessible lesions (judged by the treating physician). For patients with bone onlydisease, or patients without easily accessible lesions for the baseline researchbiopsy, availability of archival tumor material (2 x 4-5 micron section unstainedslides, plus 15-20 x 10 micron section unstained slides or a tumor rich block) fromprevious breast cancer diagnosis or treatment is required for PTEN and PIK3CAanalysis

• Age >= 18 years. Because no dosing or adverse event data are currently available onthe use of copanlisib in combination with eribulin in patients < 18 years of age,children are excluded from this study, but will be eligible for future pediatrictrials

• Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)

• Leukocytes >= 3,000/mcL

• Absolute neutrophil count >= 1,500/mcL

• Platelets >= 100,000/mcL

• Hemoglobin >= 8.0 g/dL

• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (=< 3 xinstitutional ULN for patients with Gilbert syndrome)

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) /alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 xinstitutional ULN

• Lipase =< 1.5 x ULN

• Creatinine < 1.5 mg/dL AND glomerular filtration rate (GFR) >= 50 mL/min/1.73 m^2

• International normalized ratio (INR) =< 1.5 x ULN

• Partial thromboplastin time (PTT) =< 1.5 x ULN

• Patients with history of known type I or type II diabetes must have a fastingglucose level of < 120 mg/dL on at least 2 separate occasions or glycosylatedhemoglobin measurement (HbA1c) < 8.5% at screening within 14 days prior toregistration

• Patients who are therapeutically treated with an agent such as warfarin or heparinwill be allowed to participate provided that their medication dose and INR/PTT isstable

• Prophylactic antiemetics may be administered according to standard practice. Theroutine use of standard antiemetics, including 5-HT3 blockers, such as granisetron,ondansetron, or an equivalent agent, is allowed as needed, as long as corrected QT (QTc) interval on baseline electrocardiogram (ECG) < 480 msec. The use ofcorticosteroids as antiemetics prior to copanlisib administration will not beallowed

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviraltherapy with undetectable viral load within 6 months are eligible for this trialprovided they are on a stable regimen of anti-retroviral therapy (ART) with nomedications otherwise prohibited by this protocol (e.g. drug-drug interactions)

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. For patients with HCV infection who are currently on treatment, they areeligible if they have an undetectable HCV viral load

• Patients with treated brain metastases are eligible if follow-up brain imaging aftercentral nervous system (CNS)-directed therapy shows no evidence of progression. Forpatients with history of treated brain metastases, brain scans will be performedwithin 6 weeks of study enrollment. During study enrollment in the phase 2 portionof the study, brain MRI will be performed every 12 weeks or sooner ifclinically-indicated in all patients with history of known brain metastases

• For phase 1 portion of the study only: patients with new or progressive brainmetastases (active brain metastases) or leptomeningeal disease are eligible if thetreating physician determines that immediate CNS specific treatment is not requiredand is unlikely to be required during the first cycle of therapy. This is notallowed for phase 2 portion of the study

• Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen are eligible for this trial

• Patients with known history or current symptoms of cardiac disease, or history oftreatment with cardiotoxic agents, should have a clinical risk assessment of cardiacfunction using the New York Heart Association Functional Classification. To beeligible for this trial, patients should be class 2B or better. Patients withhistory of known congestive heart failure (left ventricular ejection fraction [LVEF] < 50%) must have documented LVEF >= 50% within 12 months of study enrollment

• Known mutation status for PIK3CA and PTEN from archival tumor tissue analysis

• The effects of copanlisib on the developing human fetus are unknown. For this reasonand because maternal toxicity, developmental toxicity and teratogenic effects havebeen observed in nonclinical studies and PI3K inhibitors as well as othertherapeutic agents used in this trial are known to be teratogenic, women ofchild-bearing potential must agree to use adequate contraception (hormonal orbarrier method of birth control; abstinence) prior to study entry and for theduration of study participation, and for 1 month after the last dose of studymedication. Should a woman become pregnant or suspect she is pregnant while she orher partner is participating in this study, she should inform her treating physicianimmediately. Men treated or enrolled on this protocol must also agree to useadequate contraception prior to the study, for the duration of study participation,and 3.5 months after completion of study treatment

• Ability to understand and the willingness to sign a written informed consentdocument. Participants with impaired decision-making capacity (IDMC) who have alegally-authorized representative (LAR) and/or family member available will also beeligible

Exclusion Criteria:

• Patients who have had chemotherapy or radiotherapy within 3 weeks of treatment start (cycle 1 day 1 [C1D1])

• Patients who have had prior treatment with nitrosoureas or mitomycin C

• Patients who have had prior treatment with eribulin

• Patients who have had prior treatment with PI3K/mTOR/AKT pathway inhibitor

• Clinically significant ECG abnormality, including prolonged corrected QT (QTc)interval > 480 msec or history of risk factors for Torsades de Pointes (TdP) (i.e.congestive heart failure, hypokalemia, hypomagnesemia, bradyarrhythmias, familyhistory of long QT syndrome)

• Patients with pre-existing neuropathy of grade 2 or higher

• Myeloid growth factors within 7 days prior to treatment start

• Platelet transfusion within 7 days prior to treatment start

• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia

• Patients who are receiving any other investigational agents

• Immunosuppressive therapy is not allowed while on study

• Known tumor AKT mutation from archival tumor tissue analysis

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to copanlisib, PI3K inhibitors, or other agents used in study

• Copanlisib is primarily metabolized by CYP3A4. Therefore, the concomitant use ofstrong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin,ritonavir, indinavir, nelfinavir and saquinavir), and strong inducers of CYP3A4 (e.g. rifampin, phenytoin, carbamazepine, phenobarbital, St. John's Wort) are notpermitted from 14 days prior to enrollment until the end of the study. Othermedications that are prohibited while on copanlisib treatment:

• Herbal medications/preparations (except for vitamins)

• Anti-arrhythmic therapy other than beta blockers or digoxin

• Systemic corticosteroid therapy at a daily dose higher than 15 mg prednisone orequivalent is not permitted while on study. Previous corticosteroid therapy must bestopped or reduced to the allowed dose at least 7 days prior to the CT/MRIscreening. If a patient is on chronic corticosteroid therapy, corticosteroids shouldbe de-escalated to the maximum allowed dose before the screening. Patients may beusing topical or inhaled corticosteroids. Short-term (up to 7 days) systemiccorticosteroids above 15 mg prednisolone or equivalent will be allowed for themanagement of acute conditions (e.g., treatment non-infectious pneumonitis). The useof corticosteroids as antiemetics prior to copanlisib administration will not beallowed

• Patients with uncontrolled intercurrent illness

• Patients with psychiatric illness/social situations that would limit compliance withstudy requirements

• Patients with non-healing wound, ulcer, or bone fracture. Patients with compressionor pathologic fractures that are stable in the opinion of the investigator may beenrolled, as long as the bone fracture is not felt to pose a high likelihood oftreatment delay or difficulties in treatment adherence as per the judgement of theinvestigator

• Patients with active, clinically serious infections > grade 2 (Common TerminologyCriteria for Adverse Events Version 5.0 [CTCAEv5.0]) (viral, bacterial or fungalinfection)

• History of known Pneumocystis jiroveci pneumonia (PJP) infection

• Patients with arterial or venous thrombotic or embolic events such ascerebrovascular accident (including transient ischemic attacks), deep veinthrombosis or pulmonary embolism within 3 months before the start of studymedication

• Concurrent diagnosis of pheochromocytoma due to risk of hypertension with copanlisib

• Uncontrolled hypertension (defined as blood pressure >= 150/90 mm/Hg) despiteoptimal medical management (per investigator's opinion)

• Proteinuria as estimated by urine protein/creatinine ratio > 3.5 g/g on random urinesample or grade >= 3 as assessed by 24-hour urine protein collection

• Patients with history of or current uncontrolled autoimmune disease. Patients whohave adrenal or pituitary insufficiency who are stable on replacement therapy (i.e.thyroxine or physiologic corticosteroid replacement therapy that meets concomitantmedication restrictions) are allowed. Limited exceptions may be made to this afterdiscussion with the study principal investigator (PI)

• Patients with congenital QT prolongation

• The patient has a personal history of any of the following conditions: syncope ofcardiovascular etiology, ventricular arrhythmia of pathological origin (including,but not limited to, ventricular tachycardia and ventricular fibrillation), or suddencardiac arrest

• Pregnant women are excluded from this study because copanlisib is a PI3K inhibitoragent and eribulin is an anti-tubulin agent with the potential for teratogenic orabortifacient effects. Because there is an unknown but potential risk for adverseevents in nursing infants secondary to treatment of the mother with copanlisib anderibulin, breastfeeding should be discontinued if the mother is treated withcopanlisib and/or eribulin. These potential risks may also apply to other agentsused in this study