Testing the Addition of Copanlisib to Usual Treatment (Fulvestrant and Abemaciclib) in Metastatic Breast Cancer

Study Overview
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Brief Summary
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This phase I/II trial studies the effects (good and bad) of adding copanlisib to the usual therapy of fulvestrant and abemaciclib in treating patients with hormone receptor positive and HER2 negative breast cancer that has spread from where it first started (breast) to other places in the body (metastatic). Some breast cancer cells have receptors for the hormones estrogen or progesterone. These cells are hormone receptor positive and they need estrogen or progesterone to grow. This can affect how the cancer is treated. Hormone therapy using fulvestrant may fight breast cancer by blocking the use of estrogen by the tumor cells. Abemaciclib and copanlisib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Adding copanlisib to the usual therapy of fulvestrant and abemaciclib may work better than giving fulvestrant and abemaciclib alone in treating patients with breast cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate the safety profile of fulvestrant + abemaciclib + copanlisib hydrochloride (copanlisib) (FAC) and determine the recommended phase 2 dose (RP2D). II. To determine if FAC is superior to fulvestrant + abemaciclib (FA) using progression-free survival (PFS) as an endpoint. SECONDARY OBJECTIVES: I. To assess the objective response rate (ORR = partial response [PR] + complete response [CR]) and clinical benefit rate (CBR = PR + CR + stable disease [SD] >= 6 months) of FAC versus (vs.) FA. II. To compare the median PFS between FAC and FA arms in the following subgroups: IIa. Tumor PIK3CA/PTEN altered (PIK3CA mutation or PTEN mutation/PTEN loss). IIb. Tumor PIK3CA/PTEN not altered (wild-type PIK3CA and PTEN and without PTEN loss). IIc. Tumor phosphorylated (p)AKT levels (above or below the median). III. To assess whether triplet therapy with FAC inhibits AKT phosphorylation, reduces cyclin D1, and is more effective than FA in inhibiting Rb phosphorylation. EXPLORATORY OBJECTIVES: I. To assess whether the combination of abemaciclib and fulvestrant affect the copanlisib pharmacokinetics (PK). II. To assess the median PFS in the following molecularly defined subgroups treated with either FAC or FA: IIa. Tumor PIK3CA mutation vs. not. IIb. Tumor PTEN mutation/PTEN loss vs. not. IIc. Circulating tumor deoxyribonucleic acid (DNA) (ctDNA) PIK3CA mutation vs. not. IId. CtDNA PI3K/PTEN mutation vs. not. IIe. CtDNA ESR1 mutation vs. not. III. To assess baseline and treatment induced changes in various cancer associated pathways, including but not limited to PI3K, MAPK, ER, cyclins, CDKs and CDK inhibitors; and to correlate with treatment response and progression. IV. To correlate baseline and treatment induced changes in breast cancer intrinsic subtypes (PAM50), and PI3K messenger ribonucleic acid (mRNA) signature and expression of candidate genes with treatment response and benefit from adding copanlisib. V. To evaluate ctDNA mutations at baseline and over time for response predictors at baseline, and clonal evolution associated with treatment. VI. To correlate ctDNA mutation profiles with tumor sequencing, and correlate baseline ctDNA mutations, particularly in components of the PI3K pathway with treatment response, and correlate early changes in ctDNA variant allele frequencies (VAFs) with PFS, assess emergent resistant mutations at progression. VII. To assess resistance mechanisms to FA and FAC at baseline and at disease progression. VIII. To examine the molecular effects of FA and FAC on tumor and circulating markers. IX. To analyze tumor infiltrating lymphocytes at baseline, during treatment, and at disease progression. X. To assess whether copanlisib affects abemaciclib pharmacokinetics (PK). OUTLINE: This is a phase I two part, dose-escalation study of copanlisib hydrochloride and abemaciclib, followed by a phase II study. PHASE I (PART A): Patients receive copanlisib hydrochloride intravenously (IV) over 1 hour on days 1, 8, and 15 or days 1 and 15 (depending on dose level) and abemaciclib orally (PO) twice daily (BID) on on days 2-28 of cycle 1 and on days 1-28 of subsequent cycles. Patients also receive fulvestrant intramuscularly (IM) on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an echocardiography (ECHO) or multigated acquisition (MUGA) scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter. PHASE I (PART B): Patients receive copanlisib hydrochloride IV over 1 hour on days 1, 8, and 15 or days 1 and 15 (depending on dose level) and abemaciclib PO twice daily BID for 5 days each week (2 days off). Patients also receive fulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter. PHASE II: Patients are randomized to 1 of 2 arms. ARM I (FAC): Patients receive copanlisib hydrochloride as in phase I. Patients also receive abemaciclib PO BID as in phase I part B and fulvestrant IM on days 1 and 15 of cycle 1 and day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter. ARM II (FA): Patients receive abemaciclib PO BID on days 1-28 and fulvestrant IM on days 1 and 15 of cycle 1 and day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter. After completion of study treatment, patients are followed up every 3 months for 5 years.

Official Title
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A Randomized Phase I/II Trial of Fulvestrant and Abemaciclib in Combination With Copanlisib (FAC) Versus Fulvestrant and Abemaciclib Alone (FA) for Endocrine-Resistant, Hormone Receptor Positive, HER2 Negative Metastatic Breast Cancer (FAC vs FA)

Conditions
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Anatomic Stage IV Breast Cancer AJCC v8, Metastatic Breast Carcinoma, Metastatic HER2-Negative Breast Carcinoma, Metastatic Hormone Receptor-Positive Breast Carcinoma, Recurrent Breast Carcinoma

Intervention / Treatment
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* Drug: Abemaciclib
* Procedure: Biopsy
* Procedure: Biospecimen Collection
* Drug: Copanlisib Hydrochloride
* Procedure: Diagnostic Imaging
* Procedure: Echocardiography
* Drug: Fulvestrant
* Procedure: Multigated Acquisition Scan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically or cytologically confirmed ER and/or PR positive, HER2 negative or non-amplified breast cancer that is stage IV, with measurable or non-measurable disease. ER/PR positivity is defined as at least 1% positive or an Allred score of at least 3. HER2 status is defined per the 2018 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guideline All patients must agree to provide archival tumor material for research and must agree to undergo research tumor biopsy before treatment if presence of easily accessible lesions (judged by the treating physician). For patients with bone only disease, or patients without easily accessible lesions for the baseline research biopsy, availability of archival tumor material (2 x 4-5 micron section unstained slides, plus 15-20 x 10 micron section unstained slides or a tumor rich block) from previous breast cancer diagnosis or treatment is required for central PTEN and PIK3CA analysis No more than 1 prior chemotherapy in the metastatic setting. There is no limit on prior lines of endocrine therapy. (For patients enrolling to the phase 1 portion of the study, prior fulvestrant, CDK4/6 inhibitor, and everolimus is allowed) For patients enrolling to the randomized phase 2 portion of this study, demonstrated resistance to prior endocrine therapy in the metastatic setting is required; this is defined as: Progressed on prior endocrine therapy in the metastatic setting or, Relapsed on adjuvant endocrine therapy or, Relapsed within 12 months of completing adjuvant endocrine therapy or, If received adjuvant CDK4/6 inhibitor, relapsed at least 2 years after completion of adjuvant CDK4/6 inhibitor Washout from prior systemic anti-cancer therapy of at least 3 weeks from chemotherapy or 5 half-lives from oral targeted drugs, and treatment related adverse events recovered to grade 1 (except for alopecia) before the start of study treatment. Washout from prior radiation therapy of at least 2 weeks before the start of the study treatment. Washout from prior endocrine therapy is not required Age >= 18 years. Because no dosing or adverse event (AE) data are currently available on the use of copanlisib in combination with abemaciclib and fulvestrant in patients < 18 years of age, and because breast cancer is rare in children, children are excluded from this study Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) Leukocytes >= 3,000/mcL (no more than 7 days before starting study treatment) Absolute neutrophil count >= 1,500/mcL (no more than 7 days before starting study treatment) Platelets >= 100,000/mcL (no more than 7 days before starting study treatment) Hemoglobin >= 8.0 g/dL (no more than 7 days before starting study treatment) Total bilirubin =< 1.5 x institutional upper limit of normal (=< 3 x institutional upper limit of normal for patients with Gilbert syndrome) (no more than 7 days before starting study treatment) Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional upper limit of normal (=< 5 x institutional upper limit of normal for patients with liver involvement) (no more than 7 days before starting study treatment) Glomerular filtration rate >= 30 mL/min according to the Modification of Diet in Renal Disease (MDRD) abbreviated formula (no more than 7 days before starting study treatment) Lipase =< 1.5 x upper limit of normal (ULN) (no more than 7 days before starting study treatment) International normalized rate (INR) and partial thromboplastin time (PTT) =< 1.5 x ULN (except those on anti-coagulation therapy) (no more than 7 days before starting study treatment) Hemoglobin (Hb)A1c =< 8.5% or fasting glucose =< 120 mg/dL on at least 2 occasions within 14 days prior to registration if diabetic (no more than 7 days before starting study treatment) Left ventricular ejection fraction (LVEF) >= 50% Patients may be postmenopausal or premenopausal women on or planned to receive gonadotropin-releasing hormone (GnRH) agonist The effects of copanlisib on the developing human fetus are unknown. For this reason and because maternal toxicity, developmental toxicity and teratogenic effects have been observed in nonclinical studies and PI3K inhibitors as well as other therapeutic agents used in this trial are known to be teratogenic, 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, for the duration of study participation, and for 6 months after the last dose of copanlisib. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 6 months after completion of copanlisib administration Ability to understand and willing to sign a written informed consent document (or legally authorized representative, if applicable). Patient must agree to research team access to prior breast cancer diagnosis and treatment records, as well as reports of clinical tumor and blood sequencing results Patients with a history of treated brain metastases are allowed in the phase I portion of the trial provided there is no disease progression symptomatically and by imaging within 28 days prior to registration AND if the patient is off steroids Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial Exclusion Criteria: For patients enrolling to the randomized phase 2 portion of the study, prior treatment with a CDK4/6 inhibitor or fulvestrant, or a PI3K inhibitor in the metastatic setting is not allowed Patients who have had chemotherapy within 3 weeks or radiotherapy within 2 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study Patients who are receiving any other investigational agents Immunosuppressive therapy is not allowed while on study Receiving anti-arrhythmic therapy (beta blockers or digoxin are permitted) History of allergic reactions attributed to compounds of similar chemical or biologic composition to copanlisib, PI3K inhibitors, or other agents used in study For the randomized phase 2 portion of the study, patients with brain metastasis or a history of brain metastasis are not eligible For the phase 1 portion of the study, patients with progressive brain metastases should be excluded because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events (AEs) Copanlisib is primarily metabolized by CYP3A4. Therefore, the concomitant use of strong 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 not permitted from 14 days prior to enrollment until the end of the study It is important to regularly consult a frequently-updated medical reference for a list of drugs to avoid or minimize use of. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product Systemic corticosteroid therapy at a daily dose higher than 15 mg prednisone or equivalent is not permitted while on study. Previous corticosteroid therapy must be stopped or reduced to the allowed dose at least 7 days prior to the computed tomography (CT)/magnetic resonance imaging (MRI) screening. If a patient is on chronic corticosteroid therapy, corticosteroids should be de-escalated to the maximum allowed dose before the screening. Patients may be using topical or inhaled corticosteroids. Short-term (up to 7 days) systemic corticosteroids above 15 mg prednisolone or equivalent will be allowed for the management of acute conditions (e.g., treatment non-infectious pneumonitis) Major surgical procedure or significant traumatic injury (as judged by the investigator) within 28 days before start of treatment, or have not recovered from major side effects, open biopsy within 7 days before start of treatment Uncontrolled intercurrent illness, including but not limited to, symptomatic congestive heart failure (> New York Heart Association [NYHA] class 2), unstable angina pectoris, new-onset angina, uncontrolled hypertension despite optimal medical management, seizure disorder requiring medication, or psychiatric illness/social situations that would limit compliance with study requirements Myocardial infarction < 6 months before start of treatment Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 3 months before the start of study medication The patient has a personal history of any of the following conditions: syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest Proteinuria >= grade 3 as assessed by a 24-hour (h) protein quantification or estimated by urine protein: creatinine ratio > 3.5 on a random urine sample History of bleeding diathesis. Any hemorrhage or bleeding event >= grade 3 within 4 weeks prior to the start of study medication History or concurrent condition of interstitial lung disease of any severity and/or severely impaired lung function History of having received an allogeneic bone marrow or organ transplant Patients with non-healing wound, ulcer, or bone fracture not due to breast cancer Patients with active, clinically serious infections > grade 2 (Common Terminology Criteria for Adverse Events [CTCAE] version [v] 5.0) Patients with HbA1c > 8.5% at screening Concurrent diagnosis of pheochromocytoma Has undergone blood or platelet transfusion < 7 days prior to start of treatment Pregnant women are excluded from this study because copanlisib is a PI3K inhibitor agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with copanlisib, breastfeeding should be discontinued if the mother is treated with copanlisib. These potential risks may also apply to other agents used in this study Hepatitis B (HBV) or hepatitis C (HCV). All patients must be screened for HBV and HCV up to 28 days prior to study drug start using the routine hepatitis virus lab panel. Patients positive for hepatitis B surface antigen (HBsAg) and/or hepatitis B core antibody (HBcAb) will be eligible if they are negative for HBV DNA, these patients should receive prophylactic antiviral therapy. Patients positive for anti-HCV antibody will be eligible if they are negative for HCV RNA HIV positive patients on combination antiretroviral agents that are strong CYP3A4 inhibitors or inducers and who are unwilling or unable to change to antiretroviral therapies without such interactions are ineligible because of the potential for pharmacokinetic interactions with copanlisib, abemaciclib, and fulvestrant. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated Patients with history of, or current autoimmune disease are not eligible History of major surgical resection involving the stomach or small bowel, or preexisting Crohn's disease or ulcerative colitis or a preexisting chronic condition resulting in baseline grade 2 or higher diarrhea

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I Part A (copanlisib, abemaciclib, fulvestrant)<br>Patients receive copanlisib hydrochloride IV over 1 hour on days 1, 8, and 15 or days 1 and 15 (depending on dose level) and abemaciclib PO BID on days 2-28 of cycle 1 and on days 1-28 of subsequent cycles. Patients also receive fulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter. | Drug: Abemaciclib<br>* Given PO<br>* Other names: Verzenio;Procedure: Biopsy<br>* Undergo tissue biopsy<br>* Other names: Bx;Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Drug: Copanlisib Hydrochloride<br>* Given IV<br>* Other names: Copanlisib Dihydrochloride;Procedure: Diagnostic Imaging<br>* Undergo imaging<br>* Other names: Medical Imaging;Procedure: Echocardiography<br>* Undergo ECHO<br>* Other names: EC;Drug: Fulvestrant<br>* Given IM<br>* Other names: ZD9238;Procedure: Multigated Acquisition Scan<br>* Undergo MUGA<br>* Other names: Synchronized Multigated Acquisition Scanning;|
| Experimental: Phase I Part B (copanlisib, abemaciclib, fulvestrant)<br>Patients receive copanlisib hydrochloride IV over 1 hour on days 1, 8, and 15 or days 1 and 15 (depending on dose level) and abemaciclib PO twice daily BID for 5 days each week (2 days off). Patients also receive fulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter. | Drug: Abemaciclib<br>* Given PO<br>* Other names: Verzenio;Procedure: Biopsy<br>* Undergo tissue biopsy<br>* Other names: Bx;Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Drug: Copanlisib Hydrochloride<br>* Given IV<br>* Other names: Copanlisib Dihydrochloride;Procedure: Diagnostic Imaging<br>* Undergo imaging<br>* Other names: Medical Imaging;Procedure: Echocardiography<br>* Undergo ECHO<br>* Other names: EC;Drug: Fulvestrant<br>* Given IM<br>* Other names: ZD9238;Procedure: Multigated Acquisition Scan<br>* Undergo MUGA<br>* Other names: Synchronized Multigated Acquisition Scanning;|
| Experimental: Phase II, Arm I (FAC) (copanlisib, abemaciclib, fulvestrant)<br>Patients receive copanlisib hydrochloride as in phase I. Patients also receive abemaciclib PO BID on days 1-28 and fulvestrant IM on days 1 and 15 of cycle 1 and day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter. | Drug: Abemaciclib<br>* Given PO<br>* Other names: Verzenio;Procedure: Biopsy<br>* Undergo tissue biopsy<br>* Other names: Bx;Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Drug: Copanlisib Hydrochloride<br>* Given IV<br>* Other names: Copanlisib Dihydrochloride;Procedure: Diagnostic Imaging<br>* Undergo imaging<br>* Other names: Medical Imaging;Procedure: Echocardiography<br>* Undergo ECHO<br>* Other names: EC;Drug: Fulvestrant<br>* Given IM<br>* Other names: ZD9238;Procedure: Multigated Acquisition Scan<br>* Undergo MUGA<br>* Other names: Synchronized Multigated Acquisition Scanning;|
| Active Comparator: Phase II, Arm II (FA) (abemaciclib, fulvestrant)<br>Patients receive abemaciclib PO BID on days 1-28 and fulvestrant IM on days 1 and 15 of cycle 1 and day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo an ECHO or MUGA scan during screening and ECG during screening and as clinically indicated. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection pre-treatment, cycle 1 days 1, 8, 15, and 22, cycle 2 day 1, cycle 4 day 1, cycle 7 day 1, and then every 3 cycles thereafter and at time of progression. Patients undergo tissue biopsy pre-treatment and optionally on cycle 1 day 15 and at the time of progression. Patients also undergo imaging at screening and at the completion of cycle 3, then every 3 cycles thereafter. | Drug: Abemaciclib<br>* Given PO<br>* Other names: Verzenio;Procedure: Biopsy<br>* Undergo tissue biopsy<br>* Other names: Bx;Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Procedure: Diagnostic Imaging<br>* Undergo imaging<br>* Other names: Medical Imaging;Procedure: Echocardiography<br>* Undergo ECHO<br>* Other names: EC;Drug: Fulvestrant<br>* Given IM<br>* Other names: ZD9238;Procedure: Multigated Acquisition Scan<br>* Undergo MUGA<br>* Other names: Synchronized Multigated Acquisition Scanning;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicity (DLT) (Phase I) | DLT will be determined based on the incidence, intensity and duration of adverse events (AEs) that are related to the drug combinations and occur within 28 days of drug administration. The severity of AEs will be graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. AEs will be summarized by counts and percentages, overall as well as by dose levels and by patient characteristics. | Up to 28 days from drug administration | 
| Progression-free survival (PFS) (Phase II) | Radiographic disease recurrence/progression will be assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Will be estimated by the Kaplan-Meier (KM) product limit method and survival difference will be compared between the two arms by stratified log rank test. Hazard ratio with 95% confidence interval (CI) will be estimated between the two arms from the stratified Cox proportional hazard model, without and with adjustment for patient characteristics. | Time from randomization to the event of disease recurrence/progression or death due to any cause, assessed up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) (Phase II) | Will be defined as the proportion of response-evaluable patients who achieve complete response (CR) or partial response (PR) and assessed by RECIST 1.1 criteria. Will be estimated with a 95% exact CI and difference between the two arms will be compared by Fisher's exact test. Raw and adjusted odds ratio (OR) will be derived with 95% CI from logistic regression without and with adjustment for patient characteristics. | Up to 5 years | 
| Clinical benefit rate | Will be defined as the proportion of response-evaluable patients who achieve CR or PR or stable disease for at least 6 months and assessed by RECIST 1.1 criteria. Will be estimated with a 95% exact CI and difference between the two arms will be compared by Fisher's exact test. Raw and adjusted OR will be derived with 95% CI from logistic regression without and with adjustment for patient characteristics | Up to 5 years | 
| Overall survival | Will be assessed by RECIST 1.1 criteria. Will be estimated by the KM product limit method and survival difference will be compared between the two arms by stratified log rank test. Hazard ratio with 95% CI will be estimated between the two arms from the stratified Cox proportional hazard model, without and with adjustment for patient characteristics. | Time of randomization to time of death due to any cause or latest follow-up, whichever earlier, assessed up to 5 years | 
| Median progression-free survival (PFS) by PIK3CA/PTEN status | To investigate the predictive effect of PTEN/PIK3CA mutation, the treatment arms will be compared within the subset of patients with PIK3CA mutation or PTEN mutation, as well as in the subset of patients without these mutations, separately using the KM product limit method. Survival difference will be compared between the two arms by stratified log rank test. Hazard ratio with 95% CI will be estimated between the two arms from the stratified Cox proportional hazard model, without and with adjustment for patient characteristics. The interaction between the gene mutation and the treatment arm will be tested in a Cox proportional hazard model setting. If the interaction effect is not statistically significant, the prognostic effect of the PTEN/PIK3CA gene mutations for survival will be evaluated, PTEN/PIK3CA mutation will be associated with the survival endpoints by the KM method and Cox model among the control arm. | Baseline | 
| Median progression-free survival (PFS) by tumor phosphorylated (p)AKT levels | pAKT level at baseline will be associated with PFS by Cox proportional hazard model and by KM method in the binary scale dichotomized by median. Within each arm, the measurements at cycle 1, day 15 (C1D15) will be compared to the baseline by paired sample t-test or Wilcoxon signed rank test as appropriate. The percentage change at C1D15 from baseline will be calculated and compared between the FPC arm versus (vs.) FP arm by two sample t-test or Wilcoxon rank sum test as appropriate. | Baseline | 
| Change in tumor pAKT levels | Will be associated with PFS by Cox proportional hazard model and by KM method in the binary scale dichotomized by median. Within each arm, the measurements at C1D15 will be compared to the baseline by paired sample t-test or Wilcoxon signed rank test as appropriate. The percentage change at C1D15 from baseline will be calculated and compared between the FPC arm vs. FP arm by two sample t-test or Wilcoxon rank sum test as appropriate. | Baseline up to C1D15 | 
| Effectiveness of fulvestrant, abemaciclib, and copanlisib (FAC) compared to fulvestrant and abemaciclib (FA) | FAC will be evaluated for inhibition of AKT phosphorylation, reduction of cyclin D1, and effectiveness, compared to fulvestrant and abemaciclib, in inhibiting Rb phosphorylation. Balance/imbalance of biomarker distribution between arms will be examined by Fisher's exact test or two sample t-test. Prognostic effect of biomarker for PFS will be examined by the KM method or/and Cox proportional hazard model and for ORR using logistic regression model. Predictive effect of biomarker will be measured along multiple time points, generalized linear mixed effects model will be used to model longitudinal trajectories along time with the inference focus on the arm factor, without and with adjustment for other covariates. Two sample t-test or Wilcoxon rank sum test will be applied to compare time-matched biomarkers between the two arms or two patients' subsets. Paired sample t-test or Wilcoxon signed rank test will be applied to compare subject-specific biomarkers between two time points. | Up to 5 years |