Anatomic Stage IV Breast Cancer AJCC v8Phase 1NCT03939897
Testing the Addition of Copanlisib to Usual Treatment (Fulvestrant and Abemaciclib) in Metastatic Breast Cancer
A Phase 1 study testing Abemaciclib, Biopsy Procedure and Biospecimen Collection in people with Anatomic Stage IV Breast Cancer AJCC v8 and Metastatic Breast Carcinoma, run by National Cancer Institute (NCI) at 14 sites in United States.
Trial summary
This phase I 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). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Anatomic Stage IV Breast Cancer AJCC v8, Metastatic Breast Carcinoma, Metastatic HER2-Negative Breast Carcinoma
- What is being tested?
- Abemaciclib, Biopsy Procedure and Biospecimen Collection
- Type of treatment
- Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 24 participants
- Where
- 14 sitesUnited States
- Study dates
- 17 Jun 2020to 31 Jul 2027
- Phase
- Phase 1
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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,
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- 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
Who cannot join
- 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
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- 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
Trial locations and contacts
14 sites in 1 country.
14 sites in 1 country
United States14 sites
University of Alabama at Birmingham Cancer Center
Birmingham, Alabama, 35233
Siteman Cancer Center at Saint Peters Hospital
City of Saint Peters, Missouri, 63376
Wake Forest University at Clemmons
Clemmons, North Carolina, 27012
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, 43210
UC Irvine Health Cancer Center-Newport
Costa Mesa, California, 92627
Siteman Cancer Center at West County Hospital
Creve Coeur, Missouri, 63141
University of Kentucky/Markey Cancer Center
Lexington, Kentucky, 40536
Bellevue Hospital Center
New York, New York, 10016
Laura and Isaac Perlmutter Cancer Center at NYU Langone
New York, New York, 10016
UC Irvine Health/Chao Family Comprehensive Cancer Center
Orange, California, 92868
Washington University School of Medicine
St Louis, Missouri, 63110
Siteman Cancer Center-South County
St Louis, Missouri, 63129
Siteman Cancer Center at Christian Hospital
St Louis, Missouri, 63136
Wake Forest University Health Sciences
Winston-Salem, North Carolina, 27157
About this study
Official title: 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)
This phase I 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.
Read the detailed description
PRIMARY OBJECTIVES:
- To evaluate the safety profile of fulvestrant + abemaciclib + copanlisib hydrochloride (copanlisib) (FAC) and determine the recommended phase 2 dose (RP2D).
SECONDARY OBJECTIVES:
- 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 and medium progression free survival (PFS) with FAC.
EXPLORATORY OBJECTIVES:
- To assess whether triplet therapy with FAC inhibits AKT phosphorylation, reduces cyclin D1, and inhibits Rb phosphorylation.
II. To assess whether the combination of abemaciclib and fulvestrant affect the copanlisib pharmacokinetics (PK).
III. To assess the objective response rate (ORR), clinical benefit rate (CBR) and median PFS in the following molecularly defined subgroups treated with FAC such as mutations in genes in the PI3K pathway (PIK3CA, AKT, PTEN etc), ESR1, TP53, or PTEN IHC loss vs not.
IV. 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.
- 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.
VI. To evaluate ctDNA mutations at baseline and over time for response predictors at baseline, and clonal evolution associated with treatment.
VII. 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.
VIII. To assess resistance mechanisms to FAC at baseline and at disease progression.
IX. To examine the molecular effects of FAC on tumor and circulating markers. X. To analyze tumor infiltrating lymphocytes at baseline, during treatment, and at disease progression.
OUTLINE: This is a phase I two part, dose-escalation study of copanlisib hydrochloride and abemaciclib.
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.
After completion of study treatment, patients are followed up every 3 months for 5 years.
- As of November 2023, Bayer has decided to voluntarily withdraw the NDA for copanlisib, phase II portion removed.
- Conditions
- Anatomic Stage IV Breast Cancer AJCC v8, Metastatic Breast Carcinoma, Metastatic HER2-Negative Breast Carcinoma, Metastatic Hormone Receptor-Positive Breast Carcinoma, Recurrent Breast Carcinoma
- Being tested
- Abemaciclib, Biopsy Procedure, Biospecimen Collection, Copanlisib Hydrochloride, Diagnostic Imaging Testing
- Medical subject headings
- Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AbemaciclibDrug
Also called LY 2835219, LY-2835219, LY2835219, Verzenio
Given PO
Biopsy ProcedureProcedure or surgery
Also called Biopsy, BIOPSY_TYPE, Bx
Undergo tissue biopsy
Biospecimen CollectionProcedure or surgery
Also called Biological Sample Collection, Biospecimen Collected, Sample Collection, Specimen Collection
Undergo blood sample collection
Copanlisib HydrochlorideDrug
Also called 5-Pyrimidinecarboxamide, 2-Amino-N-(2,3-dihydro-7-methoxy-8-(3-(4-morpholinyl)propoxy)imidazo(1,2-C)quinazolin-5-yl)-, Hydrochloride (1:2), Aliqopa, BAY 80-6946 Dihydrochloride, BAY-80-6946 Dihydrochloride
Given IV
Diagnostic Imaging TestingProcedure or surgery
Also called Diagnostic Imaging, Medical Imaging
Undergo imaging
Echocardiography TestProcedure or surgery
Also called EC, Echocardiography
Undergo ECHO
FulvestrantDrug
Also called Faslodex, Faslodex(ICI 182,780), ICI 182,780, ICI 182780
Given IM
Multigated Acquisition ScanProcedure or surgery
Also called Blood Pool Scan, Equilibrium Radionuclide Angiography, Gated Blood Pool Imaging, Gated Heart Pool Scan
Undergo MUGA
| Study group | Role | What they receive |
|---|---|---|
| Phase I Part A Dose 1 (copanlisib, abemaciclib, fulvestrant) | Experimental | Patients receive 45 mg copanlisib hydrochloride IV over 1 hour on days 1 and 15 and 100 mg abemaciclib PO BID on days 2-28 of cycle 1 and on days 1-28 of subsequent cycles. Patients also receive 500 mg 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. Receives: Drug: Abemaciclib; Procedure: Biopsy Procedure; Procedure: Biospecimen Collection; Drug: Copanlisib Hydrochloride; Procedure: Diagnostic Imaging Testing; Procedure: Echocardiography Test; Drug: Fulvestrant; Procedure: Multigated Acquisition Scan |
| Phase I Part A Dose 2 (copanlisib, abemaciclib, fulvestrant) | Experimental | Patients receive 45 mg copanlisib hydrochloride IV over 1 hour on days 1, 8, and 15 and 150 mg abemaciclib PO twice daily BID for 5 days each week (2 days off). Patients also receive f500 mg 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. Receives: Drug: Abemaciclib; Procedure: Biopsy Procedure; Procedure: Biospecimen Collection; Drug: Copanlisib Hydrochloride; Procedure: Diagnostic Imaging Testing; Procedure: Echocardiography Test; Drug: Fulvestrant; Procedure: Multigated Acquisition Scan |
| Phase I Part B Dose 1b (copanlisib, abemaciclib, fulvestrant) | Experimental | Patients receive 45 mg copanlisib hydrochloride IV over 1 hour on days 1 and 15 and 100 mg abemaciclib PO twice daily BID for 5 days each week (2 days off). Patients also receive 500 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. Receives: Drug: Abemaciclib; Procedure: Biopsy Procedure; Procedure: Biospecimen Collection; Drug: Copanlisib Hydrochloride; Procedure: Diagnostic Imaging Testing; Procedure: Echocardiography Test; Drug: Fulvestrant; Procedure: Multigated Acquisition Scan |
| Phase I Part B Dose 2b (copanlisib, abemaciclib, fulvestrant) | Active comparator | Patients receive 45 mg copanlisib hydrochloride IV over 1 hour on days 1, 8, and 15 and 100 mg abemaciclib PO twice daily BID for 5 days each week (2 days off). Patients also receive 500 mg 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. Receives: Drug: Abemaciclib; Procedure: Biopsy Procedure; Procedure: Biospecimen Collection; Drug: Copanlisib Hydrochloride; Procedure: Diagnostic Imaging Testing; Procedure: Echocardiography Test; Drug: Fulvestrant; Procedure: Multigated Acquisition Scan |
What is being measured
The primary outcome is the main question the study is designed to answer.
Dose-limiting Toxicity (DLT)
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.
Measured: Up to 28 days from drug administration
Secondary outcomes (4)
Progression-free Survival (PFS)
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.
Measured: Time from randomization to the event of disease recurrence/progression or death due to any cause, assessed up to 4 years
Objective Response Rate (ORR)
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.
Measured: Time from randomization to the event of disease recurrence/progression or death due to any cause, assessed up to 4 years
Clinical Benefit Rate
Will be defined as the proportion of response-evaluable patients who achieve CR or PR or stable disease (SD) 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
Measured: Time from randomization to the event of disease recurrence/progression or death due to any cause, assessed up to 4 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.
Measured: Time of randomization to time of death due to any cause or latest follow-up, whichever earlier, assessed up to 4 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 May 2019
- Study start17 Jun 2020
- Primary completion22 Jun 2023
- Study completion31 Jul 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Anatomic Stage IV Breast Cancer AJCC v8Studies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 24 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Cynthia X Ma, Principal investigator, Yale University Cancer Center LAO
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03939897
- Sponsor's protocol ID
- NCI-2019-02752
- Other IDs
- NCI-2019-02752, 201911082, 10287, 10287, UM1CA186689, UM1CA186704
- Status last verified
- Sep 2026
- First submitted
- 6 May 2019
- Last updated
- 8 Sep 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.