Testing the Addition of Copanlisib to Usual Treatment (Fulvestrant and Abemaciclib) in Metastatic Breast Cancer
NCT ID: NCT03939897
Last Updated: 2025-09-24
Study Results
Outcome measurements, participant flow, baseline characteristics, and adverse events have been published for this study.
View full resultsBasic Information
Get a concise snapshot of the trial, including recruitment status, study phase, enrollment targets, and key timeline milestones.
ACTIVE_NOT_RECRUITING
PHASE1
24 participants
INTERVENTIONAL
2020-06-17
2026-08-14
Brief Summary
Review the sponsor-provided synopsis that highlights what the study is about and why it is being conducted.
Related Clinical Trials
Explore similar clinical trials based on study characteristics and research focus.
Phase II Trial of Capecitabine With Fulvestrant for Postmenopausal Women With Hormone Receptor Positive Metastatic Breast Cancer
NCT00534417
Abexinostat, Palbociclib, and Fulvestrant for the Treatment of Breast or Gynecologic Cancer
NCT04498520
Testing the Use of Fulvestrant and Binimetinib Targeted Treatment for NF1 Mutation in Hormone Receptor-Positive Metastatic Breast Cancer (A ComboMATCH Treatment Trial)
NCT05554354
Capecitabine and Lapatinib Ditosylate With or Without Cixutumumab in Treating Patients With Previously Treated HER2-Positive Stage IIIB-IV Breast Cancer
NCT00684983
Combination Chemotherapy in Treating Older Women With Metastatic Breast Cancer
NCT00010075
Detailed Description
Dive into the extended narrative that explains the scientific background, objectives, and procedures in greater depth.
I. To evaluate the safety profile of fulvestrant + abemaciclib + copanlisib hydrochloride (copanlisib) (FAC) and determine the recommended phase 2 dose (RP2D).
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 and medium progression free survival (PFS) with FAC.
EXPLORATORY OBJECTIVES:
I. 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.
V. 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
See the medical conditions and disease areas that this research is targeting or investigating.
Study Design
Understand how the trial is structured, including allocation methods, masking strategies, primary purpose, and other design elements.
RANDOMIZED
SEQUENTIAL
TREATMENT
NONE
Study Groups
Review each arm or cohort in the study, along with the interventions and objectives associated with them.
Phase I Part A Dose 1 (copanlisib, abemaciclib, fulvestrant)
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.
Abemaciclib
Given PO
Biopsy Procedure
Undergo tissue biopsy
Biospecimen Collection
Undergo blood sample collection
Copanlisib Hydrochloride
Given IV
Diagnostic Imaging Testing
Undergo imaging
Echocardiography Test
Undergo ECHO
Fulvestrant
Given IM
Multigated Acquisition Scan
Undergo MUGA
Phase I Part A Dose 2 (copanlisib, abemaciclib, fulvestrant)
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.
Abemaciclib
Given PO
Biopsy Procedure
Undergo tissue biopsy
Biospecimen Collection
Undergo blood sample collection
Copanlisib Hydrochloride
Given IV
Diagnostic Imaging Testing
Undergo imaging
Echocardiography Test
Undergo ECHO
Fulvestrant
Given IM
Multigated Acquisition Scan
Undergo MUGA
Phase I Part B Dose 1b (copanlisib, abemaciclib, fulvestrant)
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.
Abemaciclib
Given PO
Biopsy Procedure
Undergo tissue biopsy
Biospecimen Collection
Undergo blood sample collection
Copanlisib Hydrochloride
Given IV
Diagnostic Imaging Testing
Undergo imaging
Echocardiography Test
Undergo ECHO
Fulvestrant
Given IM
Multigated Acquisition Scan
Undergo MUGA
Phase I Part B Dose 2b (copanlisib, abemaciclib, fulvestrant)
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.
Abemaciclib
Given PO
Biopsy Procedure
Undergo tissue biopsy
Biospecimen Collection
Undergo blood sample collection
Copanlisib Hydrochloride
Given IV
Diagnostic Imaging Testing
Undergo imaging
Echocardiography Test
Undergo ECHO
Fulvestrant
Given IM
Multigated Acquisition Scan
Undergo MUGA
Interventions
Learn about the drugs, procedures, or behavioral strategies being tested and how they are applied within this trial.
Abemaciclib
Given PO
Biopsy Procedure
Undergo tissue biopsy
Biospecimen Collection
Undergo blood sample collection
Copanlisib Hydrochloride
Given IV
Diagnostic Imaging Testing
Undergo imaging
Echocardiography Test
Undergo ECHO
Fulvestrant
Given IM
Multigated Acquisition Scan
Undergo MUGA
Other Intervention Names
Discover alternative or legacy names that may be used to describe the listed interventions across different sources.
Eligibility Criteria
Check the participation requirements, including inclusion and exclusion rules, age limits, and whether healthy volunteers are accepted.
Inclusion Criteria
* 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
* 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
18 Years
ALL
No
Sponsors
Meet the organizations funding or collaborating on the study and learn about their roles.
National Cancer Institute (NCI)
NIH
Responsible Party
Identify the individual or organization who holds primary responsibility for the study information submitted to regulators.
Principal Investigators
Learn about the lead researchers overseeing the trial and their institutional affiliations.
Cynthia X Ma
Role: PRINCIPAL_INVESTIGATOR
Yale University Cancer Center LAO
Locations
Explore where the study is taking place and check the recruitment status at each participating site.
University of Alabama at Birmingham Cancer Center
Birmingham, Alabama, United States
UC Irvine Health Cancer Center-Newport
Costa Mesa, California, United States
UC Irvine Health/Chao Family Comprehensive Cancer Center
Orange, California, United States
University of Kentucky/Markey Cancer Center
Lexington, Kentucky, United States
Siteman Cancer Center at Saint Peters Hospital
City of Saint Peters, Missouri, United States
Siteman Cancer Center at West County Hospital
Creve Coeur, Missouri, United States
Washington University School of Medicine
St Louis, Missouri, United States
Siteman Cancer Center-South County
St Louis, Missouri, United States
Siteman Cancer Center at Christian Hospital
St Louis, Missouri, United States
Bellevue Hospital Center
New York, New York, United States
Laura and Isaac Perlmutter Cancer Center at NYU Langone
New York, New York, United States
Wake Forest University at Clemmons
Clemmons, North Carolina, United States
Wake Forest University Health Sciences
Winston-Salem, North Carolina, United States
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, United States
Countries
Review the countries where the study has at least one active or historical site.
Provided Documents
Download supplemental materials such as informed consent forms, study protocols, or participant manuals.
Document Type: Study Protocol and Statistical Analysis Plan
Document Type: Informed Consent Form: Research Study Informed Consent Document-Phase 1
Document Type: Informed Consent Form: Research Study Informed Consent Document-Phase 2
Other Identifiers
Review additional registry numbers or institutional identifiers associated with this trial.
NCI-2019-02752
Identifier Type: REGISTRY
Identifier Source: secondary_id
201911082
Identifier Type: -
Identifier Source: secondary_id
10287
Identifier Type: OTHER
Identifier Source: secondary_id
10287
Identifier Type: OTHER
Identifier Source: secondary_id
NCI-2019-02752
Identifier Type: -
Identifier Source: org_study_id
More Related Trials
Additional clinical trials that may be relevant based on similarity analysis.