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Testing the Addition of Copanlisib to Eribulin for the Treatment of Advanced-Stage Triple Negative Breast Cancer

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ClinicalTrials.gov Identifier: NCT04345913
Recruitment Status : Recruiting
First Posted : April 15, 2020
Last Update Posted : September 16, 2021
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This phase I/II trial studies the side effects and best dose of copanlisib and how well it works when given together with eribulin in treating patients with triple negative breast cancer that has spread to other places in the body (advanced stage). Copanlisib stops the growth of a protein called PI3K, which is often changed in tumor cells and causes resistance to treatment. Chemotherapy drugs, such as eribulin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving copanlisib and eribulin may work better in treating advanced stage triple negative breast cancer compared to eribulin alone.

Condition or disease Intervention/treatment Phase
Anatomic Stage III Breast Cancer AJCC v8 Anatomic Stage IIIA Breast Cancer AJCC v8 Anatomic Stage IIIB Breast Cancer AJCC v8 Anatomic Stage IIIC Breast Cancer AJCC v8 Anatomic Stage IV Breast Cancer AJCC v8 Metastatic Breast Carcinoma Prognostic Stage III Breast Cancer AJCC v8 Prognostic Stage IIIA Breast Cancer AJCC v8 Prognostic Stage IIIB Breast Cancer AJCC v8 Prognostic Stage IIIC Breast Cancer AJCC v8 Prognostic Stage IV Breast Cancer AJCC v8 Triple-Negative Breast Carcinoma Unresectable Breast Carcinoma Drug: Copanlisib Hydrochloride Drug: Eribulin Mesylate Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Trial Evaluating the Safety and Efficacy of Eribulin in Combination With Copanlisib in Patients With Metastatic Triple Negative Breast Cancer
Actual Study Start Date : August 10, 2020
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : December 31, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Active Comparator: Group I (eribulin)
Patients receive eribulin IV over 2-5 minutes on days 1 and 8. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Drug: Eribulin Mesylate
Given IV
Other Names:
  • B1939 Mesylate
  • E7389
  • ER-086526
  • Halaven
  • Halichondrin B Analog

Experimental: Group II (eribulin, copanlisib)
Patients receive copanlisib IV over 60 minutes and eribulin IV over 2-5 minutes on days 1 and 8 or days 1 and 15. Cycles repeat every 21 or 28 days in the absence of disease progression or unacceptable toxicity.
Drug: Copanlisib Hydrochloride
Given IV
Other Names:
  • 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
  • Copanlisib Dihydrochloride

Drug: Eribulin Mesylate
Given IV
Other Names:
  • B1939 Mesylate
  • E7389
  • ER-086526
  • Halaven
  • Halichondrin B Analog




Primary Outcome Measures :
  1. Maximum tolerated dose (MTD) (Phase I) [ Time Frame: Up to 28 days ]
    The maximum tolerated dose (MTD) is defined as the highest dose level at which at most 1 of 6 patients experience a dose limiting toxicity (DLT) during the observation window.

  2. Recommended phase 2 dose (RP2D) (Phase I) [ Time Frame: Up to 28 days ]
    Recommended phase 2 dose is the maximum tolerated dose at which at most 1 of 6 patients experience a dose limiting toxicity during the observation window.

  3. Progression free survival (PFS) (Phase II) [ Time Frame: From date of treatment start to date of progression or death, assessed up to 3 years following completion of study treatment ]
    Patients who have not experienced progression or death will be censored at last follow up. PFS will be estimated using the Kaplan-Meier product limit estimator.


Secondary Outcome Measures :
  1. Objective Response Rate (ORR) (Phase I) [ Time Frame: Up to 3 years ]
    The objective response rate (ORR) is defined as the proportion of patients with complete response, partial response by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

  2. Clinical benefit rate (CBR) (Phase I) [ Time Frame: Up to 3 years ]
    CBR defined as the proportion of patients with toxicity in each arm, in the overall population, and by PTEN/PIK3CA mutation status based on archival tumor tissue next generation sequencing.

  3. PFS (Phase I) [ Time Frame: From start of treatment to time of progression or death, whichever occurs first, assessed up to 3 years ]
    PFS is defined from date of treatment start to date of progression or death. Patients who have not experienced progression or death will be censored at last follow up.

  4. ORR (Phase II) [ Time Frame: Up to 3 years ]
    Measured in the overall population by treatment arm; by treatment arm in patients with triple negative breast cancer (TNBC) harboring mutations in PIK3CA/ PTEN or loss of PTEN expression by immunohistochemistry (IHC) of baseline (pre-treatment) biopsy; and by treatment arm in patients with TNBC harboring mutations in PIK3CA/ PTEN by circulating tumor deoxyribonucleic acid (ctDNA) at baseline (pre-treatment) biopsy and potential changes over time.

  5. CBR (Phase II) [ Time Frame: Up to 3 years ]
    Measured in the overall population by treatment arm, in patients with TNBC harboring mutations in PIK3CA/ PTEN or loss of PTEN expression by IHC of baseline (pre-treatment) biopsy, by treatment arm in patients with TNBC harboring mutations in PIK3CA/ PTEN by ctDNA at baseline (pre-treatment) biopsy and potential changes over time.

  6. PFS (Phase II) [ Time Frame: From start of treatment to time of progression or death, whichever occurs first, assessed up to 3 years ]
    Measured by treatment arm in patients with TNBC harboring mutations in PIK3CA/ PTEN or loss of PTEN expression by IHC of baseline (pre-treatment) biopsy and by treatment arm in patients with TNBC harboring mutations in PIK3CA/ PTEN by ctDNA at baseline (pre-treatment) biopsy and potential changes over time. PFS will be estimated using the Kaplan-Meier product limit estimator.

  7. Target inhibition of PI3K pathway and mitotic arrest [ Time Frame: Up to 3 years ]
    Using phospho-AKT and phospho-histone H3 with eribulin plus copanlisib versus eribulin alone.


Other Outcome Measures:
  1. Tumor tissue mutation or gene expression profiles [ Time Frame: Up to 3 years ]
    Will correlate with treatment response

  2. Intrinsic and adaptive resistance mechanisms [ Time Frame: Baseline up to 3 years ]
    Will analyze pre and post treatment biopsies for gene expression and proteomic changes.

  3. ctDNA mutation profiles and changes in mutation profile and variant allele frequencies (VAFs) [ Time Frame: Baseline, cycle 2 day 1 (C2D2), and at disease progression ]
    Will determine ctDNA mutation profiles at baseline and changes in mutation profile and VAFs on C2D1 and at disease progression compared to baseline to correlate with treatment response.

  4. Circulating biomarkers predictive of treatment response [ Time Frame: Up to 3 years ]
  5. Plasma and serum proteomics and metabolomics predictive of treatment response [ Time Frame: Up to 3 years ]
  6. PTEN IHC results [ Time Frame: Up to 3 years ]
    Will compare PTEN IHC results at disease progression compared to baseline.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have metastatic or unresectable carcinoma of the breast that is estrogen receptor (ER) negative (less than 10%), progesterone receptor (PR) negative (less than 10%), and HER2 negative/unamplified
  • Patients must have had prior treatment with an anthracycline and taxane, unless contraindicated
  • Patients must have progressed on at least one and not more than five prior chemotherapy regimens, including in the neoadjuvant, adjuvant, and metastatic settings
  • All patients must agree to provide archival tumor material (most recent archival tumor tissue immediately prior to enrollment is strongly preferred) 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 PTEN and PIK3CA analysis
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)
  • Leukocytes >= 3,000/mcL
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Hemoglobin >= 8.0 g/dL
  • Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (=< 3 x institutional ULN for patients with Gilbert syndrome)
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) / alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN
  • Lipase =< 1.5 x ULN
  • Creatinine < 1.5 mg/dL AND glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2
  • Partial thromboplastin time (PTT) =< 1.5 x ULN
  • International normalized ratio (INR) =< 1.5 x ULN
  • Patients with history of known type I or type II diabetes must have a fasting glucose level of < 120 mg/dL on at least 2 separate occasions or glycosylated hemoglobin measurement (HbA1c) < 8.5% at screening within 14 days prior to registration
  • Patients who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate provided that their medication dose and INR/PTT is stable
  • Prophylactic antiemetics may be administered according to standard practice. The routine use of standard antiemetics, including 5-HT3 blockers, such as granisetron, ondansetron, or an equivalent agent, is allowed as needed, as long as corrected QT (QTc) interval on baseline electrocardiogram (ECG) < 480 msec. The use of corticosteroids as antiemetics prior to copanlisib administration will not be allowed
  • For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
  • Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial provided they are on a stable regimen of anti-retroviral therapy (ART) with no medications otherwise prohibited by this protocol (e.g. drug-drug interactions)
  • 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 treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression. For patients with history of treated brain metastases, brain scans will be performed within 6 weeks of study enrollment. During study enrollment in the phase 2 portion of the study, brain MRI will be performed every 12 weeks or sooner if clinically-indicated in all patients with history of known brain metastases
  • For phase 1 portion of the study only: patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy. This is not allowed for phase 2 portion of the study
  • 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
  • Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better. Patients with history of known congestive heart failure (left ventricular ejection fraction [LVEF] < 50%) must have documented LVEF >= 50% within 12 months of study enrollment
  • Known mutation status for PIK3CA and PTEN from archival tumor tissue analysis
  • The effects of copanlisib on the developing human fetus are unknown. For this 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 must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation, and for 1 month after the last dose of study medication. 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 3.5 months after completion of study treatment
  • Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity (IDMC) who have a legally-authorized representative (LAR) and/or family member available will also be eligible

Exclusion Criteria:

  • Patients who have had chemotherapy or radiotherapy within 3 weeks
  • Patients who have had prior treatment with nitrosoureas or mitomycin C
  • Patients who have had prior treatment with eribulin
  • Patients who have had prior treatment with PI3K/mTOR/AKT pathway inhibitor
  • Clinically significant ECG abnormality, including prolonged corrected QT (QTc) interval > 480 msec or history of risk factors for Torsades de Pointes (TdP) (i.e. congestive heart failure, hypokalemia, hypomagnesemia, bradyarrhythmias, family history of long QT syndrome)
  • Patients with pre-existing neuropathy of grade 2 or higher
  • Myeloid growth factors within 14 days prior to treatment start
  • Platelet transfusion within 7 days prior to treatment start
  • Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia
  • Patients who are receiving any other investigational agents
  • Immunosuppressive therapy is not allowed while on study
  • Known tumor AKT mutation from archival tumor tissue analysis
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to copanlisib, PI3K inhibitors, or other agents used in study
  • 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. Other medications that are prohibited while on copanlisib treatment:

    • Herbal medications/preparations (except for vitamins)
    • Anti-arrhythmic therapy other than beta blockers or digoxin
  • Systemic corticosteroid therapy at a daily dose higher than 15 mg prednisone 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/magnetic resonance imaging (CT/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). The use of corticosteroids as antiemetics prior to copanlisib administration will not be allowed
  • Patients with uncontrolled intercurrent illness
  • Patients with psychiatric illness/social situations that would limit compliance with study requirements
  • Patients with non-healing wound, ulcer, or bone fracture
  • Patients with active, clinically serious infections > grade 2 (Common Terminology Criteria for Adverse Events Version 5.0 [CTCAEv5.0]) (viral, bacterial or fungal infection)
  • History of known Pneumocystis jiroveci pneumonia (PJP) infection
  • Patients with 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
  • Concurrent diagnosis of pheochromocytoma due to risk of hypertension with copanlisib
  • Uncontrolled hypertension (defined as blood pressure >= 150/90 mm/Hg) despite optimal medical management (per investigator's opinion)
  • Proteinuria as estimated by urine protein/creatinine ratio > 3.5 g/g on random urine sample or grade >= 3 as assessed by 24-hour urine protein collection
  • Patients with history of or current autoimmune disease
  • Patients with congenital QT prolongation
  • 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
  • Pregnant women are excluded from this study because copanlisib is a PI3K inhibitor agent and eribulin is an anti-tubulin 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 and eribulin, breastfeeding should be discontinued if the mother is treated with copanlisib and/or eribulin. These potential risks may also apply to other agents used in this study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04345913


Locations
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United States, Florida
University of Florida Health Science Center - Gainesville Recruiting
Gainesville, Florida, United States, 32610
Contact: Site Public Contact    352-273-8010    cancer-center@ufl.edu   
Principal Investigator: Karen C. Daily         
United States, Missouri
Siteman Cancer Center at West County Hospital Recruiting
Creve Coeur, Missouri, United States, 63141
Contact: Site Public Contact    800-600-3606    info@siteman.wustl.edu   
Principal Investigator: Nusayba Bagegni         
Washington University School of Medicine Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Site Public Contact    800-600-3606    info@siteman.wustl.edu   
Principal Investigator: Nusayba Bagegni         
Siteman Cancer Center-South County Recruiting
Saint Louis, Missouri, United States, 63129
Contact: Site Public Contact    800-600-3606    info@siteman.wustl.edu   
Principal Investigator: Nusayba Bagegni         
Siteman Cancer Center at Christian Hospital Recruiting
Saint Louis, Missouri, United States, 63136
Contact: Site Public Contact    800-600-3606    info@siteman.wustl.edu   
Principal Investigator: Nusayba Bagegni         
Siteman Cancer Center at Saint Peters Hospital Recruiting
Saint Peters, Missouri, United States, 63376
Contact: Site Public Contact    800-600-3606    info@siteman.wustl.edu   
Principal Investigator: Nusayba Bagegni         
United States, New York
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center Recruiting
New York, New York, United States, 10032
Contact: Site Public Contact    212-305-6361    nr2616@cumc.columbia.edu   
Principal Investigator: Meghna S. Trivedi         
United States, Oklahoma
University of Oklahoma Health Sciences Center Recruiting
Oklahoma City, Oklahoma, United States, 73104
Contact: Site Public Contact    405-271-8777    ou-clinical-trials@ouhsc.edu   
Principal Investigator: Wajeeha Razaq         
United States, Tennessee
Vanderbilt Breast Center at One Hundred Oaks Recruiting
Nashville, Tennessee, United States, 37204
Contact: Site Public Contact    800-811-8480      
Principal Investigator: Laura C. Kennedy         
Vanderbilt University/Ingram Cancer Center Recruiting
Nashville, Tennessee, United States, 37232
Contact: Site Public Contact    800-811-8480      
Principal Investigator: Laura C. Kennedy         
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Nusayba Bagegni Duke University - Duke Cancer Institute LAO
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT04345913    
Other Study ID Numbers: NCI-2020-02319
NCI-2020-02319 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
10382 ( Other Identifier: Yale University Cancer Center LAO )
10382 ( Other Identifier: CTEP )
UM1CA186689 ( U.S. NIH Grant/Contract )
UM1CA186704 ( U.S. NIH Grant/Contract )
First Posted: April 15, 2020    Key Record Dates
Last Update Posted: September 16, 2021
Last Verified: July 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: 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.
URL: https://grants.nih.gov/policy/sharing.htm

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Carcinoma
Breast Neoplasms
Triple Negative Breast Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Halichondrin B
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents